Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[CH:5]=1.C[Si](C)(C)[C:14]([F:17])([F:16])[F:15].Cl.CCOC(C)=O>C1(C)C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>[Br:10][C:6]1[CH:5]=[C:4]([C:3](=[O:11])[C:14]([F:17])([F:16])[F:15])[CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)c1cccc(Br)c1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(c1cccc(Br)c1)C(F)(F)F
Temperature: -78 °C
Reaction time: 20 h
Yield: 63.7 %

Procedure:
In a dry round bottom flask, 3-bromo-benzoic acid methyl ester (2 g, 9.3 mmol, Aldrich Chemical Company) and trimethyl(trifluoromethyl)silane (1.72 mL, 11.6 mmol, Aldrich Chemical Company) were dissolved in dry toluene (50 mL). Upon cooling the solution to −78° C., TBAF (232 μL, 0.23 mmol) was added and the reaction was allowed to warm up slowly to rt overnight. After stirring for 20 hr, 2N HCl (50 mL) and EtOAc (100 mL) were added, the layers were separated, and the aqueous layer was extracted with another portion of EtOAc. The combined organic fractions were dried (MgSO4), concentrated in vacuo, and resulting crude oil was purified using SiO2 flash chromatography (elution: 5–20% EtOAc in hexanes) to give 1.5 g (65%) the title compound as a light yellow oil. 1H-NMR (CDCl3; 400 MHz) δ 8.18 (br s, 1H), 7.98–8.00 (m, 1H), 7.82–7.85 (m, 1H), 7.42–7.46 (m, 1H). 19F-NMR (CDCl3; 400 MHz) δ −72.06 (s).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][OH:29])=[CH:24][CH:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:32]I>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]([CH2:28][O:29][CH3:32])=[CH:26][CH:27]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(CO)cc3)c2CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCc1ccc(CSc2c(Cl)ccc3c2CCN(C(=O)OC(C)(C)C)CC3)cc1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 3-tert-butoxycarbonyl-7-chloro-6-(4-hydroxymethyl-benzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (133 mg, 0.306 mmol) in anhydrous DMF (2 mL) under nitrogen, add sodium hydride (60% dispersion, 13-15 mg, 0.375 mmol) at ambient temperature and continue stirring for 30 min. Add methyl iodide (80 □L, 1.28 mmol). After 15 min, dilute with water, extract three times with EtOAc, dry over anhydrous MgSO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (15:1) to give 3-tert-butoxycarbonyl-7-chloro-6-(4-methoxymethyl-benzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a clear oil, which crystallizes on standing to a white solid (87 mg, 63%), along with recovered starting material (22 mg, 17%). Use a method similar to the General Procedure 1-4 to give the title compound as a white solid. MS (ES+) m/z: 348 (M+H-Boc)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(Oc2ccccc2)ccc1Cl
Temperature: 25 °C
Reaction time: 96 h
Yield: 21.3 %

Procedure:
A mixture of 4-chloro-3-nitro-phenol (5.00 g, 28.81 mmol), phenylboronic acid (7.03 g, 57.62 mmol), copper(II) acetate (5.23 g, 28.81 mmol) and 4 Å molecular sieves (0.5 g) in dichloromethane (200 mL) and triethylamine (20.08 mL, 144.04 mmol) was placed in a round bottomed flask. The resulting suspension was stirred under a dry ambient atmosphere at room temperature for 4 days. The mixture was filtered through diatomaceous earth and the solvent was evaporated. The resulting residue was re-dissolved in EtOAc, adhered to silica gel and flash chromatographed (2% EtOAc/hexane) to give 1-chloro-2-nitro-4-phenoxy-benzene as a yellow oil (1.53 g, 22.0% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH:4]2[CH2:5][C:6]3[C:10]([CH:3]12)=[C:9]([CH3:11])[S:8][C:7]=3[C:12]([NH:14][NH:15][C:16](=O)[C:17]1[CH:22]=[C:21]([CH3:23])[N:20]=[C:19]([CH2:24][CH3:25])[CH:18]=1)=[O:13].CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1.CC(=O)OCC>[CH2:24]([C:19]1[CH:18]=[C:17]([C:16]2[O:13][C:12]([C:7]3[S:8][C:9]([CH3:11])=[C:10]4[C:6]=3[CH2:5][C@H:4]3[C:2]([CH3:27])([CH3:1])[C@H:3]34)=[N:14][N:15]=2)[CH:22]=[C:21]([CH3:23])[N:20]=1)[CH3:25]
Reactant: CCc1cc(C(=O)NNC(=O)c2sc(C)c3c2CC2C3C2(C)C)cc(C)n1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCc1cc(-c2nnc(-c3sc(C)c4c3C[C@@H]3[C@H]4C3(C)C)o2)cc(C)n1
Temperature: 110 °C
Yield: 8.8 %

Procedure:
A mixture of crude 2-ethyl-6-methyl-isonicotinic acid N′-(1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carbonyl)-hydrazide (350 mg, ca. 0.5 mmol) and Burgess Reagent (385 mg, 1.62 mmol) in THF (5 mL) is heated at 110° C. for 3 min in a microwave oven. The mixture is diluted with EA (10 mL) and extracted with sat. aq. Na2CO3 (2×5 mL). The organic phase is dried (Na2SO4), filtered and evaporated to give crude product (50.9 mg) that is purified by HPLC to give 2-ethyl-6-methyl-4-[5-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridine (16 mg) as a light yellow powder; LC-MS: tR=0.91 min, [M+1]=366.21.
Reaction SMILES: [O:1]=[O:2].[C:3]1([CH3:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>>[CH2:9]([O:1][OH:2])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=O
Reactant: Cc1ccccc1
Product: OOCc1ccccc1

Procedure:
750 G of toluene are introduced into a 1.5 liter stainless steel autoclave which is shaken; the toluene is oxidised, at 180°C under a pressure of 20 bars, with air depleted of oxygen until it contains only 8%, with an hourly flow rate of 240 liters (measured under normal temperature and pressure). After 1 hour 30 minutes the reaction mixture is cooled. The hydroperoxide is then purified via its sodium salt. 11.4 G of benzyl hydroperoxide, containing 85% by weight of pure product, are thus obtained.
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:14]([C:16]3[CH:17]=[N:18][N:19]([CH2:22][CH3:23])[C:20]=3[OH:21])=[O:15])[C:11]=2[CH3:13])[S:6](=[O:25])(=[O:24])[CH2:5][CH2:4]1.N1C=CC=N1.C(N(CC)CC)C.[CH:38]1([C:44](Cl)=[O:45])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[CH3:1][O:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:14]([C:16]3[CH:17]=[N:18][N:19]([CH2:22][CH3:23])[C:20]=3[O:21][C:44]([CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)=[O:45])=[O:15])[C:11]=2[CH3:13])[S:6](=[O:24])(=[O:25])[CH2:5][CH2:4]1
Reactant: CCn1ncc(C(=O)c2ccc3c(c2C)C(OC)CCS3(=O)=O)c1O
Reactant: O=C(Cl)C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: c1cn[nH]c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCn1ncc(C(=O)c2ccc3c(c2C)C(OC)CCS3(=O)=O)c1OC(=O)C1CCCCC1
Yield: 54 %

Procedure:
As a starting material, 4-methoxy-5-methyl-6-(1-ethyl-5-hydroxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide corresponding to pyrazole derivative (I-H) was used. 0.4 Gram (1.1 mmol) thereof was dissolved in 4 ml of methylene chloride, and 0.22 g (2.2 mmol) of triethylamine as a base and 0.19 g (1.3 mmol) of cyclohexylcarbonyl chloride corresponding to compound B-A-Hal as a reaction reagent were added. The mixture was allowed to react at room temperature for 8 hours. A saturated sodium carbonate aqueous solution was added to the reaction mixture, and the resultant mixture was extracted with ethyl acetate. An organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resultant oil was purified by flush column chromatography (Wako Gel C-300; hexane/ethyl acetate=1:1) to give 0.28 g (yield 54%) of 4-methoxy-5-methyl-6-(5-cyclohexylcarbonyloxy-1-ethylpyrazol-4-yl)carbonylthiochroman-1,1-dioxide.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[NH2:5][C:6]1[CH:7]=[C:8]([CH3:14])[C:9]([C:12]#[N:13])=[N:10][CH:11]=1.O>C(Cl)(Cl)Cl>[N:5]([C:6]1[CH:7]=[C:8]([CH3:14])[C:9]([C:12]#[N:13])=[N:10][CH:11]=1)=[C:1]=[S:2]
Reactant: S=C(Cl)Cl
Reactant: Cc1cc(N)cnc1C#N
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1cc(N=C=S)cnc1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.7 %

Procedure:
Thiophosgene (0.24 mL, 3.1 mmol) was added to a stirred biphasic solution of 5-amino-3-methylpicolinonitrile (Intermediate 2, 275 mg, 2.07 mmol) in CHCl3 (6 mL)/water (10 mL) and the resulting orange mixture was stirred at room temperature overnight. The two layers were separated and the aqueous layer was extracted with DCM (3×). The organics were combined, washed with a saturated solution of sodium bicarbonate (2×), dried over sodium sulfate, and evaporated to dryness to afford 300 mg of 5-isothiocyanato-3-methylpicolinonitrile as an orange solid. 1H NMR (300 MHz, DMSO-d6) δ 8.66 (s, 1H), 8.06 (s, 1H), 2.5 (s, 3H).
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][S:27](=[O:31])(=[O:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[CH3:32][S:33]([C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1)(=[O:35])=[O:34].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:5]2[CH2:6][CH2:7][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([C:40]3[CH:39]=[CH:38][CH:37]=[C:36]([S:33]([CH3:32])(=[O:35])=[O:34])[CH:41]=3)[C:17]([C:22]([N:24]3[CH2:29][CH2:28][S:27](=[O:30])(=[O:31])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)c1cccc(-n2c(C(=O)N3CCS(=O)(=O)CC3)cc3cc(C(=O)N4CCN(C5CCC5)CC4)ccc32)c1
Yield: 37 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxothiomorpholin-4-yl)-methanone (example 202), 3-methylsulfonylphenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless foam (37%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=O)=[CH:9][CH:8]=1.O.ON1C2C=CC=CC=2N=N1.[CH3:28][NH:29][C:30]1[S:31][C:32]([S:36]([NH2:39])(=[O:38])=[O:37])=[C:33]([CH3:35])[N:34]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[NH2:39][S:36]([C:32]1[S:31][C:30]([N:29]([CH3:28])[C:14](=[O:16])[CH2:13][C:10]2[CH:9]=[CH:8][C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[CH:12][CH:11]=2)=[N:34][C:33]=1[CH3:35])(=[O:37])=[O:38]
Reactant: O=C(O)Cc1ccc(-c2ccccn2)cc1
Reactant: CNc1nc(C)c(S(N)(=O)=O)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(N(C)C(=O)Cc2ccc(-c3ccccn3)cc2)sc1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
300 mg (1.41 mmol) of [4-(2-pyridyl)phenyl]acetic acid and 190 mg (1.41 mmol) of 1-hydroxy-1H-benzotriazole hydrate are introduced into 4 ml of dimethylformamide at room temperature. 307 mg (1.48 mmol) of 2-methylamino-4-methyl-1,3-thiazole-5-sulfonamide and 284 mg (1.48 mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride are added, and the mixture is stirred at room temperature for 18 h. The solvent is then removed in vacuo, the residue is taken up in toluene, and the solvent is again removed in vacuo. The residue is stirred with 15 ml of water and 3 ml of methanol and then filtered off, and the filtrate is back-extracted with 20 ml of dichloromethane. Solid and dichloromethane phase are combined, and the solvent is removed in vacuo. The compound of Example 38 is obtained in the form of a white solid.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25](B4OC(C)(C)C(C)(C)O4)=[CH:24][N:23]=[C:22]([S:35][CH3:36])[N:21]=3)[C@H:14]2[CH3:37])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Br[C:41]1[S:45][C:44]([C:46]2[CH:54]=[CH:53][C:49]([C:50]([OH:52])=[O:51])=[CH:48][C:47]=2[CH3:55])=[N:43][C:42]=1[C:56]([CH3:59])([CH3:58])[CH3:57].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1COCC1.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>[F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:41]4[S:45][C:44]([C:46]5[CH:54]=[CH:53][C:49]([C:50]([OH:52])=[O:51])=[CH:48][C:47]=5[CH3:55])=[N:43][C:42]=4[C:56]([CH3:59])([CH3:58])[CH3:57])=[CH:24][N:23]=[C:22]([S:35][CH3:36])[N:21]=3)[C@H:14]2[CH3:37])[CH:6]=[C:7]([C:9]([F:10])([F:12])[F:11])[CH:8]=1
Reactant: Cc1cc(C(=O)O)ccc1-c1nc(C(C)(C)C)c(Br)s1
Reactant: CSc1ncc(B2OC(C)(C)C(C)(C)O2)c(CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CSc1ncc(-c2sc(-c3ccc(C(=O)O)cc3C)nc2C(C)(C)C)c(CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)n1
Yield: 9 %

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-{[2-(methylsulfanyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-4-yl]methyl}-1,3-oxazolidin-2-one (INTERMEDIATE 21, 2.0 g, 3.46 m mol), 4-(5-bromo-4-tert-butylthiazol-2-yl)-3-methylbenzoic acid (INTERMEDIATE 41, 1.350 g, 3.81 mmol), potassium phosphate (8.18 mL, 1.27 M, 10.39 m mol) in THF (5 mL) and water (5.00 mL) was added tetrakis(triphenylphosphine)palladium(0) (0.400 g, 0.346 mmol). It was degassed, and refilled with nitrogen. The reaction mixture was heated to reflux for 2 hours to see complete conversion by LCMS. It was distributed between 100 mL of water and 300 mL of ethyl acetate. The organic layer was collected, dried over sodium sulfate, filtered and the filtrate concentrated. The crude isolate was purified by silica gel chromatography, eluting with 30% ethyl acetate in hexanes to give the title compound as white solid (225 mg, 9.0% yield). LCMS (M+H)+: 725.0
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]([CH3:19])=[C:8]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[CH:9]=1)=[O:4].[C:20]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)(=[O:22])[CH3:21].CN(C)C=O.C([O-])(=O)C.[K+]>ClCCl>[C:20]([C:23]1[CH:28]=[CH:27][C:26]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:8]3[CH:9]=[C:5]([C:3]([OH:2])=[O:4])[O:6][C:7]=3[CH3:19])=[CH:13][CH:14]=2)=[CH:25][CH:24]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)c1ccc(B(O)O)cc1
Reactant: COC(=O)c1cc(COc2ccc(I)cc2)c(C)o1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)c1ccc(-c2ccc(OCc3cc(C(=O)O)oc3C)cc2)cc1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
A stirred mixture of 4-(4-iodo-phenoxymethyl)-5-methyl-furan-2-carboxylic acid methyl ester (20) (0.26 g), 4-acetylphenylboronic acid (0.15° g), N,N-dimethylformamide (30 mL), potassium acetate (0.26 g) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(11), complex with dichloromethane (1:1) (40 mg) was heated at 90° C. over night. The reaction mixture was concentrated in vacuo, dissolved in ethyl acetate (30 mL) and washed successively with water (30 mL), brine (30 mL), dried and 3 concentrated in vacuo. The residue was dissolved in a mixture of tetrahydrofuran/methanol (2:1 by volume) (30 mL) and 1.0 M aqueous lithium hydroxide solution (6.78 mL) and stirred for 16 hours. The reaction mixture was acidified to pH 2 using 0.1 M hydrochloric acid and extracted with ethyl acetate (3×25 mL). The extract was dried, concentrated in vacuo and the residue purified by HPLC to give compound 21 as a white solid (50 mg). LC/MS System C: Rt=4.18 mins, m/z (ES−)=349 (M− for C21H18O5).
Reaction SMILES: [CH:1]([O:3][C:4]([N:6]1[CH2:30][C@:29]2([C:31](=[O:34])[CH2:32]O)[C@@H:8]([CH2:9][C@H:10]3[C@H:23]4[C@@:14]([F:27])([C@:15]5([CH3:26])[C:20]([C@@H:21]([F:24])[CH2:22]4)=[CH:19][C:18](=[O:25])[CH:17]=[CH:16]5)[C@@H:13]([OH:28])[CH2:12][C@@:11]32[CH3:35])[CH2:7]1)=[O:5])=[CH2:2].[CH3:36][S:37](Cl)(=O)=O.CCN(C(C)C)C(C)C.C([S-])C.[Na+]>CN(C=O)C>[CH:1]([O:3][C:4]([N:6]1[CH2:30][C@:29]2([C:31](=[O:34])[CH2:32][S:37][CH3:36])[C@@H:8]([CH2:9][C@H:10]3[C@H:23]4[C@@:14]([F:27])([C@:15]5([CH3:26])[C:20]([C@@H:21]([F:24])[CH2:22]4)=[CH:19][C:18](=[O:25])[CH:17]=[CH:16]5)[C@@H:13]([OH:28])[CH2:12][C@@:11]32[CH3:35])[CH2:7]1)=[O:5])=[CH2:2]
Reactant: C=COC(=O)N1C[C@@H]2C[C@H]3[C@@H]4C[C@H](F)C5=CC(=O)C=C[C@]5(C)[C@@]4(F)[C@@H](O)C[C@]3(C)[C@]2(C(=O)CO)C1
Reactant: CS(=O)(=O)Cl
Agent: CC[S-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=COC(=O)N1C[C@@H]2C[C@H]3[C@@H]4C[C@H](F)C5=CC(=O)C=C[C@]5(C)[C@@]4(F)[C@@H](O)C[C@]3(C)[C@]2(C(=O)CSC)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.7 %

Procedure:
A mixture of compound 164 (203 mg, 0.413 mmol), methansulfonyl chloride (38.6 μl, 0.496 mmol) and DIPEA (108 μl, 0.620 mmol) in dry DMF (3 ml) is stirred at RT under nitrogen for 1 hour. Further methansulfonyl chloride (16.09 μl, 0.207 mmol) and DIPEA (54.1 μl, 0.310 mmol) are added and the mixture is stirred at RT for 2 hours. Sodiumethanethiolate (87 mg, 1.239 mmol) is added and the mixture is stirred at RT for 16 hours. The reaction the mixture is partitioned between AcOEt and brine, then the aqueous phase is extracted with AcOEt and the combined organic layers are washed with brine, dried over Na2SO4 and filtered. The solvent is evaporated to give a oil which is purified by silica gel chromatography (eluent: AcOEt/petroleum ether 2/3) to afford the title compound (118 mg, 0.226 mmol, 54.8% yield).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:16]=[N:17][C:18]([NH2:21])=[N:19][CH:20]=3)=[N:13][CH:14]=2)O1.Br[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30]([N:33]1[CH2:38][CH2:37][NH:36][C:35](=[O:39])[CH2:34]1)(=[O:32])=[O:31]>>[NH2:21][C:18]1[N:19]=[CH:20][C:15]([C:12]2[N:13]=[CH:14][C:9]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[S:30]([N:33]3[CH2:38][CH2:37][NH:36][C:35](=[O:39])[CH2:34]3)(=[O:32])=[O:31])=[CH:10][CH:11]=2)=[CH:16][N:17]=1
Reactant: O=C1CN(S(=O)(=O)c2ccccc2Br)CCN1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)nc2)OC1(C)C
Product: Nc1ncc(-c2ccc(-c3ccccc3S(=O)(=O)N3CCNC(=O)C3)cn2)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 427 using 5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pyrimidin-2-amine and 4-((2-bromophenyl)sulfonyl)piperazin-2-one. MS (ESI): mass calcd. for C19H18N6O3S, 410.12; m/z found, 411.1 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.97 (s, 2H), 8.60 (dd, J=2.2, 0.9, 1H), 8.18 (dd, J=8.0, 1.3, 1H), 7.91 (dd, J=8.2, 2.2, 1H), 7.87 (dd, J=8.2, 1.0, 1H), 7.80 (m, 1H), 7.70 (m, 1H), 7.50 (dd, J=7.5, 1.3, 1H), 3.42 (s, 2H), 3.15 (s, 4H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([C:11]1[CH:12]=[C:13]([C:22]2[N:23]=[C:24]3[N:28]([CH:29]=2)[CH2:27][CH2:26][S:25]3)[CH:14]=[C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:16]=1[OH:17])([CH3:10])([CH3:9])[CH3:8].Cl.NO.[CH3:33][N:34](C)C=O>C(Cl)CCl.N1C=CC=CC=1>[C:33]([C:29]1[N:28]2[C:24]([S:25][CH2:26][CH2:27]2)=[N:23][C:22]=1[C:13]1[CH:14]=[C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:16]([OH:17])=[C:11]([C:7]([CH3:8])([CH3:9])[CH3:10])[CH:12]=1)#[N:34]
Reactant: CC(C)(C)c1cc(-c2cn3c(n2)SCC3)cc(C(C)(C)C)c1O
Reactant: CN(C)C=O
Agent: Cl
Agent: NO
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CC(C)(C)c1cc(-c2nc3n(c2C#N)CCS3)cc(C(C)(C)C)c1O

Procedure:
To a mixed solution of 0.5 g of dimethylformamide and 10 ml of ethylene dichloride was added dropwise a solution of 0.9 g of oxalyl chloride in 5 ml of ethylene dichloride under ice-cooling. After allowing to stand the mixture for 15 minutes at room temperature, a solution of 2 g of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydroimidazo[2,1-b]thiazole dissolved in a mixture of 3 ml of dimethylformamide and 10 ml of ethylene dichloride was added dropwise to the solution and the resultant mixture was stirred for 2 hours. Then, a solution of 0.5 g of hydroxylamine hydrochloride dissolved in a mixture of 1.5 ml of dimethylformamide and 0.6 ml of pyridine was added to the reaction mixture and the resultant mixture was refluxed overnight. The reaction mixture was washed with 30 ml of an aqueous 5% sodium hydrogen carbonate solution, dried, and then concentrated. The residue thus formed was purified by silica gel column chromatography using chloroform as the eluent and further recrystallized from ethanol to provide 0.33 g of 5-cyano-6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydroimidazo[2,1-b]thiazole.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)([CH2:16][C:17]3([OH:20])[CH2:19][CH2:18]3)[O:12][C:11]2=[O:28])[CH3:9])=[CH:4][CH:3]=1.[CH3:29][C:30]1[CH:35]=[C:34](B(O)O)[CH:33]=[CH:32][N:31]=1>>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C@:13]2([CH2:16][C:17]3([OH:20])[CH2:19][CH2:18]3)[O:12][C:11](=[O:28])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:34]4[CH:33]=[CH:32][N:31]=[C:30]([CH3:29])[CH:35]=4)=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:22][CH:23]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC2(O)CC2)(c2ccc(F)cc2)OC1=O
Reactant: Cc1cc(B(O)O)ccn1
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CC4(O)CC4)(c4ccc(F)cc4)OC3=O)cc2)ccn1

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-((1-hydroxycyclopropyl)methyl)-1,3-oxazinan-2-one and 2-methylpyridine-4-boronic acid following a procedure analogous to that described in Example 459 Step 1. LC-MS Method 2 tR=0.996, m/z=461.1; 1H NMR (CDCl3) 0.35 (m, 1H), 0.17 (m, 3H), 0.51 (m, 1H), 0.61 (m, 1H), 1.48 (d, 3H), 2.11 (s, 2H), 2.28 (m, 1H), 2.42 (m, 2H), 2.56 (s, 3H), 2.71 (s, 1H), 2.95 (m, 1H), 5.63 (m, 1H), 6.91 (m, 2H), 6.98 (m, 2H), 7.19 (m, 1H), 7.26-7.38 (m, 5H), 8.49 (d, 1H).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH:17]1([C:20]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([CH2:28][O:29][CH2:30][O:31][CH3:32])[CH:23]=2)=O)[CH2:19][CH2:18]1.O>C1COCC1>[CH:17]1([C:20]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([CH2:28][O:29][CH2:30][O:31][CH3:32])[CH:23]=2)=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:18][CH2:19]1
Reactant: COCOCc1cc(C(=O)C2CC2)ccn1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C=C(c1ccnc(COCOC)c1)C1CC1

Procedure:
To a suspension of 60% sodium hydride (1.09 g) in THF (30 mL) was added ethyl diethylphosphonoacetate (6.46 mL) at 0° C., and then cyclopropyl(2-((methoxymethoxy)methyl)pyridin-4-yl)methanone (1.20 g) was added. The reaction mixture was heated under reflux for 2 hr. Water was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.36 g) as a pale-yellow oil.