Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:14][S:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].CCN(C(C)C)C(C)C>C(#N)C>[CH2:6]([O:5][C:3](=[O:4])[CH:2]([NH:19][C:18]1[CH:20]=[CH:21][CH:22]=[C:16]([S:15][CH3:14])[CH:17]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7]
Reactant: CCOC(=O)C(Br)c1ccccc1
Reactant: CSc1cccc(N)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(Nc1cccc(SC)c1)c1ccccc1
Temperature: 100 °C
Yield: 78.8 %

Procedure:
Ethyl 2-bromo-2-phenylacetate (0.22 mL, 1.23 mmol), 3-(methylthio)aniline (0.22 mL, 1.85 mmol), and DIPEA (0.32 mL, 1.85 mmol) are dissolved in acetonitrile (3 mL) and heated under microwave irradiation at 100° C. for 1 hour. Acetonitrile is evaporated and the crude residue is purified by flash chromatography (petroleum ether/EtOAc=85/15) to obtain intermediate I98 as a colorless oil (292 mg, 79% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]([S:20]([NH2:23])(=[O:22])=[O:21])[C:16]([OH:19])([CH3:18])[CH3:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:24]1([N:30]=[C:31]=S)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].BrN1C(=O)CCC1=O>CN1C(=O)CCC1.C1COCC1.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]2[C:16]([CH3:18])([CH3:17])[O:19][C:31]([NH:30][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[N:23][S:20]2(=[O:22])=[O:21])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(O)C(c1cccc(OCc2ccccc2)c1)S(N)(=O)=O
Reactant: S=C=NC1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: CC1(C)OC(NC2CCCCC2)=NS(=O)(=O)C1c1cccc(OCc2ccccc2)c1
Reaction time: 0.75 h

Procedure:
At room temperature, a solution of 1.00 g of 1-(3-benzyloxyphenyl)-2-hydroxy-2-methylpropane-1-sulfonamide and 0.45 ml of cyclohexyl isothiocyanate in 6.5 ml of NMP was admixed with 1.49 ml of a 2 N solution of sodium bis(trimethylsilyl)amide in THF. After stirring for 45 minutes, the conversion was checked by means of LCMS. Since the reaction was still incomplete, an additional 0.22 ml cyclohexyl isothiocyanate and 0.74 ml of a 2 N solution of sodium bis(trimethylsilyl)amide in THF were added. After stirring for 20 minutes, 0.53 g of N-bromosuccinimide was added and the mixture was stirred at room temperature for a further hour. The reaction solution was admixed with 150 ml of water and extracted twice with 100 ml of ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over MgSO4 and concentrated by rotary evaporation. The residue was purified in a purification laboratory by means of preparative HPLC, and the product-containing fractions were freed of the organic solvent under reduced pressure. The aqueous residue was lyophilized. This gave the product (587 mg) with a molecular weight of 442.6 g/mol (C24H30N2O4S); MS (ESI): m/e=443 (M+H+).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[H-].[Na+].Br[CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27].[Cl-].[NH4+]>O1CCCC1>[C:26]([O:25][C:24]([NH:23][CH2:22][CH2:21][CH2:20][CH:9]([P:4]([O:3][CH2:1][CH3:2])([O:6][CH2:7][CH3:8])=[O:5])[C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])=[O:30])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(CCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.9 %

Procedure:
tert-Butyl diethylphosphonoacetate (20.0 g) was dissolved in tetrahydrofuran (500 mL). To the solution, sodium hydride (63%, 3.32 g) was added at 0° C., and the mixture was stirred at 0° C. for 15 minutes and at room temperature for 1 hour. A solution of tert-butyl (3-bromopropyl)carbamate (20.0 g) in tetrahydrofuran (20 mL) was slowly added thereto at room temperature, and the mixture was stirred at room temperature for 18 hours. To the reaction solution, saturated aqueous ammonium chloride was added, and organic matter was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, then dried over anhydrous sodium sulfate, and filtered, and the solvent was distilled off under reduced pressure to obtain a crude product. This crude product was purified by silica gel column chromatography (eluting solvent: hexane/ethyl acetate=1/1-ethyl acetate) to obtain the title compound (26.6 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[N:9]2)[N:5]=[C:4]([O:17][CH3:18])[CH:3]=1.[Cl:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1.COC1C=C(C2C=CC=CC=2)N=C(N2C=CC(C(F)(F)F)=N2)N=1>>[CH3:18][O:17][C:4]1[CH:3]=[C:2]([C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:19])[CH:25]=2)[N:7]=[C:6]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[N:9]2)[N:5]=1
Reactant: COc1cc(Cl)nc(-n2ccc(C(F)(F)F)n2)n1
Reactant: OB(O)c1cccc(Cl)c1
Agent: COc1cc(-c2ccccc2)nc(-n2ccc(C(F)(F)F)n2)n1
Product: COc1cc(-c2cccc(Cl)c2)nc(-n2ccc(C(F)(F)F)n2)n1
Yield: 45 %

Procedure:
4-Methoxy-6-(3-chloro-phenyl)-2-(3-trifluoromethyl-pyrazol-1-yl)-pyrimidine 307f was synthesized from compound 305 (1 g, 3.59 mmol) and (3-chloro-phenyl)-boronic acid 306f (842 mg, 5.39 mmol), according to the procedure as described for compound 307b as a beige solid in 45% yield. MS (ESI, EI+): m/z=355 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:11][CH3:12].C([O-])([O-])=O.[K+].[K+].Br[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:7])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: BrCc1ccccc1
Reactant: COc1cc(C(=O)O)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C(=O)OCc2ccccc2)ccc1Br
Reaction time: 0.17 h
Yield: 91 %

Procedure:
4-Bromo-3-methoxy-benzoic acid (1.50 g, 6.49 mmol), K2CO3 (2.69 g, 19.5 mmol), and DMF (10 mL) were combined and the mixture was allowed to stir for 10 minutes. Bromomethylbenzene (849 gL, 7.14 mmol) was added dropwise and the mixture was allowed to stir at room temperature for 1 h. The reaction mixture was quenched with brine and was extracted with EtOAc (3×). The organic layers were dried over sodium sulfate, filter and concentrated. The residue was purified using silica gel chromatography (5%-70% EtOAc in hexanes) to provide benzyl 4-bromo-3-methoxybenzoate (91%). ESI-MS m/z calc 320.0, found 321.0/323.0 (M+I)+. Retention time: 3.24 minutes (4 min run).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[N:8]=[C:9]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])[O:10][C:6]=2[CH:5]=[C:4]([CH2:19][C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([C@H:29]([CH3:36])[CH2:30][C:31]([O:33]CC)=[O:32])=[CH:25][CH:24]=2)=[O:21])[CH:3]=1.[OH-].[Na+]>CO.O>[CH3:1][C:2]1[C:7]2[N:8]=[C:9]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])[O:10][C:6]=2[CH:5]=[C:4]([CH2:19][C:20]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([CH:29]([CH3:36])[CH2:30][C:31]([OH:33])=[O:32])=[CH:27][CH:28]=2)=[O:21])[CH:3]=1
Reactant: CCOC(=O)C[C@@H](C)c1ccc(NC(=O)Cc2cc(C)c3nc(Nc4ccccc4C)oc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccccc1Nc1nc2c(C)cc(CC(=O)Nc3ccc(C(C)CC(=O)O)cc3)cc2o1
Temperature: 50 °C
Reaction time: 2 h
Yield: 53.1 %

Procedure:
A solution of ethyl (R) 3-{4-[2-(4-methyl-2-o-tolylaminobenzoxazol-6-yl)acetylamino]phenyl}butanoate [0.14 g, Reference Example 15(a)] in methanol (2 mL) was treated with aqueous sodium hydroxide solution (1.2 mL, 1M) and then stirred at 50° C. for 2 hours. The mixture was diluted with water and partially evaporated. The residue was washed with diethyl ether and then acidified to pH 4. The precipitated solid was filtered and sucked dry to give the title compound (0.07 g) as a tan solid. LC-MS: RT=3.38 minutes (100% by ELSD); MS (ES+), 458 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][OH:12])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:16][C:17]1[N:18]=[C:19](/[CH:22]=[CH:23]/[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[F:31])[O:20][CH:21]=1.Cl>CN(C=O)C.O>[F:31][C:25]1[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:24]=1/[CH:23]=[CH:22]/[C:19]1[O:20][CH:21]=[C:17]([CH2:16][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][OH:12])=[CH:6][CH:7]=2)[N:18]=1
Reactant: Fc1ccc(/C=C/c2nc(CCl)co2)c(F)c1
Reactant: OCCCCc1ccc(O)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: OCCCCc1ccc(OCc2coc(/C=C/c3ccc(F)cc3F)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.4 %

Procedure:
To a solution of 4-(4-hydroxyphenyl)-1-butanol (1.99 g) in DMF (20 ml), 60% oily sodium hydride (528 mg) was added under ice cooling, followed by stirring at room temperature for 30 minutes. Under ice cooling, (E)-4-chloromethyl-2-[2-(2,4-difluorophenyl)ethenyl]oxazole (3.37 g) was added, followed by stirring overnight at room temperature. After water and 1 N hydrochloric acid was added, the reaction mixture was extracted with ethyl acetate. After the extract was dried over magnesium sulfate, it was concentrated under reduced pressure; the residue was recrystallized from ethyl acetate-diethyl ether-hexane to yield the titled compound (3.71 g) as colorless crystals.
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]2[C:6](=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:10][CH:11]=2)[N:7]=1.[CH2:16]([NH:18][CH2:19][CH3:20])[CH3:17]>C1COCC1>[CH2:16]([N:18]([CH2:2][C:3]1[O:4][C:5]2[C:6](=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:10][CH:11]=2)[N:7]=1)[CH2:19][CH3:20])[CH3:17]
Reactant: COC(=O)c1cccc2oc(CCl)nc12
Reactant: CCNCC
Solvent: C1CCOC1
Product: CCN(CC)Cc1nc2c(C(=O)OC)cccc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.6 %

Procedure:
A mixture of methyl 2-(chloromethyl)benzoxazole-4-carboxylate (267 mg, 1.18 mmol) and diethylamine (2.0 mL, 27.4 mmol) in THF (15 mL) was stirred at ambient temperature overnight. The solvent was removed under reduced pressure and the residue was purified by column chromatography (silica gel, 10:1:0.1 dichloromethane/methanol/concentrated ammonium hydroxide), followed by purification by preparative TLC (silica gel, 10:1:0.1 dichloromethane/methanol/concentrated ammonium hydroxide) to afford methyl 2-(diethylaminomethyl)benzoxazole-4-carboxylate (200 mg, 64%) as a yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.99 (dd, J=9.0, 1.0 Hz, 1H), 7.74 (dd, J=9.0, 1.0 (1H), 6.40 (t, J=8.1 Hz, 1H), 4.09 (s, 2H), 4.04 (s, 3H), 2.74-2.69 (m, 4H), 1.13 (t, J=6.6 Hz, 1H); MS (ESI+) m/z 263 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH3:14])=[CH:9][C:8]=1[CH2:15][CH2:16][CH2:17][O:18][CH3:19])[CH3:2].[H-].[Na+].[Na+].[I-].Cl[CH2:26][C:27]1[C:28]([CH3:43])=[N:29][C:30]([C:33]2[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=2)=[CH:31][CH:32]=1>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH3:14])[CH2:26][C:27]2[C:28]([CH3:43])=[N:29][C:30]([C:33]3[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=3)=[CH:31][CH:32]=2)=[CH:9][C:8]=1[CH2:15][CH2:16][CH2:17][O:18][CH3:19])[CH3:2]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CCl
Reactant: CCOC(=O)COc1ccc(NC)cc1CCCOC
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(N(C)Cc2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1CCCOC
Reaction time: 0.5 h

Procedure:
To 0.102 g (0.36 mmol) of the above prepared [2-(3-methoxy-propyl)-4-methylamino-phenoxy]-acetic acid ethyl ester, dissolved in 1.4 ml of abs. DMF, were added successively at 0° C. 0.017 g of NaH (60% in mineral oil, 1.2 eq.), 0.054 g (1 eq.) of NaI and 0.100 g (1 eq.) of 3-chloromethyl-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine (see below 1K]). The reaction was allowed to proceed for 5 Min. at 0° C. and for 0.5 h at ambient temperature. Pouring onto crashed ice/KHSO4, twofold extraction with AcOEt, washing with water and brine, drying over magnesium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=75/25), yielded 0.126 g of the title compound as light yellow oil.
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[Cl-].[Al+3].[Cl-].[Cl-].[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:16]=1[C:17](Cl)=[O:18].CO>ClCCl>[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:16]=1[C:17]([C:3]1[C:4]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[NH:1][CH:2]=1)=[O:18]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: c1cc2cc[nH]c2cn1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CO
Product: O=C(c1c(Cl)cccc1Cl)c1c[nH]c2cnccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.9 %

Procedure:
1H-Pyrrolo[2,3-c]pyridine (0.5 g, 4.2 mmol) was added to a stirred suspension of aluminium chloride (2.82 g, 21.1 mmol) in dry dichloromethane (100 mL) and the mixture was stirred at room temperature for 1 hour. This was followed by drop-wise addition of 2,6-dichloro benzoyl chloride (4.42 g, 21.1 mmol). The resulting reaction mixture was stirred at room temperature for 8 hours. Methanol (25 mL) was added cautiously to quench the reaction mass followed by concentration under vacuum. The resulting residue was neutralized using aqueous sodium bicarbonate solution followed by partitioning with ethyl acetate (3×100 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. Purification by silica gel column chromatography using ethyl acetate and hexane gradient as eluent afforded (2,6-dichlorophenyl)(1H-pyrrolo[2,3-c]pyridin-3-yl)methanone (0.5 g, 41.66%).
Reaction SMILES: S(Cl)(Cl)(=O)=O.[Br:6][C:7]1[CH:8]=[C:9]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:10]=[C:11]([Br:14])[C:12]=1[SH:13].S(Cl)Cl.[CH:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH3:33])([CH3:25])[CH3:24].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl.CO>[Br:6][C:7]1[CH:8]=[C:9]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:10]=[C:11]([Br:14])[C:12]=1[S:13][C:30]1[CH:29]=[CH:28][C:27]([O:32][CH3:33])=[C:26]([CH:23]([CH3:25])[CH3:24])[CH:31]=1
Reactant: COc1ccccc1C(C)C
Reactant: COC(=O)Cc1cc(Br)c(S)c(Br)c1
Agent: ClSCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O=S(=O)(Cl)Cl
Solvent: CO
Product: COC(=O)Cc1cc(Br)c(Sc2ccc(OC)c(C(C)C)c2)c(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.8 %

Procedure:
Sulfuryl chloride (0.9 mL, 0.011 mol) in 5 mL of dichloromethane was added dropwise to a solution of methyl 3,5-dibromo-4-mercaptophenylacetate (3.4 g, 0.11 mol), from Preparation E, in 50 mL dichloromethane. The pale yellow solution was allowed to stand for 1 hour and transferred to an addition funnel. The resulting sulfenyl chloride was then added dropwise to an ice-cooled suspension of 2-isopropylanisole (1.8 g, 0.022 mol) and aluminum chloride (2.8 g, 0.02 mol) in methanol. The reaction mixture was allowed to warm to room temperature and stirred for an additional 15 min. The reaction mixture was then poured on to ice water and extracted twice with dichloromethane. The combined extract was washed with water and brine, dried (Na2SO4), and evaporated on a rotary evaporator. The residue was purified by flash chromatography (silica gel, 5:1 acetone:hexane) to obtain methyl 3,5-dibromo-4-(3-isopropyl-4-methoxyphenylthio)-phenylacetate (3.5 g, 0.007 mol, 70% yield), MP: 73°-76° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9](O)=[O:10])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19].S(Cl)([Cl:22])=O>>[F:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]([Cl:22])=[O:10])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)Cc1ccc(-c2ccc(F)cc2F)c(F)c1
Product: O=C(Cl)Cc1ccc(-c2ccc(F)cc2F)c(F)c1

Procedure:
A mixture of 2,2',4'-trifluoro-4-biphenylylacetic acid (3.6 g.) and thionyl chloride (15 ml.) was refluxed for 1 hour; excess thionyl chloride was removed and the residual acid chloride distilled at 141°-143° C./1.0 mm as a yellow oil, solidifying on cooling, (3.11 g.). Recrystallisation from 62-68 petroleum ether gave colourless needles of 2,2',4'-trifluoro-4-biphenylylacetyl chloride, m.p. 70°-73° C. 1 g. of this was dissolved in ether (10 ml.) and the solution added slowly to a stirred mixture of ammonia (SG=0.880; 5 ml.) and ether (25 ml.) at room temperature. After stirring for 15 minutes, the product was isolated in ether, washed, dried and evaporated. Recrystallization of the residue from methylene chloride/40-60 petroleum ether followed by a further crystallization from 100-120 petroleum ether gave colourless plates of 2,2',4'-trifluoro-4-biphenylylacetamide, m.p. 137°-140° C.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([NH:11][S:12]([C:15]3[CH:20]=[CH:19][C:18]([NH:21]C(=O)C(F)(F)F)=[CH:17][C:16]=3[CH2:28][C:29]([O:31]C)=O)(=[O:14])=[O:13])[CH:9]=[CH:10][C:5]=2[CH2:4][O:3]1.[NH3:33].O>CO>[NH2:21][C:18]1[CH:19]=[CH:20][C:15]([S:12](=[O:14])(=[O:13])[NH:11][C:8]2[CH:9]=[CH:10][C:5]3[CH2:4][O:3][B:2]([OH:1])[C:6]=3[CH:7]=2)=[C:16]([CH2:28][C:29]([NH2:33])=[O:31])[CH:17]=1
Reactant: N
Reactant: COC(=O)Cc1cc(NC(=O)C(F)(F)F)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Solvent: CO
Solvent: O
Product: NC(=O)Cc1cc(N)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Temperature: 50 °C

Procedure:
A mixture of methyl 2-(2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5-(2,2,2-trifluoroacetamido)phenyl)acetate (0.5 g, 0.001 mol) and aq. NH3.H2O (28%, 10 mL) in CH3OH was stirred at 50° C. over night. The mixture was concentrated and the residue dissolved in ethyl acetate and washed with brine, dried and concentrated, purified by column chromatography (PE:EA 5:1˜1:3) to give the title compound, which was dissolved in MeCN, acidified with aq. HCl and freeze-dried to give the product as hydrochloride salt (200 mg, yield 53%). 1HNMR DMSO-d6 400 MH. δ9.85 (s, 1H), 9.17 (s, 1H), 7.43-6.32 (m, 6H), 5.92 (s, 2H), 4.86 (s, 2H), 3.74 (s, 2H). LC-MS m/z 360 (M−H, negative); HPLC purity: 96.93% (220 nm), 99.27% (254 nm).
Reaction SMILES: [CH2:1]([N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:36])[CH2:18][CH2:19][C:20]2[CH:35]=[CH:34][C:23]([O:24][C:25]3[CH:33]=[CH:32][C:28]([C:29]([OH:31])=O)=[CH:27][N:26]=3)=[CH:22][CH:21]=2)[CH2:13][CH2:12]1)[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.[Cl:37][C:38]1[CH:39]=[C:40]([CH:42]=[CH:43][C:44]=1[Cl:45])[NH2:41]>C1COCC1>[CH2:1]([N:11]1[CH2:12][CH2:13][N:14]([C:17](=[O:36])[CH2:18][CH2:19][C:20]2[CH:35]=[CH:34][C:23]([O:24][C:25]3[CH:33]=[CH:32][C:28]([C:29]([NH:41][C:40]4[CH:42]=[CH:43][C:44]([Cl:45])=[C:38]([Cl:37])[CH:39]=4)=[O:31])=[CH:27][N:26]=3)=[CH:22][CH:21]=2)[CH2:15][CH2:16]1)[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: O=C(O)c1ccc(Oc2ccc(CCC(=O)N3CCN(Cc4ccc5c(c4)OCO5)CC3)cc2)nc1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)c(Cl)c1)c1ccc(Oc2ccc(CCC(=O)N3CCN(Cc4ccc5c(c4)OCO5)CC3)cc2)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-{4-[3-(4-piperonylpiperazin-1-yl)-3-oxopropyl]phenoxy}nicotinic acid (1.23 g, 2.5 mmol) in THF (35 mL) was added N,N′-carbonyldiimidazole (540 mg, 3.3 mmol), and the resulting solution was stirred for 30 minutes at room temperature. The resulting reaction solution was concentrated under reduced pressure, and to the residue was added 3,4-dichloroaniline (4.07 g, 25 mmol). The resulting solution was stirred for 3 days at room temperature. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate), and the resulting product was recrystallized from diethyl ether, to thereby yield 510 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=[O:5].[Cl:12][S:13](O)(=[O:15])=[O:14]>>[Cl:12][S:13]([C:8]1[C:7]([Cl:11])=[C:3]([C:2]([Cl:1])=[CH:10][CH:9]=1)[C:4]([OH:6])=[O:5])(=[O:15])=[O:14]
Reactant: O=C(O)c1c(Cl)cccc1Cl
Reactant: O=S(=O)(O)Cl
Product: O=C(O)c1c(Cl)ccc(S(=O)(=O)Cl)c1Cl
Temperature: 10 °C
Yield: 59.3 %

Procedure:
Part A: Under an atmosphere of nitrogen gas, a reaction vessel was charged with 2,6-dichlorobenzoic acid (10 g, 53.55 mmol) (Formula F) and chlorosulfonic acid (3 ml, 472 mmol). The reaction mixture was refluxed for 1 hour and cooled to 10° C. The contents of the reaction vessel were poured slowly into 3 L of ice water. The white solid which precipitated was collected by filtration and dried in vacuo (10 mm) at 35° C. for 48 hours to give 3-(chlorosulfonyl)-2,6-dichlorobenzoic acid (Formula G) (9.2 g, 61% yield).
Reaction SMILES: O[C:2]1[C:7]([CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])=[C:6]([O:13][CH2:14][O:15][CH3:16])[CH:5]=[C:4](OCOC)[C:3]=1[C:21](=[O:23])C>C(O)C>[CH3:16][O:15][CH2:14][O:13][C:6]1[CH:5]=[CH:4][C:3]([CH:21]=[O:23])=[CH:2][C:7]=1[CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11]
Reactant: COCOc1cc(OCOC)c(C(C)=O)c(O)c1CC=C(C)C
Solvent: CCO
Product: COCOc1ccc(C=O)cc1CC=C(C)C

Procedure:
In 45 ml of ethanol were dissolved 6.99 g of the 2'-hydroxy-4',6'-bis(methoxymethoxy)-3'-(3-methyl- 2-butenyl)acetophenone obtained in Production Example 13 and 5.01 of the 4-methoxymethoxy-3-(3-methyl-2-butenyl)benzaldehyde, and the solution was cooled to 0° C. Then, 65 ml of a saturated solution of potassium hydroxide in ethanol was added to the solution and the mixture was stirred at room temperature overnight. The reaction liquid was neutralized with 6 N hydrochloric acid and extracted with ethyl acetate, and the ethyl acetate layer was washed with water, dried with anhydrous sodium sulfate and filtered. The solvent was removed from the filtrate by distillation and the residue was recrystallized from n-hexane to obtain 7.22 g (yield=61.7%) of 2'-hydroxy-4,4',6'-tris(methoxymethoxy)-3,3'-bis(3-methyl-2butenyl)chalcone.
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:6][CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:44]>>[Cl:44][CH2:2][CH2:3][C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)NCCOCCOc1ccc(CCO)cc1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)NCCOCCOc1ccc(CCCl)cc1

Procedure:
To tert-butyl 2-{2-[4-(2-hydroxyethyl)phenoxy]-ethoxy}ethylcarbamate (0.56 g, 1.7 mmol) dissolved in 10 ml carbon tetrachloride was added triphenylphosphine bound on styrene (861 mg, 2.6 mmol of about 3 mmol/g resin). The reaction mixture was heated to reflux for 2 hours. After the required time the reaction was cooled and filtered. After drying a quantitative yield of product was isolated. 1H NMR (CDCl3) δ 7.11 (d, 2H, Ar), 6.86 (d, 2H, Ar), 4.95 (bs, exchangeable, NH), 4.08 (dd, CH2—O), 3.79 (dd, CH2—O), 3.65 (t, CH2—Cl), 3.59 (t, CH2—O), 3.32 (bm, CH2—NH), 2.99 (t, CH2—Ar), 1.70 (bs, exchangeable, OH) 1.42 (s, 9H, CH3). Mass spectrum, m/e Calcd for C17H27ClNO4+: 344.16 (100%), 346.16 (32%). Found: 344.57, 346.55.