Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][C:3]=1Br.CCCCCC.C([Li])CCC.[B:32](OC(C)C)([O:37]C(C)C)[O:33]C(C)C.Cl>C1COCC1>[C:14]1([C:5]2[CH:4]=[C:3]([B:32]([OH:37])[OH:33])[C:2]([Br:1])=[CH:7][C:6]=2[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Brc1cc(-c2ccccc2)c(-c2ccccc2)cc1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OB(O)c1cc(-c2ccccc2)c(-c2ccccc2)cc1Br
Temperature: -100 °C
Reaction time: 0.5 h
Yield: 111.9 %

Procedure:
To a 100 ml Schlenk reaction vessel were added under a nitrogen atmosphere 755 mg (1.95 mmol) of 1,2-dibromo-4,5-diphenylbenzene synthesized in Synthetic Example 4 and 12 ml of THF. The solution was cooled to −100° C. and 1.3 ml (2.1 mmol) of a hexane solution of n-butyllithium (manufactured by Kanto Chemical Co., Ltd., 1.59M) was added dropwise. After 30 minutes of aging, 472 mg (2.51 mmol) of triisopropyl borate (manufactured by Tokyo Chemical Industry Co., Ltd.) was added dropwise. After the temperature was gradually raised to room temperature, 3N hydrochloric acid was added and phase separation was conducted. The organic phase was concentrated under reduced pressure to obtain 770 mg of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:16]([CH3:23])[N:15]=[C:14]3[S:24][C:25]([C:27]4[CH:28]=[N:29][NH:30][CH:31]=4)=[CH:26][C:13]=23)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[Br:32]Br>C(Cl)(Cl)Cl>[Br:32][C:26]1[C:13]2[C:14](=[N:15][C:16]([CH3:23])=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:12]=2[NH:11][S:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)(=[O:9])=[O:10])[S:24][C:25]=1[C:27]1[CH:28]=[N:29][NH:30][CH:31]=1
Reactant: CCOC(=O)c1c(C)nc2sc(-c3cn[nH]c3)cc2c1NS(=O)(=O)c1cccc(Cl)c1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1c(C)nc2sc(-c3cn[nH]c3)c(Br)c2c1NS(=O)(=O)c1cccc(Cl)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 90.7 %

Procedure:
To a stirred solution of ethyl 4-{[(3-chlorophenyl)sulfonyl]amino}-6-methyl-2-(1H-pyrazol-4-yl)thieno[2,3-b]pyridine-5-carboxylate (Description 73) (870 mg, 1.824 mmol) in CHCl3 (30 mL) at 60° C. was added bromine (0.10 mL, 2.01 mmol), prediluted in CHCl3 (5.25 mL), dropwise. The resulting mixture was stirred at 60° C. for ca. 4 h and was then cooled to RT. The resulting precipitate was filtered and the solid rinsed with DCM and dried, to give the title compound (920 mg). LCMS (A) m/z: 556/558 [M+1]+, Rt 1.25 min (acidic).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[Cl:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[C:28]([Cl:30])[CH:29]=1>>[Cl:23][C:24]1[CH:25]=[C:26]([C:2]2[CH:3]=[C:4]([C:9]3[N:13]4[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]4=[N:11][CH:10]=3)[CH:5]=[CH:6][C:7]=2[F:8])[CH:27]=[C:28]([Cl:30])[CH:29]=1
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4cc(Cl)cc(Cl)c4)c3)cnc2c1F
Yield: 2 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol and 3,5-dichlorobenzeneboronic acid were coupled in the same way as in Example 30 to give 2-[3-(3′,5′-dichloro-2-fluorobiphenyl-5-yl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]propan-2-ol as an off-white solid (3 mg, 2%): m/z (ES+) 434 [MH+].
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1F)([O-:3])=[O:2].[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH:24][C:25]2[O:29][N:28]=[C:27]([CH3:30])[C:26]=2[CH3:31])(=[O:23])=[O:22])=[CH:17][CH:16]=1.C(N(CC)CC)C>O1CCCC1>[N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH:24][C:25]2[O:29][N:28]=[C:27]([CH3:30])[C:26]=2[CH3:31])(=[O:23])=[O:22])=[CH:17][CH:16]=1)([O-:3])=[O:2]
Reactant: Cc1noc(NS(=O)(=O)c2ccc(N)cc2)c1C
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1noc(NS(=O)(=O)c2ccc(Nc3ccc([N+](=O)[O-])cc3[N+](=O)[O-])cc2)c1C
Temperature: 25 °C
Reaction time: 48 h
Yield: 84.6 %

Procedure:
2,4-Dinitrofluorobenzene (0.457 ml, 3.6 mmol) and 4-amino-N-(3,4-dimethyl-5-isoxazolyl)benzenesulfonamide (818 mg, 3.0 mmol) were dissolved in dry tetrahydrofuran (25 ml) and triethylamine (1.0 ml, 7.5 mmol) was added slowly. The reaction was stirred at room temperature for 48 h. The solvent and volatiles were removed under reduced pressure and the residue was partitioned between 1N HCl and ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated and the residue was recrystallized from methanol to give 1.1 g (85%) yellow solid, m.p. 187° C.
Reaction SMILES: [C:1]1([C:7]2[C:8](=O)[NH:9][C:10]([C:19]([F:22])([F:21])[F:20])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)(O)[O-].[Na+].P(Cl)(Cl)([Cl:31])=O>>[Cl:31][C:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:11]=[C:10]([C:19]([F:22])([F:21])[F:20])[N:9]=1
Reactant: O=c1[nH]c(C(F)(F)F)nc(-c2ccccc2)c1-c1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: FC(F)(F)c1nc(Cl)c(-c2ccccc2)c(-c2ccccc2)n1
Temperature: 25 °C
Yield: 76.6 %

Procedure:
5,6-Diphenyl-2-(trifluoromethyl)pyrimidin-4(3H)-one (8.0 g, 25 mmol) (synthesized according to the procedure described in our PCT application No. IB03/01289) was refluxed in phosphorus oxychloride (15 ml) for 5 hours and allowed to cool to room temperature. The reaction mixture was poured onto ice-water mixture and neutralised with saturated sodium bicarbonate solution. The solid thus separated was extracted with dichloromethane. The organic extract was washed with water, dried over anhydrous sodium sulphate and concentrated under reduced pressure to give crude product, which was purified by column chromatography to afford the title compound (6.5 g, 76.6%, HPLC purity 99.8%), mp: 105-107° C.
Reaction SMILES: [CH:1]1([O:7][N:8]2[C:13]([CH3:15])([CH3:14])[CH2:12][C:11](=O)[CH2:10][C:9]2([CH3:18])[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:19]([NH2:31])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>>[CH:1]1([O:7][N:8]2[C:13]([CH3:15])([CH3:14])[CH2:12][CH:11]([NH:31][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:10][C:9]2([CH3:18])[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCCCCCCCCCCN
Reactant: CC1(C)CC(=O)CC(C)(C)N1OC1CCCCC1
Product: CCCCCCCCCCCCNC1CC(C)(C)N(OC2CCCCC2)C(C)(C)C1
Yield: 82 %

Procedure:
The title compound is prepared in 82% yield as a colorless syrup from 1-cyclohexyloxy-2,2,6,6,-tetramethyl-piperidin-4-one and dodecylamine according to the procedure of Example 11B.
Reaction SMILES: [C:1]([NH2:5])(=[NH:4])[CH2:2][CH3:3].CO[CH:8]=[C:9]([CH2:12][NH:13][CH:14]=[O:15])[C:10]#[N:11]>C(O)C>[CH2:2]([C:1]1[N:5]=[C:10]([NH2:11])[C:9]([CH2:12][NH:13][CH:14]=[O:15])=[CH:8][N:4]=1)[CH3:3]
Reactant: COC=C(C#N)CNC=O
Reactant: CCC(=N)N
Solvent: CCO
Product: CCc1ncc(CNC=O)c(N)n1
Temperature: 25 °C
Yield: 100 %

Procedure:
In 50 parts by volume of ethanol is dissolved 14 parts of α-methoxymethylene-β-formylaminopropionitrile. To the solution is added 100 parts by volume of an ethanol solution containing 17 parts of propioamidine. The mixture is reacted at 30°C for 0.5 hour. After the reaction, ethanol is distilled off and the residue is cooled at 25°C, whereby 18 parts of 2-ethyl-4-amino-5-formylaminomethylpyrimidine is obtained as crystals. (Yield: 100 %). Recrystallization of the crystals from benzene-ethanol mixture gives colorless crystals melting at 185°C.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([C:14]2[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=2[C:16]([OH:18])=O)=[O:13])=[C:4]1[CH3:23])[CH3:2].[CH2:24]([N:26]([CH2:38][CH3:39])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]([CH2:36][CH3:37])[CH2:34][CH3:35])[CH:28]=1)[CH3:25].C(OC(=O)C)(=O)C>C(O)C>[CH2:34]([N:33]([CH2:36][CH3:37])[C:29]1[CH:28]=[C:27]([N:26]([CH2:24][CH3:25])[CH2:38][CH3:39])[CH:32]=[CH:31][C:30]=1[C:12]1([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:3]([CH2:1][CH3:2])[C:4]=2[CH3:23])[C:14]2[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:16](=[O:18])[O:13]1)[CH3:35]
Reactant: CCN(CC)c1cccc(N(CC)CC)c1
Reactant: CCn1c(C)c(C(=O)c2ccccc2C(=O)O)c2ccccc21
Solvent: CCO
Solvent: CC(=O)OC(C)=O
Product: CCN(CC)c1ccc(C2(c3c(C)n(CC)c4ccccc34)OC(=O)c3ccccc32)c(N(CC)CC)c1
Temperature: 25 °C
Yield: 57.9 %

Procedure:
A mixture of 12.28 g (0.04 mole) of 2-[(1-ethyl-2-methyl-3-indolyl)carbonyl]benzoic acid, prepared as described in part A above, 10.7 g (0.043 mole) of 90 percent active N,N,N',N'-tetraethyl-m-phenylenediamine and 6.0 ml of acetic anhydride was stirred at room temperature for seventeen hours. The reaction mixture was diluted with 26.0 ml of ethanol, stirred and filtered. The separated solid was washed with diethylether and dried to yield 11.8 g of 3-[2,4-bis(diethylamino)phenyl]-3-(1-ethyl-2-methyl-3-indoly)phthalide (Formula III: R°=R1 =R2 =R3 =Y1 =H; R=R6 =CH2CH3 ; R4 =N(CH2CH3)2 ; R5 =CH3), a white crystalline material which melted at 139°-140° C. The infrared spectrum showed a significant band at 1760 cm-1 (C=O; s) and the nuclear magnetic resonance spectrum was in accord with the structure. A solution of this product in benzene developed a deep blue-black color when spotted on silica gel.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([C:10]2[C:14]([Cl:15])=[C:13]([O:16][CH:17]([F:19])[F:18])[N:12]([CH3:20])[N:11]=2)[CH:6]=[CH:7][C:8]=1[Cl:9].[C:21]([O-:24])(=[O:23])[CH3:22].[Na+].O>CN(C)C=O>[C:21]([O:24][CH2:2][C:3]1[CH:4]=[C:5]([C:10]2[C:14]([Cl:15])=[C:13]([O:16][CH:17]([F:19])[F:18])[N:12]([CH3:20])[N:11]=2)[CH:6]=[CH:7][C:8]=1[Cl:9])(=[O:23])[CH3:22]
Reactant: CC(=O)[O-]
Reactant: Cn1nc(-c2ccc(Cl)c(CBr)c2)c(Cl)c1OC(F)F
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCc1cc(-c2nn(C)c(OC(F)F)c2Cl)ccc1Cl

Procedure:
A solution of 6.8 g (18 mmol) of 3-(3-bromomethyl-4-chlorophenyl)-4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazole and 1.5 g (18 mmol) of sodium acetate in 20 ml of dimethylformamide was stirred overnight and then stirred into 100 ml of cold water. The product was extracted from the aqueous phase using ethyl acetate. The ethyl acetate phase was dried over magneisum sulfate and concentrated. The crude product thus obtained was purified by silica gel chromatography (eluent: hexane/ethyl acetate=9:1). Yield: 4.7 g.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([S:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][C:15]([CH2:20][CH3:21])=[CH:14][N:13]=1)([CH3:10])([CH3:9])[CH3:8].[CH2:22](OCC)C>>[C:7]([S:11][C:12]1[C:17]([CH2:18][NH2:19])=[CH:16][C:15]([CH2:20][CH3:21])=[C:14]([CH3:22])[N:13]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CCOCC
Reactant: CCc1cnc(SC(C)(C)C)c(C#N)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCc1cc(CN)c(SC(C)(C)C)nc1C
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a suspension of lithium aluminum hydride (54 mg, 1.42 mmol) in diethyl ether (10 mL), under a nitrogen atmosphere, was added dropwise a solution of 2-t-butylthio-3-cyano-5-ethylpyridine (222 mg, 0.95 mmol) in diethyl ether (6 mL). After stirring for 3.5 hours at room temperature, the reaction was quenched with saturated aqueous sodium sulfate and the ether layer dried (Na2SO4), filtered and evaporated to give 219 mg (96%) of crude oily product.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.C(N(CC)CC)C.C1(P([N:31]=[N+:32]=[N-:33])(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C)C=O>[C:1]([N:31]=[N+:32]=[N-:33])(=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: O=C(O)c1cccnc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NC(=O)c1cccnc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
There are added to a suspension of 12.3 g of nicotinic acid in 100 ml of dimethylformamide 14.2 ml of triethylamine and then, after cooling to 0° C., 22 ml of diphenylphosphoryl azide in 50 ml of dimethylformamide. After stirring for 2 hours, the reaction mixture is poured onto ice. After extraction with ether, the organic phase is washed with a NaHCO3 solution, dried, and then concentrated to yield 9.68 g of the expected product.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:16])[C:11]([O:14][CH3:15])([CH3:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[F:8].C([Li])CCC.[C:22](=[O:24])=[O:23]>O1CCCC1>[CH3:15][O:14][C:11]([C:10]1[O:16][C:5]2[C:6]([C:22]([OH:24])=[O:23])=[C:7]([F:8])[CH:2]=[CH:3][C:4]=2[N:9]=1)([CH3:13])[CH3:12]
Reactant: O=C=O
Reactant: COC(C)(C)C(=O)Nc1ccc(F)c(Cl)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(C)(C)c1nc2ccc(F)c(C(=O)O)c2o1

Procedure:
An additional 2.1 grams of [2-(1-methoxy-1-methylethyl)-6-fluorobenzoxazol-7-yl]carboxylic acid of was prepared in the manner of Step B, Example 1, with 4.2 grams (17 mmole) of N-(3-chloro-4-fluorophenyl)-2-methoxy-2-methylpropionamide, 120 mL of tetrahydrofuran, 16 mL (40 mmole) of 2.5M n-butyllithium in hexanes, and 3.0 grams of solid carbon dioxide as reagents. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2][SH:3].[CH2:6](O)[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]>>[C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])(=[O:4])[CH2:2][SH:3]
Reactant: O=C(O)CS
Reactant: CCCCCCO
Product: CCCCCCOC(=O)CS
Reaction time: 2.5 h
Yield: 95.9 %

Procedure:
Thioglycolic acid obtained from Evans Chemetics, Inc. (75 ml, 1.0785 mole) was added dropwise to hexanol obtained from Continental Oil Company (135.6 ml, 1.0785 mole) with 12% Dowex cation exchange resin 50W×12 50/100 (12% cross-linking, 13.2 g) as a catalyst. The solution was stirred and a nitrogen atmosphere maintained. The mixture was thereafter heated, and the byproduct, water, was distilled over as an azeotrope with hexanol at 95° C. and collected. A 10 ml excess of hexanol was added to the reaction mixture to replace that lost in the azeotrope. After 2.5 hours, an 89% yield was obtained. A vacuum of 60 mm Hg was then applied to further the reaction without increasing the temperature. After an additional hour, a 95.9% yield of hexyl thioglycolate was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([C:13]2[CH:14]=[CH:15][C:16](=[O:19])[NH:17][CH:18]=2)=[O:12])[CH:5]=[C:6]([F:8])[CH:7]=1.IC.[C:22](=O)([O-])[O-].[K+].[K+]>>[F:8][C:6]1[CH:5]=[C:4](/[CH:9]=[CH:10]/[C:11]([C:13]2[CH:14]=[CH:15][C:16](=[O:19])[N:17]([CH3:22])[CH:18]=2)=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C(/C=C/c1cc(F)cc(F)c1)c1ccc(=O)[nH]c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: Cn1cc(C(=O)/C=C/c2cc(F)cc(F)c2)ccc1=O

Procedure:
In analogy to example 161, step 1, (E)-5-(3-(3,5-difluorophenyl)acryloyl)pyridin-2(1H)-one was reacted with iodomethane in the presence of potassium carbonate to give the title compound as a light yellow solid. MS (ESI+): m/z=276.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[S:8][C:9]([C:11]3[C:16]([Cl:17])=[CH:15][C:14]([CH:18]=C)=[CH:13][C:12]=3[Cl:20])=[N:10][C:6]=2[CH:5]=[CH:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C[OH:41]>C(Cl)Cl>[Cl:20][C:12]1[CH:13]=[C:14]([CH:15]=[C:16]([Cl:17])[C:11]=1[C:9]1[S:8][C:7]2[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][C:6]=2[N:10]=1)[CH:18]=[O:41]
Reactant: CO
Reactant: C=Cc1cc(Cl)c(-c2nc3ccnc(Cl)c3s2)c(Cl)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=Cc1cc(Cl)c(-c2nc3ccnc(Cl)c3s2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84 %

Procedure:
A solution of 4-chloro-2-(2,6-dichloro-4-vinyl-phenyl)-thiazolo[5,4-c]pyridine (0.168 g, 0.48 mmol) in DCM (3.8 mL) and MeOH (1 mL) was cooled to −78° C. and degassed with nitrogen then compressed air before the ozone generator was turned on. After 10 minutes, a persistent grey colour remained so the ozone generator was turned off and the reaction mixture was degassed with nitrogen. Triphenylphosphine (0.125 g, 0.48 mmol) was added and the mixture warmed to ambient temperature and stirred for 1 hour. The reaction mixture was partitioned between DCM and water. The organic layer dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 0-12% EtOAc in pentane to give the desired compound as an off-white solid (0.138 g, 84% yield). 1H NMR (300 MHz, CDCl3): δ 10.04 (s, 1H), 8.55 (d, J=5.6 Hz, 1H), 7.99-7.98 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[C:13]([CH2:15][CH2:16][CH:17]([C:19]2[CH:24]=[CH:23][C:22]([S:25][CH3:26])=[CH:21][CH:20]=2)[OH:18])[CH:12]=[C:11]([CH3:27])[C:3]=1[O:4][C:5]([CH3:10])([CH3:9])[C:6]([OH:8])=[O:7].[CH2:28](O)C.O>>[CH3:1][C:2]1[CH:14]=[C:13]([CH2:15][CH2:16][CH:17]([C:19]2[CH:24]=[CH:23][C:22]([S:25][CH3:26])=[CH:21][CH:20]=2)[O:18][CH3:28])[CH:12]=[C:11]([CH3:27])[C:3]=1[O:4][C:5]([CH3:9])([CH3:10])[C:6]([OH:8])=[O:7]
Reactant: CCO
Reactant: CSc1ccc(C(O)CCc2cc(C)c(OC(C)(C)C(=O)O)c(C)c2)cc1
Solvent: O
Product: COC(CCc1cc(C)c(OC(C)(C)C(=O)O)c(C)c1)c1ccc(SC)cc1

Procedure:
This compound was prepared following the general procedure E, using 2-[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-3-hydroxy-propyl]phenoxy]-2-methylpropanoic acid at reflux in a 2/3:1/3 ethanol/water mixture for 16 hours;
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:21])=[C:6]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)O)[CH:7]=1.C([SiH](CC)CC)C.B(F)(F)F.CCOCC>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:21])=[C:6]([CH2:8][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:17]([F:20])([F:18])[F:19])=[CH:14][CH:15]=2)[CH:7]=1
Reactant: OC(c1ccc(OC(F)(F)F)cc1)c1cc(Br)ccc1Cl
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: FC(F)(F)Oc1ccc(Cc2cc(Br)ccc2Cl)cc1
Reaction time: 16 h
Yield: 71.4 %

Procedure:
(5-bromo-2-chloro-phenyl)-[4-(trifluoromethoxy)phenyl]methanol 6g (4.37 g, 11.5 mmol) was dissolved in 35 mL dichloromethane, followed by addition of triethyl silane (5.49 mL, 34.4 mmol) and dropwise addition of boron trifluoride etherate (2.9 mL, 22.9 mmol). The reaction mixture was stirred for 16 hours. Thereafter, the reaction mixture was concentrated under reduced pressure and partitioned after 20 mL saturated sodium bicarbonate solution were added. The aqueous phase was extracted with dichloromethane (25 mL×3) and the organic extract was combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography with elution system C to obtain the title compound 4-bromo-1-chloro-2-[[4-(trifluoro-methoxy)phenyl]methyl]benzene 6h (3.0 g, colourless grease), yield: 71.6%. 1H NMR (400 MHz, CDCl3): δ 7.33-7.29 (m, 2H), 7.26-7.24 (m, 1H), 7.21-7.18 (m, 2H), 7.15 (d, 2H), 4.06 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][C:22]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[CH:21][CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2ccc(N3CCOCC3)cc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2cc(N3CCOCC3)ccc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-7-morpholin-4-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([CH3:14])=[C:8]([CH2:12]O)[CH:9]=[CH:10][CH:11]=1.C(Br)(Br)(Br)[Br:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:21][CH2:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH2:4][C:3]2[C:2]([CH3:1])=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:19])[C:7]=1[CH3:14]
Reactant: BrC(Br)(Br)Br
Reactant: Cc1cccc(C)c1COc1cccc(CO)c1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cccc(C)c1COc1cccc(CBr)c1C
Reaction time: 4 h

Procedure:
To a solution of (3-(2,6-dimethylbenzyloxy)-2-methylphenyl)methanol (Step C, 3.68 g, 14.37 mmol) and CBr4 (5.25 g, 15.8 mmol) in dry CH2Cl2 (20 ml) was added portion wise triphenylphosphine (4.14 g, 15.8 mmol) at 0° C. The reaction mixture was stirred for 4 hours, filtered, concentrated and purified by flash chromatography on a silica gel column (hex: ethyl acetate 4:1) to give the title compound. The solid was further kept under vacuum for 6 hours to dry.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:28]=[CH:27][C:16]([CH2:17][C:18]2[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=2)[C:21](Cl)=[O:22])=[CH:15][CH:14]=1.[OH-].[NH4+:30]>O1CCCC1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:28]=[CH:27][C:16]([CH2:17][C:18]2[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=2)[C:21]([NH2:30])=[O:22])=[CH:15][CH:14]=1
Reactant: [NH4+]
Reactant: O=C(Cl)c1cccc(Cc2ccc(OCc3ccc4ccccc4n3)cc2)c1
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)c1cccc(Cc2ccc(OCc3ccc4ccccc4n3)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(4-(2-Quinolinylmethyloxy)benzyl)benzoyl chloride (0.05 mol) in tetrahydrofuran (300 ml) is treated with concentrated ammonium hydroxide (25 ml). The reaction mixture is stirred overnight at room temperature andthen evaporated and partitioned between ethyl acetate and water. The ethyl acetate fraction is dried and evaporated to give 3-(4-(2-quinolinylmethyloxy)benzyl)benzamide.
Reaction SMILES: [OH2:1].[OH-].[Li+].C([C@H]1COC(=O)N1[C:17](=[O:35])[C@H:18]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:19][C:20]([N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[O:21])C1C=CC=CC=1>O1CCCC1.O>[CH2:28]([C@H:18]([CH2:19][C:20]([N:22]1[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1)=[O:21])[C:17]([OH:35])=[O:1])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O
Reactant: O=C(C[C@@H](Cc1ccccc1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)N1CCOCC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)[C@@H](CC(=O)N1CCOCC1)Cc1ccccc1
Reaction time: 3 h
Yield: 74.2 %

Procedure:
711 mg (16.9 mmole) of lithium hydroxide monohydrate were added, whilst ice-cooling, to a solution of 3.70 g (8.5 mmole) of (4S)-(-)-4-benzyl-N-[2(R)-benzyl-3-(morpholinocarbonyl)propionyl]-2-oxazolidinone (prepared as described in Preparation 10) in a mixture of 80 ml of tetrahydrofuran and 30 ml of water, and the mixture was then stirred at the same temperature for 3 hours. At the end of this time, the tetrahydrofuran was stripped from the reaction mixture by distillation under reduced pressure, and the residue was mixed with a 10% w/v aqueous solution of sodium hydroxide and then extracted with methylene chloride. The aqueous layer was adjusted to a pH value of 1 by the addition of concentrated hydrochloric acid, whilst ice-cooling, and was again extracted with methylene chloride. The latter methylene chloride extracts were combined, dried over anhydrous magnesium sulfate and concentrated by distillation under reduced pressure to afford 1.75 g (yield 75%) of the title compound as a white oily substance.