Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S([O:11][CH:12]1[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]1)(C1C=CC(C)=CC=1)(=O)=O.[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[O:11][CH:12]1[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:15]1
Reactant: Cc1ccc(S(=O)(=O)OC2CN(C(=O)OC(C)(C)C)C2)cc1
Reactant: Oc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(Oc2ccc(Cl)cc2Cl)C1
Temperature: 120 °C
Yield: 123.6 %

Procedure:
To a solution of tert-butyl 3-(tosyloxy)azetidine-1-carboxylate (1.0 g, 3.05 mmol) and 2,4-dichlorophenol (0.490 g, 3.05 mmol) in DMF (10 mL) was added potassium carbonate (0.630 g, 4.67 mmol) and the reaction mixture was heated to 120° C. for 2 h. Then reaction was quenched with water and extracted with EtOAc (2×25 mL). The organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by silica gel column chromatography provided tert-butyl 3-(2,4-dichlorophenoxy)azetidine-1-carboxylate (1.2 g, 63%) as a solid.
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:6][C:7](=[O:33])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])[CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21](=[O:24])[N:20]([CH3:25])[CH:19]=2)=O)=[CH:10][CH:9]=1)[CH2:4][OH:5].Cl.[NH2:35][OH:36].C(=O)([O-])O.[Na+]>>[OH:5][CH2:4][CH:3]([NH:6][C:7](=[O:33])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])[CH2:15]/[C:16](=[N:35]\[OH:36])/[C:18]2[CH:23]=[CH:22][C:21](=[O:24])[N:20]([CH3:25])[CH:19]=2)=[CH:10][CH:9]=1)[CH2:2][OH:1]
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)NC(CO)CO)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(C(=O)NC(CO)CO)cc1

Procedure:
In analogy to example 151, step 3, N-(1,3-dihydroxypropan-2-yl)-4-(3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxo-1-o-tolylpropyl)benzamide was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound as an off-white solid containing <10% of the corresponding Z isomer, MS (ESI+): m/z=464.2 [M+H]+.
Reaction SMILES: CSC.B.[Br:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:16][N:15]=[C:14]([CH3:17])[C:13]=2[C:18](=[O:29])[CH2:19][O:20][C@@H:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH3:22])=[CH:8][CH:7]=1>C1COCC1>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:16][N:15]=[C:14]([CH3:17])[C:13]=2[C@H:18]([OH:29])[CH2:19][O:20][C@@H:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH3:22])=[CH:8][CH:7]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(=O)CO[C@H](C)c1ccccc1
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: Cc1noc(-c2ccc(Br)cc2)c1[C@H](O)CO[C@H](C)c1ccccc1
Temperature: 0 °C
Reaction time: 0.92 h

Procedure:
The (S)-Corey-Bakshi-Shibata catalyst (0.012 g, 0.04 mmol) was dissolved in THF (2 mL) and cooled to 0° C. Borane dimethyl sulfide complex (2.0 M in THF, 0.387 mL, 0.77 mmol) was slowly added, followed by 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-2-((R)-1-phenyl-ethoxy)-ethanone (0.172 g, 0.43 mmol) in THF (3.3 mL) over 15 minutes. After stirring for 55 minutes the reaction was submitted to standard aqueous workup to afford the title compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH3:12][O:13][C:14]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)=[O:15]>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:19]2[CH:20]=[CH:21][C:16]([C:14]([O:13][CH3:12])=[O:15])=[CH:17][CH:18]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: CC(=O)Nc1ccc(O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: COC(=O)c1ccc(Oc2ccc(NC(C)=O)cc2)cc1
Yield: 75.1 %

Procedure:
Dry air is bubbled through a solution of 4-acetamidophenol (320 mg, 2.1 mmol), copper(II) acetate (384 mg, 2.1 mmol), TEA (1.5 mL, 10.5 mol), (4-methoxycarbonylphenyl)boronic acid (760 mg, 4.2 mmol), and powdered molecular sieves (2 g) in CH2Cl2 (21 mL) for 16 hours at room temperature. The resulting material is concentrated and purified by flash column chromatography (25-50% EtOAc in heptane) to give the desired product (450 mg, 75%). 1H NMR (300 MHz, DMSO) δ8.01, 7.54, 7.27, 7.05, 6.98, 3.92, 2.22.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.Cl[CH2:9][C:10]([NH:12][C:13]1[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:14]=1)=[O:11]>CN(C)C=O>[N:3]1([CH2:9][C:10]([NH:12][C:13]2[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:14]=2)=[O:11])[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: CCOC(=O)c1ccc(NC(=O)CCl)cc1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(NC(=O)Cn2ccnc2)cc1
Temperature: 80 °C
Yield: 76.9 %

Procedure:
To a suspension of 2.4 g of 50% sodium hydride in 100 ml of dry dimethylformamide was added slowly 3.4 g of imidazole at room temperature, and the mixture was heated to 80° C. A solution of 12.1 g of ethyl p-chloroacetylaminobenzoate in 45 ml of dry dimethylformamide was added to the mixture over a period of 30 minutes at 80° C., and then the reaction mixture was heated at 100° C. for 1.5 hours. After removal of the solvent under reduced pressure, the residue was dissolved in chloroform and washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residual solid was recrystallized from ethanol-n-hexane to give 10.5 g of ethyl p-(1-imidazolyl)acetylaminobenzoate as colorless needles. M.P.: 185°-187° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH2:9][OH:10])[N:3]=1.Br[CH2:12][CH:13]1[CH2:15][CH2:14]1>>[Cl:1][C:2]1[N:3]=[C:4]([CH2:9][OH:10])[CH:5]=[CH:6][C:7]=1[O:8][CH2:12][CH:13]1[CH2:15][CH2:14]1
Reactant: OCc1ccc(O)c(Cl)n1
Reactant: BrCC1CC1
Product: OCc1ccc(OCC2CC2)c(Cl)n1

Procedure:
Using 2-chloro-6-(hydroxymethyl)pyridin-3-ol and (bromomethyl)cyclopropane, and in the same manner as in Example 5, the title compound was obtained.
Reaction SMILES: [Li]CCCC.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[C:15]([F:18])([F:17])[F:16].CN(CCN(C)C)C.CN([CH:30]=[O:31])C.Cl>C(OCC)C>[Cl:6][C:7]1[C:8]([C:15]([F:16])([F:17])[F:18])=[CH:9][C:10]([O:13][CH3:14])=[C:11]([CH:12]=1)[CH:30]=[O:31]
Reactant: CN(C)C=O
Reactant: COc1ccc(Cl)c(C(F)(F)F)c1
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1cc(C(F)(F)F)c(Cl)cc1C=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A 1.61 M hexanes solution of n-BuLi (18.7 mL, 30.1 mmol) was added to a −78° C. diethyl ether solution (45 mL) of 1-chloro-4-methoxy-2-(trifluoromethyl)benzene (5.3 g, 25.1 mmol) and TMEDA (4.5 mL, 30.1 mmol). After 30 min at −78° C. the reaction was transferred to an ice bath and stirred at 0° C. After 5 min DMF (5.0 mL, 65.0 mmol) was added and the reaction was maintained in the ice bath. After 2 hrs at 0° C. 6 M aqueous HCl (aq) (17.0 mL, 102 mmol) was added and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with 4 M NaCl and 5 M K2CO3, dried (Na2SO4), and concentrated to yield the title compound, which was used in the next step without further purification.
Reaction SMILES: [O:1]1[C@H:5]2[O:6][CH2:7][CH2:8][C@H:4]2[C@@H:3]([OH:9])[CH2:2]1.C1COCC1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[O:1]1[C@H:5]2[O:6][CH2:7][CH2:8][C@H:4]2[C:3](=[O:9])[CH2:2]1
Reactant: O[C@H]1CO[C@H]2OCC[C@H]21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C1CO[C@H]2OCC[C@@H]12
Temperature: 0 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
Enantiomerically pure (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol (bis-THF) 27 (85 mg, 0.65 mmol) was diluted in dry CH2Cl2 (6 mL) under argon, the solution was cooled to 0° C. and anhydrous Na2HPO4 (52 mg, 0.36 mol) was added. Dess-Martin periodinane (360 mg, 0.85 mmol) was added at once at 0° C. and the resulting suspension warmed to 23° C. and stirred for 3 h. The reaction was then quenched by successive addition of sat. aq. NaHCO3 and sat. aq. Na2SO3 solutions (1.5+1.5 mL). The phases were separated and the aqueous phase was extracted with CH2Cl2 then EtOAc. The combined organic phases were dried (Na2SO4), filtered on a small pad of silica gel, and evaporated to dryness. The residue was purified by column chromatography on silica gel using hexanes/EtOAc (3:1) to furnish ketone 28 (73 mg, 87%) as a white crystalline solid. TLC: Rf=0.57 (hexanes/EtOAc=1:1); Spectral data corresponded to those previously reported in the literature.35
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=[O:10].CO[CH:21](OC)[N:22]([CH3:24])[CH3:23]>CN(C=O)C>[CH3:21][N:22]([CH3:24])[CH:23]=[C:11]([C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=1)[C:9]([C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])=[O:10]
Reactant: COC(OC)N(C)C
Reactant: O=C(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1Cl
Solvent: CN(C)C=O
Product: CN(C)C=C(C(=O)c1ccc(Cl)cc1Cl)c1ccc(Cl)cc1

Procedure:
A solution of 4-chlorobenzyl 2,4-dichlorophenyl ketone (4.5 g, 14.4 mmol) and dimethyl-formamide dimethylacetal (7.7 mL, 58 mmol) in DMF (60 mL) was heated at 75° C. for 20 h. The volatiles were removed in vacuo to provide the crude product which was used directly in the next step. HPLC/MS: 354 (M+1), 356 (M+3); Rt=3.47 min.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH:13]2[CH2:15][CH2:14]2)=[C:11]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[NH:21][N:20]=[C:19]3[NH2:25])[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[CH:30](=O)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C)C=O>[CH2:30]([NH:25][C:19]1[C:18]2[C:22](=[CH:23][CH:24]=[C:16]([C:11]3[N:10]=[N:9][N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:12]=3[CH:13]3[CH2:15][CH2:14]3)[CH:17]=2)[NH:21][N:20]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Nc1n[nH]c2ccc(-c3nnn(Cc4ccccc4)c3C3CC3)cc12
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: c1ccc(CNc2n[nH]c3ccc(-c4nnn(Cc5ccccc5)c4C4CC4)cc23)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 89B (18.3 mg, 0.05 mmol) in dimethylformamide (2 mL) was added acetic acid (15 mg, 0.25 mmol) and benzaldehyde (6.4 mg, 0.06 mmol). The reaction mixture was stirred at room temperature overnight. Sodium triacetoxyborohydride (NaBH(OAc)3, 32 mg, 0.15 mmol) was added to the mixture. The reaction was stirred at room temperature for 3 hours, concentrated and purified by reverse phase-HPLC (CH3CN/H2O/NH4OAc) to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 13.09 (s, 1H), 9.24 (s, 1H), 8.02-8.10 (m, 3H), 7.84-7.90 (m, 1H), 7.49-7.67 (m, 4H), 7.25-7.45 (m, 5H), 5.70 (s, 2H), 3.30 (s, 2H), 1.88-1.95 (m, 1H), 1.01-1.09 (m, 2H), 0.43 (d, J=4.04 Hz, 2H). MS (ESI+) m/z 421 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH3:17])=[C:12](Br)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:19][S:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.N>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH3:17])=[C:12]([C:24]3[CH:25]=[CH:26][C:21]([S:20][CH3:19])=[CH:22][CH:23]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1c(Br)cnn(-c2ccc(F)c(Cl)c2)c1=O
Reactant: CSc1ccc(B(O)O)cc1
Agent: N
Product: COc1c(-c2ccc(SC)cc2)cnn(-c2ccc(F)c(Cl)c2)c1=O

Procedure:
The title compound is prepared according to the method of Example 6 starting with 2-(3-chloro-4-fluorophenyl)-4-methoxy-5-bromo-3(2H)-pyridazinone in place of 2-benzyl-5-methoxy-4-bromo-3(2H)-pyridazinone and substituting 4-(methylthio)benzeneboronic acid in place of 4-fluorobenzeneboronic acid (yield: 3.2 g, 63%). 1H NMR (300 MHz, CDCl3) δ 2.53 (s, 3H), 4.13 (s, 3H), 7.25 (t J=9 Hz, 1H), 7.35 (d, J=9 Hz 2H), 7.52 (d, J=9 Hz, 2H), 7.55-7.64 (m, 1H), 7.78 (dd, J=9 Hz, 3 Hz, 1H), 7.93 (s, 2H). MS (DCI/NH3) m/z 377 (M+H)+, 394 (M+NH4)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH2:11][CH2:12][CH3:13])[C:9]=1[OH:10])[CH2:5][OH:6].Br[CH:15]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=1)[C:16]([O:18][CH3:19])=[O:17].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:7]=[C:8]([CH2:11][CH2:12][CH3:13])[C:9]=1[O:10][CH:15]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=1)[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)C(Br)c1cccc(Cl)c1
Reactant: CCCc1cc(CO)cc(Cl)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1cc(CO)cc(Cl)c1OC(C(=O)OC)c1cccc(Cl)c1
Temperature: 25 °C
Yield: 80.7 %

Procedure:
To a magnetically stirred solution of 0.600 g (2.99 mmol) of the product of Step B in 6 mL acetone was added 0.869 g (3.30 mmol) of methyl α-bromo-(3-chlorophenyl)acetate, 0.829 g (6.00 mmol) of potassium carbonate and the reaction mixture was heated at reflux for 4 hours. The reaction mixture was cooled to room temperature, filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 15% EtOAc-hexane. Evaporation of the purified fractions and drying in vacuo afforded 0.925 g (80%) of the title compound.
Reaction SMILES: Cl[CH:2]([CH2:8][C:9]([Cl:12])([F:11])[F:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].CC1C=CC=C(C)N=1.[H][H]>O1CCCC1.[Pd]>[Cl:12][C:9]([F:10])([F:11])[CH2:8][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: [H][H]
Reactant: CCOC(=O)C(Cl)CC(F)(F)Cl
Agent: [Pd]
Solvent: Cc1cccc(C)n1
Solvent: C1CCOC1
Product: CCOC(=O)CCC(F)(F)Cl
Yield: 75 %

Procedure:
22.1 g of ethyl 2,4-dichloro-4,4-difluorobutyrate are dissolved in 100 ml of absolute tetrahydrofuran. 10.7 g of 2,6-dimethylpyridine and 2.0 g of 5% palladium/carbon catalyst are added and then gaseous hydrogen is passed in under atmospheric pressure until the hydrogen uptake is 100% of theory. The catalyst is removed by filtration and the tetrahydrofuran is removed by distillation and then the remaining oil is poured onto water, and the organic phase is separated off, dried with sodium sulfate, filtered and distilled under atmospheric pressure. 14.0 g of ethyl 4-chloro-4,4-difluorobutyrate are obtained in the form of a colourless oil of boiling point 154°-156° C.
Reaction SMILES: C(N)C1C=CC=CC=1.[CH:9]1([CH2:12][CH2:13][NH2:14])[CH2:11][CH2:10]1.[CH3:15][C:16]1[N:17]=[C:18]([N:24]2[CH2:28][CH2:27][N:26]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=3)[C:25]2=[O:41])[S:19][C:20]=1[C:21](O)=[O:22]>>[CH:9]1([CH2:12][CH2:13][NH:14][C:21]([C:20]2[S:19][C:18]([N:24]3[CH2:28][CH2:27][N:26]([CH2:29][C:30]4[CH:31]=[CH:32][C:33]([O:36][C:37]([F:38])([F:39])[F:40])=[CH:34][CH:35]=4)[C:25]3=[O:41])=[N:17][C:16]=2[CH3:15])=[O:22])[CH2:11][CH2:10]1
Reactant: Cc1nc(N2CCN(Cc3ccc(OC(F)(F)F)cc3)C2=O)sc1C(=O)O
Reactant: NCCC1CC1
Solvent: NCc1ccccc1
Product: Cc1nc(N2CCN(Cc3ccc(OC(F)(F)F)cc3)C2=O)sc1C(=O)NCCC1CC1
Yield: 26 %

Procedure:
Following the procedure as describe in Example 8, making variations as required to replace benzylamine with 2-cyclopropylethylamine to react with 4-methyl-2-(2-oxo-3-(4-(trifluoromethoxy)benzyl)imidazolidin-1-yl)thiazole-5-carboxylic acid, the title compound was obtained as a white powder in 26% yield: mp 195-196° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.32 (d, J=8.4 Hz, 2H), 7.18 (d, J=8.4 Hz, 2H), 5.76 (s, 1H), 4.47 (s, 2H), 4.12-4.07 (m, 2H), 3.49-3.42 (m, 4H), 2.59 (s, 3H), 1.50-1.43 (m, 2H), 0.72-0.62 (m, 1H), 0.47-0.41 (m, 2H), 0.14-0.02 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 162.3, 157.1, 155.4, 152.0, 148.9, 134.3, 129.7, 121.4, 120.4, 118.0, 47.3, 42.1, 41.8, 40.2, 34.3, 17.0, 8.6, 4.1; MS (ES+) m/z 469.3 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH2:6][C:7]1([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[S:11][CH:10]([CH2:12][SH:13])[CH2:9][S:8]1)[CH3:2].[CH2:22]([C:25]1[C:37]([OH:38])=[C:36]([C:39](=[O:41])[CH3:40])[CH:35]=[CH:34][C:26]=1[O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]Br)[CH2:23][CH3:24].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[C:39]([C:36]1[CH:35]=[CH:34][C:26]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][S:13][CH2:12][CH:10]2[CH2:9][S:8][C:7]([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])([CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:21])[S:11]2)=[C:25]([CH2:22][CH2:23][CH3:24])[C:37]=1[OH:38])(=[O:41])[CH3:40]
Reactant: CCOC(=O)CCC1(CCC(=O)OCC)SCC(CS)S1
Reactant: CCCc1c(OCCCCCBr)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCc1c(OCCCCCSCC2CSC(CCC(=O)OCC)(CCC(=O)OCC)S2)ccc(C(C)=O)c1O

Procedure:
The title compound was prepared according to the procedure of Example 2 using the mercaptan produced in Example 31 (0.5 g, 0.0014 mol), 5-(2-n-propyl-3-hydroxy-4-acetylphenoxy)-1-bromopentane (described in U.S. Pat. No. 4,565,882, Example 1) (0.484 g, 0.0014 mol) and anhydrous potassium carbonate (0.70 g) in methyl ethyl ketone (5 ml). The crude product was chromatographed on silica gel using 30% ethyl acetate/hexane as eluent to give 0.52 g (75%) of the product as an oil.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Br.Br[C:9]1[S:13][C:12]([NH2:14])=[N:11][CH:10]=1.[SH:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19]>CN(C=O)C.O>[NH2:14][C:12]1[S:13][C:9]([S:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:10][N:11]=1
Reactant: COC(=O)CCS
Reactant: Nc1ncc(Br)s1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCSc1cnc(N)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.6 %

Procedure:
K2CO3 (14.0 g, 100 mmol) was added to a solution of 5-bromothiazol-2-amine hydrobromide (13.0 g, 50 mmol) in 90 ml of dry DMF at 0° C. under nitrogen. After 0.5 h, methyl 3-sulfanylpropanoate (6.0 g, 50 mmol) was added dropwise to the mixture over the course of 30 min and stirred at ambient temperature for 48 h. Then the mixture was diluted with 500 ml of water and extracted with TBME. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuum. The residue was purified by column chromatography on silica gel to give the title compound (7.6 g, 70% yield) 1H NMR (400 Mz, CDCl3) δ2.53 (t, 2H), 2.75 (t, 2H), 3.58 (s, 3H), 7.25 (s, 1H).
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.CC(=O)OCC>>[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:19][CH2:20][N:21]([CH2:2][C:3]2[S:4][C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][N:6]=3)[CH2:22][CH2:23]1
Reactant: ClCc1nc2cccnc2s1
Reactant: c1ccc(N2CCNCC2)nc1
Solvent: CCOC(C)=O
Product: c1ccc(N2CCN(Cc3nc4cccnc4s3)CC2)nc1

Procedure:
The product from Example 38A (150 mg, 0.81 mmol), 1-(2-pyridinyl)piperazine (160 mg, 0.98 mmol), and D1 EA (280 μL, 1.6 mmol) were processed as described in Example 38B to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.80 (m, 4H) 3.55 (m, 4H) 4.04 (s, 2H) 6.63 (m, 1H) 6.81 (m, 1H) 7.53 (m, 2H) 8.11 (m, 1H) 8.33 (dd, J=8.14, 1.70 Hz, 1H) 8.59 (dd, J=4.58, 1.53 Hz, 1H); (ESI) m/z 312 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[CH:17]([C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1)([CH3:19])[CH3:18]>>[Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([CH:17]([CH3:19])[CH3:18])=[CH:21][CH:22]=2)=[O:28])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1ccc(N)cc1-c1c(Cl)cnn1C
Reactant: CC(C)c1ccc(N=C=O)cc1
Product: COc1ccc(NC(=O)Nc2ccc(C(C)C)cc2)cc1-c1c(Cl)cnn1C
Yield: 2 %

Procedure:
3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine was treated with 4-isopropylphenyl isocyanate in a similar manner as described in Example 1.53, providing 1.3 mg (2%) of Compound 76 (Note: Compound 76 did not precipitate out). Therefore, the CH2Cl2 was removed under reduced pressure, the residue was dissolved in 5 mL DMSO, and purified by preparative HPLC): LCMS m/z (%)=401 (M+H37Cl, 31), 399 (M+H35Cl, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.63 (s, 1H), 8.52 (s, 1H), 7.59 (dd, J1=8 Hz, J2=4 Hz, 1H), 7.41 (d, J=2 Hz, 1H), 7.37 (dd, J1=12 Hz, J2=2 Hz, 2H), 7.33 (s, 1H), 7.17 (dd, J1=8 Hz, J2=2 Hz, 2H), 7.00 (d, J=12 Hz, 1H), 3.68 (s, 3H), 3.54 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(O)ccc1Br
Reactant: OB(O)c1ccccc1
Solvent: ClCCl
Product: Cc1cc(Oc2ccccc2)ccc1Br
Temperature: 25 °C

Procedure:
Into a 100 mL round bottom flask was added 4-bromo-3-methylphenol (0.90 g, 0.0048 mol), phenylboronic acid (2.4 g, 0.019 mol), cupric acetate (1.4 g, 0.0077 mol) and DCM (49.99 mL). TEA (4.0 mL, 0.029 mol) was then added followed by 4 A° molecular sieves and the reaction mixture was stirred at rt over night. Reaction mixture was then filtered through celite. The filtrate was concentrated in vacuo to give a residue which was purified by silica gel chromatography, eluting with 5% EtOAc in hexane. 1H NMR (400 MHz, CDCl3): δ=2.35 (s, 3H), 6.72 (dd, J=8.59, 3.03 Hz, 1H), 6.91 (d, J=2.78 Hz, 1H), 6.98-7.05 (m, 2H), 7.08-7.16 (m, 1H), 7.31-7.38 (m, 2H), 7.46 (d, J=8.59 Hz, 1H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[F:9][C:10]1[CH:15]=[C:14]([Br:16])[CH:13]=[CH:12][C:11]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl>[F:9][C:10]1[CH:15]=[C:14]([Br:16])[CH:13]=[CH:12][C:11]=1[C:17]1[CH:22]=[CH:21][C:20]([C:5](=[O:7])[CH3:6])=[CH:19][CH:18]=1
Reactant: Fc1cc(Br)ccc1-c1ccccc1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc(-c2ccc(Br)cc2F)cc1
Temperature: 25 °C

Procedure:
In a reactor were placed 113 g of anhydrous aluminum chloride and 600 1 of methylene chloride, to which was added 113 g of acetylchloride under stirring at 0° C. or less. Subsequently, a solution of 100 g of 2-fluoro-4-bromobiphenyl in 400 ml methylene chloride was added dropwise, stirred and reacted together for 7 hours while increasing the temperature up to room temperature. After adding the reaction solution to ice/dilute hydrochloric acid, the methylene chloride layer was washed sequentially with water, aqueous sodium hydrogencarbonate solution, and water, followed by dehydration over Glauber's salt and distillation of the solvent. The remaining fraction was recrystallized with acetone to obtain 2-fluoro-4-bromo-4'-acetylbiphenyl.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]3[CH2:26][C:25]4[C:20](=[CH:21][C:22]([O:29][CH2:30][CH2:31][N:32]5[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]5)=[C:23]([O:27][CH3:28])[CH:24]=4)[C:17]=3[NH:18][N:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:40][Si:41]([CH3:48])([CH3:47])[CH2:42][CH2:43][O:44][CH2:45]Cl>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:16]3[CH2:26][C:25]4[C:20](=[CH:21][C:22]([O:29][CH2:30][CH2:31][N:32]5[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]5)=[C:23]([O:27][CH3:28])[CH:24]=4)[C:17]=3[N:18]([CH2:45][O:44][CH2:43][CH2:42][Si:41]([CH3:48])([CH3:47])[CH3:40])[N:19]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: COc1cc2c(cc1OCCN1CCCCC1)-c1[nH]nc(-c3ccc(OCc4ccccc4)cc3)c1C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OCCN1CCCCC1)-c1c(c(-c3ccc(OCc4ccccc4)cc3)nn1COCC[Si](C)(C)C)C2
Reaction time: 0.5 h
Yield: 56.5 %

Procedure:
To the solution of Example 301C (7.71 g, 15.56 mmol) in DMF (200 mL) was added 95% NaH (0.412 g, 16.34 mmol). After 0.5 hour, 2-(trimethylsilyl)ethoxymethyl chloride (2.89 mL, 16.34 mmol) was added dropwise. Then the reaction was run at room temperature for 2 hours. All the DMF was removed. The residue was purified by flash chromatography to give the desired product (5.50 g, 56%). MS (APCI) m/z 626 (M+H)+.