Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1([O:17][CH2:18][CH:19]=[CH2:20])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)C=C>C1C=CC=CC=1>[O:17]1[C:4]2([CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH2:8][CH2:9]2)[CH2:1][CH:20]=[CH:19][CH2:18]1
Reactant: C=CCOC1(CC=C)CCN(C(=O)OC(C)(C)C)CC1
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N1CCC2(CC=CCO2)CC1
Reaction time: 18 h

Procedure:
A solution of Example 518B (0.79 g, 2.81 mmol) in degassed benzene (100 mL) at room temperature was treated with bis-tricyclohexylphosphine benzylidene ruthenium (IV) dichloride (150 mg), stirred for 18 hours, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 10%-25% ethyl acetate/heptane to provide the desired product. MS (DCI(+)) m/e 254 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH:3]1([N:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)[CH2:7][CH2:6][CH2:5][CH2:4]1.CN(C=O)C.F[C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][CH:28]=2)=[CH:23][N:22]=1>O>[CH:3]1([N:8]2[CH2:9][CH2:10][CH:11]([O:14][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][CH:28]=4)=[CH:23][N:22]=3)[CH2:12][CH2:13]2)[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: OC1CCN(C2CCCC2)CC1
Reactant: N#Cc1ccc(-c2ccc(F)nc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(-c2ccc(OC3CCN(C4CCCC4)CC3)nc2)cc1
Temperature: 130 °C
Reaction time: 7 h

Procedure:
60% sodium hydride (13 mg) and 1-cyclopentyl-4-hydroxypiperidine (60 mg) were added to a DMF solution (3 ml) of 2-fluoro-5-[4-cyanophenyl]pyridine (56 mg), and stirred at 130° C. for 7 hours. The reaction mixture was cooled to room temperature, and water was added thereto and extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (C-300, chloroform:methanol=9:1) to obtain the entitled compound.
Reaction SMILES: CN.[C:3]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:5][CH:4]=1.[C:24]([BH3-])#[N:25].[Na+].C(O)(=O)C>C1COCC1>[C:3]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:8]=[CH:7][C:6]([CH:9]([NH:25][CH3:24])[CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:5][CH:4]=1
Reactant: [BH3-]C#N
Reactant: O=C(CN1CCOCC1)c1ccc(-c2ccccc2)cc1
Agent: CN
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CNC(CN1CCOCC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.9 %

Procedure:
2.0 M methylamine solution in THF (18 mL, 36.0 mmol) was added to a solution of 1-(4-biphenylyl)-2-(4-morpholinyl)ethanone (2.52 g, 8.93 mmol) in anhydrous THF (20 mL), The reaction mixture was stirred at room temperature for 1 h and then sodium cyanoborohydride (1.68 g, 26.79 mmol) and acetic acid (1 mL) were added. The resulting mixture was stirred at room temperature for 72 h until the starting material was consumed completely. At this point, saturated K2CO3 solution (40 mL) was added to and after stirring for 15 min, the solution was extracted with ethyl acetate (2×50 mL). The combined organic layer was dried over Na2SO4 and concentrated. The resulting residue was isolated by column chromatography on silica gel (MeOH/EtOAc, 1:10) to yield [1-(4-biphenylyl)-2-(4-morpholinyl)ethyl]methylamine as an off-white solid (1.40 g, 53%), MS (ES) m/e 296[M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.[C:10](OCC)(=[O:16])[C:11](OCC)=[O:12]>>[OH:12][C:11]1[C:10]([OH:16])=[N:9][C:4]2[C:5](=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[N:8]=1
Reactant: Nc1ccc(F)cc1N
Reactant: CCOC(=O)C(=O)OCC
Product: Oc1nc2ccc(F)cc2nc1O
Temperature: 25 °C

Procedure:
A mixture consisting of 26.3 g. (0.19 mole) of 4-fluoro-1,2-phenylenediamine [Journal of the American Chemical Society, Vol. 75, P. 1294 (1953)] and 150 ml. of diethyl oxalate was refluxed under a nitrogen atmosphere for a period of 18 hours. Upon completion of this step, the reaction mixture was cooled to room temperature (~20° C.), filtered and the recovered product subsequently washed with four-100 ml. portions of ethanol and air-dried to constant weight to ultimately afford 19.3 g. (80%) of pure 2,3-dihydroxy-6-fluoroquinoxaline, m.p. >300° C. (literature m.p. 387°-390° C., according to U.S. Pat. No. 3,992,378). Mass Spectrum: m/e, 180 (P+).
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[C:18]([CH3:19])=[C:17]([O:20][CH3:21])[C:16]([CH3:22])=[C:15]([CH3:23])[C:14]=1[O:24][CH3:25].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCCC1>[CH2:26]([C:13]1[C:18]([CH3:19])=[C:17]([O:20][CH3:21])[C:16]([CH3:22])=[C:15]([CH3:23])[C:14]=1[O:24][CH3:25])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COc1c(C)c(C)c(OC)c(Br)c1C
Reactant: BrCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1c(C)c(C)c(OC)c(Cc2ccccc2)c1C
Reaction time: 0.33 h
Yield: 82.6 %

Procedure:
A 24.1 ml (38.6 mmole) of n-butyllithium.hexane solution was added dropwise to 10.0 g (38.6 mmole) of 1-bromo-2,5-dimethoxy-3,4,6-trimethylbenzene dissolved in anhydrous tetrahydrofuran (100 ml), under an atmosphere of argon at -40° C. over the period of 10 minutes, followed by stirring for another 20 minutes. Then, 3.32 g (38.6×0.6 mmole) of cuprous bromide was added, followed by stirring at -40° to -20° C. for 1 hour. After addition of a solution of 6.60 g (38.6 mmole)of benzyl bromide in tetrahydrofuran (15 ml), the cooling bath was removed, the reaction solution was stirred at 70° C. for 1 hour and cooled with ice, followed by addition of 1N hydrochloric acid (50 ml) and stirring. The tetrahydrofuran was distilled off under reduced pressure, and isopropyl ether was added to the residue. The insoluble matter was filtered through a bed of Hyflo Supercell, and the isopropyl ether layer was separated out, washed with water and aqueous sodium chloride solution successively, dried (magnesium sulfate) and evaporated. The residual solution was distilled under reduced pressure to give 8.62 g (83%) of 1-benzyl-2,5-dimethoxy-3,4,6-trimethylbenzene, b.p.140°-142° C. (0.3 torr) and m.p. 70° to 71° C.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9]([Mg]Cl)([CH3:12])([CH3:11])[CH3:10].C(OCC)C.[Cl-].[Na+]>C1COCC1.[Cu](I)I>[C:9]([C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)[Mg]Cl
Reactant: Clc1cccnc1Cl
Agent: I[Cu]I
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)c1ncccc1Cl
Temperature: 0 °C
Yield: 9 %

Procedure:
2,3-Dichloropyridine (1.0 g, 0.0068 mol) and copper iodide (0.065 g, 0.341 mmol) were dissolved in THF (6 mL). The mixture was degassed three times then cooled to 0° C. with an ice bath. Then tert-butyl(chloro)magnesium in diethylether (5.10 mL, 0.0102 mol) was added drop wise to the reaction mixture under nitrogen keeping the temperature at 0° C. with an ice bath. When the addition was complete, it was left to warm up to room temperature for 16 hours. A saturated aqueous solution of sodium chloride was slowly added to the reaction mixture (20 mL). The product was then extracted with tert-butyl methyl ether (20 mL). The organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting crude was purified by silica gel chromatography eluting with 0 to 5% EtOAc in heptanes to yield the title compound as a yellow oil (0.108 g, 9% yield).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13](=[O:21])[CH2:14][CH2:15][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH:10]=2)[N:5]=[CH:4][N:3]=1.C[O:23][CH:24]=[C:25]([C:30](OC)=O)[C:26]([O:28][CH3:29])=[O:27].O>CN(C)C=O>[O:23]=[C:24]1[N:3]2[CH:4]=[N:5][C:6]3[CH:7]=[CH:8][C:9]([NH:12][C:13](=[O:21])[CH2:14][CH2:15][CH:16]4[CH2:20][CH2:19][CH2:18][CH2:17]4)=[CH:10][C:11]=3[C:2]2=[N:1][CH:30]=[C:25]1[C:26]([O:28][CH3:29])=[O:27]
Reactant: Nc1ncnc2ccc(NC(=O)CCC3CCCC3)cc12
Reactant: COC=C(C(=O)OC)C(=O)OC
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cnc2c3cc(NC(=O)CCC4CCCC4)ccc3ncn2c1=O
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 22.1 %

Procedure:
A mixture of 4-amino-6-(3-cyclopentylpropionamido)quinazoline (7.05 g) and dimethyl methoxymethylenepropanedioate (6.48 g) in N,N-dimethylformamide (28 ml) was stirred at 100° C. for 1 hour and 10 minutes. After cooling to ambient temperature, water was added to the reaction mixture. The resulting solid was separated by filtration, washed with water, and dried. The crude crystals were dissolved in a mixture of chloroform and methanol, treated with activated charcoal, and evaporated under reduced pressure until crystallizaton began. After cooling, the resulting solid was collected, washed with methanol and with dichloromethane, and dried. There was obtained crystalline methyl 4-oxo-10-(3-cyclopentylpropionamido)-4H-pyrimido[1,2-C]quinazoline-3-carboxylate (2.16 g). The filtrate was evaporated under reduced pressure to give a residue which was chromatographed on silica gel with 1% methanol-dichloromethane. The first fractions contained methyl 4-oxo-10-(3-cyclopentylpropionamido)-4H-pyrimido[1,2-C]quinazoline-3-carboxylate (1.9 g). The second fractions contained dimethyl [[6-(3-cyclopentylpropionamido)-4-quinazolinylamino]methylene]propanedioate (5.16 g).
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[CH2:13][C:14]([OH:16])=O.[CH3:17][NH2:18]>C1(C)C=CC=CC=1>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[CH2:13][C:14]([NH:18][CH3:17])=[O:16]
Reactant: CN
Reactant: O=C(O)Cc1cc(F)ccc1Br
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: CNC(=O)Cc1cc(F)ccc1Br
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Thionyl chloride (9.4 mL, 129 mmol) is added to a solution of (2-bromo-5-fluoro-phenyl)-acetic acid (20.0 g, 85.8 mmol) in dry toluene (400 mL). The mixture is heated at reflux for 4 hours and the solvent is removed in vacuo. The remanence is redissolved in dry toluene (400 mL) and cooled to 0° C. 40% methylamine (aq.) (17.7 mL, 515 mmol) is added dropwise at 0-5° C. The mixture is then stirred at ambient temperature for 16 hours, poured onto water (250 mL) and extracted with ethyl acetate (3×200 mL). The combined organic fractions are washed successively with saturated sodium bicarbonate solution (150 mL) and brine (150 mL), dried (MgSO4) and concentrated in vacuo. This gives 16.2 g (77%) of crystalline 2-(2-bromo-5-fluoro-phenyl)-N-methyl-acetamide.
Reaction SMILES: Cl.[NH2:2][OH:3].[N+:4]([C:7]1[CH:23]=[CH:22][C:10]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=O)=[CH:9][CH:8]=1)([O-:6])=[O:5]>C(O)C>[N+:4]([C:7]1[CH:23]=[CH:22][C:10]([C:11](=[N:2][OH:3])[C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)([O-:6])=[O:5]
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1
Reactant: NO
Agent: Cl
Solvent: CCO
Product: O=[N+]([O-])c1ccc(C(=NO)c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Yield: 69.6 %

Procedure:
A solution of hydroxylamine hydrochloride (10.2 g, 147 mmol) was added to a suspension of 4,4'-dinitrobenzophenone (19 g, 70 mmol) in 100 ml of ethanol. The reaction mixture was heated to reflux for 2 hours, cooled to room temperature, and the solid collected by filtration. Recrystallization from ethanol provided the title compound (14.0 g, 70%) as pale yellow crystals. mp 194° C.; 1H NMR (D6 -DMSO) 12.25 (s, 1H), 8.35 (d, 2H), 8.20 (d, 2H), 7.60 (d, 4H). 4,4'-Dinitrobenzophenone Oxime Boc-Asp(OcHex)-2-aminomethylphenylacetate
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:13][C:14](=[O:16])[CH3:15])=[CH:4][CH:3]=1.[C:19]([C:23]([CH2:25][C:26](OCC)=[O:27])=O)([F:22])([F:21])[F:20].CS(O)(=O)=O.[OH-].[Na+]>O>[O:27]=[C:26]1[CH:25]=[C:23]([C:19]([F:22])([F:21])[F:20])[C:18]2[C:2](=[CH:3][CH:4]=[C:5]([CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:13][C:14](=[O:16])[CH3:15])[CH:17]=2)[O:1]1
Reactant: CC(=O)Nc1ccccc1Cc1ccc(O)cc1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Nc1ccccc1Cc1ccc2oc(=O)cc(C(F)(F)F)c2c1
Temperature: 20 °C
Yield: 26 %

Procedure:
A solution of N-[2-(4-hydroxybenzyl)phenyl]acetamide (200 mg, 0.83 mmol) in CF3COCH2CO2Et (305 mg, 1.66 mmol) & MeSO3H (750 μL, 11.55 mmol) was heated at 75° C. for 2 d. On cooling to 20° C., the mixture was treated with H2O (20 mL), then the pH was adjusted to 12 with NaOH. The mixture was extracted with EtOAc (150 mL), then the extracts were washed with 0.5 M NaOH (2×50 mL), before being dried (MgSO4). Filtration, solvent evaporation, & column chromatography (1:2 PE-EtOAc) yielded N-[2-(2-oxo-4-trifluoromethyl-2H-chromen-6-ylmethyl)-phenyl]acetamide (78 mg, 26%): m/z (ES+)=362.2 [M+H]+. A solution of this compound in AcOH-12 M HCl (1:6, 3.5 mL) was heated at 95° C. for 6 h. On cooling to 20° C., H2O (8 mL) was added, then the mixture was treated with NaOH then Na2CO3 to adjust the pH to 10. Extraction with EtOAc (10 mL) & solvent evaporation furnished a residue which was subjected to column chromatography (2:1 PE-EtOAc) to give the title compound (8 mg, 12%): δH (CDCl3)=3.50 (br s, 2H), 4.00 (s, 2H), 6.70 (d, 1H), 6.80 (m, 2H), 7.00 (d, 1H), 7.10 (t, 1H), 7.35 (d, 1H), 7.40 (d, 1H), 7.55 (s, 1H); m/z (ES+)=320.1 [M+H]+. Compounds of Formula I
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]3[CH2:25][CH2:24][CH:23]([N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22]3)=[N:19][CH:20]=1)=[CH:11][C:10](Br)=[CH:9][CH:8]=2)(=[O:3])[CH3:2].[Cl:36][C:37]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[C:39]([F:52])[C:38]=1[OH:53]>>[C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]3[CH2:25][CH2:24][CH:23]([N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22]3)=[N:19][CH:20]=1)=[CH:11][C:10]([C:41]1[CH:40]=[C:39]([F:52])[C:38]([OH:53])=[C:37]([Cl:36])[CH:42]=1)=[CH:9][CH:8]=2)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(N2CCC(N(C)C(=O)OC(C)(C)C)C2)nc1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Product: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1Nc1ccc(N2CCC(N(C)C(=O)OC(C)(C)C)C2)nc1
Yield: 93.5 %

Procedure:
Following general procedure M, tert-butyl (1-(5-((3-acetyl-6-bromoquinolin-4-yl)amino)pyridin-2-yl)pyrrolidin-3-yl)(methyl)carbamate (80 mg, 0.15 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (68 mg, 0.25 mmol) to afford the desired product (85 mg, 95%) as a brown solid. ESI MS m/z 606 [C32H33ClFN5O4+H]+
Reaction SMILES: [OH-].[K+].C([O:5][C:6]([C:8]1([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]2([C:26](=[O:28])[NH2:27])[CH2:25][CH2:24]2)[CH2:10][CH2:9]1)=[O:7])C.Cl>C(O)C.O>[C:26]([C:23]1([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:8]2([C:6]([OH:7])=[O:5])[CH2:9][CH2:10]2)[CH2:24][CH2:25]1)(=[O:28])[NH2:27]
Reactant: CCOC(=O)C1(CCCCCCCCCCCCC2(C(N)=O)CC2)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: NC(=O)C1(CCCCCCCCCCCCC2(C(=O)O)CC2)CC1
Reaction time: 8.5 h
Yield: 73.3 %

Procedure:
To a solution of KOH (0.9 g, 16.0 mmol) in 90% ethanol (25 mL) was added product of Example 11 (0.7 g, 1.9 mmol) at 80° C. and stirred at same temperature for 8.5 h. The crude product obtained upon evaporation of the solvent was diluted with water (2.0 mL), acidified to pH=2 (1N HCl), and extracted with ethyl acetate (100 mL×2). The organic layer was dried over sodium sulphate and concentrated. The residue obtained was washed with n-hexane (20.0 mL×2) and dried under high vacuum to give product as white solid 470 mg (73%); mp: 116.6-118.1° C.
Reaction SMILES: [C:1]([NH2:16])(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]CC.N[C:18](C)(C(O)C)[CH:19]([OH:21])[CH3:20]>>[CH3:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([NH:16][C:19]([OH:21])([CH3:20])[CH3:18])=[O:15]
Reactant: CCCCCCCCCCCCCC(N)=O
Reactant: CC(O)C(C)(N)C(C)O
Product: CCCCCCCCCCCC(=O)NC(C)(C)O

Procedure:
myristic acid amide of 3-amino-3-methyl-2,4-pentanediol.
Reaction SMILES: C(OC(=O)/[N:10]=[C:11](/[NH2:35])\[C:12]1[CH:17]=[CH:16][C:15]([CH2:18][NH:19][C:20](=[O:34])[C@H:21]([O:31][CH2:32][CH3:33])[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=2[F:30])=[CH:14][CH:13]=1)C1C=CC=CC=1.[CH3:37][C:38]([OH:40])=[O:39]>CCO.[Pd]>[C:38]([OH:40])(=[O:39])[CH3:37].[C:11]([C:12]1[CH:13]=[CH:14][C:15]([CH2:18][NH:19][C:20](=[O:34])[C@H:21]([O:31][CH2:32][CH3:33])[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=2[F:30])=[CH:16][CH:17]=1)(=[NH:10])[NH2:35]
Reactant: CCO[C@@H](C(=O)NCc1ccc(/C(N)=N\C(=O)OCc2ccccc2)cc1)c1ccc(OC)cc1F
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CCO[C@@H](C(=O)NCc1ccc(C(=N)N)cc1)c1ccc(OC)cc1F

Procedure:
A solution of [1-amino-1-(4-{[(R)-2-ethoxy-2-(2-fluoro-4-methoxy-phenyl)-acetylamino]-methyl}-phenyl)-meth-(E)-ylidene]-carbamic acid benzyl ester (195 mg) in EtOH (20 ml) was treated with HOAc (0.05 ml) and Pd/C 10% (20 mg) and hydrogenated over night at normal pressure. The catalyst was filtered off, the filtrate was concentrated to give (R)-N-(4-carbamimidoyl-benzyl)-2-ethoxy-2-(2-fluoro-4-methoxy-phenyl)-acetamide acetate (151 mg, 96.3% ee) as white solid.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][C:9](=[N:30]O)[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([N:16]2[CH2:21][CH2:20][N:19]([C:22](=[O:29])[CH2:23][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:18][CH2:17]2)[CH:11]=1>>[CH3:26][C:25]([CH3:28])([CH3:27])[CH2:24][CH2:23][C:22]([N:19]1[CH2:20][CH2:21][N:16]([C:12]2[CH:11]=[C:10]([C:9]3[N:30]=[C:5]([CH3:6])[O:7][N:8]=3)[CH:15]=[CH:14][N:13]=2)[CH2:17][CH2:18]1)=[O:29]
Reactant: CC(C)(C)CCC(=O)N1CCN(c2cc(C(N)=NO)ccn2)CC1
Reactant: CC(=O)OC(C)=O
Product: Cc1nc(-c2ccnc(N3CCN(C(=O)CCC(C)(C)C)CC3)c2)no1

Procedure:
Acetic anhydride (2 mL) was added to 1-{4-[amino(hydroxyimino)methyl]pyridin-2-yl}-4-(4,4-dimethylpentanoyl)piperazine (104 mg) obtained in Example 56-1), heated under reflux for 2 hours, then the excess acetic anhydride was evaporated away, the residue was diluted with ethyl acetate, washed with aqueous saturated sodium hydrogencarbonate solution and saturated saline water, and dried with anhydrous sodium sulfate. The solvent was evaporated away, and the resulting residue was isolated and purified through thin-layer silica gel chromatography (hexane/ethyl acetate=1/1) to obtain 14.5 mg of the entitled compound as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH3:12])[C:9]=1[OH:10])[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH:21]1[CH2:23][CH2:22]1>CN(C=O)C.C(OCC)(=O)C>[CH:21]1([CH2:20][O:10][C:9]2[C:8]([O:11][CH3:12])=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=2[F:1])[CH2:23][CH2:22]1
Reactant: BrCC1CC1
Reactant: COc1cc(C=O)cc(F)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(C=O)cc(F)c1OCC1CC1
Temperature: 70 °C

Procedure:
To a solution of 3-fluoro-4-hydroxy-5-methoxybenzaldehyde (5.00 g) in DMF (50 mL) were added potassium carbonate (6.09 g) and (bromomethyl)cyclopropane (3.42 mL), and the mixture was stirred with heating at 70° C. for 1 hr. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate, and washed with saturated brine. The obtained organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (6.59 g).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)[C:12]2N=CC=[CH:16][C:11]=2[N:10]=N1.[NH2:25][C:26]1[N:27]=[C:28]([C:38]2[CH:43]=[C:42]([O:44][CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:41]([Cl:52])=[CH:40][C:39]=2[Cl:53])[C:29]2[CH:34]=[C:33]([C:35]([OH:37])=O)[S:32][C:30]=2[N:31]=1.C(N)(C)C>CN(C=O)C>[CH:11]([NH:10][C:35]([C:33]1[S:32][C:30]2[N:31]=[C:26]([NH2:25])[N:27]=[C:28]([C:38]3[CH:43]=[C:42]([O:44][CH2:45][C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)[C:41]([Cl:52])=[CH:40][C:39]=3[Cl:53])[C:29]=2[CH:34]=1)=[O:37])([CH3:16])[CH3:12]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Nc1nc(-c2cc(OCc3ccccc3)c(Cl)cc2Cl)c2cc(C(=O)O)sc2n1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(C)N
Solvent: CN(C)C=O
Product: CC(C)NC(=O)c1cc2c(-c3cc(OCc4ccccc4)c(Cl)cc3Cl)nc(N)nc2s1
Temperature: 60 °C

Procedure:
O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.176 g; 3.07 mmol) was added to 2-Amino-4-(5-benzyloxy-2,4-dichloro-phenyl)-thieno[2,3-d]pyrimidine-6-carboxylic acid. 2NaCl (1.33 g; 2.38 mmol) then DMF (25 ml) was added to afford a turbid brown solution. Isopropylamine (1.01 ml; 11.9 mmol) was added and reaction mixture was heated at 60° C. (oil bath temperature) for 18 hours. Reaction mixture was allowed to cool to room temperature and DMF was removed in vacuo. The residue was partitioned between ethyl acetate (200 ml) and water (200 ml). The phases were separated and the organic phase was washed with saturated aqueous sodium chloride solution (200 ml) the dried over anhydrous sodium sulphate, filtered and the filtrate solvents removed in vacuo to afford a yellow solid. The crude product was purified by flash chromatography on silica gel (50 g IST Flash Si cartridge) eluting with a solvent gradient of 20 to 50% ethyl acetate in hexane. This affords product as a colourless solid (0.612 g; 53%)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]([OH:16])([CH3:15])[CH3:14])[N:10]=[C:9]2[C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])=[CH:4][CH:3]=1.[CH3:25][S:26]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)(=[O:28])=[O:27].C(=O)([O-])[O-].[K+].[K+].COCCOC>[Pd].O>[F:24][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]([F:23])[C:17]=1[C:9]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([C:33]3[CH:32]=[CH:31][CH:30]=[C:29]([S:26]([CH3:25])(=[O:28])=[O:27])[CH:34]=3)=[CH:3][CH:4]=2)[CH:12]=[C:11]([C:13]([OH:16])([CH3:15])[CH3:14])[N:10]=1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: CC(C)(O)c1cn(-c2ccc(Br)cc2)c(-c2c(F)cccc2F)n1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(O)c1cn(-c2ccc(-c3cccc(S(C)(=O)=O)c3)cc2)c(-c2c(F)cccc2F)n1
Temperature: 80 °C
Yield: 76.7 %

Procedure:
2-[1-(4-Bromo-phenyl)-2-(2,6-difluoro-phenyl)-1H-imidazol-4-yl]-propan-2-ol (250 mg, 0.64 mmol), (3-methylsulfonylphenyl)boronic acid (254 mg, 1.27 mmol), and potassium carbonate (398 mg, 2.88 mmol) were placed into a flask. 6 mL, of mixture of DME (1,2-dimethoxyethane) and water (9:1, V/V) was added. The flask was flushed with argon for 15 min, and then Pd catalyst (Dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct, 52 mg, 0.064 mmol) was added. The mixture was heated to 80° C. overnight. After cooling to room temperature, all solvent was removed. The crude product was purified by column chromatography on silica gel (45→99% EtOAc/Hexane) to give an off-white solid (230 mg, 77% yield). 1H-NMR (400 MHz, CDCl3): δ 1.70 (s, 6H), 2.71 (s, 1H), 3.09 (s, 3H), 6.92-6.88 (m, 2H), 7.21 (s, 1H), 7.39-7.28 (m, 3H), 7.59-7.57 (m, 2H), 7.66 (t, 1H, J=7.8), 7.86-7.83 (M, 1H), 7.95-7.92 (m, 1H), 8.12 (t, 1H, J=1.7). MS (ES): 491.4 [M+Na]+