Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[N:4][N:3]=1.C(N(CC)CC)C.[C:21]1([CH2:27][C:28](Cl)=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1(C)C=CC=CC=1>[CH2:8]([N:7]([C:5]1[S:6][C:2]([CH3:1])=[N:3][N:4]=1)[C:28](=[O:29])[CH2:27][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CCCCCCNc1nnc(C)s1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCN(C(=O)Cc1ccccc1)c1nnc(C)s1
Reaction time: 24 h

Procedure:
N-(5-Methyl-1,3,4-thiadiazol-2-yl)-hexylamine (5.98 g, 0.03 mole) in toluene (60 ml) was stirred together with triethylamine (4.59 ml) and phenylacetyl chloride (4.64 g, 0.03 mole) and refluxed overnight. Further triethylamine (4.6 ml) and phenylacetyl chloride (4 ml) were added and refluxing was continued for a further 24 hours. The mixture was evaporated to dryness, treated with water and extracted with chloroform. The chloroform extract was washed with 2 N sodium hydroxide solution and with water, and was dried (Na2SO4), filtered and evaporated to yield the title product as an oil, b.p. 190° C./0.1 mm (8.03 g). This was recrystallised from ethanol to give the title compound as a solid, m.p. 90° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16]C)=[C:12]([F:18])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-].O>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([F:18])[CH:11]=2)=[O:9])=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)c2ccc(Br)cc2)cc1F
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: c1ccccc1
Product: O=C(c1ccc(Br)cc1)c1ccc(O)c(F)c1
Temperature: 25 °C
Yield: 92.9 %

Procedure:
A mixture of 81 (1.28 g, 4.34 mmol) and AlCl3 (3.50 g, 26.2 mmol) were refluxed in benzene (50 mL) for 3 h and cooled to RT. Water (100 mL) was cautiously added dropwise, and the mixture was extracted with ether (3×100 mL). The combined ethereal extracts were washed with water (200 mL), brine (200 mL), and dried over MgSO4. Concentration afforded 1.19 g (98%) of 82 that was used without further purification. 1H NMR (400 MHz, CDCl3): δ 5.80 (br s, 1H), 7.09 (t, J=8.4 Hz, 1H), 7.53 (d, J=8.4 Hz, 1H), 7.61-7.64 (m, 5H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH2:11][OH:12].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:20]=[C:21]([O:23][CH3:24])[CH:22]=1)[CH:18]=O.[C:25](#[N:29])[CH2:26][C:27]#[N:28]>>[NH2:29][C:25]1[O:1][C:2]2[C:10]([CH:18]([C:17]3[CH:16]=[C:15]([O:14][CH3:13])[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=3)[C:26]=1[C:27]#[N:28])=[CH:9][CH:8]=[C:7]1[N:6]([CH2:11][OH:12])[CH:5]=[CH:4][C:3]=21
Reactant: COc1cc(C=O)cc(OC)c1
Reactant: N#CCC#N
Reactant: OCn1ccc2c(O)cccc21
Product: COc1cc(OC)cc(C2C(C#N)=C(N)Oc3c2ccc2c3ccn2CO)c1

Procedure:
The title compound was prepared from 4-hydroxy-1-hydroxymethylindole (30 mg, 0.18 mmol), 3,5-dimethoxy-benzaldehyde (31 mg, 0.18 mmol) and malononitrile (12 mg, 0.18 mmol) similar to Example 24 to yield 19 mg (27%) of white solids. 1H NMR (CDCl3): 7.20-7.15 (m, 2H), 6.85 (d, J=8.1 Hz, 1H), 6.62 (d, J=3.3 Hz, 1H), 6.36-6.32 (m, 3H), 5.60 (s, 2H), 4.76 (s, 1H), 4.64 (brs, 2H), 3.75 (s, 6H), 2.43 (brs, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.[Cl:9][CH2:10][C:11](=O)[CH2:12][C:13](OCC)=[O:14]>>[Cl:9][CH2:10][C:11]1[N:1]=[C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]2[C:13](=[O:14])[CH:12]=1
Reactant: Cc1cccc(N)n1
Reactant: CCOC(=O)CC(=O)CCl
Product: Cc1cccc2nc(CCl)cc(=O)n12
Temperature: 125 °C
Reaction time: 5.5 h

Procedure:
A mixture of 2-amino-6-methylpyridine (10.00 g, 92.47 mmol), ethyl 4-chloro-acetoacetate (16.24 mL, 120.2 mmol), and polyphosphoric acid (50.00 g) was stirred at 125° C. After 5.5 h, the mixture was removed from the heat. To the cooled mixture was added ice-water (200 mL) and neutralized with 2 N NaOH (400 mL) to pH 6-7. The resulting precipitate was collected by filtration, washed with water (˜400 mL), and dried to give 2-(chloromethyl)-6-methyl-4H-pyrido-[1,2-a]pyrimidin-4-one as a dark brown solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 7.68 (1 H, dd, J=9.0, 7.0 Hz), 7.40 (1 H, dd, J=9.0, 0.8 Hz), 6.93 (1 H, d, J=6.7 Hz), 6.36 (1 H, s), 4.58 (2 H, s), 2.93 (3 H, s); Mass Spectrum (ESI) m/e=208.9 (M+1).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:9][N:8]([CH2:10][CH2:11][C@H:12]([N:15]2[C:21](=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH2:13][OH:14])[CH2:7][CH2:6][C:3]21[CH2:5][CH2:4]2.C(N(CC)CC)C.Cl[Si](C)(C)C.[Cl:35][C:36]1[CH:37]=[C:38]([N:43]=[C:44]=[O:45])[CH:39]=[CH:40][C:41]=1[Cl:42]>ClCCl.CN(C)C=O>[Cl:35][C:36]1[CH:37]=[C:38]([NH:43][C:44]([N:18]2[CH2:19][CH2:20][C:21](=[O:22])[N:15]([C@H:12]([CH2:13][OH:14])[CH2:11][CH2:10][N:8]3[CH2:7][CH2:6][C:3]4([CH2:4][CH2:5]4)[C@H:2]([OH:1])[CH2:9]3)[CH2:16][CH2:17]2)=[O:45])[CH:39]=[CH:40][C:41]=1[Cl:42]
Reactant: O=C1CCNCCN1[C@H](CO)CCN1CCC2(CC2)[C@H](O)C1
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCC(=O)N([C@H](CO)CCN2CCC3(CC3)[C@H](O)C2)CC1
Temperature: 25 °C
Yield: 62 %

Procedure:
A solution of 0.066 g (0.21 mmol) of 4-[(S)-3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-1-hydroxymethyl-propyl]-[1,4]diazepan-5-one (example 51B) 1.3 ml of N,N-dimethylformamide was treated at room temperature with 0.097 ml (0.70 mmol) of triethylamine and 0.088 ml (0.70 mmol) of chlorotrimethylsilane. The suspension was diluted with 1 ml of dichloromethane and stirred over night at room temperature. A solution of 0.044 g (0.23 mmol) of 3,4-dichlorophenyl isocyanate was added and stirred for 3 h at room temperature. The reaction was evaporated under reduced pressure, redissolved in 2 ml of methanol and 0.2 ml of 1 M aq. hydrochloric acid solution and after 5 min again evaporated. Partitioning between sat. aq. sodium hydrogencarbonate solution and dichloromethane (3×), drying of the organic phase over Na2SO4 and purification by flash silica gel column (dichloromethane/methanol 95:5 to 4:1) yielded 0.065 g (61%) of the title compound as yellow foam. MS: 499.2 (MH+, 2Cl).
Reaction SMILES: C1(C[O:8][C@H:9]2[C@@H:14]([NH:15]CC3C=CC=CC=3)[CH2:13][CH2:12][N:11]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:10]2)C=CC=CC=1.[H][H]>[Pd].CO>[NH2:15][C@H:14]1[CH2:13][CH2:12][N:11]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:10][C@H:9]1[OH:8]
Reactant: [H][H]
Reactant: CCOC(=O)N1CC[C@H](NCc2ccccc2)[C@H](OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)N1CC[C@H](N)[C@H](O)C1

Procedure:
A mixture of 170 parts of ethyl cis-3-(phenylmethoxy)-4-[(phenylmethyl)amino]-1-piperidinecarboxylate and 400 parts of methanol was hydrogenated at normal pressure and at 80° C. with 20 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The oily residue was distilled, yielding 75 parts of ethyl cis-4-amino-3-hydroxy-1-piperidinecarboxylate; bp. 175°-185° C. at 0.4 mm. pressure. (intermediate 49).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:27])[C:10]2[CH:15]=[CH:14][C:13]([S:16][C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)=[C:12]([N+:24]([O-])=O)[CH:11]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C.C(O)C.O.[Fe]>[NH2:24][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[S:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)=[O:27]
Reactant: O=C(Nc1ccc(Br)cc1)c1ccc(Sc2ccc(O)cc2)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1cc(C(=O)Nc2ccc(Br)cc2)ccc1Sc1ccc(O)cc1
Temperature: 25 °C
Yield: 75.9 %

Procedure:
A suspension of the product of Example 53A (409.9 mg, 0.9205 mmol) and iron powder (206 mg, 3.682 mmol) in acetic acid (7 mL) and ethanol (7 mL) was heated at reflux under a nitrogen atmosphere for 1 hour. The reaction was cooled to room temperature. The mixture was diluted with water (30 mL), the pH adjusted to 6 with solid sodium carbonate, and the aqueous extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with brine (25 mL), dried over sodium sulfate, filtered, and concentrated under vacuum to provide the title compound as a tan solid (290 mg, 0.6983 mmol, 76%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:15]([CH2:17][C@@H:18]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])=[O:16]>ClCCl>[N:1]1([C:15]([CH2:17][C@@H:18]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:19]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:20])=[O:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: CC(C)C[C@H](CC(=O)Cl)C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C[C@H](CC(=O)N1CCCCC1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
To a mixture of piperidine (0.281 g) and triethylamine (0.304 g) in dichloromethane (10 ml) was added dropwise a solution of benzyl (2R)-2-(chlorocarbonylmethyl)-4-methylvalerate (0.816 g) in dichloromethane (5 ml). The solution was stirred at room temperature for 30 minutes and the solvent was evaporated in vacuo. The residue was dissolved in ethyl acetate (30 ml), and washed with 7% hydrochloric acid, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution successively. The organic layer was dried over magnesium sulfate, and concentrated in vacuo to give benzyl (2R)-2-(piperidinocarbonylmethyl)-4-methylvalerate (0.931 g) as an oil.
Reaction SMILES: [CH:1]1([NH:5][C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:30])[CH2:14][O:15][C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([C:27](O)=[O:28])[CH:17]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH:50]1([O:54][C:55]([N:57]2[CH2:62][CH2:61][N:60]([C:63](=[O:78])[C@@H:64]([NH2:77])[CH2:65][CH2:66][CH2:67][CH2:68][O:69][CH2:70][C:71]3[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=3)[CH2:59][CH2:58]2)=[O:56])[CH2:53][CH2:52][CH2:51]1>CN(C=O)C.C(Cl)CCl>[CH:50]1([O:54][C:55]([N:57]2[CH2:62][CH2:61][N:60]([C:63](=[O:78])[C@@H:64]([NH:77][C:27]([C:18]3[CH:17]=[C:16]([O:15][CH2:14][C:13]([N:9]4[CH2:10][CH2:11][CH2:12][C@H:8]4[C:6](=[O:7])[NH:5][CH:1]4[CH2:2][CH2:3][CH2:4]4)=[O:30])[N:20]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:19]=3)=[O:28])[CH2:65][CH2:66][CH2:67][CH2:68][O:69][CH2:70][C:71]3[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=3)[CH2:59][CH2:58]2)=[O:56])[CH2:53][CH2:52][CH2:51]1
Reactant: O=C(O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Reactant: N[C@@H](CCCCOCc1ccccc1)C(=O)N1CCN(C(=O)OC2CCC2)CC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H](CCCCOCc1ccccc1)C(=O)N1CCN(C(=O)OC2CCC2)CC1)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Reaction time: 12 h

Procedure:
To a solution of 480 mg 5-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carboxylic acid in 10 ml DMF were added 232 mg HOBt, 290 mg EDC and 0.48 ml DIPEA. After 5 minutes 470 mg (S)-4-(2-Amino-6-benzyloxy-hexanoyl)-piperazine-1-carboxylic acid cyclobutyl ester were added and the mixture stirred for 12 h. The reaction mixture was concentrated, diluted with ethyl acetate and washed with aqueous LiCl (4%), 0.1 M HCl and saturated aqueous NaHCO3. The crude product was obtained by evaporation of the solvent. An aliquot (80 mg) was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA) to give the title compound. Yield: 40 mg MS (ES+): m/e=798.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:32][C:33]1[CH:38]=[CH:37][N:36]=[CH:35][N:34]=1>CN(C=O)C>[ClH:1].[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:32][C:33]4[CH:38]=[CH:37][N:36]=[CH:35][N:34]=4)=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1
Reactant: ClCc1ccncn1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCc1ccncn1
Product: Cl
Temperature: 80 °C
Yield: 76.7 %

Procedure:
A mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline 319.5 mg, 1 mmol), (prepared as described for the starting material in Example 24), potassium carbonate (414 mg, 3 mmol), potassium iodide (16 mg, 0.1 mmol) and 4-chloromethylpyrimidine (257 mg, 2 mmol) in DMF (20 ml) was heated at 80° C. for 2 hours. The solvent was removed by evaporation and the residue was triturated with water. The solid was collected by filtration and dried under vacuum. The solid was purified by column chromatography eluting with methylene chloride/methanol (95/5). The purified white solid was suspended in methanol (25 ml) and a solution of 7.5M hydrogen chloride in methanol (20 ml) was added. The resulting solid product was collected by filtration, washed with methanol and then pentane and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-((pyrimidin-4-yl)methoxy)quinazoline hydrochloride (172 mg, 42%). m.p. 237-239° C. 1H NMR Spectrum: (DMSOd6; CF3COOD) 4.07(s, 3H); 5.53(s, 2H); 7.40(s, 1H); 7.46(dd, 1H); 7.65(t, 1H); 7.68-7.72(m, 2H); 8.26(s, 1H); 8.85(s, 1H); 8.91(d, 1H); 9.25(s, 1H) MS-ESI: 412 [MH]+
Reaction SMILES: [O:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[CH:10][N:9]=[C:8]([S:12][CH3:13])[N:7]=2)[CH:3]=[N:2]1.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.CO>[CH3:13][S:12][C:8]1[N:7]=[C:6]([CH:4]([CH:5]=[O:1])[C:3]#[N:2])[CH:11]=[CH:10][N:9]=1
Reactant: CSc1nccc(-c2cnoc2)n1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CSc1nccc(C(C#N)C=O)n1
Temperature: 70 °C
Reaction time: 6 h
Yield: 89.2 %

Procedure:
A mixture of 4-(isoxazol-4-yl)-2-(methylthio)pyrimidine (4) (112.0 g, 0.58 mol) and NaOH (23.2 g) in water/MeOH (350 mL/350 mL) was stirred at 70° C. for 6 h. The reaction mixture was allowed to cool to room temperature and adjusted to pH 3.5 with citric acid. The resulting precipitate was filtered, washed with water (500 mL×3) and ethyl ether (500 mL×3). Then the precipitate was dried in vacuum to give 2-(2-(methylthio)pyrimidin-4-yl)-3-oxopropanenitrile (5) (100 g, 89.3%) as a yellow solid.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[N:8]=1)=O.[CH:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([NH:36][NH2:37])=[CH:28][N:27]=1>>[CH:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([N:36]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:15]=[CH:16][C:17]([O:20][C:21]([F:22])([F:24])[F:23])=[CH:18][CH:19]=4)[N:8]=3)=[CH:4][CH:3]=[N:37]2)=[CH:28][N:27]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OC(F)(F)F)cc2)ccc1=O
Reactant: NNc1cncc2ccccc12
Product: O=c1ccn(-c2ccc(OC(F)(F)F)cc2)nc1-c1ccnn1-c1cncc2ccccc12

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-8) and isoquinolin-4-yl-hydrazine according to the method described for example 91. MS: M=450.1 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[O:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:23][CH2:22][C:21]4[C:16](=[CH:17][C:18]([OH:25])=[C:19]([OH:24])[CH:20]=4)[CH2:15]3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Br[C:27](Br)([C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:28]([O:30][CH2:31][CH3:32])=[O:29].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:36]([O:35][C:33]([C:27]1([C:28]([O:30][CH2:31][CH3:32])=[O:29])[O:24][C:19]2[CH:20]=[C:21]3[C:16](=[CH:17][C:18]=2[O:25]1)[CH2:15][C@H:14]([N:10]1[CH2:9][C@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[O:12][C:11]1=[O:13])[CH2:23][CH2:22]3)=[O:34])[CH3:37]
Reactant: CCOC(=O)C(Br)(Br)C(=O)OCC
Reactant: O=C1OC(c2cccc(Cl)c2)CN1C1CCc2cc(O)c(O)cc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1(C(=O)OCC)Oc2cc3c(cc2O1)C[C@H](N1C[C@H](c2cccc(Cl)c2)OC1=O)CC3
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.9 %

Procedure:
A mixture of 0.90 g of the above catechol derivative, 0.836 g of diethyl dibromomalonate and 1.8 g of powdered anhydrous potassium carbonate in 15 ml of acetone is stirred at room temperature for 18 hours. The reaction mixture is filtered and concentrated in vacuo to give 0.708 g of a mixture of diastereomers as a colorless oil.
Reaction SMILES: O[CH2:2][C:3]1[O:7][N:6]=[C:5]([O:8][CH3:9])[CH:4]=1.S(Cl)([Cl:12])=O>>[Cl:12][CH2:2][C:3]1[O:7][N:6]=[C:5]([O:8][CH3:9])[CH:4]=1
Reactant: COc1cc(CO)on1
Reactant: O=S(Cl)Cl
Product: COc1cc(CCl)on1
Yield: 70 %

Procedure:
The mixture of 12.05 g of 5-hydroxymethyl-3-methoxy-isoxazole and 43 g of thionylchloride is heated to reflux for 30 minutes. After cooling, the reaction mixture is poured slowly over crushed ice and is extracted with ether. The organic phase is separated, washed with water and the solution is dried over magnesium sulfate. The solvent is evaporated then distilled in vacuo. 9.64 g of the expected product are obtained.
Reaction SMILES: C[O:2][C:3](=[O:43])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]4[N:23]([C:24](=[O:34])[C:25]5[C:30]([F:31])=[CH:29][C:28]([F:32])=[CH:27][C:26]=5[F:33])[N:22]=[C:21]([C:35]5[CH:40]=[CH:39][C:38]([F:41])=[C:37]([F:42])[CH:36]=5)[S:20]4)[C:13]=3[N:14]=2)[CH:5]=1.[Li+].[OH-].Cl>C1COCC1.CO>[F:42][C:37]1[CH:36]=[C:35]([C:21]2[S:20][CH:19]([C:15]3[C:13]4[N:14]=[C:10]([C:6]5[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=5)[C:3]([OH:43])=[O:2])[O:11][C:12]=4[CH:18]=[CH:17][CH:16]=3)[N:23]([C:24](=[O:34])[C:25]3[C:26]([F:33])=[CH:27][C:28]([F:32])=[CH:29][C:30]=3[F:31])[N:22]=2)[CH:40]=[CH:39][C:38]=1[F:41]
Reactant: COC(=O)c1cccc(-c2nc3c(C4SC(c5ccc(F)c(F)c5)=NN4C(=O)c4c(F)cc(F)cc4F)cccc3o2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cccc(-c2nc3c(C4SC(c5ccc(F)c(F)c5)=NN4C(=O)c4c(F)cc(F)cc4F)cccc3o2)c1

Procedure:
3-{4-[5-(3,4-Difluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-benzooxazol-2-yl}-benzoic acid methyl ester (0.02 mmol) is dissolved in THF/MeOH (1 mL/0.5 mL) and treated with aqueous LiOH (1 M) (0.5 mL) at room temperature for 30 minutes. Aqueous HCl (3 M) is added to adjust the pH to 5-6. The solvent is removed and the residue is purified by preparative HPLC (20-100% MeCN/H2O) to yield 3-{4-[5-(3,4-difluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-benzooxazol-2-yl}-benzoic acid: 1H NMR (400 MHz, CDCl3) 8.95 (s, 1H), 8.48 (d, J=7.9 Hz, 1H), 8.27 (d, J=7.8 Hz, 1H), 7.92 (s, 1H), 7.66 (t, J=7.8 Hz, 1H), 7.6 (dd, J1=7.7 Hz, J2=1.2 Hz, 1H), 7.46 (m, 1H), 7.29-7.42 (m, 3H), 7.19 (q, J=8.2 Hz, 1H), 6.76-6.81 (m, 2H); LC/MS (ES+): (M+1) 596.0, (M+Na) 618.0.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]1[CH:22]=[CH:21][C:6]([C:7]([N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C@H:12]([NH2:19])[CH2:11][C@@H:10]2[CH3:20])=[O:8])=[CH:5][CH:4]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.N1C=CC=CC=1.C(OCC)(=O)C>CN(C=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:23][N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([C:7]([N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C@H:12]([NH:19][C:28]3[CH:29]=[CH:30][C:25]([Cl:24])=[CH:26][CH:27]=3)[CH2:11][C@@H:10]2[CH3:20])=[O:8])=[CH:21][CH:22]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: C[C@H]1C[C@@H](N)c2ccccc2N1C(=O)c1ccc(N(C)C)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: C[C@H]1C[C@@H](Nc2ccc(Cl)cc2)c2ccccc2N1C(=O)c1ccc(N(C)C)cc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of (±)-cis-1-(4-dimethylamino-benzoyl)-2-methyl-1,2,3,4-tetrahydro-4-aminoquinoline (423 mg, 1.36 mmol) in DMF (15 mL, dry) was added 4-chlorophenylboronic acid (425 mg, 2.72 mmol), pyridine (322 mg, 330 uL, 4.08 mmol) and copper(II)acetate (494 mg, 2.72 mmol). The heterogeneous green mixture was stirred open to air for 1 h and then warmed to 60° C. and stirred over night (14 h). The mixture was then cooled to rt, poured into rapidly stirred ethyl acetate (150 mL); solids were removed by filtration. The extracts were washed several times with water and then once with brine.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([CH3:9])[N:3]=1.[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[CH2:18][NH:19][C:20]([CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:21].C(N(C(C)C)CC)(C)C>C(#N)C>[Cl:8][C:6]1[N:5]=[C:4]([CH3:9])[N:3]=[C:2]([N:25]2[CH2:26][CH2:27][CH:22]([C:20]([NH:19][CH2:18][C:12]3[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:11]=3[Cl:10])=[O:21])[CH2:23][CH2:24]2)[N:7]=1
Reactant: Cc1nc(Cl)nc(Cl)n1
Reactant: O=C(NCc1ccc(Cl)cc1Cl)C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1nc(Cl)nc(N2CCC(C(=O)NCc3ccc(Cl)cc3Cl)CC2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 51.6 %

Procedure:
To a 25 mL round-bottomed flask was added 2,4-dichloro-6-methyl-1,3,5-triazine (800 mg, 2.79 mmol) and N-[(2,4-dichlorophenyl)methyl]-4-piperidinecarboxamide (859 mg, 2.79 mmol) in acetonitrile (8.7 mL). Diisopropylethylamine (1.46 mL, 8.36 mmol) was added to give a yellow suspension. The reaction mixture was stirred at room temperature for 15 minutes, at which time LC-MS showed the reaction was complete. This suspension was filtered through a Buchner funnel to afford 1-(4-chloro-6-methyl-1,3,5-triazin-2-yl)-N-[(2,4-dichlorophenyl)methyl]-4-piperidinecarboxamide (596 mg, 1.44 mmol, 52%) as a white solid which was used in the next step without further purification. MS (ES) m/e 416 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13](=[O:15])[CH3:14].[N:16]1([CH2:21][CH2:22][C:23]2[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=2)[NH2:26])[CH2:20][CH2:19][CH2:18][CH2:17]1>>[Cl:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:13](=[O:15])[CH3:14])=[C:2]2[NH:26][C:25]1[CH:27]=[CH:28][CH:29]=[C:23]([CH2:22][CH2:21][N:16]2[CH2:17][CH2:18][CH2:19][CH2:20]2)[CH:24]=1
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Cl
Reactant: Nc1cccc(CCN2CCCC2)c1
Product: CC(=O)c1cnc2ccc(Cl)nc2c1Nc1cccc(CCN2CCCC2)c1
Yield: 58.2 %

Procedure:
Following general procedure I, 1-(4,6-dichloro-1,5-naphthyridin-3-yl)ethanone (250 mg, 1.0 mmol) was reacted with 3-[2-(pyrrolidin-1-yl)ethyl]aniline (240 mg, 1.3 mmol) to afford the desired product (230 mg, 57%) as a yellow solid: 1H NMR (500 MHz, CDCl3) δ 10.79 (br s, 1H), 8.99 (s, 1H), 8.16 (d, J=8.7 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H), 7.29-7.20 (m, 1H), 7.07 (d, J=7.7 Hz, 1H), 7.03-6.96 (m, 2H), 2.85-2.77 (m, 2H), 2.72-2.66 (m, 2H), 2.59-2.49 (m, 4H), 2.53 (s, 3 H), 1.84-1.74 (m, 4H); ESI MS m/z 395 [M+H]+
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C1(C)C=CC=CC=1.[C:12]([NH:20][C:21]1[CH:29]=[C:28]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:37]C)[CH:32]=2)[CH:27]=[CH:26][C:22]=1[C:23]([OH:25])=[O:24])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>C(OCC)(=O)C>[C:12]([NH:20][C:21]1[CH:29]=[C:28]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([OH:37])[CH:32]=2)[CH:27]=[CH:26][C:22]=1[C:23]([OH:25])=[O:24])(=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COc1cccc(Oc2ccc(C(=O)O)c(NC(=O)c3ccccc3)c2)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C(Nc1cc(Oc2cccc(O)c2)ccc1C(=O)O)c1ccccc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 56.2 %

Procedure:
0.22 g of aluminum chloride was added to 1.0 ml of toluene solution containing 0.10 g of 2-(benzamido)-4-(3-methoxyphenoxy)benzoic acid at room temperature and stirred at 80° C. for 8 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 1.0 mol/b hydrochloric acid were added. The organic layer was separated, and dried over anhydrous magnesium sulfate after washed with 1.0 mol/L hydrochloric acid and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane:ethyl acetate; acetic acid=15:10:1]to obtain 54 mg of 2-(benzamido)-4-(3-hydroxyphenoxy)benzoic acid as white solid.