Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].Br[C:14]1[S:18][C:17]([S:19]([N:22]2[CH:26]=[CH:25][CH:24]=[CH:23]2)(=[O:21])=[O:20])=[CH:16][CH:15]=1>>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:14]2[S:18][C:17]([S:19]([N:22]3[CH:26]=[CH:25][CH:24]=[CH:23]3)(=[O:20])=[O:21])=[CH:16][CH:15]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: O=S(=O)(c1ccc(Br)s1)n1cccc1
Reactant: CC(C)c1ccc(B(O)O)cc1
Product: CC(C)c1ccc(-c2ccc(S(=O)(=O)n3cccc3)s2)cc1
Yield: 84 %

Procedure:
N-[5-(4-isopropylphenyl)thiophene-2-sulfonyl]pyrrole was prepared in the same manner as described in Example 33C, from 4-isopropylphenyl boronic acid and N-(5-bromothiophene sulfonyl)-pyrrole. Purification by column chromatography using 10% ethyl acetate/hexanes gave the pure sulfonamide as an off white colored solid in 84% yield, m.p. 112-114° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[N:22]([C:23]=2[C:24]([OH:26])=O)[CH:21]=[CH:20][S:19]3)[CH2:3][CH2:2]1.[F:27][C:28]([F:38])([F:37])[O:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl.CN(C=O)C>[CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[N:22]([C:23]=2[C:24]([NH:34][C:33]2[CH:35]=[CH:36][C:30]([O:29][C:28]([F:27])([F:37])[F:38])=[CH:31][CH:32]=2)=[O:26])[CH:21]=[CH:20][S:19]3)[CH2:3][CH2:2]1
Reactant: COc1cccc(/C=C/c2nc3sccn3c2C(=O)O)c1OCC1CC1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cccc(/C=C/c2nc3sccn3c2C(=O)Nc2ccc(OC(F)(F)F)cc2)c1OCC1CC1

Procedure:
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 1 (95 mg, 0.256 mmol) with 4-(trifluoromethoxy)aniline (54 mg, 0.307 mmol) in the presence of EDCI hydrochloride (98 mg, 0.512 mmol) and DMAP (47 mg, 0.384 mmol) in a mixture of DCM and DMF (4:1, 5 mL) to give 68 mg of the product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.23-0.26 (m, 2H), 0.43-0.47 (m, 2H), 1.13-1.15 (m, 1H), 3.73 (d, J=6.6 Hz, 2H), 3.78 (s, 3H), 6.92-6.96 (m, 1H), 7.04 (t, J=7.8 Hz, 1H), 7.22-7.25 (m, 1H), 7.35-7.38 (m, 3H), 7.44 (d, J=16.2 Hz, 1H), 7.77-7.81 (m, 2H), 7.86 (d, J=16.2 Hz, 1H), 8.01 (d, J=4.2 Hz, 1H), 10.47 (s, 1H); ESI-MS (m/z) 530.37 (MH)+.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:15]([C:17]2([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[CH2:20][CH2:19][CH2:18]2)=[O:16])[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C:17]2([C:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([OH:8])[CH:10]=3)=[O:16])[CH2:20][CH2:19][CH2:18]2)=[CH:22][CH:23]=1
Reactant: O=C(c1cccc(OCc2ccccc2)c1)C1(c2ccc(Cl)cc2)CCC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(c1cccc(O)c1)C1(c2ccc(Cl)cc2)CCC1
Reaction time: 4 h

Procedure:
(3-Benzyloxy-phenyl)-[1-(4-chloro-phenyl)-cyclobutyl]-methanone (780 mg, 2 mmol) was dissolved in ethyl acetate, containing Pd/C (80 mg, 10% on C). Hydrogenation was performed at room temperature during 4 hours. Reaction was filtered through celite and the solvent evaporated. The product (548 mg) was used in the next step without further purification.
Reaction SMILES: C(=O)([O-])OCC[C:5](=[O:18])[C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[C:8]([O:16][CH3:17])[CH:7]=1.[S].N1C2C(=CC=CC=2)C=CC=1.[H][H]>[Pd]>[CH3:17][O:16][C:8]1[CH:7]=[C:6]([CH:11]=[C:10]([O:12][CH3:13])[C:9]=1[O:14][CH3:15])[CH:5]=[O:18]
Reactant: [H][H]
Reactant: COc1cc(C(=O)CCOC(=O)[O-])cc(OC)c1OC
Agent: [Pd]
Agent: [S]
Solvent: c1ccc2ncccc2c1
Product: COc1cc(C=O)cc(OC)c1OC
Reaction time: 12 h
Yield: 0.9 %

Procedure:
To a solution of 28.4 g (10.1 moles) of 3,4,5-trimethoxy-benzoylethyl carbonate in ml 300, prepared as described in step (a), 14.2 g of Pd supported on BaSO4 (10%) and 0.1 ml of a solution of sulfur and quinoline prepared following Rosemund and Zetzsche and diluted 1:3000 are added. The mixture is hydrogenated in a PARR apparatus in an hydrogen atmosphere at ordinary pressure and 25° C. under efficient shaking during 12 hours. The catalyst is removed by filtration and recovered, whereas the organic solution is washed with a 5% NaOH solution and finally evaporated in a vacuum. 17.64 g of 3,4,5-trimethoxybenzaldehyde are obtained, with the same characteristics generally described in the literature.
Reaction SMILES: IC.[CH3:3]N(C)C=O.C(=O)([O-])[O-].[K+].[K+].[CH:14]([O:17][NH:18][C:19](=[O:31])[C:20](=[N:26][O:27][CH:28]([CH3:30])[CH3:29])[N:21]1[CH:25]=[N:24][CH:23]=[N:22]1)([CH3:16])[CH3:15]>O>[CH:28]([O:27][N:26]=[C:20]([N:21]1[CH:25]=[N:24][CH:23]=[N:22]1)[C:19](=[N:18][O:17][CH:14]([CH3:16])[CH3:15])[O:31][CH3:3])([CH3:30])[CH3:29]
Reactant: CN(C)C=O
Reactant: CC(C)ON=C(C(=O)NOC(C)C)n1cncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: COC(=NOC(C)C)C(=NOC(C)C)n1cncn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 29 %

Procedure:
0.22 g (1.55 mmol) of iodomethane was added, with ice-cooling, to 5 ml of an N,N-dimethylformamide solution containing 0.22 g (1.59 mmol) of potassium carbonate and 0.4 g (1.57 mmol) of the N-isopropoxy-2-isopropoxyimino-2-(1H-1,2,4-triazol-1-yl)acetamide produced in Example 8, followed by stirring at room temperature for 20 hours. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The extract solution was washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elutant:ethyl acetate/hexane=1/2) to obtain 0.12 g (yield: 29%) of a title compound.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].CCCCCC.C([C@H]1C[O:17][C:16]([CH3:20])([CH3:19])[N:15]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH3:19][C:16]1([CH3:20])[N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@@H:2]([CH:3]=[CH2:4])[CH2:1][O:17]1
Reactant: CC(C)(C)OC(=O)N1[C@@H](C=O)COC1(C)C
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
To a suspension of methyl triphenylphosphonium bromide (5.63 g, 15.8 mmol) in tetrahydrofuran (140 mL) was added 2.5 M n-butyllithium in hexane (7.35 mL, 18.4 mmol). The deep red solution was stirred at 0° C. for 1 h. Then a solution of tert-butyl (4R)-4-formyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (from Aldrich, 3.01 g, 13.1 mmol) in tetrahydrofuran (7.3 mL) was added drop wise at 0° C. The red solution was warmed to room temperature and stirred for 12 h. Hexanes was added to the reaction mixture in 4:1 (v/v) ratio. The suspension was filtered through Celite and the filtrate concentrated. The resultant residue was purified by flash chromatography (eluting with 10% ethyl acetate in hexanes) to give the desired compound as colorless oil (1.92 g, 64%).
Reaction SMILES: [CH:1]([N:14]1C(C2C=CC(OC)=CC=2)[O:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.NO>CO>[CH:1]([NH:14][OH:15])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C2ON2C(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: NO
Solvent: CO
Product: ONC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 20.3 %

Procedure:
To a solution of 2-benzhydryl-3-(4-methoxyphenyl)-1,2-oxaziridine 40 (3.52 g, 11.1 mmol) in methanol (100 mL) was added hydroxylamine-HCl (2.31 g, 33.3 mmol) and stirred at room temperature. for 16 h. The reaction mixture was concentrated under vacuum and diluted with aqueous NaOH solution (to pH=13), followed by extraction with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The crude material was concentrated and purified by silica gel column chromatography with gradient of ethyl acetate (10-50%) in hexane to afford compound 41 as a light yellow solid (450 mg, 20%). LRMS (ESI): (calc.) 199.3 (found) 167.2 (M-NHOH)+.
Reaction SMILES: [CH3:1][CH:2]1[N:9]2[CH:10]=[N:11][C:12]3[CH:13]([CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])[C:14](=[O:16])[CH:15]=[C:7]([C:8]=32)[NH:6][CH2:5][CH2:4][C:3]1=[O:25].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][CH:2]1[N:9]2[CH:10]=[N:11][C:12]3[CH:13]([CH2:17][C:18]([OH:20])=[O:19])[C:14](=[O:16])[CH:15]=[C:7]([C:8]=32)[NH:6][CH2:5][CH2:4][C:3]1=[O:25]
Reactant: CC1C(=O)CCNC2=CC(=O)C(CC(=O)OC(C)(C)C)c3ncn1c32
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1C(=O)CCNC2=CC(=O)C(CC(=O)O)c3ncn1c32
Reaction time: 2 h

Procedure:
To a solution of tert-butyl (8-methyl-2,7-dioxo-5,6,7,8-tetrahydro-4H-imidazo[1,5,4-fg][1,6]benzodiazocin-1(2H)-yl)acetate from Step A (45 mg, 0.13 mmol) in CH2Cl2 (6 mL) was added TFA (2 mL). After 2 h, the mixture was concentrated under reduced pressure to give the title compound. MS: m/z=290 (M+1).
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)=[CH2:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH3:15][Si:16]([CH3:43])([CH3:42])[CH2:17][CH2:18][S:19]([N:22]1[CH2:27][CH2:26][CH2:25][CH:24]([CH:28]([O:36][CH2:37][CH2:38][CH2:39][O:40][CH3:41])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2Br)[CH2:23]1)(=[O:21])=[O:20]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[CH3:15][Si:16]([CH3:43])([CH3:42])[CH2:17][CH2:18][S:19]([N:22]1[CH2:27][CH2:26][CH2:25][CH:24]([CH:28]([O:36][CH2:37][CH2:38][CH2:39][O:40][CH3:41])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH2:2][CH2:1][CH:3]2[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)[CH2:23]1)(=[O:21])=[O:20]
Reactant: C=CC1CCCCC1
Reactant: COCCCOC(c1ccccc1Br)C1CCCN(S(=O)(=O)CC[Si](C)(C)C)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COCCCOC(c1ccccc1CCC1CCCCC1)C1CCCN(S(=O)(=O)CC[Si](C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
A sealed tube designed for a microwave reactor was filled with nitrogen and charged with vinylcyclohexane (66 mg, 0.595 mmol, 5.0 equiv) 9-BBN (0.5 M solution in THF, 1.07 mL, 4.5 equiv) and the clear solution was stirred overnight at rt. The flask was briefly opened and Cs2CO3 (213 mg, 0.119 mmol, 3.3 equiv), PdCl2(dppf) (11 mg, 0.119 mmol, 0.05 equiv), 1-(2-(trimethylsilyl)ethanesulfonyl)-3-((3-methoxypropoxy)(2-bromophenyl)methyl)-piperidine (100 mg, 0.197 mmol, 1.0 equiv), and dioxane (4 mL) added. The tube was degassed by three evacuate/N2 backfill cycles, then placed in a CEM microwave reactor and heated to 120° C. for 10 min. The solvent was removed and the product was extracted with EtOAc and filtered through a pad of Celite. The product was purified by flash chromatography on 12 g of silica, eluting with 0 to 27% EtOAc in hexanes, to afford 1-(2-(trimethylsilyl)ethanesulfonyl)-3-((3-methoxypropoxy)(2-(2-cyclohexylethyl)phenyl)methyl)piperidine (82%) as a mixture of diastereomers. 1H NMR (CDCl3) δ 0.02 (s, 9H), 0.8-1.9 (m, 24H), 2.5-2.8 (m, 4H), 3.3-4.4 (m, 11H), 7.1-7.3 (m, 4H). MS ESI +ve m/z 561 (M+Na+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:18]3[CH:19]=[CH:20][C:21]([F:24])=[C:22]([OH:23])[C:17]=3[O:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25]C(C)([O-])C.[K+].IC>CN1CCCC1=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[C:18]3[CH:19]=[CH:20][C:21]([F:24])=[C:22]([O:23][CH3:25])[C:17]=3[O:16][N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2noc3c(O)c(F)ccc23)CC1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: CN1CCCC1=O
Product: COc1c(F)ccc2c(C3CCN(C(=O)OC(C)(C)C)CC3)noc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 90.1 %

Procedure:
To a stirred solution of 4-(6-fluoro-7-hydroxy-benzo[d]isoxazol-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (1.28 g, 3.80 mmol) in N-methyl-2-pyrrolidone (33 mL) was added potassium tert-butoxide (2.09 g, 17.12 mmoles). To the resulting deep red solution was added iodomethane (1.20 mL, 19.02 mmoles). The resulting yellow solution was stirred at room temperature for 6 hours when the reaction was quenched with water (55 mL) and acidified with HClaq. The resulting mixture was extracted with Et2O (4×110 mL). The combined extracts were washed with brine (110 mL), dried (MgSO4), filtered and evaporated. The residue was separated via column chromatography (1:1; Et2O/Pet. ether) yielding 1.2 g of the methyl ether. The white, solid product was further purified via recrystallization from 1:1; Et2O/Pet. ether yielding 963 mg (72%) as a white, crystalline solid, mp 94-96° C. Analysis calculated for C18H23N2FO4: 61.70% C, 6.62% H, 7.99% N. Found: 61.75% C, 6.73% H, 7.94% N.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:3]=1[CH2:4][O:5][CH3:6].O.[S-2].[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(O)C.O>[CH3:6][O:5][CH2:4][C:3]1[CH:7]=[C:8]([CH:9]=[CH:10][C:2]=1[CH3:1])[NH2:11]
Reactant: COCc1cc([N+](=O)[O-])ccc1C
Agent: O=C([O-])O
Agent: [Na+]
Agent: [S-2]
Solvent: O
Solvent: CCO
Product: COCc1cc(N)ccc1C
Yield: 96.9 %

Procedure:
Methyl 2-methyl-5-nitrobenzyl ether (11.5 g) is dissolved in absolute ethanol (125 ml). A solution of sodium sulfide monohydrate (48.3 g) and sodium bicarbonate (16.7 g) in water (75 ml) is added to the alcoholic solution. The resulting mixture is refluxed until thin layer chromatography indicates that the starting material is exhausted. The reaction mixture is then concentrated under vacuum to an oily solid. Methylene chloride is added and the mixture filtered. The methylene chloride layer is separated, dried, and is concentrated under vacuum to yield 9.3 g of a mobile orange liquid.
Reaction SMILES: C[C:2]1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([F:21])[CH:15]=2)[O:11][CH3:12])=[O:9])[C:4](=[O:22])[O:3]1>CO>[CH3:2][O:3][C:4](=[O:22])[C:5]([OH:6])=[CH:7][C:8](=[O:9])[N:10]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([F:21])[CH:15]=1)[O:11][CH3:12]
Reactant: CON(Cc1ccc(C)c(F)c1)C(=O)C=C1OC(C)(C)OC1=O
Solvent: CO
Product: COC(=O)C(O)=CC(=O)N(Cc1ccc(C)c(F)c1)OC
Yield: 49 %

Procedure:
2-(2,2-Dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-(3-fluoro-4-methylbenzyl)-N-methoxy-acetamide, prepared using the methods described in the previous examples, was treated with methanol as described in the preparation of Compound 44-C and gave the title ester as white crystals (49% yield); mp 88° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 2.25 (3H, d, J=1.5 Hz, CH3), 3.70 (3H, s, OCH3), 3.90 (3H, s, OCH3), 4.78 (2H, s, NCH2), 6.47 (1H, s, CH), 6.96 (2H, m, aromatics), 7.26 (1H, m, aromatic). HRMS (MAB N2) calculated for C14H16FNO5, [M]+: 297.101251. found: 297.101261.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][P:13](=[O:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16].[CH2:21]([Li])CCC.CI.[Cl-].[Na+]>CCCCCC.C(OCC)(=O)C.O1CCCC1>[CH3:21][CH:12]([P:13](=[O:20])([O:14][CH2:15][CH3:16])[O:17][CH2:18][CH3:19])[CH2:11][CH2:10][CH2:9][CH2:8][O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1
Reactant: [Li]CCCC
Reactant: CCOP(=O)(CCCCCOC1CCCCO1)OCC
Agent: [Cl-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(C)CCCCOC1CCCCO1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
30 g (0.097 mol) of diethyl 5-(tetrahydropyran-2-yloxy)pentylphosphonate were initially introduced into 200 ml of absolute tetrahydrofuran under an argon atmosphere, cooled to -70° C. and treated with 42.8 ml (0.107 mol) of a 2.5 molar solution of butyllithium in hexane. After addition, the solution was stirred for a further 30 minutes and 15.6 g (0.11 mol) of methyl iodide were then slowly added dropwise. The mixture was stirred at -70° C. for a further 2 hours and at room temperature for 4 hours, cautiously treated with a saturated sodium chloride solution and taken up in ethyl acetate. The organic phase was washed with water and a saturated sodium chloride solution, dried over sodium sulfate and distilled in a bulb tube.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[F:32][C:33]([F:42])([F:41])[CH2:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:38]5[CH2:37][CH2:36][N:35]([CH2:34][C:33]([F:41])([F:42])[F:32])[CH2:40][CH2:39]5)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:29])[F:30])[CH:3]=1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: FC(F)(F)CN1CCNCC1
Product: O=C1N=C(N2CCN(CC(F)(F)F)CC2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2,2,2-trifluoro-ethyl)-piperazin-1-yl]-thiazol-4-one was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 1-(2,2,2-trifluoro-ethyl)piperazine following General Procedure C.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10]C)=[O:9])=[C:6]([S:14][CH3:15])[C:5]=1[C:16]([CH3:18])=[CH2:17].C(O)C>O>[Cl:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([OH:10])=[O:9])=[C:6]([S:14][CH3:15])[C:5]=1[C:16]([CH3:18])=[CH2:17]
Reactant: C=C(C)c1c(Cl)ccc(C(=O)OC)c1SC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=C(C)c1c(Cl)ccc(C(=O)O)c1SC
Yield: 89.1 %

Procedure:
A solution of sodium hydroxide (7.0 g) in water was added to methyl 4-chloro-3-isopropenyl-2-(methylsulphenyl)benzoate (7.3 g) and the resulting mixture was heated at reflux for 2 hours. Ethanol was added and the mixture was heated at reflux for 1 hour. The ethanol was removed by evaporation and the aqueous residue was acidified to pH 1. It was extracted with ethyl acetate, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness to give 4-chloro-3-isopropenyl-2-(methylsulphenyl)benzoic acid (6.15 g) NMR (CDCl3) 2.05 (s,3H), 2.4 (s,3H), 4.85 (s,1H), 5.35 (s,1H), 7.45 (d,1H), 7.85 (d,1H).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([OH:14])=O)[CH:10]=2)[N:5]=[CH:4][CH:3]=1.CN([C:18]([O:22][N:23]1N=NC2C=CC=N[C:24]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(Cl)Cl.O>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([N:23]([O:22][CH3:18])[CH3:24])=[O:14])[CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc2nccc(Br)c2c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CON(C)C(=O)c1ccc2nccc(Br)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-bromoquinoline-6-carboxylic acid (5 g), CH3ONH(CH3) hydrochloride salt (1.8 eq. 3.5 g), and HATU (1.15 eq. 8.67 g) in CH2Cl2 (100 mL) was slowly added triethylamine (4 eq. 11 mL) at 0° C. and the resulting reaction mixture was stirred at room temperature overnight. The reaction was diluted with CH2Cl2 and water. The combined organics were washed with water several times, concentrated and then purified by chromatography (60-70% EtOAc/hexanes) to yield 4-bromo-N-methoxy-N-methylquinoline-6-carboxamide as a white solid.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH3:13].C([Mg]Cl)(C)C.[Li+].[Cl-].[CH2:21]([Sn:25](Cl)([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH3:24]>C1COCC1>[CH2:30]([Sn:25]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:26][CH2:27][CH2:28][CH3:29])[C:2]1[S:6][C:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH3:13])[CH2:31][CH2:32][CH3:33]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cc1nc(-c2cccnc2)sc1Br
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1sc(-c2cccnc2)nc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.3 %

Procedure:
In a dry flask under argon, 5-bromo-4-methyl-2-(3-pyridyl)thiazole (15.00 g, 55.85 mmol) was dissolved in THF (140 mL), and with cooling to keep the temperature at 25°-30° C., treated dropwise with i-PrMgCl.LiCl (TurboGrignard, 60 mL, 78.19 mmol,). The resulting mixture was allowed to stir at ambient temperature for 1 hour. The reaction mixture was then cooled to 10° C., and tri-n-butyl tin chloride (19 mL, 67.02 mmol) was added over 5 min. The reaction was stirred for 30 min at ambient temperature and then at reflux (66° C.) for 18 hours. The reaction mixture was quenched with saturated NH4Cl solution and diluted with ethyl acetate. Then aqueous layer was extracted 3 times with ethyl acetate and the combined organic layers washed with brine, dried over MgSO4, filtrated and evaporated. Purification by Combi flash chromatography with a column of 24 g and a gradient cyclohexane: 0-100% ethyl acetate to give the title compound as a yellow solid (9.17 g, 26%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH2:4][C:5]1[CH:10]=[C:9]([Br:11])[C:8]([O:12][C:13]2[CH:18]=[C:17]([CH:19]([CH3:21])[CH3:20])[C:16]([O:22]C)=[CH:15][C:14]=2[C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:7]([Br:32])[CH:6]=1.B(Br)(Br)Br>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:33])[CH2:4][C:5]1[CH:10]=[C:9]([Br:11])[C:8]([O:12][C:13]2[CH:18]=[C:17]([CH:19]([CH3:21])[CH3:20])[C:16]([OH:22])=[CH:15][C:14]=2[C:24](=[O:31])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[C:7]([Br:32])[CH:6]=1
Reactant: COC(=O)Cc1cc(Br)c(Oc2cc(C(C)C)c(OC)cc2C(=O)c2ccccc2)c(Br)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)Cc1cc(Br)c(Oc2cc(C(C)C)c(O)cc2C(=O)c2ccccc2)c(Br)c1
Yield: 72.2 %

Procedure:
(4-(2-Benzoyl-5-isopropyl-4-methoxy-phenoxy)-3,5-dibromo-phenyl)-acetic acid methyl ester (100 mg, 0.17 mmol) in 5 ml CH2Cl2 was cooled to −20° C. BBr3 (0.52 ml, 3 eq) was added dropwise and the reaction was allowed to reach room temperature and then poured into ice. The two phases were separated and the water phase extracted with CH2Cl2. The combined organic phases were dried over MgSO4 and concentrated. Purification on silica gel gave 69mg (71%) (4-(2-Benzoyl-5-isopropyl-4-hydroxy-phenoxy)-3,5-dibromo-phenyl)-acetic acid methyl ester as a white solid. 1H NMR (CD3COCD3): d 8.46 (s, 1H), 7.95 (d, 2H), 7.64 (s, 2H), 7.54 (m, 3H), 7.01 (s, 1H), 6.29 (s, 1H), 3.73 (s, 2H), 3.65 (s, 3H), 3.27 (m, 1H), 1.09 (d, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[C:20]([O:28][CH2:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1[CH2:38][O:39][C:40](=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH2:33]Br)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>>[C:21]1([C:20]([O:28][CH2:29][C:30]2[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=2[CH2:38][O:39][C:40]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:47])[CH2:33][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:9]=3)[CH:7]=2)=[O:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)c1ccc(-c2cc(O)ccc2C)cc1
Reactant: O=C(OCc1ccc(CBr)cc1COC(=O)c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1ccc(-c2cc(OCc3ccc(COC(=O)c4ccccc4)c(COC(=O)c4ccccc4)c3)ccc2C)cc1

Procedure:
In a manner similar to that of Example 1(i), by reaction of 3.07 g (12 mmol) of ethyl 5′-hydroxy-2′-methylbiphenyl-4-carboxylate with 6.7 g (15 mmol) of 3,4-bis(benzoyloxymethyl)benzyl bromide and 2 mg (14 mmol) of potassium carbonate, the desired product is obtained in the form of a colourless oil (m=5.7 g; Y=77%).