Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([O:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH2:4][CH2:3]1.C(Cl)(Cl)Cl.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>CC(O)=O.CCOCC>[O:1]=[C:2]1[CH2:3][CH2:4][CH:5]([O:8][S:9]([C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=2)(=[O:11])=[O:10])[CH2:6][CH2:7]1
Reactant: Cc1ccc(S(=O)(=O)OC2CCC(O)CC2)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)OC2CCC(=O)CC2)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 59.8 %

Procedure:
step 2—To a solution of 76 (2.23 g, 8.22 mmol) and CHCl3 (30 mL) was added PCC (1.77 g, 8.22 mmol) and CHCl3 (20 mL). One drop of HOAc was added and the mixture was stirred at RT for 2.5 days. An additional 1.77 g (8.22 mmol) of PCC was added and stirring continued at RT for an additional 6 h. The reaction was diluted with Et2O and filtered through a bed of SiO2. The cake was washed with Et2O and the filtrate was passed through a second plug of SiO2 while washing the cake with Et2O. The filtrate was stripped in vacuo and the crude material was purified by SiO2 chromatography eluting with a DCM/MeOH gradient (0 to 4% MeOH). The recovered material was re-purified by SiO2 chromatography eluting with a gradient of hexane/acetone (15 to 25% acetone) to afford 1.32 g (58%) of toluene-4-sulfonic acid 4-oxo-cyclohexyl ester (78) as a colorless oil: 1H NMR (CDCl3, 300 MHz): δ 7.83 (d, 2H), 7.37 (d, 2H), 4.92-4.86 (m, 1H), 2.78-2.53 (m, 2H), 2.46 (s, 3H), 2.34-2.13 (m, 4H), 2.03-1.83 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:42])[C@@H:4]([NH:32][C@H:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:34][CH3:35])[CH2:5][C:6]1[CH:31]=[CH:30][C:9]2[O:10][C@H:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=4)=[CH:16][CH:15]=3)[CH2:12][O:13][C:8]=2[CH:7]=1.C=O.F[C:46](F)(F)C(O)=O>O1CCOCC1.CCOC(C)=O>[CH3:1][O:2][C:3]([C@@H:4]1[CH2:5][C:6]2[CH:7]=[C:8]3[O:13][CH2:12][C@@H:11]([C:14]4[CH:15]=[CH:16][C:17]([O:20][CH2:21][C:22]5[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=5)=[CH:18][CH:19]=4)[O:10][C:9]3=[CH:30][C:31]=2[CH2:46][N:32]1[C@H:33]([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[CH2:34][CH3:35])=[O:42]
Reactant: O=C(O)C(F)(F)F
Reactant: CC[C@H](N[C@@H](Cc1ccc2c(c1)OC[C@@H](c1ccc(OCc3ccc(Cl)c(Cl)c3)cc1)O2)C(=O)OC)c1ccccc1
Agent: C=O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)OC)OC[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Temperature: 25 °C
Reaction time: 20 h

Procedure:
(S)-3-{(R)-2-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxin-6-yl}-2-((S)-1-phenyl-propylamino)-propionic acid methyl ester (1.0 g) was dissolved in 37 mL dry dioxane and 149 mg paraformaldehyde added. 30 mL dry dioxane and 17 mL trifluoroacetic acid were mixed, cooled on ice and added to the reaction mixture. The reaction was stirred for 20 hours at room temperature and diluted with EtOAc. The organic layer was washed with 10% sodium, dried over Na2SO4 and evaporated. The residue was purified by silica gel flash chromatography (DCM+0.2% TEA) to give 934 mg of product after drying. 1H NMR (400 MHz, acetone-d6): 7.71 (d, 1H), 7.61 (d, 1H), 7.50-7.41 (m, 3H), 7.38-7.26 (m, 5H), 7.09 (m, 2H), 6.67 (s, 1H), 6.60 (s, 1H), 5.19 (s, 2H), 5.10 (m, 1H), 4.32 (m, 1H), 4.12 (m, 2H), 4.01 (m, 1H), 3.92 (m, 1H), 3.59 (m, 1H), 3.51 (s, 3H), 2.97-2.78 (m, 2H), 2.16 (m, 1H), 1.68 (m, 1H), 0.66 (t, 3H).
Reaction SMILES: [CH-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.[Fe+2:11].[O:12]1[C:16]2([CH2:20][CH2:19][CH2:18][O:17]2)[CH2:15][CH2:14][CH2:13]1.B(F)(F)F.CCOCC>C(Cl)Cl>[C-:1]1([C:16]2([CH2:20][CH2:19][CH2:18][OH:17])[CH2:15][CH2:14][CH2:13][O:12]2)[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.[Fe+2:11]
Reactant: C1COC2(C1)CCCO2
Agent: [Fe+2]
Agent: FB(F)F
Agent: c1cc[cH-]c1
Solvent: CCOCC
Solvent: ClCCl
Product: OCCCC1([c-]2cccc2)CCCO1
Yield: 55 %

Procedure:
Ferrocene, 7.44 g (0.040 mole), and 1,6-dioxaspiro-[4,4]-nonane (I), 1.28 g (0.010 mole), were dissolved in 100 ml of methylene chloride and 3.6 ml (0.03 mole) of boron trifluoride etherate [BF3 . 0(Et)2 ] was added with stirring. After 2 hours of stirring, the reaction mixture was poured onto a dry alumina column (5 cm by 25 cm). Unreacted ferrocene, 6.3 g, was eluted from the column using ethylene dichloride. The chromatogram was then developed with a 1 to 1 mixture of ether (ethyl) and ethylacetate. The principal band (middle portion of the column) was cut out and extracted with methyl alcohol to give 1.72 g (55% yield) of II, mp 50°-53°C, after recrystallization from a 1 to 1 mixture of pentane and cyclohexane.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:11]([C@@H:18]1[CH2:22][O:21][C:20](=[O:23])[N:19]1[C:24](=[O:31])[CH2:25][CH2:26][C:27]([F:30])([F:29])[F:28])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.I[CH3:33]>C1COCC1>[CH2:11]([C@@H:18]1[CH2:22][O:21][C:20](=[O:23])[N:19]1[C:24](=[O:31])[C@H:25]([CH3:33])[CH2:26][C:27]([F:28])([F:29])[F:30])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(CCC(F)(F)F)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: CI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H](CC(F)(F)F)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 73.7 %

Procedure:
To a solution of sodium bis(trimethylsilyl)amide (57 mL, 1.0 M in THF, 57 mmol) in THF (250 mL) at −40° C. was added (4R)-4-benzyl-3-(4,4,4-trifluorobutanoyl)-1,3-oxazolidin-2-one (15.60 g, 51.78 mmol) in THF (250 mL) dropwise over 15 min. After 1 h, iodomethane (4.2 mL, 67 mmol) was added. After 3 h, the reaction mixture was warmed to −20° C. for about 20 min. The mixture was quenched with saturated aqueous ammonium chloride (NH4Cl) (300 mL) and then extracted with EtOAc (2×300 mL), dried using Na2SO4, and concentrated. Flash chromatography (eluent: 1:9 EtOAc-hexane) provided (4R)-4-benzyl-3-[(2R)-4,4,4-trifluoro-2-methylbutanoyl]-1,3-oxazolidin-2-one (12.04 g, 74%) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.[CH:21]1([C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:25])[CH2:23][CH2:22]1.[NH4+].[Cl-]>C1COCC1.O.CCOC(C)=O>[C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][C:24]([CH:21]2[CH2:22][CH2:23]2)([OH:25])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(c1ccccc1)C1CC1
Reactant: Cc1ccnc(NC(=O)OC(C)(C)C)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cc(CC(O)(c2ccccc2)C2CC2)ccn1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 82.3 %

Procedure:
(4-Methyl-pyridin-2-yl)-carbamic acid tert-butyl ester (200 mg, 0.96 mmol) is dissolved in dry THF (10 mL) and it is cooled down to −78° C. After 1.6 M n-BuLi (3.0 mL, 4.8 mmol) is added at −78° C., the cooling bath is removed and the mixture is stirred at room temperature for 15 min. Then the reaction mixture is cooled down to −78° C. again and cyclopropyl-phenyl-methanone (0.68 mL, 4.8 mmol) is added. After the mixture is stirred for 30 min at −78° C., saturated NH4Cl aqueous solution (35 mL) is added and the reaction is warmed up to room temperature. EtOAc (70 mL) is added along with water (70 mL). The mixture is stirred for another 10 min and the aqueous layer is separated, extracted with EtOAc (2×35 ml). The organic layers are combined and concentrated to give the crude product. Purification by silica flash column chromatography using MeOH in DCM (gradient from 0% to 10%) affords 280 mg of the desired product.
Reaction SMILES: C(N)(CC(C)(C)C)(C)C.[CH2:10]1[C:13](=[O:14])[N:12]2[C@@H:15]([C:21]([OH:23])=[O:22])/[C:16](/[O:20][C@H:11]12)=[CH:17]/[CH2:18][OH:19].C([O-])(=O)C.[K+:28]>C(O)C(C)C.O.C(O)(=O)C>[CH2:10]1[C:13](=[O:14])[N:12]2[C@@H:15]([C:21]([O-:23])=[O:22])/[C:16](/[O:20][C@H:11]12)=[CH:17]/[CH2:18][OH:19].[K+:28]
Reactant: O=C(O)[C@H]1/C(=C/CO)O[C@@H]2CC(=O)N21
Agent: CC(=O)[O-]
Agent: CC(C)(C)CC(C)(C)N
Agent: [K+]
Solvent: CC(=O)O
Solvent: CC(C)CO
Solvent: O
Product: O=C([O-])[C@H]1/C(=C/CO)O[C@@H]2CC(=O)N21
Reaction time: 0.25 h

Procedure:
5.5 g of the tert.octylamine salt of clavulanic acid are dissolved in 55 ml of iso-butanol containing 3.0% of water at a temperature of about 35°. 2.1 g of potassium acetate are dissolved in 55 ml of iso-butanol containing 0.25 ml of water and 0.2 ml of acetic acid. 6.0 ml of the potassium acetate solution are added dropwise to the solution of the clavulanic acid. 0.32 g of active carbon (Norit CG 1) are added. The suspension is stirred for ca. 15 minutes, filtrated and the filter is washed with 20 ml of iso-butanol. The solution is cooled to ca. 10° and the remaining solution of potassium acetate prepared as described above is added slowly. The mixture is cooled to ca. 5° and stirred for ca. 2 hours. A precipitate is formed which is filtrated off, washed with 30 ml of acetone and dried for about 20 hours in vacuo at ca. 45°. Potassium clavulanate is obtained (confirmed by 1H-NMR).
Reaction SMILES: [N+:1]([CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[N:10][CH:11]=1)([O-:3])=O.C[O-].[Li+].[C:22]([C:24]1[C:25]([NH2:31])=[N:26][C:27]([NH2:30])=[CH:28][CH:29]=1)#[CH:23].C(N(CC)CC)C>ClCCl.[Ti](Cl)(Cl)(Cl)Cl.O.CS(C)=O.O1CCCC1.CO>[N:15]1[CH:16]=[CH:17][CH:18]=[C:13]([O:12][C:9]2[N:10]=[CH:11][C:6]([CH2:5][C:4]3[CH:23]=[C:22]([C:24]4[C:25]([NH2:31])=[N:26][C:27]([NH2:30])=[CH:28][CH:29]=4)[O:3][N:1]=3)=[CH:7][CH:8]=2)[CH:14]=1
Reactant: C#Cc1ccc(N)nc1N
Reactant: O=[N+]([O-])CCc1ccc(Oc2cccnc2)nc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: C[O-]
Agent: [Li+]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: Nc1ccc(-c2cc(Cc3ccc(Oc4cccnc4)nc3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 8.3 %

Procedure:
To a mixture of 5-(2-nitro-ethyl)-2-(pyridin-3-yloxy)pyridine (157.0 mg, 0.64 mmol) described in Manufacturing Example 100-1-2 and methanol (6 mL) was added lithium methoxide (48.7 mg, 1.28 mmol) at room temperature, which was stirred for 1 hour. The reaction mixture was then concentrated under a reduced pressure, which gave a white solid. To a mixture of this solid in dichloromethane (4 mL) and tetrahydrofuran (2 mL) was added titanium tetrachloride (155.0 μL, 1.41 mmol) under nitrogen atmosphere at −78° C., which was stirred for 3 hours at 0° C. Water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under a reduced pressure. To a mixture of the resulting residue (30.7 mg), 3-ethynyl-pyridin-2,6-diamine (15.4 mg, 0.12 mmol) described in Manufacturing Example 13-1-3, tetrahydrofuran (1 mL), and dimethyl sulfoxide (1 mL) was added triethylamine (32.4 μL, 0.23 mmol) at room temperature, which was stirred for 1 hour at 55° C. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure. The residue thus obtained was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid), and then further purified by preparative thin-layer chromatography (NH silica gel, ethyl acetate) to obtain the title compound (3.6 mg, 9%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:33]=[CH:32][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29](O)=[O:30])[CH:25]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH:67]1[CH2:71][CH2:70][C@@H:69]([OH:72])[CH2:68]1.Cl>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:33]=[CH:32][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([N:67]4[CH2:71][CH2:70][C@@H:69]([OH:72])[CH2:68]4)=[O:30])[CH:25]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11]
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)cc2)c1
Reactant: O[C@@H]1CCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)N5CC[C@@H](O)C5)c[nH]4)c3)cc2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (50 mg, 0.1 mmol), HATU (51 mg, 0.13 mmol) and N,N-diisopropylethylamine (31 mg, 0.24 mmol) in anhydrous DMF (10 ml) was stirred at room temperature for 10 minutes, followed by addition of (R)-3-pyrrolidinol (14 mg, 0.16 mmol). The mixture was stirred for another 10 minutes and poured into 100 ml of water. 2M HCl was added dropwise until pH=4˜5. The precipitates were filtered, washed with water and dried in vacuo to give 1-(2-fluoro-5-methylphenyl)-3-(4-{[2-(4-{[(3R)-3-hydroxypyrrolidin-1-yl]carbonyl}-1H-pyrrol-2-yl)pyridin-4-yl]oxy}phenyl)urea as white solid. Yield: 40 mg, 71%.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([CH:23]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[C@H:16]2[CH2:21][CH2:20][C@H:19]([CH3:22])[CH2:18][CH2:17]2)=[O:14])=[N:9][CH:8]=1)C.C1(N[C@H]2CC[C@H](C)CC2)CCCCCC1.NC1SC=NC=1.C(OC(=O)CS)C>>[CH:23]1([N:15]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH3:22])[CH2:18][CH2:17]2)[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:30])=[O:3])=[CH:8][N:9]=2)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(C2CCCCCC2)[C@H]2CC[C@H](C)CC2)s1
Agent: CCOC(=O)CS
Agent: C[C@H]1CC[C@H](NC2CCCCCC2)CC1
Agent: Nc1cncs1
Product: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCCCCC2)CC1

Procedure:
{2-[3-Cycloheptyl-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester prepared as described in general procedures (A) and (B) using cycloheptyl-(trans-4-methyl-cyclohexyl)-amine and 5-aminothiazole-2-mercaptoacetic acid ethyl ester. Hydrolysis using general procedure (F) gave the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.CC(C)([O-])C.[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2OC2C=CC=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N#N>CCOCC.C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: Nc1ccccn1
Reactant: Clc1ccc2ccccc2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: c1ccc(Nc2ccc3ccccc3n2)nc1

Procedure:
To a 250-mL round-bottom flask were added 2-aminopyridine (2.30 g, 24.4 mmol), 2-chloroquinoline (4.0 g, 24.4 mmol), sodium tert-butoxide (3.29 g, 34.2 mmol), palladium (II) acetate (0.22 g, 0.98 mmol), bis(2-diphenylphosphinophenyl)ether (0.49 g, 0.91 mmol), and toluene (100 mL sparged with N2). The reaction mixture was heated at 105° C. for 18 h under an atm of N2. The reaction mixture was diluted with ether and THF, and washed with water. This solution was passed through a pad of celite to remove insoluble particles. The organic layer was dried over MgSO4. The crude product was purified by column chromatography eluting with 90:10 CH2Cl2/CH3CN. 2-Pyridyl-2-quinolylamine was isolated as an olive powder (4.66 g, 86%). Results of 1H NMR spectroscopy are consistent with the product. 1H NMR (300 MHz, CDCl3): δ 6.93 (m, 1H), 7.30 (d, J=8.8 Hz, 1H), 7.35 (t, J=7.4 Hz, 1H), 7.62 (m, 1H), 7.70 (m, 2H), 7.86 (d, J=8.4 Hz, 1H), 8.0 (m, 2H), 8.31 (m, 1H), 8.38 (d, J=8.5 Hz, 1H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[O:5][CH2:6][C:7]1[N:8]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:10][C:11]=1[CH3:12].[OH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][C:31]([O:33][CH3:34])=[O:32].CN(C)C=O.[H-].[Na+]>O>[CH3:12][C:11]1[O:10][C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:8][C:7]=1[CH2:6][O:5][C:4]1[CH:19]=[CH:20][CH:21]=[CH:22][C:3]=1[CH2:2][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][C:31]([O:33][CH3:34])=[O:32]
Reactant: COC(=O)Cc1ccccc1O
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccccc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1ccccc1OCc1ccccc1OCc1nc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 53.2 %

Procedure:
To a mixture of 4-(2-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (1.04 g), methyl 2-(2-hydroxyphenyl)acetate (0.50 g) and N,N-dimethylformamide (30 mL) was added sodium hydride (60%, oil, 0.13 g) under ice-cooling, and the mixture was stirred at room temperature for 15 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After concentration of the organic layer, the residue was subjected to silica gel column chromatography to give methyl 2-[2-[2-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetate as an oil (0.71 g, 53%) from a fraction eluted with ethyl acetate-hexane (1:6, v/v).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][NH:12][C:13]2[N:21]=[C:20](Cl)[N:19]=[C:18]3[C:14]=2[N:15]=[CH:16][N:17]3[CH:23]([CH3:28])[C:24]([O:26][CH3:27])=[O:25])=[CH:2]1.[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[N:34][CH:35]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCOCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][NH:12][C:13]2[N:21]=[C:20]([C:32]3[CH:33]=[N:34][CH:35]=[C:30]([F:29])[CH:31]=3)[N:19]=[C:18]3[C:14]=2[N:15]=[CH:16][N:17]3[CH:23]([CH3:28])[C:24]([O:26][CH3:27])=[O:25])=[CH:2]1
Reactant: OB(O)c1cncc(F)c1
Reactant: COC(=O)C(C)n1cnc2c(NCCc3c[nH]c4ccccc34)nc(Cl)nc21
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)C(C)n1cnc2c(NCCc3c[nH]c4ccccc34)nc(-c3cncc(F)c3)nc21
Temperature: 130 °C

Procedure:
A 150 ml pressure tube was charged with methyl 2-(6-(2-(1H-indol-3-yl)ethylamino)-2-chloro-9H-purin-9-yl)propanoate (c) (300 mg, 0.75 mmol), 5-fluoropyridin-3-ylboronic acid (159 mg, 1.1 mmol), tetrakis(triphenylphosphine)-palladium(0) (87 mg, 0.075 mmol), K3PO4 (638 mg, 3.0 mmol), and anhydrous dioxane (15 mL). The pressure tube was sparged with nitrogen and was sealed, then the reaction mixture was heated at 130° C. for 6 h with stirring. Water was added to the cooled mixture, and the mixture was extracted with ethyl acetate (50 ml×3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (10 to 80% ethyl acetate in hexane eluant) to afford the title compound contaminated with a small amount of triphenylphosphine oxide. MS m/z 460.1 (M+1).
Reaction SMILES: [OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:14][O:15][CH3:16])[NH:8][C:9]=1[C:10]([O:12][CH3:13])=[O:11])([CH3:4])[CH3:3].CC(C)([O-])C.[K+].[C:23]([O:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36]1[CH:43]=[CH:42][C:39]([CH2:40]Br)=[CH:38][CH:37]=1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[C:23]([O:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36]1[CH:43]=[CH:42][C:39]([CH2:40][N:8]2[C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:5]([C:2]([OH:1])([CH3:3])[CH3:4])[N:6]=[C:7]2[CH2:14][O:15][CH3:16])=[CH:38][CH:37]=1)=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: COCc1nc(C(C)(C)O)c(C(=O)OC)[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: COCc1nc(C(C)(C)O)c(C(=O)OC)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Yield: 93.9 %

Procedure:
Following a procedure similar to that described in Example 82(a), but using 230 mg of methyl 4-(1-hydroxy-1-methylethyl)-2-methoxymethylimidazole-5-carboxylate [prepared as described in Preparation 42(v)], 119 mg of potassium t-butoxide and 420 mg of 4-[2-(t-butoxycarbonyl)phenyl]benzyl bromide and then purifying the product by column chromatography through silica gel using a 1:2 by volume mixture of hexane and ethyl acetate as the eluent, 468 mg of the title compound were obtained as a syrup.
Reaction SMILES: C(=O)=O.[CH3:4][C:5](C)=O.Br[C:9]1[CH:10]=[C:11]([CH:35]=[CH:36][CH:37]=1)[CH2:12][CH:13]1[C:19](=[O:20])[N:18]([CH3:21])[C:17]2[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:16]=2[C:15]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)=[N:14]1.[Zn](CC)CC>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:26][C:24]1[CH:23]=[CH:22][C:17]2[N:18]([CH3:21])[C:19](=[O:20])[CH:13]([CH2:12][C:11]3[CH:35]=[CH:36][CH:37]=[C:9]([CH2:4][CH3:5])[CH:10]=3)[N:14]=[C:15]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[C:16]=2[CH:25]=1
Reactant: CC(C)=O
Reactant: COc1ccc(C2=NC(Cc3cccc(Br)c3)C(=O)N(C)c3ccc(Cl)cc32)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC[Zn]CC
Solvent: C1CCOC1
Product: CCc1cccc(CC2N=C(c3ccc(OC)cc3)c3cc(Cl)ccc3N(C)C2=O)c1
Temperature: 25 °C
Yield: 88 %

Procedure:
To a stirred and cooled (dry ice-acetone bath) solution of (Z)-3-(3-bromobenzyl)-7-chloro-5-(4-methoxyphenyl)-1-methyl-1H-benzo[e][1,4]diazepin-2(3H)-one (1.21 g, 2.5 mmol) and PdCl2(dppf) [0.22 g] in dry THF (10 mL) was added 1 M Et2Zn (9.3 mL, 10 mmol, 4 eq). After warming to RT, the reaction mixture was stirred at 50° C. until HPLC indicated reaction to be complete. After aqueous workup, chromatography gave 0.95 g (yield of 88%) of title product. 1H NMR (300 MHz, CDCl3) δ 1.22 (t, 3H), 2.62 (q, 2H), 3.55 (d, 2H), 3.70 (t, 1H), 3.84 (s, 3H), 6.89 (d, 2H), 7.03 (m, 1H), 7.1-7.3 (m, 5H), 7.4-7.55 (m, 3H). The following compound was prepared based on the above procedure: (Z)-7-Chloro-3-(3-ethylbenzyl)-1-(4-methoxybenzyl)-5-(4-methoxyphenyl)-1H-benzo[e][1,4]diazepin-2(3H)-one. 1H NMR (300 MHz, CDCl3) δ 1.23 (t, 3H), 2.63 (q, 2H), 3.55-3.65 (m, 2H), 3.68 (s, 3H), 3.80 (dd, 1H), 3.83 (s, 3H), 4.59 (d, 1H), 5.63 (d, 1H), 6.61 (d, 2H), 6.85 (d, 2H), 6.88 (d, 2H), 7.04 (dt, 1H), 7.10 (fine d, 1H), 7.13-7.26 (m, 5H), 7.30 (d, 1H), 7.37 (dd, 1H).