Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][C:13]2([CH2:24][C:23](=[O:25])[C:22]3[C:17](=[CH:18][CH:19]=[C:20](/[CH:26]=[CH:27]/[C:28](O)=[O:29])[CH:21]=3)[O:16]2)[CH2:12][CH2:11]1.[NH2:31][O:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][C:13]2([CH2:24][C:23](=[O:25])[C:22]3[C:17](=[CH:18][CH:19]=[C:20](/[CH:26]=[CH:27]/[C:28]([NH:31][O:32][CH:33]4[CH2:38][CH2:37][CH2:36][CH2:35][O:34]4)=[O:29])[CH:21]=3)[O:16]2)[CH2:12][CH2:11]1
Reactant: O=C(O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(CCc3ccccc3F)CC1)O2
Reactant: NOC1CCCCO1
Solvent: ClCCl
Product: O=C(/C=C/c1ccc2c(c1)C(=O)CC1(CCN(CCc3ccccc3F)CC1)O2)NOC1CCCCO1

Procedure:
(E)-3-{1′-[2-(2-Fluoro-phenyl)-ethyl]-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid (165 mg, 0.370 mmol) was suspended in DCM (5 ml). TEA (0.075 ml, 0.54 mmol) was added and the clear solution was treated with NH2OTHP following the procedure described in Example 1, Step B, giving (E)-3-{1′-[2-(2-fluoro-phenyl)-ethyl]-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide (163 mg) as a yellow solid. The compound was then dissolved in DCM (5 ml) and treated with 4 M HCl in dioxane (0.5 ml, 2 mmol) as described in Example 55, Step D, giving the hydroxamic acid as a light yellow solid (103 mg, hydrochloride salt).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[CH2:14][CH:13]3[C:15](=[O:16])[CH:10]([CH2:11][CH2:12]3)[CH2:9]2)=[CH:5][CH:4]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([Mg]Br)[CH:24]=[CH:25][CH:26]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH2:9][CH:10]3[C:15]([C:25]4[CH:24]=[CH:23][CH:22]=[C:21]([O:20][CH3:19])[CH:26]=4)([OH:16])[CH:13]([CH2:12][CH2:11]3)[CH2:14]2)=[CH:17][CH:18]=1
Reactant: COc1cccc([Mg]Br)c1
Reactant: COc1ccc(CN2CC3CCC(C2)C3=O)cc1
Solvent: C1CCOC1
Product: COc1ccc(CN2CC3CCC(C2)C3(O)c2cccc(OC)c2)cc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 111.5 %

Procedure:
3-(4-Methoxy-benzyl)-3-aza-bicyclo[3.2.1]octan-8-one (1.09 g, 4.44 mmol) was azeotroped from THF (3×50 mL) then dissolved in anhydrous THF (20 mL) under N2 and cooled to −78° C. This was treated with 3-methoxyphenylmagnesiumbromide (4.89 mL, 4.89 mmol) dropwise and stirred at −78° C. for 5 min, then warmed to room temperature. The reaction was quenched with 1N HCl (pH 1), washed with ether (2×50 mL), then the organic layer was back extracted with water (1×50 mL). The combined aqueous layers were neutralized to pH 8 with saturated aqueous NaHCO3 solution, extracted with CH2Cl2 (3×50 mL), washed with saturated aqueous NaCl solution (1×50 mL), dried through a cotton plug, and concentrated to yield a yellow oil (1.75 g, 100%). (TLC 50% EtOAc/hexanes Rf 0.30); 1H NMR (400 MHz, CDCl3) δ 7.26 (t, J=7.9 Hz; 2H), 7.05 (d, J=7.4 Hz, 1H), 7.01 (s, 1H), 6.84–6.78 (m, 4H), 3.77 (s, 3H), 3.76 (s, 3H), 3.52 (s, 2H), 2.83 (d, J=10.3 Hz, 2H), 2.58 (d, J=8.3 Hz, 2H), 2.36 (s, 2H), 1.75 (d, J=7.5 Hz, 2H), 1.41 (m, 2H); GCMS m/z 353 (M)+; APCI MS m/z 354.4 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]2[O:11]C=CC=2)=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1[CH3:8].[Mn]([O-])(=O)(=O)=[O:16].[K+]>CC(C)=O.O>[NH2:1][C:2]1[C:3]([C:10]([OH:11])=[O:16])=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cc(Cl)nc(-c2ccco2)c1N
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1cc(Cl)nc(C(=O)O)c1N
Temperature: 0 °C
Reaction time: 2 h
Yield: 73.2 %

Procedure:
3-Amino-6-chloro-2-(2-furanyl)-4-methylpyridine (400 mg) was dissolved in acetone (10 mL) and cooled in an ice bath to 0° C. A solution prepared of potassium permanganate (909 mg) in water (15 mL) was added drop wise to this solution. After complete addition, the reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The mixture was cooled again to 0° C. and a second portion of potassium permanganate (600 mg) in water (10 mL) was added and the cool bath removed. After stirring for 2 hours, the reaction mixture was filtered through a pad of celite, the filter cake was washed carefully with water, methanol and ethyl acetate and concentrated to approx. 10 mL on a rotary evaporator. 2N Sodium hydroxide solution was added to adjust the pH-value to −12 and the aqueous layer was washed 2× with MTB-ether. The aqueous layer was then adjusted to pH ˜2 by addition of 6N hydrochloric acid and extracted 3× with MTB-ether. The combined organic layer was washed with brine, dried over MgSO4 and concentrated in vacuum to afford 262 mg of the title compound of the formula
Reaction SMILES: C(OC([N:8]([CH2:25][C@H:26]1[CH2:35][CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:36]3[CH:37]=[C:38]([CH:42]=[CH:43][CH:44]=3)[C:39](O)=[O:40])[CH:32]=2)[O:27]1)[CH2:9][C@H:10]([O:17][Si](C(C)(C)C)(C)C)[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=O)(C)(C)C.CN(C1C=CC=CN=1)C.[CH3:54][S:55]([NH2:58])(=[O:57])=[O:56].Cl>C(Cl)Cl.O1CCOCC1>[OH:17][C@H:10]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[CH2:9][NH:8][CH2:25][C@H:26]1[CH2:35][CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:36]3[CH:37]=[C:38]([CH:42]=[CH:43][CH:44]=3)[C:39]([NH:58][S:55]([CH3:54])(=[O:57])=[O:56])=[O:40])[CH:32]=2)[O:27]1
Reactant: CC(C)(C)OC(=O)N(C[C@H]1CCc2cc(-c3cccc(C(=O)O)c3)ccc2O1)C[C@H](O[Si](C)(C)C(C)(C)C)c1cccnc1
Reactant: CS(N)(=O)=O
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CS(=O)(=O)NC(=O)c1cccc(-c2ccc3c(c2)CC[C@H](CNC[C@H](O)c2cccnc2)O3)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
The product of Example 86 (100 mg, 0.16 mmol), 1-[(3-dimethylamino)propyl]-3-ethylcarbodiimide (36 mg, 0.19 mmol), dimethylaminopyridine (20 mg, 0.16 mmol), and methylsulfonamide (17 mg, 0.18 mmol) were dissolved in 2 mL methylene chloride and stirred overnight at room temperature. The mixture was treated with 0.5 mL 4 M HCl in 1,4-dioxane was added, the solution stirred for 0.5 hours, concentrated to dryness and the residue was purified by preparative HPLC to obtain the title compound (47 mg, 62%). 1H NMR (CD3CN-d3) δ: 8.91 (s, 1 H), 8.76 (d, 1 H), 8.51 (d, 1 H), 8.07 (s, 1 H), 7.97 (t, 1 H), 7.88-7.83 (m, 2 H), 7.62-7.56 (m, 1 H), 7.50-7.47 (m, 2 H), 6.98 (d, 1 H), 5.46 (d, 1 H), 4.54-4.47 (m, 1 H), 3.52 (dd, 2 H), 3.37 (s, 3 H), 3.39-3.25 (m, 2 H), 2.99-2.90 (m, 2 H), 2.14-2.09 (m, 1 H), 1.86-1.79 (m, 1 H). MH+=482.2
Reaction SMILES: [F:1][C:2]1[C:10](C(O)=O)=[C:9]([F:14])[C:8]([F:15])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].N1C2C(=CC=CC=2)C=CC=1>[Cu]>[F:1][C:2]1[CH:10]=[C:9]([F:14])[C:8]([F:15])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(F)c(F)c(C(=O)O)c1F
Agent: [Cu]
Solvent: c1ccc2ncccc2c1
Product: O=C(O)c1cc(F)c(F)cc1F
Temperature: 200 °C

Procedure:
A mixture of 2.20 g (0.01 mole) of 2,4,5-trifluoroisophthalic acid (dried under high vacuum), 1.0 ml of quinoline and 0.23 g of copper powder was heated on an oil bath at 200° C. After a while, the mixture liquefied and released a gas (ca. 280 ml by top purging). After the gas had been completely released, the liquefied mixture was cooled to room temperature, followed by addition of 15 ml of a mixture (1:1 by weight) of conc. HCl and water.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]([CH3:12])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH2:11])[CH:6]=1.C(N(CC)CC)C.Cl[C:21](Cl)([O:23]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH3:3][N:4]([CH3:12])[C:5]1[CH:6]=[C:7]([N:11]=[C:21]=[O:23])[CH:8]=[CH:9][CH:10]=1
Reactant: CN(C)c1cccc(N)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)c1cccc(N=C=O)c1
Temperature: 20 °C
Reaction time: 20 h

Procedure:
1.46 g (7 mmol) of N1,N1-dimethylbenzene-1,3-diamine dihydrochloride, followed by 9.9 cm3 (71.64 mmol) of triethylamine, are added, at a temperature in the region of 5° C., under an argon atmosphere, to 2.82 g (9.5 mmol) of triphosgene in solution in 150 cm3 of dichloromethane. After stirring for 20 hours at a temperature in the region of 20° C., the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa), to give a residue which is triturated in 50 cm3 of tetrahydrofuran. After filtration, a solution of 3-dimethylaminophenyl isocyanate in approximately 0.14 N tetrahydrofuran is obtained, which solution is used directly in the subsequent step.
Reaction SMILES: F[B-](F)(F)F.[O:6]=[N+:7]=[O:8].[Cl:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH2:16][CH2:15][CH2:14][CH2:13]2>ClCCl>[Cl:9][C:10]1[CH:11]=[C:12]2[C:17]([CH2:16][CH2:15][CH2:14][CH2:13]2)=[C:18]([N+:7]([O-:8])=[O:6])[CH:19]=1
Reactant: Clc1ccc2c(c1)CCCC2
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(Cl)cc2c1CCCC2
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 50.3 %

Procedure:
To a suspension of 85% nitronium tetrafluoroborate (6.19 g, 39.6 mmol) in dichloromethane (60 mL) was added dropwise a solution of 6-chlorotetralin (6.0 g, 36 mmol) in dichloromethane (60 mL) over 15 min at 0° C. The mixture was stirred for 40 min at 0° C. and quenched by addition of ice-water (100 mL). The organic layer was separated, washed with water, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography with 30:1~4:1 hexane/toluene to give 3.83 g of the title compound (54%): 1H NMR (CDCl3) δ7.65 (d, 1H, J=2.3 Hz), 7.30 (d, 1H, J=8.9 Hz), 2.90 (m, 4H), 1.76 (m, 4H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[CH:15][C:14]=2[CH2:32][CH3:33])[N:3]=1.[C:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[CH2:42][C:43]([O:45][CH3:46])=[O:44])#[CH:35].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>[Cu]I.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.CN(C=O)C>[CH2:32]([C:14]1[CH:15]=[C:16]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)[CH:17]=[CH:18][C:13]=1[NH:12][C:4]1[N:3]=[C:2]([C:35]#[C:34][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[CH2:42][C:43]([O:45][CH3:46])=[O:44])[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=1)[CH3:33]
Reactant: C#Cc1ccccc1CC(=O)OC
Reactant: CCc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc(C(F)(F)F)c(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc(C(F)(F)F)c(C#Cc2ccccc2CC(=O)OC)n1
Temperature: 120 °C
Yield: 85.5 %

Procedure:
A mixture of tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-ethylphenyl)piperidine-1-carboxylate (I41) (283 mg, 0.584 mmol), methyl 2-(2-ethynylphenyl)acetate (I4) (122 mg, 0.700 mmol), copper(I) iodide (17 mg, 15 mol %), triphenylphosphine (23 mg, 15 mol %), bis(triphenylphosphine)palladium(II) chloride (41 mg, 10 mol %), triethylamine (0.33 mL, 2.3 mmol) and DMF (3 mL) was degassed with a nitrogen then heated under microwave irradiation (120° C./15 min). The cooled mixture was poured into water (30 mL) and extracted with ethyl acetate (3×25 mL). The combined organic extracts were washed with brine (2×50 mL), dried over sodium sulfate and evaporated. Chromatography (12 g silica cartridge, 0-80% ethyl acetate/petroleum benzine 40-60° C.) gave the title compound (I42) (311 mg, 86% yield) as a brown oil; 1H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 7.73-7.65 (m, 2H), 7.46-7.28 (m), 7.15-7.08 (m), 4.25 (s, 2H), 3.95 (s, J=9.6 Hz, 2H), 3.70 (s, 3H), 2.80 (t, J=12.1 Hz, 2H), 2.70-2.59 (m, 3H), 1.84 (d, J=12.9 Hz, 2H), 1.65 (td, J=12.8, 4.1 Hz, 2H), 1.49 (s, 9H), 1.25 (t, J=7.6 Hz, 3H). LCMS: rt 7.01 min; m/z 623.1 [M+H]+, 567.1 [M-tBu+2H]+, 523.1 [M-Boc+2H]+; m/z 621.2 [M−H]−.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.[CH2:15]([O:22][C:23](=[O:26])[CH:24]=[CH2:25])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C.C(N(CC)CC)C>[O:26]=[C:23]([O:22][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)/[CH:24]=[CH:25]/[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Br)c2ccccc12
Reactant: C=CC(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(/C=C/c1ccc(C(=O)O)c2ccccc12)OCc1ccccc1
Temperature: 95 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-bromo-1-naphthalenecarboxylic acid (100 g), benzylacrylate (96.8 g), triphenylphosphine (10.2 g) palladium(II) acetate (2 g), triethylamine (258 ml) and DMF (600 ml) are heated at 90-100° C. for 4-12 h (typically 10-12 h). Two further portions of palladium(II) acetate (20 g) are added at four hour intervals during the stir period. The mixture is treated with charcoal (3×15 g) at 50-80° C. (typically 70-80° C.) filtering after each charge at 40-45° C. The DMF is then distilled off at 80-90° C. under vacuum and the residue is cooled to 25-35° C. Dichloromethane (100 ml) and water (100 ml) are added to the residue and the mixture is acidified with concentrated hydrochloric acid and is stirred at 20-35° C. for about 30 min. The mixture is filtered, and the solid product dried. The residue is dissolved in a mixture of DMF (600 ml) then water (400 ml) at 90-100° C. and stirred for 1-1.5 h. The solution is filtered at 80-85° C., cooled to 20-35° C., and stirred for about 2 h. The product is filtered off and dried (dry weight 43 g).
Reaction SMILES: [C:1]([C:4]1([NH:10][CH3:11])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)(=[O:3])[NH2:2].Br[CH2:13][CH2:14][O:15][CH3:16]>>[CH3:16][O:15][CH2:14][CH2:13][N:7]1[CH2:8][CH2:9][C:4]([NH:10][CH3:11])([C:1]([NH2:2])=[O:3])[CH2:5][CH2:6]1
Reactant: CNC1(C(N)=O)CCNCC1
Reactant: COCCBr
Product: CNC1(C(N)=O)CCN(CCOC)CC1

Procedure:
4-Carbamoyl-4-methylaminopiperidine was coupled with 2-bromoethylmethyl ether using an analogous method to that described for the equivalent step in Example 22 to give 1-(2-methoxyethyl)-4-(methylamino)piperidine-4-carboxamide as a white crystalline solid; 1H NMR Spectrum: (DMSO-d6) 1.44 (m, 2H); 1.78 (m, 2H); 1.89 (s, 1H); 2.05 (s, 3H); 2.28-2.44 (m, 6H); 3.21 (s, 3H); 3.38 (t, 2H); 6.84 (s, 1H); 7.16 (s, 1H).
Reaction SMILES: Cl.[C:2]([O:5][C@H:6]1[C@H:11]([NH2:12])[C@@H:10]([O:13][C:14](=[O:16])[CH3:15])[C@H:9]([O:17][C:18](=[O:20])[CH3:19])[C@@H:8]([CH2:21][O:22][C:23](=[O:25])[CH3:24])[O:7]1)(=[O:4])[CH3:3].Cl.CN(C)CCCN=C=NCC.[CH:38]1([CH2:41][C:42](O)=[O:43])[CH2:40][CH2:39]1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:2]([O:5][C@H:6]1[C@H:11]([NH:12][C:42](=[O:43])[CH2:41][CH:38]2[CH2:40][CH2:39]2)[C@@H:10]([O:13][C:14](=[O:16])[CH3:15])[C@H:9]([O:17][C:18](=[O:20])[CH3:19])[C@@H:8]([CH2:21][O:22][C:23](=[O:25])[CH3:24])[O:7]1)(=[O:4])[CH3:3]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](N)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=C(O)CC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](NC(=O)CC2CC2)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 12 h
Yield: 45.5 %

Procedure:
To a suspension of (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-amino-tetrahydro-2H-pyran-2,4,5-triyl triacetate hydrochloride (0.500 g, 1.31 mmol) in CH2Cl2 (20 mL) was added 4-(dimethylamino)pyridine (0.478 g, 3.91 mmol), followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.300 g, 1.57 mmol), and 2-cyclopropylacetic acid (0.146 mL, 1.57 mmol). The reaction was stirred for 12 h. Additional CH2Cl2 (80 mL) was added and the organic layer was washed once with saturated aqueous NaHCO3 (10 mL). The organic layer was then dried (MgSO4) and concentrated in vacuo. Flash chromatography of the crude material on silica gel (3:2 EtOAc:hexanes) afforded (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-(2-cyclopropylacetamido)-tetrahydro-2H-pyran-2,4,5-triyl triacetate as a white solid (0.256 g, 56% yield).
Reaction SMILES: [CH3:1][CH:2]([S:4](Cl)(=[O:6])=[O:5])[CH3:3].[NH2:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:31])([CH3:30])[CH2:22][NH:23][S:24]([N:27]([CH3:29])[CH3:28])(=[O:26])=[O:25])=[CH:17][CH:16]=2)[CH:12]=[CH:13][CH:14]=1.C1CCN2C(=NCCC2)CC1>C1COCC1>[CH3:29][N:27]([CH3:28])[S:24]([NH:23][CH2:22][C:21]([F:31])([C:18]1[CH:17]=[CH:16][C:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([NH:8][S:4]([CH:2]([CH3:3])[CH3:1])(=[O:6])=[O:5])[CH:10]=2)=[CH:20][CH:19]=1)[CH3:30])(=[O:25])=[O:26]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: CN(C)S(=O)(=O)NCC(C)(F)c1ccc(-c2cccc(N)c2)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)Nc1cccc(-c2ccc(C(C)(F)CNS(=O)(=O)N(C)C)cc2)c1
Temperature: 0 °C

Procedure:
In a 250 mL 3 neck flask fitted with a stirrer and thermometer, 356 mg of 2-propanesulfonyl chloride is added dropwise to 350 mg of {2-[4-(3-aminophenyl)phenyl]-2-fluoropropyl}[(dimethylamino)sulfonyl]amine (prepared in example 38) and 380 mg of DBU in THF (125 mL) while stirring at 0° C. under a nitrogen atmosphere. The reaction is allowed to warm to room temperature and then stirred overnight at this temperature. In the morning, the reaction is concentrated under reduced vacuum. The resulting material is taken into ethyl acetate and the organic layer is washed two times with H2O, dried over Na2SO4, filtered, and concentrated under reduced vacuum. This crude material is purified via silica gel chromatography employing the Chromatotron and using a 4000 micron rotor with hexane/ethyl acetate eluent to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([O:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:3]=1.Cl[C:17]1[C:18]2[C:25]([CH3:26])=[C:24]([C:27]([O:29][CH3:30])=[O:28])[S:23][C:19]=2[N:20]=[CH:21][N:22]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:17]2[C:18]3[C:25]([CH3:26])=[C:24]([C:27]([O:29][CH3:30])=[O:28])[S:23][C:19]=3[N:20]=[CH:21][N:22]=2)=[C:4]([O:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:3]=1
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1C
Reactant: Nc1ccc(F)cc1OC1CCOCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Product: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC3CCOCC3)c2c1C
Temperature: 25 °C
Yield: 90.1 %

Procedure:
4-Fluoro-2-(tetrahydro-2H-pyran-4-yloxy)aniline (3.47 g, 16.4 mmol), methyl 4-chloro-5-methylthieno[2,3-d]pyrimidine-6-carboxylate (3.99 g, 16.4 mmol) and para-toluene sulfonic acid (0.313 g, 1.64 mmol) were heated at reflux in anhydrous 1,4-dioxane (30 mL) for 1.5 hours. The solution was cooled to ambient temperature, the precipitate collected and washed with cold 1,4-dioxane to yield the title compound as yellow solid (6.17 g, 90%).
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]1[N:7]([C:8]2[C:13]([Cl:14])=[CH:12][C:11]([Cl:15])=[CH:10][C:9]=2[Cl:16])[N:6]=[C:5]([S:17][CH3:18])[C:4]=1[CH2:19][N:20]1[CH:29]([CH2:30][OH:31])[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21]1.[H-].[Na+].[CH3:35]I>O1CCCC1>[CH3:35][O:31][CH2:30][CH:29]1[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][N:20]1[CH2:19][C:4]1[C:5]([S:17][CH3:18])=[N:6][N:7]([C:8]2[C:9]([Cl:16])=[CH:10][C:11]([Cl:15])=[CH:12][C:13]=2[Cl:14])[C:3]=1[N:2]([CH3:1])[CH3:32]
Reactant: CI
Reactant: CSc1nn(-c2c(Cl)cc(Cl)cc2Cl)c(N(C)C)c1CN1Cc2ccccc2CC1CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCC1Cc2ccccc2CN1Cc1c(SC)nn(-c2c(Cl)cc(Cl)cc2Cl)c1N(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 57.5 %

Procedure:
To a solution of the racemic mixture of Example 7 (200 mg, 0.39 mmol) in anhydrous tetrahydrofuran (2.0 ml), sodium hydride (78 mg of 60% sodium hydride mineral oil dispersion; 46 mg, 2.0 mmol of sodium hydride) was added; and the resulting mixture was stirred for 15 minutes at ambient temperature. Methyl iodide (0.10 ml, 1.6 mmol) was added, and the mixture was stirred for 18 hours at ambient temperature. The solvent was removed in vacuo, and the residue was dissolved in ethyl acetate/water (20 ml of each). The aqueous phase was separated and extracted with three equal volumes of ethyl acetate. The combined organic extracts were dried (anhydrous sodium sulfate) and concentrated in vacuo to a yellow oil. Flash chromatography of the entire sample (silica gel, 40 micron mesh; elution with ethyl acetate/hexane=1:10 in volume) afforded the title compound (118 mg) as a light-yellow oil.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:4]=1[NH2:5].Cl.C(OC1C=CC([NH:27]N)=CC=1)(=O)C1C=CC=CC=1>>[ClH:1].[F:2][C:3]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:4]=1[NH:5][NH2:27]
Reactant: Nc1ccc(F)cc1F
Reactant: NNc1ccc(OC(=O)c2ccccc2)cc1
Agent: Cl
Product: NNc1ccc(F)cc1F

Procedure:
The 2,4-difluorophenylhydrazine hydrochloride (m.p. 244°-246°C.) was prepared from 2,4-difluoroaniline hydrochloride using a procedure similar to that described in Example 5 for the preparation of 4-benzoyloxyphenylhydrazine hydrochloride.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([CH2:25][OH:26])[CH:24]=1)[O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19].C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>ClCCl>[CH3:34][S:35]([O:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([CH2:25][O:26][S:35]([CH3:34])(=[O:37])=[O:36])[CH:24]=1)[O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])(=[O:37])=[O:36]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)CCOCCOCCOCCOc1cc(CO)cc(CO)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCOCCOCCOCCOc1cc(COS(C)(=O)=O)cc(COS(C)(=O)=O)c1
Temperature: -5 °C
Reaction time: 1 h

Procedure:
To a stirred solution of methyl 3-(2-(2-(2-(3,5-bis(hydroxymethyl)phenoxy)ethoxy)ethoxy)ethoxy)propanoate (263b) (145 mg, 0.389 mmol) in anhydrous dichloromethane (5.5 ml) was added triethylamine (0.163 ml, 1.168 mmol). The mixture was cooled to −5° C. and methanesulfonyl chloride (0.076 ml, 0.973 mmol) was added slowly. After stirring for one hour at −5° C. the reaction was quenched with cold water and extracted with cold ethyl acetate. The organic extracts were washed with cold water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give methyl 3-(2-(2-(2-(3,5-bis((methylsulfonyloxy)methyl)phenoxy)ethoxy)ethoxy)ethoxy)propanoate. MS (m/z). found 551.1 (M+Na)+. To a stirred mixture of methyl 3-(2-(2-(2-(3,5-bis((methylsulfonyloxy)methyl)phenoxy)ethoxy)ethoxy)ethoxy)propanoate (206 mg, 0.390 mmol) and compound 8 (287 mg, 0.974 mmol) in anhydrous DMF (3.9 ml) was added potassium carbonate (269 mg, 1.949 mmol). The reaction was allowed to stir at room temperature for 18 hours. The mixture was quenched with water and extracted three times with dichloromethane. The organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification by flash silica gel chromatography (5% MeOH/CH2Cl2) followed by preparative reverse phase HPLC (C18 column, eluted with CH3CN/H2O) gave compound 263c (110 mg, 30%) as a white solid. 1H NMR (400 Hz, CDCl3): δ 8.18 (d, J=8.0 Hz, 2H), 7.77 (m, 2H), 7.49 (s, 2H), 7.19 (m, 4H), 7.02 (m, 2H), 6.89 (s, 2H), 6.87 (s, 1H), 6.75 (s, 2H), 5.10 (m, 4H), 4.39 (m, 2H), 4.05 (m, 2H), 3.90 (s, 6H), 3.77 (m, 2H), 3.67 (t, J=6.4 Hz, 2H), 3.64 (m, 2H), 3.59 (s, 3H), 3.70-3.54 (m, 8H), 3.40 (m, 2H), 2.51 (t, J=6.4 Hz, 2H); MS (m/z). found 965.3 (M+H2O+Na)+, 983.3 (M+2H2O+Na)+.