Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].[OH-:10].[Na+].[Na][Na]>O>[OH:10][CH:2]([C:7]([OH:9])=[O:8])[CH:3]([NH:1][CH:2]([CH2:3][C:4]([OH:6])=[O:5])[C:7]([OH:9])=[O:8])[C:4]([OH:6])=[O:5]
Reactant: [OH-]
Reactant: N[C@@H](CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [Na][Na]
Solvent: O
Product: O=C(O)CC(NC(C(=O)O)C(O)C(=O)O)C(=O)O

Procedure:
In one particularly preferred embodiment of the production process, aspartic acid is initially introduced into water in such a quantity that a 20% by weight to 30% by weight solution or suspension is formed and approximately 2 mol equivalents of an alkali metal hydroxide, preferably sodium hydroxide, and then approximately 1 mol equivalent epoxysuccinic acid dialkali metal salt, preferably disodium salt, are added to the resulting solution or suspension. The mixture is then stirred, preferably until the reactants have completely reacted, which generally takes about 1 to 8 hours. To accelerate the reaction, elevated temperatures, for example in the range from 80° to 100° C., may be applied. After removal of the solvent, for example in a rotary evaporator, the tetraalkali metal salt of 3-hydroxy-2,2'-iminodisuccinic acid is obtained as a more or less colorless solid in a substantially quantitative yield. The 3-hydroxy-2,2'-iminodisuccinic acid can be released from this solid or from the solvent-containing crude product in known manner by addition of typical acids, for example hydrochloric acid or sulfuric acid. The acidification step may be omitted if the salt is to be subsequently used as such. The solvent removal step can be omitted if the product is to be incorporated in liquid formulations or intermediates, for example in pastes or slurries.
Reaction SMILES: C([O:3][C:4](=O)/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][N:10]2[CH:13]=[CH:14][N:15]=[C:9]2[CH:8]=1)C.[H-].C([Al+]CC(C)C)C(C)C.CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1.ClCCl>[N:15]1[CH:14]=[CH:13][N:10]2[CH:11]=[CH:12][C:7](/[CH:6]=[CH:5]/[CH2:4][OH:3])=[CH:8][C:9]=12
Reactant: CCOC(=O)/C=C/c1ccn2ccnc2c1
Agent: CC(C)C[Al+]CC(C)C
Agent: CC(C)C[AlH]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: OC/C=C/c1ccn2ccnc2c1
Temperature: 25 °C
Yield: 78.2 %

Procedure:
(E)-3-Imidazo[1,2-a]pyridin-7-yl-acrylic acid ethyl ester (prepared according to Procedure H1 to H4 using triethylphosphono acetate, 519 mg, 2.4 mmol) was dissolved in a mixture of toluene/dichloromethane (1:1, 12 ml) and cooled on a dry ice/acetone bath. Diisobutylaluminium hydride (1 M in toluene, 3 ml) was added dropwise. After 45 minutes the reaction was transferred to a salt/ice bath and further portions of DIBAL were added until the reaction was complete. The reaction was quenched by the cautious addition of methanol and was allowed to warm to room temperature. The reaction was concentrated in vacuo and 2N sodium hydroxide solution was added. This was extracted twice with dichloromethane and the combined liquors were dried and concentrated to furnish the desired monomer (327 mg) as a yellow solid MS: [M+H]+=175
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])[CH2:2][CH3:3].[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Br.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(C(C)=O)C>[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:1][CH2:2][CH3:3]
Reactant: CCCc1ccccc1O
Reactant: BrCCCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCc1ccccc1OCCCCCBr
Yield: 63.7 %

Procedure:
A mixture of 90 g (0.66 mole) of 2-propylphenol, 300 g (1.30 mole) of 1,5-dibromopentane, 120 g of anhydrous potassium carbonate, and 9 g of sodium iodide in 1.2 l of methyl ethyl ketone was stirred at reflux for two days. After cooling, the mixture was filtered to remove insolubles and the filtrate was concentrated in vacuo. The residue was distilled under vacuum to give 120 g of the title compound as an analytically pure oil, b.p. 123°-125° at 0.1 mm Hg.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=1[F:18])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.I[CH2:20][CH3:21].[Cl-].[Na+]>CN(C)C=O>[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:20][CH3:21])=[CH:13][C:12]=1[F:18])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Oc1ccc(OCc2ccccc2)c(F)c1
Reactant: CCI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1ccc(OCc2ccccc2)c(F)c1
Reaction time: 0.25 h
Yield: 95.3 %

Procedure:
Sodium hydride (60% dispersion; 55 mg, 1.38 mmol) was added to a mixture of 4-benzyloxy-3-fluoro-phenol (Bionet Research, Camelford, Cornwall, UK; 250 mg, 1.15 mmol) in dimethylformamide (4 mL). After stirring for 15 min, iodoethane (Aldrich Chemical Company, Inc., Milwaukee, Wis., USA 215 mg, 1.38 mmol) was added and the reaction mixture was stirred overnight. Saturated sodium chloride was added to quench the reaction and the aqueous layer was extracted three times with ethyl acetate. The combined organic extracts were washed with saturated ammonium chloride and saturated sodium carbonate, and then dried over sodium sulfate. The mixture was filtered, concentrated and purified by flash chromatography on silica gel, eluting with 5% ethyl acetate/hexane to give 1-benzyloxy-4-ethoxy-2-fluoro-benzene (270 mg, 96%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 1.26 (t, 3H, J=7.0 Hz), 3.93 (q, 2H, J=7.0 Hz), 5.07 (s, 2H), 6.62-6.67 (m, 1H), 6.82-6.87 (m, 1H), 7.11 (t, 1H, J=9.0 Hz), 7.31-7.42 (m, 5H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10]/[C:11](=[C:18]2\[C:19](=[O:30])[NH:20][C:21]3[C:26]\2=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.[CH:31](=O)[CH2:32][CH3:33].C([BH3-])#N.[Na+]>CO>[CH2:31]([NH:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10]/[C:11](=[C:18]2\[C:19](=[O:30])[NH:20][C:21]3[C:26]\2=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)/[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:8][CH:9]=1)[CH2:32][CH3:33]
Reactant: CCC=O
Reactant: NCc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCCNCc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 159 from (Z)-3-[1-(4-aminomethyl-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone-hydrochloride, propionaldehyde and sodium cyanoborohydride in methanol.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:16][CH2:17][CH:18]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:20][C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:16][CH2:17][CH2:18][N:31]2[CH2:32][CH2:33][N:28]([C:22]3[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:21]=3[CH3:20])[CH2:29][CH2:30]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Reactant: CC(C)(C)n1nc(CCC=O)cc1-c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N2CCN(CCCc3cc(-c4ccccc4)n(C(C)(C)C)n3)CC2)c(C)c1

Procedure:
99 mg (68%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-phenyl-1H-pyrazol-3-yl)propanal (80 mg, 0.312 mmol), 1-(2,4-dimethylphenyl)piperazine (59 mg, 0.312 mmol), DIPEA (82 mL, 0.468 mmol) and NaBH(OAc)3 (198 mg, 0.936 mmol).
Reaction SMILES: O[C:2]1([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH:16]=[CH:15][C:14]3[O:17][CH2:18][O:19][C:13]=3[CH:12]=2)=[C:3]1[C:20]([O:22]CC)=[O:21].C([SiH](CC)CC)C.[B]>C(Cl)Cl>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([CH:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]([C:11]3[CH:16]=[CH:15][C:14]4[O:17][CH2:18][O:19][C:13]=4[CH:12]=3)[CH:3]2[C:20]([OH:22])=[O:21])=[CH:26][CH:27]=1
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1(O)c1ccc(OC)cc1
Agent: CC[SiH](CC)CC
Agent: [B]
Solvent: ClCCl
Product: COc1ccc(C2c3ccccc3C(c3ccc4c(c3)OCO4)C2C(=O)O)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Ethyl (RS)-1-(4-Methoxyphenyl)-3-(3,4-methylene-dioxyphenyl)indene-2-carboxylate. To a solution of ethyl (1RS)-1-hydroxy-1-(4-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)-indene-2-carboxylate (0.80 g, 1.9 mmol) in CH2Cl2 (10 ml) at 0° C. under an argon atmosphere was added triethylsilane (0.28 g, 2.4 mmol), followed by boron trfluoride etherate (1 ml, 8.1 mmol). The resulting solution was stirred at 0° C. for 10 min, and was then partitioned between EtOAc and 3 M HCl. The organic extract was washed with saturated aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo, and the residue was filtered through a pad of silica gel, eluting with CH2Cl2. The title compound (mixture of Δ1 and Δ2 double bond isomers) was obtained as a glassy, yellow solid (0.72 g, 94%).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9]([NH:11][NH2:12])=[S:10].[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=O)[CH:14]=1>>[CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9](=[S:10])[NH:11][N:12]=[CH:19][C:15]1[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=1
Reactant: NNC(=S)NC1CC2C=CC1C2
Reactant: O=Cc1cccnc1
Product: S=C(NN=Cc1cccnc1)NC1CC2C=CC1C2

Procedure:
The title compound was prepared from a mixture of N1-bicyclo[2.2.1]hept-5-en-2-ylhydrazine-1-carbothioamide (100 mg, 0.56 mmol) and 3-pyridine carboxaldehyde (53 μL, 0.56 mmol) similar to Example 3 and isolated as a white solid (59 mg, 39%). 1H NMR (CDCl3): 9.51 (s, 1H), 8.85 (d, J=1.8 Hz, 1H), 8.64 (dd, J=1.7, 5.0 Hz, 1H), 7.96-7.92 (m, 1H), 7.82 (s, 1H), 7.46 (d, J=6.3 Hz, 1H), 7.38-7.34 (m, 1H), 6.24-6.14 (m, 2H), 4.30-4.25 (m, 1H), 3.06 (s, 1H), 2.97 (s, 1H), 1.95-1.87 (m, 1H), 1.67 (d, J=8.7 Hz, 1H), 1.5 (d, J=9.0 Hz, 1H), 1.45-1.39 (m, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][OH:9].[H][H]>[Ru]=O>[NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][OH:9]
Reactant: [H][H]
Reactant: OCCc1ccccn1
Agent: O=[Ru]
Product: OCCC1CCCCN1

Procedure:
Hydrogenations were carried out by charging solvent, when utilized, 246 g of 2-pyridineethanol, and 2.5 g of ruthenium oxide (RuO2) into a pressure vessel capable of agitation, agitating the resulting mixture and pressurizing the vessel and its contents to 500 psig or 1000 psig with hydrogen. Under constant hydrogen pressure and continued agitation, the reaction mixture was heated to the reaction temperature until hydrogen uptake ceased. The pressure vessel and its contents were cooled, vented and the catalyst removed with vacuum filtration. Upon distillation of the filtrate, 2-piperidineethanol was obtained and analyzed on two separate gc columns (6′ CW 20M 160° C. and 15M DB-1 80° C.→220° C.@ 16° C./m capillary column) to provide product yield and composition of the distillate. The results are provided in Table IV. Hydrogenations were also carried out with recycled RuO2 catalyst under the conditions described above. The results of these reactions utilizing recycled catalyst are provided in Table V.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:14])/[CH:6]=[CH:7]/[C:8]1[N:9]=[N:10][N:11]([CH3:13])[CH:12]=1>>[CH3:13][N:11]1[CH:12]=[C:8](/[CH:7]=[CH:6]/[C:5]([OH:14])=[O:4])[N:9]=[N:10]1
Reactant: COC(=O)/C=C/c1cn(C)nn1
Agent: [Na+]
Agent: [OH-]
Product: Cn1cc(/C=C/C(=O)O)nn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 25.5 %

Procedure:
10% Sodium hydroxide solution (3 ml) was added to a solution of the product from step 1 (3.2 g). The mixture was stirred at room temperature for 15 hours, further 10% sodium hydroxide solution (2 ml) added and then heated to reflux for 3 hours. On cooling the reaction mixture was partitioned between ethyl acetate and water. The organics were re-extracted with saturated sodium hydrogen carbonate solution and the combined aqueous extracts acidified to pH 1 with conc. hydrochloric acid. After extraction into ethyl acetate and dying over magnesium sulphate the solvent was removed to afford the title compound, (748 mg); 1H NMR (d6-DMSO) 4.07 (3H, s), 6.53 (1H, d, J 16.0 Hz), 7.53 (1H, d, J 16.0 Hz), 8.44 (1H, s), 12.48 (1H, br).
Reaction SMILES: [CH3:1][NH2:2].C(O[C:6](=[O:18])[CH2:7][NH:8][C:9](=[O:17])[CH2:10][N:11]1[CH2:15][CH2:14][CH2:13][C:12]1=[O:16])C>>[CH3:1][NH:2][C:6](=[O:18])[CH2:7][NH:8][C:9](=[O:17])[CH2:10][N:11]1[CH2:15][CH2:14][CH2:13][C:12]1=[O:16]
Reactant: CCOC(=O)CNC(=O)CN1CCCC1=O
Reactant: CN
Product: CNC(=O)CNC(=O)CN1CCCC1=O
Reaction time: 8 h
Yield: 92 %

Procedure:
31 g (1 mole) of methylamine are added to 18.24 g (0.08 mole) of N-(2-oxo-1-pyrrolidineacetyl)-glycine ethyl ester and the reaction mixture is kept at -20° C. for 8 hours, while stirring. It is then evaporated and the residue is recrystallized from absolute ethanol, 15.7 g. of N-methyl-2-(2-oxo-1-pyrrolidineacetamido)-acetamide being obtained (yield: 92% of theory); M.P. 139°-140° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:22][C:23](=[O:28])[CH2:24][C:25]([OH:27])=[O:26])[CH:5]=[C:6]([CH3:21])[C:7]=1[O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH:18]([CH3:20])[CH3:19].[OH-].[Ca+2:30].[OH-]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:22][C:23](=[O:28])[CH2:24][C:25]([O-:27])=[O:26])[CH:5]=[C:6]([CH3:21])[C:7]=1[O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH:18]([CH3:19])[CH3:20].[Cl:1][C:2]1[CH:3]=[C:4]([NH:22][C:23](=[O:28])[CH2:24][C:25]([O-:27])=[O:26])[CH:5]=[C:6]([CH3:21])[C:7]=1[O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH:18]([CH3:19])[CH3:20].[Ca+2:30]
Reactant: Cc1cc(NC(=O)CC(=O)O)cc(Cl)c1Oc1ccc2[nH]cc(C(C)C)c2c1
Agent: [Ca+2]
Agent: [OH-]
Product: Cc1cc(NC(=O)CC(=O)[O-])cc(Cl)c1Oc1ccc2[nH]cc(C(C)C)c2c1

Procedure:
This compound is obtained in a manner analogous to Example 6a starting from 3-({3-chloro-4-[(3-isopropyl-1H-indol-5-yl)oxy]-5-methylphenyl}amino)-3-oxo-propionic acid (Example 6) and calcium hydroxide.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=2[F:16])=[C:4]([C:17]([NH:19][O:20][CH2:21][C@H:22]2[CH2:26][O:25]C(C)(C)[O:23]2)=[O:18])[CH:3]=1>C(O)(=O)C.O>[OH:23][CH:22]([CH2:26][OH:25])[CH2:21][O:20][NH:19][C:17]([C:4]1[CH:3]=[C:2]([Cl:1])[N:7]=[N:6][C:5]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=1[F:16])=[O:18]
Reactant: CC1(C)OC[C@H](CONC(=O)c2cc(Cl)nnc2Nc2ccc(I)cc2F)O1
Solvent: CC(=O)O
Solvent: O
Product: O=C(NOCC(O)CO)c1cc(Cl)nnc1Nc1ccc(I)cc1F

Procedure:
6-Chloro-N-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}-3-[(2-fluoro-4-iodophenyl)amino]pyridazine-4-carboxamide (38 mg, 0.07 mmol) was heated at 90° C. in acetic acid/water (85%, 1.5 mL) for 2 hours. The mixture was concentrated and purified by flash chromatography to give the desired adduct. LC/MS [Method B: rt: 7.02 min; m/z: 483 (M+1)].
Reaction SMILES: [NH2:1][C:2](=[N:33][OH:34])[C:3]1[CH:32]=[CH:31][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:28]=[CH:27][C:17]([C:18]([N:20]([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])=[O:19])=[CH:16][C:15]=2[O:29]C)=[CH:5][CH:4]=1.[Cl-].[Al+3].[Cl-].[Cl-].C(S)C>ClCCl>[NH2:1][C:2](=[N:33][OH:34])[C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:28]=[CH:27][C:17]([C:18]([N:20]([CH:24]([CH3:25])[CH3:26])[CH:21]([CH3:23])[CH3:22])=[O:19])=[CH:16][C:15]=2[OH:29])=[CH:31][CH:32]=1
Reactant: COc1cc(C(=O)N(C(C)C)C(C)C)ccc1OCCCCCOc1ccc(C(N)=NO)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Solvent: ClCCl
Product: CC(C)N(C(=O)c1ccc(OCCCCCOc2ccc(C(N)=NO)cc2)c(O)c1)C(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A stirred solution of 4-[5-[4-[amino(hydroxyimino)methyl]phenoxy]pentyloxy]-3-methoxy-N,N-bis(1-methylethyl)benzamide (200 mg, 0.4 mmol) in 4 mL of dichloromethane at 0° C. is treated with aluminum chloride (292 mg, 2.2 mmol) and ethanethiol (4 mL, 54 mmol). After stirring at 0° C. for 1 hour, reaction mixture is partitioned between ethyl acetate and saturated ammonium hydroxide solution. The organic phase is dried with magnesium sulfate and concentrated in vacuo. The resulting material is purified by chromatography on silica gel (10 g) with 5% methanol/dichloromethane as the eluent to afford 4-[5-[4-[amino(hydroxyimino)methyl]phenoxy]pentyloxy]-3-hydroxy-N,N-bis(1-methylethyl)benzamide as a colorless foam;
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Br:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[C:19](Cl)[N:18]=[CH:17]2.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[NH4+].[Cl-]>C1COCC1>[Br:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[C:19]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[N:18]=[CH:17]2
Reactant: Clc1ncc2cccc(Br)c2n1
Reactant: Nc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Brc1cccc2cnc(Nc3ccccc3)nc12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
LHMDS (1.0M in THF; 4.11 mL, 4.11 mmol) was added to a solution of 8-bromo-2-chloroquinazoline (Ark Pharm, Inc., Libertyville, Ill.; 500 mg, 2.053 mmol) and aniline (0.337 mL, 3.70 mmol) in THF (10 mL) at 0° C., and the resulting solution was stirred at 0° C. for 10 min. Saturated aq. NH4Cl (10 mL) was added, and the resulting mixture was partitioned between EtOAc (50 mL) and additional saturated aq. NH4Cl (30 mL). The organic layer was separated, washed with brine (30 mL), dried over Na2SO4, filtered and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-10% MeOH/DCM) furnished 8-bromo-N-phenylquinazolin-2-amine (616 mg, 2.052 mmol, 100% yield) as a yellow solid: m/z (ESI, +ve) 300.0 (M+H)+.
Reaction SMILES: C(O[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH:19]C(OC(C)(C)C)=O)[CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C.C(OC(=O)NC1C=CC=C(C=O)C=1)(C)(C)C.[CH3:43][C:44]([NH:48]C(C1CCNCC1)=O)([CH3:47])[CH2:45][CH3:46]>>[CH3:43][C:44]([NH:48][C:4]([CH:6]1[CH2:7][CH2:8][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[CH:14]=2)[CH2:10][CH2:11]1)=[O:5])([CH3:47])[CH2:45][CH3:46]
Reactant: CCOC(=O)C1CCN(Cc2cccc(NC(=O)OC(C)(C)C)c2)CC1
Reactant: CCC(C)(C)NC(=O)C1CCNCC1
Agent: CC(C)(C)OC(=O)Nc1cccc(C=O)c1
Product: CCC(C)(C)NC(=O)C1CCN(Cc2cccc(N)c2)CC1

Procedure:
The title compound is prepared according to the reaction 1.001a and 1.001d described above using (3-formyl-phenyl)-carbamic acid tert-butyl ester and piperidine-4-carboxylic acid (1,1-dimethyl-propyl)-amide: LC-MS A: tR=0.48 min; [M+H]+=304.23.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[N:28]=[C:27]([C:32]([OH:34])=[O:33])[CH:26]=[CH:25]4)=[CH:18][CH:17]=2)=[C:12]([CH:35]([CH3:37])[CH3:36])[O:11][N:10]=1.[OH-].[Na+:39]>CO>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[N:28]=[C:27]([C:32]([O-:34])=[O:33])[CH:26]=[CH:25]4)=[CH:18][CH:17]=2)=[C:12]([CH:35]([CH3:37])[CH3:36])[O:11][N:10]=1.[Na+:39]
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc3nc(C(=O)O)ccc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc3nc(C(=O)[O-])ccc3c2)cc1
Reaction time: 1 h
Yield: 98.8 %

Procedure:
To a stirring suspension of 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylic acid (4.12 g, 7.73 mmol) in methanol (100 mL) was added 1 N sodium hydroxide (7.73 mL, 7.73 mmol). The mixture was stirred for approximately 1 hour and then concentrated. Ether was added followed by a little water. After stirring the solid turned into a paste. The solvent was decanted and the paste triturated with ether and then dried on a rotary evaporator at 35° C. under vacuum for approximately 1.5 hours to afford sodium 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylate (4.24 g, 98%). 1H-NMR (400 MHz, DMSO-d6) δ 8.28-8.22 (m, 2H), 8.09-7.96 (m, 3H), 7.68 (d, J=9 Hz, 2H), 7.63-7.51 (m, 3H), 6.90 (d, J=9 Hz, 2H), 4.87 (s, 2H), 3.46 (septet, J=7 Hz, 1H), 1.33 (d, J=7 Hz, 6H). LRMS (APCI) C29H21Cl2N2O4Na calculated: 533 (M+H)+, found: 533 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH:4]([C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([F:26])[CH:17]=2)[CH:12]=[C:13]([OH:15])[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[F:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1>>[CH3:1][O:2][C:3](=[O:27])[CH:4]([C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[C:20]([C:22]([F:24])([F:23])[F:25])[CH:19]=[C:18]([F:26])[CH:17]=2)[CH:12]=[C:13]([O:15][C:31]2[CH:32]=[C:33]([C:35]([F:37])([F:36])[F:38])[CH:34]=[C:29]([F:28])[CH:30]=2)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)C(CC(C)C)c1cc(O)cc(-c2cc(F)cc(C(F)(F)F)c2)c1
Reactant: OB(O)c1cc(F)cc(C(F)(F)F)c1
Product: COC(=O)C(CC(C)C)c1cc(Oc2cc(F)cc(C(F)(F)F)c2)cc(-c2cc(F)cc(C(F)(F)F)c2)c1
Yield: 73 %

Procedure:
The title compound was prepared in 73% yield from 2-(3′-fluoro-5-hydroxy-5′-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoic acid methyl ester (prepared in Example B) and 3-fluoro-5-trifluoromethylbenzene boronic acid under the conditions described in Example 15, step (g).
Reaction SMILES: [Cl:1]/[C:2](=[C:6](\[Cl:10])/[C:7](O)=[O:8])/[C:3](O)=[O:4].[F:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1>>[F:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.[F:11][C:12]1[CH:18]=[CH:17][C:15]([N:16]2[C:3](=[O:4])[C:2]([Cl:1])=[C:6]([Cl:10])[C:7]2=[O:8])=[CH:14][CH:13]=1
Reactant: O=C(O)/C(Cl)=C(/Cl)C(=O)O
Agent: Nc1ccc(F)cc1
Product: O=C1C(Cl)=C(Cl)C(=O)N1c1ccc(F)cc1

Procedure:
To react 2,3-dichloromaleic acid, an anhydride or an ester thereof with 4-fluoroaniline, the latter may be added to the former dropwise with mixing. In this case, however, if the reaction is carried out at higher temperature, for example at reflux temperatures, then byproducts tend to be formed through the reaction of p-fluoroaniline with N-(4-fluorophenyl)-2,3-dichloromaleimide, thereby reducing the purity of the product. This danger may be eliminated by employment of a two-stage reaction method wherein the starting material is mixed with 4-fluoroaniline dropwise at comparatively lower temperatures (first stage) and then the reaction is completed at elevated temperatures (second stage) to minimize the formation of byproducts. The reaction temperature for the first stage is lower than 60° C, preferably in the range of room temperature -- 50° C; the reaction temperature for the second stage is preferably in the range of 60° C to reflux temperature. When the reaction is to be effected in a single stage, it is advisable to add 4-fluoroaniline dropwise into 2,3-dichloromaleic acid, an anhydride or an ester thereof. Whereas when a two-stage reaction is adopted, the desired product may be obtained at a similar high yield by adding the former to the latter dropwise or vice versa. The reaction time is not specially limited and may be selected within a wide range: the reaction may usually be fully completed within 1-6 hours. In the two-stage reaction the dropping time for the first stage may be in the range of 10-60 minutes and the reaction time for the second stage may be in the range of 1-6 hours. In this way the desired substance may be obtained at a high purity after completion of the reaction by merely cooling the reaction mixture and then separating the crystals by filtration.