Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1[CH2:5][O:4][CH2:3][CH2:2]1.[Cl-].COC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[CH2:35]([O:37][C:38]1(C=O)[CH:43]=[CH:42][C:41]([C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([F:50])[C:45]=2[F:51])=[C:40]([F:52])[CH:39]1[F:53])[CH3:36]>O>[CH2:35]([O:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2[CH:49]=[CH:48][C:47]([CH:2]=[CH:3][O:4][CH3:5])=[C:46]([F:50])[C:45]=2[F:51])=[C:40]([F:52])[C:39]=1[F:53])[CH3:36]
Reactant: CCOC1(C=O)C=CC(c2cccc(F)c2F)=C(F)C1F
Reactant: C1CCOC1
Agent: CC(C)(C)[O-]
Agent: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Solvent: O
Product: CCOc1ccc(-c2ccc(C=COC)c(F)c2F)c(F)c1F
Temperature: -20 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
THF (150 ml) was added to methoxymethyltriphenylphosphonium chloride (26.8 g) in a reaction vessel under an atmosphere of nitrogen and the solution was cooled to −20° C. Potassium t-butoxide (10.1 g) was added, and the stirring was continued for 1 hour. A THF (100 ml) solution of 4-ethoxy-2,2′,3,3′-tetrafluorobiphenyl-4-carboaldehyde (7) (17.9 g) prepared in the fifth step was added dropwise, and the stirring was continued for 1 hour. The reaction mixture was warmed to room temperature and water (200 ml) was added to give two layers. The water layer was extracted with toluene (100 ml) three times, and the combined organic layer was washed with water and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (silica gel: 20 g, eluent: toluene) to give 4-ethoxy-2,2′,3,3′-tetrafluoro-4′-(2-methoxyvinyl)biphenyl (8) (18.5 g) in 94.5% yield.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][N:3]=1.N1C=CC=CC=1.O.Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26]>CN(C)C=O>[O:27]([C:25]([NH:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][N:3]=1)=[O:26])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCCNc1nc(N)ncc1C(=O)OCC
Reactant: O=C(Cl)Oc1ccccc1
Solvent: O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCCNc1nc(NC(=O)Oc2ccccc2)ncc1C(=O)OCC
Reaction time: 0.67 h

Procedure:
To a solution of ethyl 2-amino-4-(propylamino)pyrimidine-5-carboxylate (C3, 5.00 g) and pyridine (2.2 mL) in N,N-dimethylformamide (45 mL), phenyl chloroformate (3.1 mL) was added dropwise under ice cooling, and the mixture was stirred at the same temperature for 40 minutes. To the reaction mixture, pyridine (1.0 mL) and phenyl chloroformate (1.5 mL) were added under ice cooling, and the mixture was stirred at the same temperature for 40 minutes. The reaction mixture was poured into water. The solid matter was taken by filtration, and dried under reduced pressure to obtain ethyl 2 -((phenoxycarbonyl)amino)-4-(propylamino)pyrimidine-5-carboxylate (E7, 2.89 g) as white solid.
Reaction SMILES: C(N[C:6]([NH:8][S:9]([C:12]1[C:13]([S:22]([N:25]([CH3:27])[CH3:26])(=[O:24])=[O:23])=[CH:14][CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1)(=[O:11])=[O:10])=[O:7])CCC.C1N2CCN(CC2)C1.C(Cl)(Cl)=O>>[CH3:26][N:25]([CH3:27])[S:22]([C:13]1[CH:14]=[CH:15][C:16]([C:18]([F:20])([F:19])[F:21])=[CH:17][C:12]=1[S:9]([N:8]=[C:6]=[O:7])(=[O:11])=[O:10])(=[O:23])=[O:24]
Reactant: CCCCNC(=O)NS(=O)(=O)c1cc(C(F)(F)F)ccc1S(=O)(=O)N(C)C
Agent: C1CN2CCN1CC2
Agent: O=C(Cl)Cl
Product: CN(C)S(=O)(=O)c1ccc(C(F)(F)F)cc1S(=O)(=O)N=C=O
Reaction time: 0.5 h

Procedure:
A solution of 12.5 g of N'-(butylaminocarbonyl)-N,N-dimethyl-4-(trifluoromethyl)-1,2-benzenedisulfonamide, and 0.1 g of DABCO in 75 ml of mixed xylenes was heated to 136°. To this solution was added 2.2 ml of liquid phosgene over a period of two hours at a rate that the temperature was maintained between 125° and 135°. The temperature was kept at 130° for 1/2 hour after the addition. The solution was cooled and filtered under a nitrogen atmosphere to remove a small amount of insoluble solid then concentrated at 60°-70° in vacuo. The residue of 2-(N,N-dimethylsulfamoyl)-5-(trifluoromethyl)benzenesulfonylisocyanate was an oil weighing 10.4 g and was sufficiently pure for further reaction.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([OH:18])=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[OH:19][CH2:20][CH:21]([CH2:23]O)[OH:22].C1(N=C=NC2CCCCC2)CCCCC1.CCOC(C)=O.CCCCCC>CN(C)C1C=CN=CC=1.C(Cl)Cl.CO>[C:1]([NH:11][C@H:12]([C:16]([O:18][CH2:23][CH:21]([CH2:20][OH:19])[OH:22])=[O:17])[CH:13]([CH3:14])[CH3:15])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: OCC(O)CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(O)CO
Reaction time: 8 h

Procedure:
CBz-L-valine (4.35 g, 17.3 mmol) was added to a fivefold excess of glycerol (8 ml, 86.9 mmol) together with dicyclohexylcarbodiimide (4.29 g 20.8 mmol) and 4-dimethylaminopyridine (0.212 g) at room temperature. After stirring overnight the suspension was filtered and DMF removed in vacuo from the filtrate. The residue was redissolved in CH2Cl2, washed successively with saturated NaHCO3, brine, and water and then dried. The crude material was chromatographed on silica gel with 4/1 EtOAc-hexane as eluent to yield 2.465 g. Rf (4/1 EtOAc-hexane) 0.17, (20/1 CH2Cl2-methanol) 0.12.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]([C:15]2[S:16][C:17](Br)=[CH:18][CH:19]=2)=[O:14])[CH:7]=1)[CH3:2].[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]([C:15]2[S:16][C:17]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:18][CH:19]=2)=[O:14])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(NC(=O)c2ccc(Br)s2)c1
Reactant: OB(O)c1ccccc1
Product: CCOC(=O)Cc1cccc(NC(=O)c2ccc(-c3ccccc3)s2)c1
Temperature: 80 °C

Procedure:
{3-[(5-Bromo-thiophene-2-carbonyl)-amino]-phenyl}-acetic acid ethyl ester (220 mg, 0.60 mmol) was coupled to phenylboronic acid using Method E except that the reaction mixture was heated at 80° C. for 25 min under microwave conditions. The crude product was purified by column chromatography using 33% EtOAc in heptane to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][C@:13]2([CH3:18])[C@H:16]([CH3:17])[C@H:9]1[CH2:10][C:11]1[CH:22]=[CH:21][C:20]([C:23]([NH:25][NH2:26])=[O:24])=[CH:19][C:12]=12)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:27]([CH3:37])(OCC)(OCC)OCC>>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][C@:13]2([CH3:18])[C@H:16]([CH3:17])[C@H:9]1[CH2:10][C:11]1[CH:22]=[CH:21][C:20]([C:23]3[O:24][C:27]([CH3:37])=[N:26][N:25]=3)=[CH:19][C:12]=12)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(C)(OCC)OCC
Reactant: C[C@@H]1[C@H]2Cc3ccc(C(=O)NN)cc3[C@]1(C)CCN2C(=O)OC(C)(C)C
Product: Cc1nnc(-c2ccc3c(c2)[C@]2(C)CCN(C(=O)OC(C)(C)C)[C@H](C3)[C@H]2C)o1
Temperature: 25 °C

Procedure:
(2R,6R,11S)-8-Hydrazinocarbonyl-6,11-dimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylic acid tert-butyl ester (0.50 g) in (EtO)3CMe (2 mL) is heated in a microwave oven at 120° C. for 30 min. After cooling to room temperature, the mixture is concentrated under reduced pressure and the residue is purified by HPLC on reversed phase (MeCN/H2O/NH4OH) to give the title compound.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([CH:14]=[C:15]([NH:17][C:18](=[O:20])[CH3:19])[N:16]=3)[N:13]=2)[CH:5]=[CH:4][N:3]=1.CN(C=O)C.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[SH:33].[H-].[Na+]>O>[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([CH:14]=[C:15]([NH:17][C:18](=[O:20])[CH3:19])[N:16]=3)[N:13]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Fc1ccccc1S
Reactant: CC(=O)Nc1cn2nc(-c3ccnc(F)c3)ccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1cn2nc(-c3ccnc(Sc4ccccc4F)c3)ccc2n1
Temperature: 110 °C
Reaction time: 42 h

Procedure:
To a 10-mL, round-bottomed flask was added N-(6-(2-fluoropyridin-4-yl)imidazo[1,2-b]pyridazin-2-yl)acetamide (Example 3) (0.034 g, 0.13 mmol), DMF (2.0 mL), 2-fluorothiophenol (0.045 mL, 0.42 mmol, Aldrich, St. Louis, Mo.), and sodium hydride (17 mg, 0.45 mmol, 60% dispersion in mineral oil, Aldrich, St. Louis, Mo.). The mixture was stirred at 110° C. for 42 h. The mixture was poured into water and extracted with EtOAc (3×30 mL). The combined extracts were washed with water (2×30 mL) and brine (30 mL) then dried (Na2SO4), and concentrated onto silica. Purification by silica gel chromatography (0 to 3.5% MeOH (2 M in NH3)/CH2Cl2), followed by further purification by preparative HPLC (Phenomenex Synergi 4μ MAX-RP 150×21.2 mm, 2 to 100% CH3CN/H2O, 0.1% TFA, over 15 min) (Phenomenex, Torrance, Calif.) and conversion to the free base by elution of the isolated material through an SCX cartridge (Radleys Discovery Technologies, Essex, UK) with MeOH (2 M in NH3)/CH2Cl2 afforded the title compound as a yellow solid. MS (ESI positive ion) m/z: 380 (M+1). 1H NMR (400 MHz, DMSO-d6): δ ppm 10.99 (s, 1H), 8.53 (d, J=5.0 Hz, 1H), 8.28 (s, 1H), 8.13 (d, J=9.5 Hz, 1H), 7.82-7.84 (m, 3H), 7.71 (t, J=7.3 Hz, 1H), 7.62 (q, J=6.7 Hz, 1H), 7.43 (t, J=8.8 Hz, 1H), 7.35 (t, J=7.5 Hz, 1H), 2.11 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[S:15][C:14]([C:16]3[N:20]=[C:19]([CH2:21][C@@H:22]([C:30]([O:32]CC)=[O:31])[NH:23]C(=O)C(F)(F)F)[O:18][N:17]=3)=[N:13][N:12]=2)[CH2:7][CH2:6]1.[OH-].[Na+].Cl>CCO.O>[Br:1][C:2]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[S:15][C:14]([C:16]3[N:20]=[C:19]([CH2:21][C@@H:22]([C:30]([OH:32])=[O:31])[NH2:23])[O:18][N:17]=3)=[N:13][N:12]=2)[CH2:7][CH2:6]1
Reactant: CCOC(=O)[C@H](Cc1nc(-c2nnc(N3CCC(Oc4cc(F)ccc4Br)CC3)s2)no1)NC(=O)C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: N[C@@H](Cc1nc(-c2nnc(N3CCC(Oc4cc(F)ccc4Br)CC3)s2)no1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of ethyl 3-(3-{5-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-1,3,4-thiadiazol-2-yl}-1,2,4-oxadiazol-5-yl)-N-(trifluoroacetyl)-L-alaninate (550 mg, 0.86 mmol) in EtOH (5 mL) and water (5 mL) was added NaOH (104 mg, 2.6 mmol) and the resulting solution was stirred at rt overnight. The solution was adjusted to pH 7 with HCl solution (1 mol/L), then extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated in vacuo. The crude product was washed with petroleum ether/EtOAc to afford the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl[CH2:29][CH2:30]CCCCO.C1(C(Cl)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Li].Cl>O.CCOCC.CS(C)=O>[C:10]1([C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:29]#[CH:30])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: ClCCCCCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCCCCCCCl
Agent: Cl
Agent: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Li]
Solvent: CS(C)=O
Solvent: CCOCC
Solvent: O
Product: C#CCCCCCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a stirred suspension of 68.1 g. (0.18 moles) of 1-chloro-6-triphenymethoxyhexane, prepared from 1-chloro-6-hydroxyhexane and triphenylmethyl chloride in the manner of Example 277, in 60 ml. of dimethylsulfoxide is added a solution of 19.9 g. (0.216 moles) of lithium acetylideethylenediamine complex in 120 ml. of dimethylsulfoxide during 20 minutes. The temperature is maintained at 25° C. with an ice bath during the addition, after which the mixture is stirred at ambient temperature for 3.5 hours and then at 30° C. for 15 minutes. The mixture is diluted with 100 ml. of ether and treated dropwise with 150 ml. of water with ice bath cooling. The mixture is diluted with 400 ml. of water and 250 ml. of 2:1 ether-pet ether and acidified with 120 ml. of 4N hydrochloric acid in the ice bath. The phases are separated, and the aqueous phase is extracted with 3:1 ether-pet ether. The combined extracts are washed successively with water and saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. Column chromatography of the residue on Florisil affords the subject compound as white crystals, m.p. 43°-45° C. after recrystallization from pet-ether, ν max 3300 (acetylenic hydrogen), 2360 (triple bond), 1600, 1068, and 706 cm-1 (triphenylmethoxy group).
Reaction SMILES: [Mg].BrCCBr.Br[C:7]1[CH:8]=[C:9]([CH:23]=[CH:24][CH:25]=1)[N:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[B:26](OC)([O:29][CH3:30])[O:27][CH3:28]>C1COCC1>[C:11]1([N:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]2[CH:8]=[C:7]([B:26]3[O:29][CH2:30][CH2:28][O:27]3)[CH:25]=[CH:24][CH:23]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COB(OC)OC
Reactant: Brc1cccc(N(c2ccccc2)c2ccccc2)c1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: c1ccc(N(c2ccccc2)c2cccc(B3OCCO3)c2)cc1
Temperature: 25 °C
Yield: 88 %

Procedure:
First, 0.45 g of magnesium and 5 ml of THF were suspended, and a tiny amount of 1,2-dibromoethane was added to the obtained suspension. A mixed solution of 3.0 g of 3-bromo-N,N-diphenylaniline and 30 mL of THF was dripped to this suspension, and the mixture was stirred while being heated under reflux for 1.5 hours to cause a reaction. After the reaction, the solution which was naturally cooled to room temperature was cooled to −78° C., and 1.95 g of trimethyl borate was added thereto. The mixture was stirred while the temperature was increased to room temperature to cause a reaction. After the reaction, the solution was concentrated, and 4.8 mL of ethylene glycol and 30 mL of toluene were added to the obtained residue. The mixture was stirred while being heated under reflux for 12 hours to cause a reaction. After the reaction, the solution was filtered and the obtained filtrate was concentrated, so that a while solid was obtained (88% yield). The synthesis scheme of Step 1 is shown by (a-1).
Reaction SMILES: C(O[Na])(C)(C)C.Br[C:8]1[CH:9]=[N:10][CH:11]=[C:12]([O:14][CH2:15][C@@H:16]2[CH2:20][CH2:19][CH2:18][N:17]2[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:13]=1.Cl.[CH:29]12[CH2:36][CH:33]([CH2:34][CH2:35]1)[CH2:32][NH:31][CH2:30]2.O1CCOCC1>[Pd].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.O>[C:24]([O:23][C:21]([N:17]1[CH2:18][CH2:19][CH2:20][C@H:16]1[CH2:15][O:14][C:12]1[CH:13]=[C:8]([N:31]2[CH2:32][CH:33]3[CH2:36][CH:29]([CH2:35][CH2:34]3)[CH2:30]2)[CH:9]=[N:10][CH:11]=1)=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(Br)c1
Reactant: C1CC2CNCC1C2
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(N2CC3CCC(C3)C2)c1
Temperature: 100 °C
Reaction time: 5 h
Yield: 65 %

Procedure:
Palladium catalyst A (6.2 mg, 7.5 μmol, 83 mequiv.), 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (Xphos, 3.7 mg, 7.5 μmol, 83 mequiv.), tert-BuONa (206 mg, 2.1 mmol, 2.8 equiv.), 3-bromo-5-[[1-(tert-butoxycarbonyl)-2(S)-pyrrolidinyl]methoxy]pyridine (268 mg, 0.75 mmol) and 3-azabicyclo[3.2.1]octane hydrochloride (Arkè Organics srl, Zona Industriale della Botte No. 4, 56012 Fornacette (PI), Italy; 133 mg, 0.90 mmol, 1.2 equiv.) were filled into a 25 mL round bottom-flask with a side neck. The flask was equipped with a stir bar, a condenser, and rubber septa. The atmosphere was exchanged with Ar (3 times), and anhydrous dioxane (3 mL) was added via syringe. The mixture was stirred at 100° C. for 5 h and cooled to room temperature. Water (10 mL) was added to quench the reaction. The product was extracted into EtOAc (40 mL). The organic phase was washed with brine (10 mL), dried over Na2SO4, and concentrated. The residue was purified by CC (SiO2, 25×2.5 cm, EtOAc) to give the crude product, which was further purified by preparative HPLC (Supelco Discovery C18, 250×21.2 mm, 5 μm particle size, UV detection at 270 nm, flow rate 12.5 mL/min, gradient from 20% to 100% CH3CN in water within 40 min, then 100% CH3CN for 20 min; tR 32.6-36.9 min) to give the title compound as a yellowish oil (198 mg, 65%). MS (EI) m/z 387 (M+, 16%).
Reaction SMILES: [OH:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH3:12])[C:6]=2[CH:5]=[C:4]([C:13]([N:15]([CH3:17])[CH3:16])=[O:14])[CH:3]=1.Cl[CH:19]1[C:28]2[C:23](=[CH:24][C:25]([F:30])=[CH:26][C:27]=2[F:29])[O:22][CH2:21][CH2:20]1>>[F:29][C:27]1[CH:26]=[C:25]([F:30])[CH:24]=[C:23]2[C:28]=1[CH:19]([O:1][C:2]1[C:10]3[N:9]=[C:8]([CH3:11])[N:7]([CH3:12])[C:6]=3[CH:5]=[C:4]([C:13]([N:15]([CH3:16])[CH3:17])=[O:14])[CH:3]=1)[CH2:20][CH2:21][O:22]2
Reactant: Fc1cc(F)c2c(c1)OCCC2Cl
Reactant: Cc1nc2c(O)cc(C(=O)N(C)C)cc2n1C
Product: Cc1nc2c(OC3CCOc4cc(F)cc(F)c43)cc(C(=O)N(C)C)cc2n1C
Yield: 49 %

Procedure:
The title compound was prepared as a white solid in 49% yield (0.12 g) from 4-hydroxy-N,N,1,2-tetramethyl-1H-benzimidazole-6-carboxamide (0.14 g, 0.61 mmol, WO 2004054984) and 4-chloro-5,7-difluorochromane (0.15 g, 0.73 mmol, STEP 2) by the same manner in STEP 1 of Example 1:
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=3)=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=O)C.[OH-].[Na+].Cl>C(O)C.O1CCOCC1>[NH:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=3)=[CH:10][CH:11]=2)[CH2:6][CH2:5]1
Reactant: CC(=O)N1CCc2cc(-c3ccnc(N)n3)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1COCCO1
Product: Nc1nccc(-c2ccc3c(c2)CCN3)n1
Yield: 97.2 %

Procedure:
To a solution of 4-(1-acetyl-2,3-dihydro-1H-indol-5-yl)pyrimidin-2-amine (1.27 g) in ethanol (60 mL) and 1,4-dioxane (40 mL) was added sodium hydroxide (pellet) (2.8 g) and the mixture was refluxed for 6 hours. The resultant solution was cooled to ambient temperature and neutralized by addition of 1N hydrochloric acid. The mixture was evaporated in vacuo and the residue was extracted with chloroform. The organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo to afford crude 4-(2,3-dihydro-1H-indol-5-yl)pyrimidin-2-amine (1.03 g) as a powder.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-].[CH2:21]([C:25]1[O:26][C:27]2[CH:50]=[CH:49][CH:48]=[CH:47][C:28]=2[C:29]=1[C:30](=[O:46])[C:31]1[CH:36]=[C:35](I)[C:34]([O:38][CH2:39][O:40][CH2:41][CH2:42][O:43][CH3:44])=[C:33](I)[CH:32]=1)[CH2:22][CH2:23][CH3:24]>COCCOC.O.CCOCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:21]([C:25]1[O:26][C:27]2[CH:50]=[CH:49][CH:48]=[CH:47][C:28]=2[C:29]=1[C:30]([C:31]1[CH:36]=[C:35]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:34]([O:38][CH2:39][O:40][CH2:41][CH2:42][O:43][CH3:44])=[C:33]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:32]=1)=[O:46])[CH2:22][CH2:23][CH3:24]
Reactant: OB(O)c1ccccc1
Reactant: CCCCc1oc2ccccc2c1C(=O)c1cc(I)c(OCOCCOC)c(I)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Ba+2]
Solvent: O
Solvent: COCCOC
Solvent: CCOCC
Product: CCCCc1oc2ccccc2c1C(=O)c1cc(-c2ccccc2)c(OCOCCOC)c(-c2ccccc2)c1
Temperature: 80 °C
Yield: 42.1 %

Procedure:
At ambient temperature, to a stirred mixture containing phenylboronic acid (0.454 g, 3.73 mmol), barium hydroxide octahydrate (1.60 g, 5.08 mmol) and palladium (II) acetate (7.60 mg, 0.0339 mmol) in DME:H2O (6:1, 20 mL) was added a solution of 2-n-butyl-3-(4-[(2-methoxyethoxy)methoxy]-3,5-diiodobenzoyl)benzofuran (1.07 g, 1.69 mmol) in DME:H2O (6:1, 20 mL). After the addition was complete, the reaction was heated at 80° C. for 16h. The reaction was cooled to ambient temperature, diluted with ether (50 mL), washed sequentially with sat. aq. NaHCO3 (3×), with brine (3×), dried (MgSO4) and concentrated. The crude product was purified on Biotage KP-Sil eluting with 25% ether/pet. ether to give 0.380 g (42%) of the title compound. 1H NMR (DMSO-d6) δ0.76 (t, 3 H), 1.22 (sextet, 2 H), 1.64 (quintet, 2 H), 2.81-2.92 (m, 6 H), 3.03 (s, 3 H), 4.44 (s, 2 H), 7.31-7.67 (m, 14 H), 7.76 (s, 2 H).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([OH:14])=O)[O:3]1.[NH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]([O:30][CH3:31])[CH:21]=1.CCN=C=NCCCN(C)C.O>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:31][O:30][C:22]1[CH:21]=[C:20]([NH:19][C:12](=[O:14])[C:11]2[CH:15]=[CH:16][CH:17]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:1])([CH3:18])[O:3]3)[CH:10]=2)[CH:29]=[CH:28][C:23]=1[C:24]([O:26][CH3:27])=[O:25]
Reactant: CC1(C)OB(c2cccc(C(=O)O)c2)OC1(C)C
Reactant: COC(=O)c1ccc(N)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC(=O)c2cccc(B3OC(C)(C)C(C)(C)O3)c2)cc1OC
Temperature: 25 °C
Reaction time: 38 h
Yield: 21.9 %

Procedure:
A mixture of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (600 mg, 2.4 mmol), methyl 4-amino-2-methoxybenzoate (362 mg, 2 mmol), EDCI (764 mg, 4 mmol) and DMAP (488 mg, 4 mmol) in 10 mL of DMF was stirred at room temperature for 38 hours. The mixture was poured into water and extracted with EtOAc (3×15 mL). The organic layer was washed with brine and dried over Na2SO4. After filtration and concentration, the residue was purified by column chromatography on silica gel eluting with (petroleum ether:EtOAc=4:1) to give methyl 2-methoxy-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamido)benzoate (180 mg, 22%) as solid. 1H NMR (300 MHz, CD3OD): δ 8.31 (s, 1H), 8.05-8.01 (m, 1H), 7.97-7.94 (m, 1H), 7.81 (d, 1H, J=8.7 Hz), 7.71 (d, 1H, J=1.8 Hz), 7.53 (d, 1H, J=7.5 Hz), 7.37 (dd, 1H, J1=8.7 Hz, J2=2.1 Hz), 3.91 (s, 3H), 3.85 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]([CH:18]=[O:19])=[CH:16][C:15]3[C:10](=[C:11]([O:20][CH3:21])[CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.O1CCCC1.[BH4-].[Na+]>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]([CH2:18][OH:19])=[CH:16][C:15]3[C:10](=[C:11]([O:20][CH3:21])[CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc2cc(C=O)c(-c3cccc(F)c3)nc12
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cccc2cc(CO)c(-c3cccc(F)c3)nc12
Temperature: 0 °C

Procedure:
To a solution of 2-(3-fluorophenyl)-8-methoxyquinoline-3-carbaldehyde (2.2967 g, 8.165 mmol) in tetrahydrofuran (40.83 mL, 8.165 mmol) at 0° C. was added sodium borohydride (0.4634 g, 12.25 mmol) and the mixture was stirred at 0° C. After 1 h of stirring at 0° C., the mixture was partitioned between EtOAc (100 mL) and H2O (100 mL), and the organic layer was washed with brine (100 mL×2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give (2-(3-fluorophenyl)-8-methoxyquinolin-3-yl)methanol as a brown solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.43 (1H, s), 7.46-7.60 (5H, m), 7.29-7.36 (1H, m), 7.19 (1H, dd, J=7.4, 1.6 Hz), 5.50 (1H, t, J=5.3 Hz), 4.61 (2H, dd, J=5.5, 0.8 Hz), 3.96 (3H, s); LC-MS (ESI) m/z 284.0 [M+H]+. The brown solid was carried on crude without purification for the next step.