Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:28])=[CH:4][C:5]([F:27])=[C:6]([C:8]2[C:9](=[O:26])[N:10]([CH2:24][CH3:25])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:18][C:19](=[O:23])[CH2:20][C:21]#[N:22])[CH:12]=3)[CH:7]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:36]([O:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:37]>C1COCC1>[C:21]([CH2:20][C:19]([NH:18][C:13]1[CH:12]=[C:11]2[C:16]([CH:17]=[C:8]([C:6]3[C:5]([F:27])=[CH:4][C:3]([F:28])=[C:2]([NH:1][C:36](=[O:37])[O:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[CH:7]=3)[C:9](=[O:26])[N:10]2[CH2:24][CH3:25])=[CH:15][N:14]=1)=[O:23])#[N:22]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2F)cc2cnc(NC(=O)CC#N)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCn1c(=O)c(-c2cc(NC(=O)Oc3ccccc3)c(F)cc2F)cc2cnc(NC(=O)CC#N)cc21
Temperature: 60 °C
Yield: 61.1 %

Procedure:
A solution of N-(3-(5-amino-2,4-difluorophenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)-2-cyanoacetamide (0.5 g, 1.3 mmol) and K2CO3 (448 mg, 3.25 mmol) in THF (4 mL) was treated drop-wise with phenyl chloroformate (408 mg, 2.6 mmol) and heated at 60° C. overnight. The mixture was cooled to RT, concentrated to dryness, treated with water and extracted with EtOAc (2×). The combined organics were washed with brine, dried over Na2SO4, concentrated and purified via silica gel chromatography to afford phenyl (5-(7-(2-cyanoacetamido)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)carbamate (400 mg, 61% yield).
Reaction SMILES: C([O:4][P:5]([CH2:11][O:12][CH2:13][CH2:14][C:15]1[C:16]([O:28]CC[Si](C)(C)C)=[C:17]2[C:21](=[C:22]([CH3:26])[C:23]=1[O:24][CH3:25])[CH2:20][O:19][C:18]2=[O:27])(=[O:10])[O:6]C(C)C)(C)C.N1C(C)=CC=CC=1C.C[Si](Br)(C)C>C(#N)C>[OH:28][C:16]1[C:15]([CH2:14][CH2:13][O:12][CH2:11][P:5](=[O:4])([OH:10])[OH:6])=[C:23]([O:24][CH3:25])[C:22]([CH3:26])=[C:21]2[C:17]=1[C:18](=[O:27])[O:19][CH2:20]2
Reactant: COc1c(C)c2c(c(OCC[Si](C)(C)C)c1CCOCP(=O)(OC(C)C)OC(C)C)C(=O)OC2
Agent: C[Si](C)(C)Br
Solvent: Cc1cccc(C)n1
Solvent: CC#N
Product: COc1c(C)c2c(c(O)c1CCOCP(=O)(O)O)C(=O)OC2
Reaction time: 18 h

Procedure:
To a solution of {2-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-ethoxymethyl}-phosphonic acid diisopropyl ester (7.5 mg, 0.014 mmol) in acetonitrile (2 mL) and 2,6-lutidine (25 μL, 0.21 mmol) was added trimethylsilyl bromide (27 μL, 0.21 mmol) at room temperature. The reaction was allowed to proceed for 18 hours when completion of the reaction was indicated by LCMS. The reaction was quenched by addition of MeOH and concentration. The residue was purified by RP-HPLC using a C18 column. The collected product was dissolved in a solution of 10% TFA/CH2Cl2 to assure complete deprotection. The reaction mixture was lyophilized to provide the desired product. 1H NMR (300 MHz, CD3OD) δ 2.12 (s, 3H), 2.98 (t, 2H, J=7 Hz), 3.66-3.76 (m, 4H), 3.78 (s, 3H), 5.21 (s, 2H) ppm; MS (m/z) 331 [M−H]−.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1B(O)O.Cl[C:13]1[CH:18]=[C:17]([CH3:19])[C:16]([N+:20]([O-:22])=[O:21])=[CH:15][N:14]=1.C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>CCOC(C)=O.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.CCO.O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:13]1[CH:18]=[C:17]([CH3:19])[C:16]([N+:20]([O-:22])=[O:21])=[CH:15][N:14]=1
Reactant: Cc1cc(Cl)ncc1[N+](=O)[O-]
Reactant: Cc1cccc(C)c1B(O)O
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: CCOC(C)=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1cc(-c2c(C)cccc2C)ncc1[N+](=O)[O-]
Temperature: 110 °C

Procedure:
A mixture of 2,6-dimethylphenylboronic acid (6.5 g, 43.5 mmol), 2-chloro-4-methyl-5-nitro-pyridine (5 g, 28.9 mmol), Pd(PPh3)4, (1.5 g, 1.5 mmol), Na2CO3 (4.6 g, 43.5 mmol), toluene (60 mL), water (20 mL), and EtOH (5 mL) is heated in a sealed tube under nitrogen at 110° C. for 18 hours. The mixture is cooled to room temperature, diluted with EtOAc (150 mL), washed with saturated solution of Na2CO3 (50 mL 3×), water (50 mL) and brine (50 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue is purified by chromatography on silica gel (Hexane/EtOAc, 6:1) to afford 2-(2,6-dimethyl-phenyl)-4-methyl-5-nitro-pyridine as a colorless oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH:7]2[C:13]3=[CH:14][CH:15]=[CH:16][N:12]3[CH2:11][C:10]3[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=3[O:8]2)[CH2:3][CH2:2]1.CS(O[CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[F:34])(=O)=O.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[F:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[CH2:27][CH2:26][N:1]1[CH2:2][CH2:3][CH:4]([CH:7]2[C:13]3=[CH:14][CH:15]=[CH:16][N:12]3[CH2:11][C:10]3[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=3[O:8]2)[CH2:5][CH2:6]1
Reactant: CS(=O)(=O)OCCc1ccccc1F
Reactant: c1ccc2c(c1)Cn1cccc1C(C1CCNCC1)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1ccccc1CCN1CCC(C2Oc3ccccc3Cn3cccc32)CC1
Temperature: 85 °C

Procedure:
A mixture of 11-(piperidin-4-yl)-5H,11H-pyrrolo[2,1-c][1,4]benzoxazepine (5.0 g, 0.019 mole), (2-fluorophenyl)-ethyl methanesulfonate (4.47 g, 0.02 mole), K2CO3 (11 g) and 150 ml dimethylformamide was heated at 85° C. for 9 hours.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]3[N:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[N:16][C:11]3=[N:10][CH:9]=2)=[CH:4][C:3]=1[O:21]C.B(Br)(Br)Br.[OH-].[Na+]>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]3[N:13]=[CH:14][C:15]([C:17]([F:18])([F:19])[F:20])=[N:16][C:11]3=[N:10][CH:9]=2)=[CH:4][C:3]=1[OH:21]
Reactant: COc1cc(-c2cnc3nc(C(F)(F)F)cnn23)ccc1F
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Oc1cc(-c2cnc3nc(C(F)(F)F)cnn23)ccc1F
Temperature: 25 °C
Reaction time: 21 h
Yield: 92.1 %

Procedure:
To a stirred solution of 7-(4-fluoro-3-methoxyphenyl)-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine (0.123 g, 0.397 mmol) in chloroform (5 ml) was added boron tribromide (1.19 ml, 1.91 mmol) and the mixture was stirred under nitrogen at room temperature for 21 h. 2 M NaOH (5 ml) was added and the mixture was stirred for 5 min producing a solid which was filtered and washed with water. The filtrate was washed with dichloromethane, and the aqueous layer was neutralised with concentrated hydrochloric acid causing a solid to precipitate. The solid was filtered, washed with water and dried under a vacuum to leave 109 mg (93%) of the title compound: 1H NMR (360 MHz, DMSO-d6) δ 7.38 (1H, dd, J 8.8, 11.2 Hz), 7.60-7.64 (1H, m), 7.88 (1H, dd, J 1.9, 8.6 Hz), 9.32 (1H, s), 10.26 (1H, s); MS (ES+) m/z 299 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[C:5]([CH2:17][O:18][Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])[CH:4]=1.[H-].[Na+].[CH3:33]I>O1CCCC1>[CH3:33][O:16][C:9]1([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:29])([F:1])[F:30])=[CH:4][C:5]=2[CH2:17][O:18][Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:24])[CH3:25])[CH:20]([CH3:22])[CH3:21])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CC(C)[Si](OCc1cc(C(F)(F)F)ccc1C1(O)CCCCCC1)(C(C)C)C(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1(c2ccc(C(F)(F)F)cc2CO[Si](C(C)C)(C(C)C)C(C)C)CCCCCC1
Reaction time: 16 h
Yield: 95.2 %

Procedure:
To a solution of 1-(4-(trifluoromethyl)-2-((triisopropylsilyloxy)methyl)phenyl)cycloheptanol (284 mg; 0.639 mmol) in tetrahydrofuran (3.5 mL) at room temperature was added sodium hydride (40 mg; 1 mmol; 60% dispersion in mineral oil). After stirring at room temperature for 15 minutes methyl iodide (80 uL; 1.28 mmol) was added. Reaction stirred for 16 hours. More sodium hydride (20 mg; 0.5 mmol; 60% dispersion in mineral oil) was added. After 5 minutes methyl iodide (0.1 mL; 1.6 mmol) was added. The reaction was stirred for 16 hours. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with water (2×) and brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified over a 12 g RediSep column (Teledyne Isco Inc., Lincoln Nebr.) (eluted with 5-15% ethyl acetate in heptanes) to yield 279 mg (95.2%) of the title compound as a colorless oil. MS-GC (El): Calc: 458.6 Found: 439 (M−F). 1H NMR (400 MHz, CDCl3) δ ppm 8.22 (d, J=1.24 Hz, 1H), 7.44 (dd, J=8.30, 1.24 Hz, 1H), 7.34 (d, J=8.30 Hz, 1H), 5.11 (s, 2H), 2.95 (s, 3H), 2.16 (m, 2H), 2.01 (m, 2H), 2.0 (dd, J=14.94, 14.52 Hz, 1H), 1.97 (dd, J=14.94, 14.52 Hz, 1H), 1.83-1.58 (m, 6H), 1.3-1.16 (m, 2H), 1.13 (s, 12H), 1.11 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][CH2:11][C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[F:8].ClC1C=C(C=CC=1F)N.C(O)(=O)C=C.C(OC)(=O)C=C>ClCCl.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([C:12](=[O:14])[CH2:11][CH2:10][NH:9]2)=[CH:6][C:7]=1[F:8]
Reactant: O=C(O)CCNc1ccc(F)c(Cl)c1
Agent: C=CC(=O)O
Agent: Nc1ccc(F)c(Cl)c1
Solvent: ClCCl
Solvent: C=CC(=O)OC
Solvent: O
Product: O=C1CCNc2cc(Cl)c(F)cc21
Temperature: 110 °C
Reaction time: 1.17 h
Yield: 57.4 %

Procedure:
A mixture of polyphosphoric acid (600 g) and 3-(3-chloro-4-fluorophenylamino)propionic acid (38 g), which was synthesized from 3-chloro-4-fluoroaniline and acrylic acid or methyl acrylate by the method of W. S. Johnson et al. (The Journal of American Chemical Society, volume 71, page 1901, (1949)), was stirred at 110° C. for 70 minutes. The reaction mixture was poured into 1500 ml of water, then shaken with dichloromethane (1500 ml). The organic layer was washed twice with saturated aqueous NaCl solution (200 ml each) and dried over anhydrous sodium sulfate. Dichloromethane was removed in vacuo and the residue was subjected to silica gel column chromatography using a mixed solvent (n-hexane : ether=4:1) to obtain 7-chloro-6-fluoro-2,3-dihydro-4(1H)-quinolinone (yield 20 g) as pale yellow crystal.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH:6]2[CH2:7][CH2:8][CH:3]1[CH:4]1[C:12](=[O:13])[O:11][C:9](=[O:10])[CH:5]12.[Br:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1>C(Cl)(Cl)Cl>[Br:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:9]([C@@H:5]2[C@H:6]3[C:2]([CH3:1])([CH3:14])[C@H:3]([CH2:8][CH2:7]3)[C@@H:4]2[C:12]([OH:11])=[O:13])=[O:10])=[CH:18][CH:17]=1
Reactant: Nc1ccc(Br)cc1
Reactant: CC1(C)C2CCC1C1C(=O)OC(=O)C12
Solvent: ClC(Cl)Cl
Product: CC1(C)[C@@H]2CC[C@H]1[C@@H](C(=O)Nc1ccc(Br)cc1)[C@H]2C(=O)O

Procedure:
Following General Procedure A, Compound 3 (0.047 g, 0.24 mmol) and 4-bromoaniline (0.041 g, 0.24 mmol) in chloroform (4 mL) were converted into the title compound, which was isolated as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([C:7]([C:9]2[CH:10]=[CH:11][C:12]([S:19][CH3:20])=[C:13]([S:15]([NH2:18])(=[O:17])=[O:16])[CH:14]=2)=[O:8])=[CH:5][CH:4]=1.ClC1C=C(C=CC=1)C(OO)=[O:28]>C(Cl)Cl>[CH3:20][S:19]([C:12]1[CH:11]=[CH:10][C:9]([C:7](=[O:8])[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:22][CH:21]=2)=[CH:14][C:13]=1[S:15]([NH2:18])(=[O:17])=[O:16])=[O:28]
Reactant: COc1ccc(C(=O)c2ccc(SC)c(S(N)(=O)=O)c2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(C(=O)c2ccc(S(C)=O)c(S(N)(=O)=O)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.6 %

Procedure:
To a solution of 5-(4-methoxy-benzoyl)-2-methylsulfanyl-benzenesulfonamide (0.06 g, 0.18 mmol) dissolved in methylene chloride (3 mL) at 0° C. is added m-chloroperoxybenzoic acid (0.061 g, 0.36 mmol). The reaction mixture is stirred at room temperature for 30 minutes Then, the reaction is quenched with saturated sodium sulfite and sodium bicarbonate solution. The aqueous layer is extracted with methylene chloride three times. The combined organic extracts are washed with a saturated sodium chloride solution, dried with magnesium sulfate, and concentrated in vacuo. Purification by silica gel chromatography (75% ethyl acetate-hexane) followed by recrystallization (methylene chloride-hexane) provides 0.022 g (35%) of the title compound as a pale yellow solid. 1H NMR (CDCl3): δ 8.35 (d, J=8 Hz, 1H), 8.10 (dd, J=8, 1 Hz, 1H), 7.80 (d, J=9 Hz, 2H), 7.00 (d, J=9 Hz, 2H), 5.60 (s, 2H), 3.95 (s, 3H), 3.00 (s, 3H). Analytics calculated for C15H15NO5S2: C, 50.98; H, 4.28; N, 3.96. Found: C, 50.17; H, 4.46; N, 3.40. MS (m/z): 352 (M−1).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[CH3:19][N:20]1[C:24]([C:25]2[O:29][N:28]=[C:27]([C:30](O)=[O:31])[CH:26]=2)=[CH:23][CH:22]=[N:21]1>>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:30]([C:27]3[CH:26]=[C:25]([C:24]4[N:20]([CH3:19])[N:21]=[CH:22][CH:23]=4)[O:29][N:28]=3)=[O:31])[CH3:18])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: Cn1nccc1-c1cc(C(=O)O)no1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cc(-c2ccnn2C)on1
Yield: 28.2 %

Procedure:
(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(1-methyl-1H-pyrazol-5-yl)isoxazole-3-carboxamide was prepared using the method of Example 34(d) starting from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (200 mg, 0.69 mmol) and 5-(1-methyl-1H-pyrazol-5-yl)isoxazole-3-carboxylic acid (173 mg, 0.898 mmol). The product was purified by triturated using acetonitrile and methanol. Yield 28.2%. 1H-NMR (400 MHz; DMSO): δ 1.19 (d, 3H), 4.06 (s, 3H), 4.35 (d, 2H), 4.43-4.57 (m, 1H), 6.91 (d, 1H), 6.96 (d, 1H), 7.20 (s, 1H), 7.59 (d, 1H), 7.85 (d, 1H), 7.93 (dd, 1H), 7.97 (d, 1H), 8.09 (d, 1H), 8.94 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH:12]=[O:13])[CH:6]=1.[Br:15]N1C(=O)CCC1=O>CN(C=O)C.C(OC(=O)C)(C)C.C(O)(C)C>[Br:15][C:9]1[CH:10]=[C:5]([CH2:4][C:3]([O:2][CH3:1])=[O:14])[CH:6]=[C:7]([CH:12]=[O:13])[C:8]=1[OH:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Cc1ccc(O)c(C=O)c1
Solvent: CC(=O)OC(C)C
Solvent: CC(C)O
Solvent: CN(C)C=O
Product: COC(=O)Cc1cc(Br)c(O)c(C=O)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 84.8 %

Procedure:
To a 2 L round bottom flask with magnetic stirrer, thermocouple, and ice water bath was added (3-formyl-4-hydroxyphenyl)acetic acid methyl ester (308 g, 1.59 mol) and N,N-dimethylformamide (1 L). The reaction mixture was stirred and cooled to −5 to 5° C. A solution of N-bromosuccinimide (311 g, 1.75 mol) in DMF (1.5 to 2 L) was added dropwise, at such a rate to keep the internal temperature between 5 and 10° C. Once the addition was complete, the reaction mixture was allowed to warm to room temperature and monitored for completion by HPLC analysis. The reaction time was about 4 h. The reaction mixture was diluted with isopropylacetate (3 L), and the resulting solution was extracted with water to remove the DMF. Concentration of the organic phase afforded a reddish solid that was dissolved in hot isopropanol (400 mL) and allowed to cool while stirring. The resulting off-white crystalline product was filtered and washed with cold IPA (−20° C.; 400 mL) to yield methyl (3-bromo-5-formyl-4-hydroxyphenyl)acetate (368 g, 84.7%) as off-white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24](O)=[O:25])=[CH:15][C:13]=2[N:14]=1.S(Cl)(Cl)=O.[F:31][C:32]([F:44])([F:43])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]1([NH2:42])[CH2:41][CH2:40]1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:22])([CH3:23])[O:21][C:17]=3[C:16]([C:24]([NH:42][C:39]3([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=4[C:32]([F:31])([F:43])[F:44])[CH2:41][CH2:40]3)=[O:25])=[CH:15][C:13]=2[N:14]=1
Reactant: NC1(c2ccccc2C(F)(F)F)CC1
Reactant: CC1(C)Cc2c(c(C(=O)O)cc3nc(Nc4c(F)cccc4Cl)[nH]c23)O1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)Cc2c(c(C(=O)NC3(c4ccccc4C(F)(F)F)CC3)cc3nc(Nc4c(F)cccc4Cl)[nH]c23)O1
Yield: 8.1 %

Procedure:
The title compound was prepared by following the procedure described for Example-108 using 2-[(2-chloro-6-fluorophenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-15, 0.100 g, 0.266 mmol), thionyl chloride (2.0 mL), 1-[2-(trifluoromethyl)phenyl]cyclopropanamine (Intermediate-38, 0.078 g, 0.388 mmol), THF (5.0 mL) and DIPEA (2 mL). The obtained crude product was purified by column chromatography on basic alumina eluting with 0.7-1.0% MeOH:DCM to afford 0.012 g of the desired product. 1HNMR (CDCl3): δ 1.08-1.33 (m, 4H), 1.47 (s, 6H), 3.02 (s, 2H), 7.32-7.38 (m, 4H), 7.47 (t, J=6.6 Hz, 1H), 7.61-7.69 (m, 2H), 7.97 (d, J=7.8 Hz, 1H), 8.56 (s, 1H), 10.80-11.00 (s, 2H); MS [M+H]+: 559.26.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH2:36]([O:38][C:39]1[CH:45]=[C:44]([CH2:46][CH2:47][N:48]2[CH2:53][CH2:52][N:51]([CH3:54])[CH2:50][CH2:49]2)[CH:43]=[CH:42][C:40]=1[NH2:41])[CH3:37].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C(Cl)Cl.CC(O)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:41][C:40]3[CH:42]=[CH:43][C:44]([CH2:46][CH2:47][N:48]4[CH2:49][CH2:50][N:51]([CH3:54])[CH2:52][CH2:53]4)=[CH:45][C:39]=3[O:38][CH2:36][CH3:37])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: CCOc1cc(CCN2CCN(C)CC2)ccc1N
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Product: CCOc1cc(CCN2CCN(C)CC2)ccc1Nc1nccc(-c2c(-c3ccc(OC)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 130 °C
Yield: 69.4 %

Procedure:
5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (100 mg, 0.2 mmol), 2-(ethyloxy)-4-[2-(4-methyl-1-piperazinyl)ethyl]aniline (44 mg, 0.17 mmol), and p-toluenesulfonic acid (93 mg, 0.49 mmol) were weighed into a 20 mL microwave vial. 7 mL of iPrOH was added and the mixture was heated to 130° C. for 72 h. The mixture was transferred to a 50 mL round bottom and neutralized with 2 mL of 0.5 N sodium methoxide. The solvent was rotovaped down. The residue was taken up in 10 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (85 mg, 0.118 mmol, 71%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.77 (s, 1H), 9.32 (d, J=6.96 Hz, 1H), 8.39 (s, 1H), 8.27 (d, J=5.31 Hz, 1H), 8.11 (s, 1H), 7.76 (d, J=8.42 Hz, 1H), 7.68 (dd, J=11.81, 8.52 Hz, 2H), 7.33-7.45 (m, 2H), 7.26 (d, J=8.79 Hz, 1H), 7.17 (t, J=7.97 Hz, 2H), 6.88-6.99 (m, 2H), 6.74 (d, J=8.06 Hz, 1H), 6.61 (d, J=5.13 Hz, 1H), 4.06 (q, J=6.96 Hz, 2H), 3.97 (s, 3H), 2.62-2.72 (m, 2H), 2.19-2.57 (m, 10H), 2.11 (s, 3H), 1.27 (t, J=7.05 Hz, 3H). MS (ESI): 719 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]([CH3:20])[CH:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)=[C:8]([CH3:21])[C:6]=2[N:7]=1.[NH2:28][C:29]1[N:34]=[CH:33][C:32](C2N=C(N3CCOCC3)C3SC(CN4CCC(C(NC)=O)CC4)=CC=3N=2)=[CH:31][N:30]=1>>[CH3:19][N:16]1[CH2:17][CH2:18][CH:13]([N:12]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[N:3][C:2]([C:32]4[CH:31]=[N:30][C:29]([NH2:28])=[N:34][CH:33]=4)=[N:7][C:6]=3[C:8]=2[CH3:21])[CH3:20])[CH2:14][CH2:15]1
Reactant: Cc1c(CN(C)C2CCN(C)CC2)sc2c(N3CCOCC3)nc(Cl)nc12
Reactant: CNC(=O)C1CCN(Cc2cc3nc(-c4cnc(N)nc4)nc(N4CCOCC4)c3s2)CC1
Product: Cc1c(CN(C)C2CCN(C)CC2)sc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc12
Yield: 5 %

Procedure:
N-((2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-N,1-dimethylpiperidin-4-amine following Example 115 (0.23 mmol) was reacted using General Procedure A: Suzuki Coupling to give 190 (TFA salt) in a 5% yield after reverse-phase HPLC purification. MS (Q1) 469 (M)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:5][C:6]=1[C:7]#[N:8].[H-].[Na+].F[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23].Cl>C1COCC1>[C:9]([C:4]1[S:3][C:2]([NH:1][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N+:22]([O-:24])=[O:23])=[C:6]([C:7]#[N:8])[CH:5]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)c1cc(C#N)c(N)s1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(C#N)c(Nc2ccccc2[N+](=O)[O-])s1
Reaction time: 0.25 h
Yield: 74.8 %

Procedure:
Add a solution of 2-amino-5-tert-butyl-thiophene-3-carbonitrile (16.9 g, 94 mmol) in THF (50 mL) to a mixture of washed NaH (from 6.76 g of 60% mineral oil dispersion) in THF (200 mL) in a water bath at room temperature. Stir 15 minutes, then add a solution of 2-fluoro-nitrobenzene (13.2 g, 94 mmol) in THF (50 mL) dropwise. Stir overnight. Pour the purple reaction mixture unto 6 N HCl (400 mL). Extract the mixture with diethyl ether (400 mL). Wash the ether layer with 2 N HCl (400 mL), brine (250 mL), dry (Na2SO4), and concentrate to afford a mixture of crystals in a dark oily residue. Triturate the crystals with hexanes and filter to afford the title compound as a red powder (21.2 g, 75%) mp 85-90° C.: 1H NMR (CDCl3) δ 1.39 (s, 9H), 6.81 (s, 1H), 6.97 (t, 1H), 7.23 (d, 1H), 7.53 (t, 1H), 8.25 (d, 1H), 9.66 (bs, 1H).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([CH:26]=[C:27]([O:29][CH2:30][C:31]2[N:32]=[C:33]([C:36]3[CH:41]=[N:40][CH:39]=[CH:38][N:37]=3)[S:34][CH:35]=2)[CH:28]=1)[CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:9]1.I[CH2:43][CH3:44].O>CN(C)C=O>[CH2:43]([O:3][C:4]1[CH:5]=[C:6]([CH:26]=[C:27]([O:29][CH2:30][C:31]2[N:32]=[C:33]([C:36]3[CH:41]=[N:40][CH:39]=[CH:38][N:37]=3)[S:34][CH:35]=2)[CH:28]=1)[CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:9]1)[CH3:44]
Reactant: CCOC(=O)CCc1cn(Cc2cc(O)cc(OCc3csc(-c4cnccn4)n3)c2)cc1-c1ccccc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2cc(OCC)cc(OCc3csc(-c4cnccn4)n3)c2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97 %

Procedure:
Sodium hydride (60%, oily, 28.0 mg) was added to a solution of ethyl 3-[1-[3-hydroxy-5-[2-(2-pyrazinyl)-4-thiazolylmethoxy]benzyl]-4-phenyl-3-pyrrolyl]propionate (378 mg) in N,N-dimethylformamide (5 ml) at 0° C., which was stirred at room temperature for 15 minutes. Iodoethane (0.0672 ml) was added to the mixture, which was stirred at room temperature for 1 hour. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[1-[3-ethoxy-5-[2-(2-pyrazinyl)-4-thiazolylmethoxy]benzyl]-4-phenyl-3-pyrrolyl]propionate (385 mg, yield: 97%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).