Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11](/[CH:14]=[CH:15]/[C:16]([OH:18])=O)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[CH3:19][NH:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:23][CH:22]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11](/[CH:14]=[CH:15]/[C:16]([N:20]([CH3:19])[C:21]3[CH:22]=[CH:23][C:24]([CH2:27][N:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:25][CH:26]=3)=[O:18])=[N:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CNc1ccc(CN2CCCCC2)cc1
Reactant: O=C(O)/C=C/c1ccc(-c2ccc(Cl)cc2)cn1
Product: CN(C(=O)/C=C/c1ccc(-c2ccc(Cl)cc2)cn1)c1ccc(CN2CCCCC2)cc1

Procedure:
Prepared analogously to Example 143 starting from (E)-3-[5-(4-chloro-phenyl)-pyridin-2-yl]-acrylic acid (Z34b) and methyl-(4-piperidin-1-ylmethyl-phenyl)-amine. The crude product was purified by column chromatography (silica gel, dichloromethane/EtOH/conc. aqueous ammonia 50:10:0.1).
Reaction SMILES: [F:1][CH:2]([F:24])[O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17](=O)/[CH:18]=[CH:19]/[N:20](C)C)=[N:11]2)[CH:7]=[CH:8][CH:9]=1.[NH:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)N>C(O)C.Cl>[F:1][CH:2]([F:24])[O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17]3[N:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=4)[N:20]=[CH:19][CH:18]=3)=[N:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)F)c2)ccc1=O
Reactant: NNc1ccccn1
Agent: Cl
Solvent: CCO
Product: O=c1ccn(-c2cccc(OC(F)F)c2)nc1-c1ccnn1-c1ccccn1
Yield: 40.5 %

Procedure:
1-(3-Difluoromethoxy-phenyl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-10) (0.05 g; 0.149 mmol) and 2-hydrazinopyridine (0.021 g; 0.194 mmol) are dissolved in a sealed tube in ethanol (0.6 ml) with catalytic amounts of HCl and irradiated at 160° C. for 5 min. The solvent of the reaction mixture is removed and the crude product is purified by preparative HPLC yielding 0.023 g (40.5%) of the final product. MS: M=382.2 (M+H)+
Reaction SMILES: Br[CH2:2][CH:3]1[N:9]2[C:10](=[O:13])[O:11][N:12]=[C:8]2[CH2:7][CH2:6][CH2:5][CH2:4]1.[S-:14][CH2:15][CH3:16].[Na+]>>[CH2:15]([S:14][CH2:2][CH:3]1[N:9]2[C:10](=[O:13])[O:11][N:12]=[C:8]2[CH2:7][CH2:6][CH2:5][CH2:4]1)[CH3:16]
Reactant: O=c1onc2n1C(CBr)CCCC2
Reactant: CC[S-]
Agent: [Na+]
Product: CCSCC1CCCCc2noc(=O)n21

Procedure:
The product of Example 37a or the product of Example 15 is reacted with sodium thioethoxide by the methods of Example 37 to generate the title material.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:15]=[C:14]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:13]=[CH:12][C:11]=2[O:20][CH:21]([CH3:23])[CH3:22])=[O:9])[CH2:4][CH2:3]1.[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1O>>[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([C:10]2[CH:15]=[C:14]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:13]=[CH:12][C:11]=2[O:20][CH:21]([CH3:23])[CH3:22])=[O:9])[CH2:6][CH2:7]1
Reactant: Oc1ccc(F)cc1F
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(O)CC1
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(Oc2ccc(F)cc2F)CC1
Yield: 21 %

Procedure:
Prepared in analogy to Example 4 from (4-hydroxy-piperidin-1-yl)-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanone (Example 3(a)) and 2,4-difluorophenol. The crude material was purified by reversed phase HPLC (acetonitrile/water) to yield the title compound as an amorphous white solid (yield 21%). MS (m/e): 454.3 (M+H+, 100%).
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].Cl.[NH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].C(=O)(O)[O-].[Na+]>>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([NH:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:7]=1
Reactant: CCOC(=O)CN
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)CNc1nc(Cl)nc(Cl)n1

Procedure:
36.9 g of cyanuric chloride, 27.9 g of ethyl glycinate hydrochloride and 33.6 g of sodium bicarbonate were heated under reflux in 200 ml of dioxanefor 30 minutes. At the end of this time, the dioxane was removed by distillation under reduced pressure, and a mixture of ethyl acetate and water was added to the resulting residue, after which the mixture was shaken. The ethyl acetate layer was separated, dried and concentrated by evaporation under reduced pressure, and the resulting residue was recrystallized from a mixture of hexane and ethyl acetate, to yield 45.0 gof the title compound as crystals melting at 82° to 87° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:17][OH:18])[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[Si:24](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25].C(OCC)C>CN(C=O)C.[Cl-].[Na+].O>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:17][O:18][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)CCC[C@@H](CO)NC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: COC(=O)CCC[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
To a solution of (S)-methyl 5-(tert-butoxycarbonylamino)-6-hydroxyhexanoate (12 g, 46 mmol) in DMF (100 mL) was added imidazole (7.8 g, 115 mmol, 2.5 equiv.). TBS-Cl (8.25 g, 55 mmol, 1.2 equiv.) was then added in 3 portions. The reaction was complete in 30 min. Diethyl ether (200 mL) and brine (300 mL) were added to the reaction solution. The organic layer was further washed with brine (300 mL), dried, and concentrated to give (S)-methyl 5-(tert-butoxycarbonylamino)-6-(tert-butyldimethylsilyloxy)hexanoate (15.9 g, 92%) as a colorless oil. LRMS (M-Boc+H+) m/z 276.1.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][CH:7]=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].[Cl:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:14]=1[CH2:15]Cl>CN(C)C=O>[CH2:1]([C:5]1[N:6]([CH2:15][C:14]2[C:17]([F:21])=[CH:18][CH:19]=[CH:20][C:13]=2[Cl:12])[CH:7]=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc[nH]1
Reactant: Fc1cccc(Cl)c1CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1nccn1Cc1c(F)cccc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
A solution of 2 n-butylimidazole (3.75 g, 0.03 mol) in dry dimethylformamide (4 ml) was added to sodium hydride (0.95 g) in dimethylformamide (18 ml). After the gas evolution subsided, the mixture was stirred one hour under argon and 2-chloro-6-fluorobenzylchloride (5.5 q, 0.031 mol) in dimethylformamide (7 ml) was added slowly. The mixture was stirred for 17 hours at ambient temperature, diluted with ice water and extracted with ethyl acetate. The washed, dried, concentrated organic layer provided 7.63 g (94%) of 2-n-butyl-1-(2-chloro-6-fluorophenyl)methyl-1H-imidazole whose NMR was consistent with the structure. This material was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:32]([N:39]1[CH2:44][CH2:43][CH:42](O)[CH2:41][CH2:40]1)([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C(OCC)(=O)C>[OH:1][C:2]1[CH:11]=[C:10]([O:12][CH:42]2[CH2:43][CH2:44][N:39]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:40][CH2:41]2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(O)cc1O
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl 2,4-dihydroxybenzoate (5.1 g, 30.33 mmol) and triphenylphosphine (9.52 g, 36.3 mmol) were stirred in THF (200 ml) under nitrogen. The mixture was cooled in an ice bath and treated with a solution of 1-Boc-4-hydroxypiperidine (6.8 g, 33.8 mmol) and diethyl azodicarboxylate (5.73 ml, 6.34 g, 36.4 mmol) in THF (100 ml) added dropwise over 30 min. The mixture was stirred at ambient temperature for 18 hours, then diluted with ethyl acetate and washed with 1M NaOH, saturated aqueous sodium bicarbonate, and brine. The organic layer was dried over sodium sulfate, filtered, and evaporated to dryness in vacuo. The residue was chromatographed on silica gel eluted with 10% ethyl acetate in hexane, and the product fractions were evaporated to dryness in vacuo to give methyl 2-hydroxy-4-(1-Boc-4-piperidyloxy)benzoate.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)([CH3:12])[CH3:11])=[CH:6][CH:5]=1.Cl[CH2:21][C@H:22]1[CH2:26][O:25][C:24]([CH3:28])([CH3:27])[O:23]1>CN(C)C=O>[CH3:27][C:24]1([CH3:28])[O:23][C@@H:22]([CH2:21][O:3][C:4]2[CH:5]=[CH:6][C:7]([C:10]([C:13]3[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=3)([CH3:12])[CH3:11])=[CH:8][CH:9]=2)[CH2:26][O:25]1
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: CC1(C)OC[C@H](CCl)O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)OC[C@H](COc2ccc(C(C)(C)c3ccc(O)cc3)cc2)O1
Yield: 23.7 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 1750 mg, 43.80 mmol, 1.0 equiv) was added slowly to a stirred solution of Bisphenol A (10000 mg, 43.80 mmol, 1 equiv) in anhydrous dimethyl formamide (30 mL), at room temperature, and the contents were stirred under an atmosphere of argon for 20 min. (R)-(+)-4-chloromethyl-2,2-dimethyl-1,3-dioxolane 98% (7.10 mL, 52.56 mmol, 1.2 equiv) was added via syringe and the mixture was allowed to react at 70-80° C. for 40 h. Then, the reaction was quenched by the addition of a saturated solution of ammonium chloride (10 mL), and the mixture was extracted with ethyl acetate (3×20 mL). The organic layer was washed with deionized water (25 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: 10% ethyl acetate in hexane) to provide the title compound (3560 mg, 24%, 25-30% conversion) as a foam.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NOC1CCCCC1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(NOC1CCCCC1)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.3 %

Procedure:
To a solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.2 g, 0.72 mmol) in dry DCM (20 mL) were added (aminooxy)cyclohexane 21 (0.1 g, 0.86 mmol, US 2008/146625 A1), 1-hydroxybenzotriazole (0.14 g, 1.1 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.2 g, 1.1 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight, and then concentrated under vacuum. The residue was purified by column chromatography to give (2S,5R)-6-(benzyloxy)-N-(cyclohexyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide 22 (0.24 g, 89.5%) as a clear thick oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]=1[O:15][CH3:16].Br[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)P(=O)(N(C)C)N(C)C.[Cu]>[CH3:16][O:15][C:3]1[CH:4]=[C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:7][C:2]=1[O:1][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)/C=C/c1ccc(O)c(OC)c1
Reactant: Brc1cccnc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)/C=C/c1ccc(Oc2cccnc2)c(OC)c1
Temperature: 160 °C
Reaction time: 3 h
Yield: 21.5 %

Procedure:
6.67 g of ethyl (E)-3-(4-hydroxy-3-methoxyphenyl)acrylate and 5.69 g of 3-bromopyridine were dissolved in 13.3 ml of hexamethyl phosphoric triamide. To the solution were added 4.15 g of potassium carbonate and 0.57 g of a copper powder. The mixture was stirred for 3 hours at 160° C. in a nitrogen atmosphere. The reaction mixture was mixed with 100 ml of ice water and 100 ml of ethyl acetate. The resulting insolubles were removed by filtration. An organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by a column chromatography (eluant: benzene/ethyl acetate=10/1) to obtain 1.93 g of light yellow oily ethyl (E)-3-[3-methoxy-4-(3-pyridyloxy)phenyl]acrylate.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][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)=[N:6][CH:7]=1.[C:17]([O:21][C:22](=[O:42])[NH:23][C:24]1[CH:29]=[CH:28][C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][C:25]=1[N+:39]([O-:41])=[O:40])([CH3:20])([CH3:19])[CH3:18].[F-].[Cs+]>O1CCOCC1.CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:17]([O:21][C:22](=[O:42])[NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[CH:3]=[N:4][C:5]([O:8][C@@H:9]3[CH:14]4[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]4)[CH2:10]3)=[N:6][CH:7]=2)=[CH:26][C:25]=1[N+:39]([O-:41])=[O:40])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1[N+](=O)[O-]
Reactant: Brc1cnc(O[C@H]2CN3CCC2CC3)nc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cnc(O[C@H]3CN4CCC3CC4)nc2)cc1[N+](=O)[O-]

Procedure:
The product of Example 19A (0.57 g, 2.0 mmol) was coupled with the product of Example 34B (1.50 g, 4 mmol) under the catalysis of Pd2(dba)3 (24 mg, 0.025 mmol) and (tBu3P)2Pd (26 mg, 0.05 mmol) with CsF (Strem Chemicals, 1.80 g, 12.0 mmol) in dioxane (20 mL) and DMF (Aldrich, 2 mL) at 80° C. under N2 for 16 hours according to the procedure of Example 34C. The title compound was purified by chromatography (SiO2, EtOAc: MeOH (v. 2% NH3.H2O), 50:50, Rf. 0.3) as oil (590 mg, 67%). 1H NMR (300 MHz, MeOH-D4) δ 1.38 (s, 9 H), 1.46-1.59 (m, 1 H), 1.61-1.73 (m, 1 H), 1.74-1.88 (m, 1 H), 1.95-2.10 (m, 1 H), 2.22-2.33 (m, 1 H), 3.38-3.48 (m, 1 H), 5.15-5.25 (m, 1 H), 7.58 (d, J=8.2 Hz, 1 H), 7.97 (dd, J=8.8, 2.1 Hz, 1 H), 8.56 (d, J=4.9 Hz, 1 H), 8.97 (s, 2 H) ppm. MS (DCl/NH3): 442 (M+H)+.
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]([F:13])([F:12])[C:7](=[CH2:11])[C:8](O)=[O:9]>>[F:5][C:6]([F:13])([F:12])[C:7](=[CH2:11])[C:8]([Cl:3])=[O:9]
Reactant: O=S(Cl)Cl
Reactant: C=C(C(=O)O)C(F)(F)F
Product: C=C(C(=O)Cl)C(F)(F)F
Yield: 65.8 %

Procedure:
Thionyl chloride (11.5 ml; 158 mmoles) was added to α-trifluoromethylacrylic acid (19.7 g; 141 mmoles), and the mixture was heated under reflux for 22 hours. Distillation of the reaction mixture under atmospheric pressure gave 14.7 g (yield:66%) of α-trifluoromethylacryloyl chloride, B.p. 89°-90° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([NH:22][S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[CH:5]=[CH:4][N:3]=1.[NH2:33][CH2:34][C:35]([OH:37])=[O:36].C([O-])([O-])=O.[K+].[K+]>C(O)CCC>[F:32][C:28]1[CH:27]=[C:26]([S:23]([NH:22][C:18]2[CH:17]=[C:16]([C:9]3[N:10]=[C:11]([CH:13]([CH3:15])[CH3:14])[S:12][C:8]=3[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:33][CH2:34][C:35]([OH:37])=[O:36])[N:7]=3)[CH:21]=[CH:20][CH:19]=2)(=[O:25])=[O:24])[CH:31]=[CH:30][CH:29]=1
Reactant: NCC(=O)O
Reactant: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3cccc(F)c3)c2)c(-c2ccnc(Cl)n2)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3cccc(F)c3)c2)c(-c2ccnc(NCC(=O)O)n2)s1
Temperature: 60 °C
Reaction time: 16 h
Yield: 25 %

Procedure:
To a solution of N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]phenyl}-3-fluorobenzenesulfonamide (100 mg, 0.20 mmol) in 1-butanol (5 mL) was added glycine (153 mg, 2.0 mmol) and K2CO3 (566 mg, 4.0 mmol). The reaction was stirred at 60° C. for 16 h, then partitioned between water and EtOAc. The pH of the aqueous layer was adjusted to below 4 with 1 N HCl, and the aqueous layer was extracted with EtOAc. This organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to generate the title compound as a white powder (24 mg, 0.05 mmol, 22.8% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.04 (d, J=4.5 Hz, 1H), 7.46-7.64 (m, 5H), 7.33 (t, J=8.1 Hz, 1H), 7.18-7.24 (m, 3H), 6.07 (s, 1H), 3.89 (s, 2H), 3.25-3.29 (m, 1H), 1.36 (d, J=6.7 Hz, 6H). MS (ESI): 528.1 [M+H]+.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11]C)=[CH:7][C:5]=2[N:6]=1.[C:13]1(C)C=CC(S(OC)(=O)=O)=CC=1>CC#N>[OH:11][C:8]1[CH:9]=[CH:10][C:4]2[S:3][C:2]([S:1][CH3:13])=[N:6][C:5]=2[CH:7]=1
Reactant: COc1ccc2sc(S)nc2c1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Solvent: CC#N
Product: CSc1nc2cc(O)ccc2s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76 %

Procedure:
To a 250 mL flask was added 2-mercapto-5-methoxybenzothiazole (5.1 g, 26 mmol), MeCN (63 mL), methyl p-toluenesulfonate (4.8 g, 26 mmol) and TEA (4.4 mL, 31 mmol). After stirring 16 h at ambient temperature, the solution was concentrated under reduced pressure. The crude material was diluted with EtOAc (200 mL), washed with water (2×75 mL), dried over Na2SO4, filtered, and concentrated. The resulting viscous oil was dissolved in DCM (40 mL), and transferred to an argon-purged 250 mL flask. The solution was cooled to −78° C. prior to the addition of a 1.0 M BBr3 solution in DCM (64 mL). The reaction suspension was allowed to warm to room temperature. After 16 h the reaction solution was cooled to −78° C. and quenched by addition of MeOH (100 mL). The resulting precipitates were isolated by vacuum filtration to yield 5-hydroxy-2-methylthio-benzothiazole (3.9 g, 76%) as a white solid.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=O)=[CH:7][C:6]=1[Cl:15])[CH:2]=[CH2:3].Cl.[CH2:17]([O:19][C:20](=[O:23])[CH2:21][NH2:22])[CH3:18].C(N(CC)CC)C.C1CCC(N=C=NC2CCCCC2)CC1>O1CCCC1.C(Cl)(Cl)Cl>[CH2:17]([O:19][C:20](=[O:23])[CH2:21][NH:22][C:12](=[O:14])[CH2:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[C:6]([Cl:15])[CH:7]=1)[CH3:18]
Reactant: CCOC(=O)CN
Reactant: C=CCOc1ccc(CC(=O)O)cc1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: C=CCOc1ccc(CC(=O)NCC(=O)OCC)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Allyloxy-3-chloro-phenylacetic acid (4.3 g) was dissolved in dry tetrahydrofuran (20 ml). To the solution was added glycine ethyl ester hydrochloride (2.85 g) in dry chloroform (30 ml) containing dry triethylamine (2.8 ml). DCC (4.1 g) was added and the reaction mixture was stirred overnight at room temperature.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[CH2:14][CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:20][S:21][C:22]1[S:26][C:25]([CH:27]=O)=[CH:24][CH:23]=1>[OH-].[K+].CCO>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[C:14](=[CH:27][C:25]2[S:26][C:22]([S:21][CH3:20])=[CH:23][CH:24]=2)[CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C1CCCc2cc(OCCn3ccnc3)ccc21
Reactant: CSc1ccc(C=O)s1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CSc1ccc(C=C2CCc3cc(OCCn4ccnc4)ccc3C2=O)s1
Yield: 75.4 %

Procedure:
According to the method of Example 4, 6-(2-imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (0.25 g, 0.98 mmol) was reacted with 5-(methylthio)thiophene-2-carboxaldehyde (0.233 g, 1.47 mmol) in 4 mL of 4% KOH in EtOH for 2 hours at room temperature to afford 0.293 g (36%) of the title compound as a dark yellow powder, mp 102-104° C.: APCI-MS m/e 397.5 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[NH:6][C:7](=[CH:10][C:11]([O-:13])=[O:12])[CH2:8][O:9][C:4]=2[CH:3]=1.[CH3:16][CH2:17]O>FC(F)(F)S([O-])(=O)=O.[Zn+2].FC(F)(F)S([O-])(=O)=O>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[NH:6][C@@H:7]([CH2:10][C:11]([O:13][CH2:16][CH3:17])=[O:12])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: CCO
Reactant: O=C([O-])C=C1COc2cc(Cl)ccc2N1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Zn+2]
Product: CCOC(=O)C[C@H]1COc2cc(Cl)ccc2N1
Temperature: 60 °C
Reaction time: 16 h
Yield: 93.6 %

Procedure:
Zinc trifluoromethanesulfonate (2.87 g, 7.91 mmol) was added to a well-stirred solution of (2E or Z)-(7-chloro-2H-1,4-benzoxazin-3(4H)-ylidene)acetate (Intermediate 19, 20 g, 79.1 mmol) in EtOH (150 mL, HPLC grade) at 20° C. The resulting mixture was evacuated and purged with N2 for several times, then (+)-1,2-bis(2s, 5s)-2,5-diphenylphospholanol ethane(1,5-cyclooctadiene) rhodium(I)tetrafluoroborate (0.51 g, 0.63 mmol) was added at 20° C. The resulting solution was evacuated and purged with N2 for several times again. Then the reaction was stirred at 60° C. for 16 h under H2 (15 bar pressure). The mixture was concentrated. The crude product was purified by silica gel column chromatography with EtOAc in PE from 0 to 20%. The pure product fraction was concentrated. This resulted in the title compound (18.9 g, 93.6%) as an orange oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[Br:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[OH:18])[CH:13]=O>CO>[S:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:13]1[C:12]1[CH:15]=[CH:16][C:17]([OH:18])=[C:10]([Br:9])[CH:11]=1
Reactant: Nc1ccccc1S
Reactant: O=Cc1ccc(O)c(Br)c1
Solvent: CO
Product: Oc1ccc(-c2nc3ccccc3s2)cc1Br
Temperature: 25 °C
Yield: 38 %

Procedure:
In a methanol solvent, a solution including 2-aminothiophenol (1.0 eq.) and 3-bromo-4-hydroxybenzaldehyde (1.0 eq.) was stirred at room temperature. The produced precipitate was filtered and the filtered product was washed with cold methanol to obtain Compound 26.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:15]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:14][C:13]([C:21]([O:23][CH3:24])=[O:22])=[CH:12][N+:11]=1[O-].P(Cl)(Cl)([Cl:28])=O>>[Cl:28][C:12]1[N:11]=[C:10]([C:3]2[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=2[F:1])[C:15]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:14][C:13]=1[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)c1cc(OCC(C)C)c(-c2cc(OC)ccc2F)[n+]([O-])c1
Reactant: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cc(OCC(C)C)c(-c2cc(OC)ccc2F)nc1Cl

Procedure:
A mixture of 2-(2-fluoro-5-methoxyphenyl)-3-isobutoxy-5-(methoxycarbonyl)pyridine 1-oxide (600 mg) and phosphoryl chloride (5.0 mL) was heated under reflux for 1 hr. 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 (315 mg) as a pale-yellow oil.