Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]2[CH:11]=[CH:12][C:13](OS(C(F)(F)F)(=O)=O)=[CH:14][C:9]=2[O:8][C:7]=1[C:23](=[O:32])[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[Cl:31])=[O:5])[CH3:2].[CH3:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)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>[CH2:1]([O:3][C:4]([C:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:38]3[CH:39]=[C:34]([CH3:33])[CH:35]=[CH:36][CH:37]=3)=[CH:14][C:9]=2[O:8][C:7]=1[C:23](=[O:32])[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[Cl:31])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C(=O)c2ccc(Cl)cc2Cl)oc2cc(OS(=O)(=O)C(F)(F)F)ccc12
Reactant: Cc1cccc(B(O)O)c1
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: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C(=O)c2ccc(Cl)cc2Cl)oc2cc(-c3cccc(C)c3)ccc12
Temperature: 80 °C
Reaction time: 4 h
Yield: 62.9 %

Procedure:
To a solution of 2-(2,4-Dichloro-benzoyl)-6-trifluoromethanesulfonyloxy-benzofuran-3-carboxylic acid ethyl ester from step 4 (162 mg, 0.32 mmol, 1 eq) in anhydrous N,N-dimethylformamide (2 mL) were sequential added 3-methyl benzene boronic acid (64.6 mg, 0.63 mmol, 1.5 eq), potassium carbonate (87.6 mg, 0.63 mmol, 2 eq) and tetrakis(triphenylphosphine)palladium(0) (73.2 mg, 0.06 mmol, 0.2 eq) under argon. The reaction mixture was degassed for 5 min. The reaction was then stirred at 80° C. for 4 h followed by stirred at rt for 12 h. The mixture was cooled to room temperature then poured into ethyl acetate (10 mL) and water (10 mL). The aqueous layer was extracted with ethyl acetate (2×10 mL). Combined the organic layer was washed by water (2×10 mL), dried over Na2SO4, filtrated, and evaporated in vacuo. The residue was purified by pre-HPLC to afford an yellow solid (91.3 mg, 63%) as product. 1H-NMR (CDCl3): δ 8.04 (d, J=8.3 Hz, 1H), 7.73 (s, 1H), 7.64 (dd, J=1.5, 8.3 Hz, 1H), 7.57 (d, J=8.3 Hz, 1H), 7.47 (d, J=1.9 Hz, 1H), 7.41 (m, 2H), 7.36 (dd, J=1.9, 8.3 Hz, 1H), 7.34 (t, 1H), 7.19 (d, J=8.3 Hz, 1H), 4.245 (q, 2H), 2.43 (s, 3H), 1.28 (t, 3H); LC-MS (MH+=453/455).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].C(N(C(C)C)CC)(C)C.[Cl:28][C:29]1[N:34]=[C:33](Cl)[C:32]([Cl:36])=[CH:31][N:30]=1>CN(C=O)C.CN1C(=O)CCC1>[Cl:28][C:29]1[N:34]=[C:33]([NH:1][C:2]2[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:3]=2[C:4]([NH:6][CH3:7])=[O:5])[C:32]([Cl:36])=[CH:31][N:30]=1
Reactant: CNC(=O)c1cc(C)ccc1N
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CNC(=O)c1cc(C)ccc1Nc1nc(Cl)ncc1Cl
Yield: 138.3 %

Procedure:
2-Amino-5,N-dimethyl-benzamide (2.0 g, 12.2 mmol), potassium carbonate (2 eq) or diisopropylethylamine (2 eq) and 2,4,5-trichloropyrimidine (2.24 g, 12.2 mmol) were combined in DMF or NMP (25 mL) and heated at 50-100° C. until HPLC indicated consumption of the starting materials. The reaction can either be concentrated in vacuo or directly partitioned between water and dichloromethane. The product is extracted, dried and concentrated to afford the crude material, which is then chromatographed on silica gel (ethyl acetate:hexanes) to afford 2-(2,5-dichloro-pyrimidin-4-ylamino)-5,N-dimethyl-benzamide (5.25 g, 56%) as a light yellow solid. m.p.=192-210° C.; LCMS (m/e) 311 (M+1); 1H-NMR (DMSO-d6, 400 MHz) δ 12.02 (s, 1H), 8.82 (m, 1H), 8.45 (s, 1H), 8.38 (d, 1H, J=8.5 Hz), 7.63 (s, 1H), 7.42 (d, 1H, J=8.5 Hz), 2.80 (d, 3H, J=4.4 Hz), 2.34 (s, 3H).
Reaction SMILES: [Na].[CH2:2]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13])[CH2:3][CH2:4][CH3:5].Cl.[N:15]1([CH2:21][CH2:22]Cl)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>C(O)C>[CH2:2]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH2:22][CH2:21][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCOc1ccccc1O
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCCCOc1ccccc1OCCN1CCCCC1

Procedure:
The compound was prepared as described in Example 1, using sodium (2.3 g, 100 mmole), o-butoxyphenol (8.30 g, 50 mmole) and piperidinoethylchloride hydrochloride (9.2 g, 50 mmole) in 150 ml of ethanol. Yield 4.4 g (32%) of product boiling at 121° C under a pressure of 0.02 mm Hg; nD25 1.5135.
Reaction SMILES: [CH2:1]([O:4][CH:5]([O:16][CH2:17][CH2:18][CH3:19])[CH2:6][NH:7][CH2:8][CH:9]1[O:14][CH:13]([CH3:15])[CH2:12][CH2:11][O:10]1)[CH2:2][CH3:3].C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:32][CH2:33][C:34](Cl)=[O:35]>O>[CH2:17]([O:16][CH:5]([O:4][CH2:1][CH2:2][CH3:3])[CH2:6][N:7]([CH2:8][CH:9]1[O:14][CH:13]([CH3:15])[CH2:12][CH2:11][O:10]1)[C:34](=[O:35])[CH2:33][Cl:32])[CH2:18][CH3:19]
Reactant: O=C(Cl)CCl
Reactant: CCCOC(CNCC1OCCC(C)O1)OCCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CCCOC(CN(CC1OCCC(C)O1)C(=O)CCl)OCCC

Procedure:
N-(2,2-Dipropoxyethyl)-N-(4-methyl-1,3-dioxan-2-yl-methyl)amine (0.05 mole), benzene (100 ml), water (100 ml) and sodium carbonate (2 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is cooled to a temperature of from 5° to 10° C and chloroacetyl chloride (0.05 mole) is added dropwise with stirring. After the addition is completed stirring is continued until the reaction mixture has reached room temperature. After this time the organic phase is separated from the aqueous phase and is washed with water. The washed solution is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-(2,2-dipropoxyethyl)-N-(4-methyl-1,3-dioxan-2-ylmethyl)-α-chloroacetamide as the residue.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([I:9])[C:5]([OH:8])=[N:6][CH:7]=1.[C:10](=O)([O-])[O-].[Cs+].[Cs+].IC.Cl>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([I:9])[C:5](=[O:8])[N:6]([CH3:10])[CH:7]=1
Reactant: Oc1ncc(F)cc1I
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Cs+]
Solvent: CI
Solvent: CC(C)=O
Product: Cn1cc(F)cc(I)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5-fluoro-3-iodo-pyridin-2-ol (31, 200 g, 838 mmol) in 3000 mL of acetone was cooled in an ice water bath. Cesium carbonate (354 g, 1088 mmol) was added, then iodomethane (58.1 mL, 929 mmol) was added dropwise over 30 minutes. The reaction was stirred overnight at room temperature. The reaction was concentrated under vacuum and the resulting material partitioned between ethyl acetate and water. The aqueous layer was isolated and adjusted to pH 3-4 with 3 N hydrochloric acid, then extracted with ethyl acetate. The combined organic layers were concentrated under vacuum to provide the desired compound as an off white solid. (32, 150 g, 593 mmol, 70.8%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1I)[C:15]#[N:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:21]([O:25][CH2:26][CH3:27])(=[O:24])[CH:22]=[CH2:23].C(N(CC)CC)C.C(OCC)(=O)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([C:15]#[N:16])[CH:17]=[CH:18][C:19]=1[CH:23]=[CH:22][C:21]([O:25][CH2:26][CH3:27])=[O:24])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCOc1cc(C#N)ccc1I
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)C=Cc1ccc(C#N)cc1OCCNC(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 8 h

Procedure:
11.0 g (28.4 mmol) of 3-[2-(t-butoxycarbonylamino)ethoxy]-4iodobenzonitrile was dissolved in 200 ml of DMF. 15.4 ml (142 mmol) of ethyl acrylate, 20 ml (142 mmol) of triethylamine and 127 mg (0.567 mmol) of palladium acetate were added to the obtained solution. They were stirred at 100° C. overnight and then treated with ethyl acetate as the extraction solvent in an ordinary manner to obtain the crude product. After the purification by the silica gel column chromatography, the title compound was obtained.
Reaction SMILES: [CH2:1]1[CH2:11][CH2:10]N2[C:4](=NCCC2)[CH2:3][CH2:2]1.[CH2:12]([OH:18])[CH2:13][CH2:14][CH2:15]CC.CCCCCCCCCC>CCCCCC>[CH2:12]([OH:18])[CH2:13][CH2:14][CH2:15][CH2:10][CH2:11][CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: C1CCC2=NCCCN2CC1
Reactant: CCCCCCO
Solvent: CCCCCC
Solvent: CCCCCCCCCC
Product: CCCCCCCCCCO
Reaction time: 1 h

Procedure:
In an inert atmosphere, 26.8 mmol each of DBU (95 ppm H2O) and 1-hexanol (26 ppm H2O) were charged into a flame-dried flask. N-Decane (2 mL, undried) was added and was found to be miscible at room temperature; only one homogeneous liquid phase was observed. CO2 (H2O<5 ppm) was slowly bubbled through the decane/1-hexanol/DBU mixture at 1 bar overnight. The resultant mixture appeared split into two separate liquids. Argon was then bubbled through the two-phase liquid mixture for 1 h at 35° C. After 1 h, the two liquids had merged into one liquid. A schematic representation of this reversible reaction appears in FIG. 4. Similar experiments were performed with hexane in place of decane and with several alcohols (1-propanol, 1-butanol, 1-hexanol, 1-octanol, and 1-decanol) in place of 1-hexanol; similar results were obtained except that with 1-decanol, no phase split was observed even after the treatment with CO2. Miscibility data for alcohol/DBU systems is presented in Table 1.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([O:8][C@@H:9]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH:26]=[CH:27][C:28]3[NH:29][C:30]4[C:35]([C:36]=3[CH:37]=2)=[CH:34][CH:33]=[CH:32][CH:31]=4)O1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:11]12[CH2:16][CH2:15][CH:14]([CH2:13][CH2:12]1)[C@@H:9]([O:8][C:5]1[N:6]=[N:7][C:2]([C:25]3[CH:26]=[CH:27][C:28]4[NH:29][C:30]5[C:35]([C:36]=4[CH:37]=3)=[CH:34][CH:33]=[CH:32][CH:31]=5)=[CH:3][CH:4]=1)[CH2:10]2
Reactant: CC1(C)OB(c2ccc3[nH]c4ccccc4c3c2)OC1(C)C
Reactant: Clc1ccc(O[C@H]2CN3CCC2CC3)nn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Product: c1ccc2c(c1)[nH]c1ccc(-c3ccc(O[C@H]4CN5CCC4CC5)nn3)cc12

Procedure:
The product of Example 9A (0.173 g, 0.72 mmol) was coupled with the product of Example 38A (0.267 g, 0.91 mmol) under the catalysis of dichlorobis(triphenylphosphine)palladium(II) (Aldrich, 5.3 mg, 0.007 mmol) and 2-(dicyclohexylphosphino)biphenyl (Strem Chemicals, 7.3 mg, 0.021 mmol) at 150° C. for 10 min. according to the procedure of Example 29A. The title product was purified by preparative HPLC (Xterra™, column, Xterra RP-18 5 μm, 30×100 mm. Eluting Solvent, MeCN/H2O (NH4HCO3, 0.1 M, pH=10) (v. 40/60 to 70/30 over 20 min.) Flow rate, 75 mL/min., uv, 250 nm) as solid. 1H NMR (300 MHz, CD3OD) δ 1.45-1.62 (m, 1H), 1.68-1.92 (m, 2H), 2.00-2.15 (m, 1H), 2.27-2.40 (m, Hz, 1H), 2.75-3.05 (m, 5H), 3.43-3.59 (m, Hz, 1H), 5.22-5.42 (m, Hz, 1H), 7.16-7.24 (m, 1H), 7.28 (d, J=9 Hz, 1H), 7.36-7.44 (m, 1H), 7.45-7.52 (m, 1H), 7.57 (d, J=8 Hz, 1H), 8.02 (dd, J=9, 2 Hz, 1H), 8.17 (t, J=9 Hz, 2H), 8.67 (s, 1H) ppm; MS (DCI/NH3) m/z 371 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][O:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([CH2:41][CH2:42][O:43]S(C)(=O)=O)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[NH:57]1[CH2:62][CH2:61][O:60][CH2:59][CH2:58]1>C1COCC1>[CH:42]([OH:43])=[O:60].[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][O:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([CH2:41][CH2:42][N:57]2[CH2:62][CH2:61][O:60][CH2:59][CH2:58]2)[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C1COCCN1
Reactant: C[C@H]1COCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4CCOS(C)(=O)=O)c4ccccc43)cn12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C[C@H]1COCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4CCN4CCOCC4)c4ccccc43)cn12
Product: O=CO
Temperature: 50 °C
Reaction time: 24 h
Yield: 64.9 %

Procedure:
To a solution of Intermediate 142a (0.092 mmol) in THF (2 mL) was added DIPEA (64 μL, 0.37 mmol) and morpholine (21 μL, 0.37 mmol) and the reaction stirred at 50° C. for 24 h. The crude reaction mixture was cooled and partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 0-10% [2M NH3 in MeOH] in DCM, followed by MDAP (Method 7) purification, to give the title compound (21 mg, 34%). LCMS (Method 5): Rt 3.16 min, m/z 658 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.83 (3H, d, J=5.6 Hz), 1.16 (9H, s), 1.83-1.96 (2H, m), 1.97-2.07 (1H, m), 2.08-2.17 (1H, m), 3.34 (4H, t, J=4.5 Hz), 2.57 (2H, t, J=7.1 Hz), 2.95 (1H, ddd, J=12.0, 7.2, 4.9 Hz), 3.17 (1H, dt, J=12.2, 3.3 Hz), 3.36-3.43 (2H, m), 3.50 (4H, t, J=4.5 Hz), 3.72-3.80 (2H, m), 3.81-3.88 (1H, m), 3.92-3.98 (2H, t, J=7.1 Hz), 4.82 (1H, td, J=8.5, 6.1 Hz), 5.52 (1H, t, J=4.2 Hz), 5.99 (1H, s), 6.89 (1H, d, J=8.6 Hz), 7.18 (1H, dd, J=9.9, 2.1 Hz), 7.22-7.27 (1H, m), 7.30-7.38 (3H, m), 7.62 (1H, d, J=9.9 Hz), 7.79 (1H, d, J=1.9 Hz), 8.16 (1H, s), 8.16 (0.2H, s).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH:9]2[C:17](=[O:18])[CH:16]3[CH:11]([CH:12]4[O:19][CH:15]3[CH2:14][CH2:13]4)[C:10]2=[O:20])=[C:4]([CH3:21])[CH:3]=1.[C:22](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[C:17](=[O:18])[CH:16]3[CH:11]([C:10]=2[O:20][CH3:22])[CH:12]2[O:19][CH:15]3[CH2:14][CH2:13]2)=[C:4]([CH3:21])[CH:3]=1
Reactant: Cc1cc(Br)cc(C)c1C1C(=O)C2C3CCC(O3)C2C1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC1=C(c2c(C)cc(Br)cc2C)C(=O)C2C3CCC(O3)C12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of 4-(4-Bromo-2,6-dimethylphenyl)-10-oxatricyclo[5.2.1.0*2,6*]decane-3,5-dione (1.0 g, 2.86 mmol) (reported in WO 2009019005) in acetone (50 ml) is added potassium carbonate (0.59 g, 4.3 mmol) followed by iodomethane (2.0 g, 0.89 ml, 14 mmol). The mixture is stirred at room temperature for 18 hours then acetone is removed in vacuo and the residue is partitioned between water and ethyl acetate. The crude product is extracted with ethyl acetate and the combined organic fractions are washed with distilled water then brine, dried over magnesium sulfate, filtered and concentrated in vacuo to afford (1RS,2SR,6RS,7SR)-4-(4-bromo-2,6-dimethylphenyl)-5-methoxy-10-oxa-tricyclo[5.2.1.02,6]dec-4-en-3-one.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[C:25](=[O:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[NH:27][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH2:18]2)[CH2:13][CH2:14][NH:15][OH:16])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[CH:33](OCC(F)(F)F)=[O:34]>C1COCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:12]([N:17]2[C:25](=[O:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[NH:27][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH2:18]2)[CH2:13][CH2:14][N:15]([CH:33]=[O:34])[OH:16])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CCOc1cc(C(CCNO)N2Cc3cccc(NC(=O)C(C)C)c3C2=O)ccc1OC
Reactant: O=COCC(F)(F)F
Solvent: C1CCOC1
Product: CCOc1cc([C@@H](CCN(O)C=O)N2Cc3cccc(NC(=O)C(C)C)c3C2=O)ccc1OC

Procedure:
(1R)-N-{2-[1-(3-Ethoxy-4-methoxy-phenyl)-3-(N-formyl-N-hydroxy-amino)-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-isobutyramide was prepared by the procedure of Example 7 from N-{2-[1-(3-Ethoxy-4-methoxy-phenyl)-3-hydroxyamino-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-isobutyramide (1.6 g, 3.6 mmol) and 2,2,2-trifluoroethyl formate (5 g, 39 mmol) in THF (20 mL) to give a white solid (0.7 g, 41% yield): mp: 81-83° C. 1H NMR (DMSO-d6) δ 1.18 (d, J=7 Hz, 6H, 2CH3), 1.31 (t, J=7 Hz, 3H, CH3), 2.34-2.38 (m, 2H, CH2), 2.56-2.65 (m, 1H, CH), 3.39-3.51 (m, 2H, CH2), 3.73 (s, 3H, CH3), 3.96-4.05 (m, 2H, CH2), 4.16 (d, J=17 Hz, 1H, NCHH), 4.55 (d, J=17 Hz, 1H, NCHH), 5.25-5.29 (m, 1H, NCH), 6.93-6.97 (m, 3H, Ar), 7.18 (d, J=8 Hz, 1H, Ar), 7.50 (t, J=8 Hz, 1H, Ar), 7.83 (s, 0.5H, CH), 8.25 (s, 0.5H, CH), 8.28 (d, J=8 Hz, 1H, Ar), 9.63 (s, 0.5H, OH), 10.07 (s, 0.5H, OH), 10.47 (s, 1H, NH); 13C NMR (DMSO-d6) δ 14.69, 19.16, 19.21, 28.39, 28.60, 35.94, 43.35, 45.92, 46.26, 46.73, 51.17, 51.92, 55.44, 63.78, 111.97, 112.34, 116.55, 117.54, 117.58, 119.68, 131.54, 132.16, 151.12, 142.28, 147.94, 148.53, 157.36, 161.80, 168.37,168.53, 174.93; Anal Calcd for C25H31N3O6+0.4H2O: C, 62.98; H, 6.72; N, 8.81; H20, 1.51. Found: C, 62.96; H, 6.80; N, 8.84; H20, 1.48.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.[Cl:10][S:11](O)(=[O:13])=[O:12]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:11]([Cl:10])(=[O:13])=[O:12])=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: O=S(=O)(O)Cl
Reactant: c1ccc2c(c1)CCO2
Product: O=S(=O)(Cl)c1ccc2c(c1)CCO2
Yield: 30.2 %

Procedure:
2,3-dihydrobenzofuran (6.0 g, 49.94 mmol) is added over 20 minutes to chlorosulfonic acid (29.09 g, 249.69 mmol) at -20° C. The reaction mixture is quenched by addition of ice followed by water (20 mL). The mixture is then extracted with ethyl acetate. The combined organic estracts are washed with brine, dried (Na2SO4), and the solvent is evaporated. The crude product is purified by silica gel chromatography (30% ethyl acetate/hexane) to give 2,3-dihydrobenzofuran-5-sulfonyl chloride (3.3 g).
Reaction SMILES: [C:1]([OH:6])#[C:2][CH2:3][CH2:4][OH:5].[H-].[Na+].[C:9](Cl)(=[O:11])[CH3:10]>C1COCC1>[CH2:1]([OH:6])[C:2]#[C:3][CH2:4][OH:5].[CH3:10][C:9]([O-:11])=[O:5]
Reactant: CC(=O)Cl
Reactant: OC#CCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)[O-]
Product: OCC#CCO
Temperature: 25 °C
Reaction time: 4.3 h

Procedure:
To a solution of butyne-1,4-diol (5 g, 58 mmol) in dry THF at room temperature (RT) was added portion-wise sodium hydride (60% dispersion in oil, 2.32 g, 58 mmol). After 4.3 hr, acetyl chloride (4.12 mL, 58 mmol) was added. After stirring at RT for 22 hr, the mixture was concentrated under reduced pressure. The residue was concentrated twice from toluene before purification on silica gel using ethyl acetate/dichloromethane (1:3) as eluent to give 2-Butyne-1,4-diol, monoacetate as an oil in 49% yield. 1H NMR (DMSO-d6) δ 5.23 (1H, bs), 4.70 (2H, t, J=1.8 Hz), 4.09 (2H, s), 2.03 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([CH3:12])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].CO[CH:15]1[CH2:19][CH2:18][CH:17](OC)O1.CCCCCC.C(OCC)(=O)C>C(O)(=O)C>[N:1]1([C:2]2[CH:3]=[C:4]([C:9]([CH3:12])=[CH:10][CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH:15]=[CH:19][CH:18]=[CH:17]1
Reactant: COC1CCC(OC)O1
Reactant: COC(=O)c1cc(N)ccc1C
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)c1cc(-n2cccc2)ccc1C
Yield: 89.9 %

Procedure:
158 mg of methyl 3-amino-6-methylbenzoate was dissolved in 3 ml of acetic acid, and 139 mg of 2,5-dimethoxytetrahydrofuran was added. The mixture was heated under reflux for 1 hour. The reaction mixture was evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography Wakogel C-200, 10 g; eluting solvent: hexane/ethyl acetate=10/1) to give 185 mg (yield 87%) of methyl 3-(1-pyrrolyl)-6-methylbenzoate, m.p. 56°-57° C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([CH2:8][CH2:9][OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[S:20](Cl)([C:23]1[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=1)(=[O:22])=[O:21]>C(Cl)Cl>[S:20]([C:23]1[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=1)([O:10][CH2:9][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=1)(=[O:22])=[O:21]
Reactant: O=[N+]([O-])c1ccc(CCO)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
4-Nitrophenethyl alcohol (15 g, 89.7 mmol) was dissolved in 450 mL methylene chloride. Triethylamine (37.5 mL, 269 mmol) was added over 10 min and the reaction mixture was stirred at 0° C. for 1 hour (h). Tosyl chloride (20.52 g, 110 mmol) was added slowly to the mixture at 0° C. The reaction was stirred at room temperature (rt) overnight and was concentrated. The residue was dissolved in methylene chloride and washed with water, 1 N HCl, then water. The organic layer was dried over sodium sulfate and evaporated. The residue was triturated with hexanes and 25.32 g of white solid was collected. Yield 88%; 1H NMR (400 MHz, CDCl3) δ 8.07 (d, J=8 Hz, 2H), 7.63 (d, J=8 Hz, 2H), 7.24 (d, 4H), 4.26 (t, J=6 Hz, 2H), 3.04 (t, J=6 Hz, 2H), 2.41 (s, 3H).
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[CH3:6][C@H:7]1[C:15]2[C:14](O)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9][CH2:8]1.C([O-])(O)=O.[Na+]>ClCCCl>[Cl:3][C:14]1[C:15]2[C@H:7]([CH3:6])[CH2:8][CH2:9][C:10]=2[N:11]=[CH:12][N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: C[C@@H]1CCc2ncnc(O)c21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: C[C@@H]1CCc2ncnc(Cl)c21
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 61.1 %

Procedure:
Neat POCl3 (463.9 ml, 5067 mmol) was added slowly by addition funnel to a 0° C. solution of (R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (152.2 g, 1013 mmol) in DCE (1.2 L). After the addition was complete, the reaction mixture was warmed to room temperature, then heated to reflux and stirred for 70 minutes. The reaction was complete as determined by HPLC. The reaction mixture was cooled to room temperature, and the excess POCl3 was quenched in 4 portions as follows: Reaction mixture transferred to separatory funnel and dripped into a beaker containing ice and saturated NaHCO3 solution cooled in an ice bath. Once the addition of each portion of the reaction mixture was completed, the quenched mixture was stirred 30 minutes to ensure complete destruction of POCl3 prior to transfer to separatory funnel. The mixture was transferred to the separatory funnel and extracted twice with DCM. The combined extracts were dried (Na2SO4), filtered, and concentrated. The crude was purified on silica gel as follows: silica gel (1 kg) was slurried in 9:1 hexane:ethyl acetate onto a 3 L fritted funnel, silica settled under vacuum, topped with sand. The crude was loaded with a DCM/hexane mixture, and the compound was eluted using 1 L sidearm flasks under vacuum. High Rf byproducts eluted first, then (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (104.4 g, 61.09% yield) as a brown oil. Triethylamine (93.0 ml, 534 mmol) and tert-butyl piperazine-1-carboxylate (34.8 g, 187 mmol) was added to a solution of (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (30.0 g, 178 mmol) in n-BuOH (250 mL). The reaction mixture was heated to reflux under nitrogen and stirred overnight (17 hours), after which it was concentrated on a rotavap. The resulting oil was dissolved in DCM, washed with H2O, dried (Na2SO4), filtered, and was concentrated. The resulting brown oil was purified on silica gel eluting first with 2:1 hexanes:ethyl acetate until product eluting cleanly, then gradient 1:1 to 1:5 DCM:ethyl acetate to give (R)-tertbutyl 4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (42.0 g, 74.1% yield) as a beige powder. LC/MS (APCI+) m/z 319.1 [M+H]+.