Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([C:13]2[CH:18]=[CH:17][C:16](OC)=[CH:15][CH:14]=2)=[CH:10]OC)[C:5]([NH2:8])=[N:6][CH:7]=1.Cl(O)(=O)(=O)=O.[O:26]1CCOC[CH2:27]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[O:26][CH3:27])=[CH:10][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: C1COCCO1
Reactant: COC=C(c1ccc(OC)cc1)c1cc(Br)cnc1N
Agent: [O-][Cl+3]([O-])([O-])O
Product: COc1ccccc1-c1c[nH]c2ncc(Br)cc12
Temperature: 100 °C
Yield: 82 %

Procedure:
A 50 ml round bottomed flask was charged with 403 mg of 5-bromo-3-[2-methoxy-1-(4-methoxy-phenyl)-vinyl]-pyridin-2-ylamine (1.2 mmol; combined E- and Z-isomers), 1,4-dioxane (5 ml), and 70% aqueous perchloric acid (250 μl). The flask was fitted with a reflux condenser and nitrogen inlet adapter and heated in an oil bath to 100° C. for 8 hours. The reaction mixture was concentrated, then treated with 15 ml of a saturated aqueous solution of sodium bicarbonate followed by ethyl acetate (20 ml). The layers were separated, and the aqueous fraction was extracted twice with ethyl acetate. The combined organic fractions were washed with brine, dried (Na2SO4), filtered, and concentrated. The residue was triturated with ether to afford 300 mg (82%) of 5-bromo-3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine as a tan powder. 1H-NMR (d6-DMSO) δ=12.16 (br. s, 1H), 8.36 (d, 1H), 8.18 (d, 1H), 7.82 (d, 1H), 7.58 (d, 1H), 7.36 (t, 1H), 7.19 (d, 1H),7.10 (t, 1H), 3.88 (s, 3H); MS m/z: 303 [MH]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.Cl.[CH2:10]([O:12][NH2:13])[CH3:11]>CO>[CH2:10]([O:12][N:13]=[CH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH3:11]
Reactant: CCON
Reactant: O=Cc1cccnc1
Agent: Cl
Solvent: CO
Product: CCON=Cc1cccnc1
Yield: 87.9 %

Procedure:
3-Pyridinecarboxaldehyde (10.7 100 mmol) and ethoxyamine, hydrochloride (10 g, 102.5 mmol) were dissolved in CH3OH (100 ml) and heated at reflux for three hours. The solvent was removed under vacuum and 10% aqueous Na2CO3 solution was added to the residue until the solution remained basic. The aqueous solution was extracted with EtOAc (3×100 ml), dried over MgSO4, filtered, and the solvent removed under vacuum. 13.2 g of 3-pyridinecarboxaldehyde-O-ethyloxime as a clear liquid was obtained 88% yield.
Reaction SMILES: [BH4-].[Na+].[N:3]1[CH:4]=[CH:5][N:6]2[C:11]=1[CH:10]=[CH:9][C:8]([C:12](OC)=[O:13])=[N:7]2>C1COCC1.CO>[N:3]1[CH:4]=[CH:5][N:6]2[C:11]=1[CH:10]=[CH:9][C:8]([CH2:12][OH:13])=[N:7]2
Reactant: COC(=O)c1ccc2nccn2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: OCc1ccc2nccn2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.2 %

Procedure:
Sodium borohydride (1.1 g, 31.1 mmol) was added to a solution of methyl imidazo[1,2-b]pyridazine-6-carboxylate (2.4 g, 15.5 mmol) in THF (35 mL) and methanol (2.5 ml) at RT. The reaction mixture was stirred at RT for 2 h (the reaction was monitored by TLC) upon which the mixture was concentrated under reduced pressure. The reaction mixture was diluted with water and extracted with EtOAc. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford imidazo[1,2-b]pyridazin-6-ylmethanol (1.6 g, 81%,) as a white solid. 1H NMR: 200 MHz, DMSO-d6: δ 8.5 (s, 1H), 8.3 (d, 1H), 7.9 (s, 1H), 7.55 (d, 1H), 5.65 (t, 1H), 4.6 (d, 2H). MS: [M+H]+: m/z=311.2.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[C@@H:14]([OH:15])[CH2:13][C@H:12]([N:16]2[CH:24]=[N:23][C:22]3[C:17]2=[N:18][CH:19]=[N:20][C:21]=3[CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].[CH3:35]I>C1COCC1>[Si:1]([O:8][CH2:9][C@H:10]1[O:11][C@@H:12]([N:16]2[CH:24]=[N:23][C:22]3[C:17]2=[N:18][CH:19]=[N:20][C:21]=3[CH2:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:13][C@@H:14]1[O:15][CH3:35])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(CCc4ccccc4)ncnc32)C[C@@H]1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CO[C@H]1C[C@H](n2cnc3c(CCc4ccccc4)ncnc32)O[C@@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 65 %

Procedure:
To a solution of (2R,3S,5R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-[6-(2-phenylethyl)-9H-purin-9-yl]tetrahydrofuran-3-ol (98 mg, 0.22 mmol) in THF (1.5 mL) at 0° C. was added NaH (60% in oil, 13 mg, 0.33 mmol) and the suspension stirred for 10 minutes. MeI (26 μL, 0.26 mmol) was added dropwise and the reaction was warmed to room temperature. After one hour the reaction was quenched with saturated aq NH4Cl, partitioned between brine and EtOAc, separated, and the aq layer was extracted with EtOAc (5×). The combined organics were washed with brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by flash chromatography (20 to 50% EtOAc/hexanes) to give the title compound (67 mg, 65%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[C:20]2[C:6]([C:7](=[O:23])[C:8](=[O:22])[C:9]3[S:19][CH2:18][C:12]4([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]4)[O:11][C:10]=32)=[CH:5][CH:4]=1.[Cl:24][C:25]1[CH:35]=[CH:34][C:28]([O:29][CH2:30][C@@H:31]2[CH2:33][O:32]2)=[CH:27][CH:26]=1>>[Cl:24][C:25]1[CH:35]=[CH:34][C:28]([O:29][CH2:30][C@@H:31]([OH:32])[CH2:33][N:15]2[CH2:16][CH2:17][C:12]3([O:11][C:10]4[C:20]5[C:6]([C:7](=[O:23])[C:8](=[O:22])[C:9]=4[S:19][CH2:18]3)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:21]=5)[CH2:13][CH2:14]2)=[CH:27][CH:26]=1
Reactant: Clc1ccc(OC[C@@H]2CO2)cc1
Reactant: COc1ccc2c(c1)C1=C(SCC3(CCNCC3)O1)C(=O)C2=O
Product: COc1ccc2c(c1)C1=C(SCC3(CCN(C[C@H](O)COc4ccc(Cl)cc4)CC3)O1)C(=O)C2=O

Procedure:
Compound 210 was synthesized using 9-methoxyspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (2S)-2-[(4-chlorophenoxy)methyl]oxirane and conditions outlined in procedure Y. M.p.=109-110° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.88 (d, J=8.8 Hz, 1H), 7.32 (d, J=8.8 Hz, 2H), 7.21 (brs, 1H), 7.10 (dd, 1H), 6.97 (d, J=9.2 Hz, 2H), 4.84 (s, 1H), 3.98 (brm, 6H), 3.07 (s, 2H), 2.80 (m, 2H), 2.41 (m, 4H), 1.99 (m, 2H), 1.82 (m, 2H); LCMS: 516 [M+H].
Reaction SMILES: C1(S[CH2:8][N:9]2[C:13](=[O:14])[CH:12]([CH2:15][CH2:16][C:17]([CH3:20])([Cl:19])[CH3:18])[N:11]([CH3:21])[S:10]2(=[O:23])=[O:22])C=CC=CC=1.S(Cl)([Cl:27])(=O)=O>C(Cl)Cl>[Cl:27][CH2:8][N:9]1[C:13](=[O:14])[CH:12]([CH2:15][CH2:16][C:17]([CH3:20])([Cl:19])[CH3:18])[N:11]([CH3:21])[S:10]1(=[O:23])=[O:22]
Reactant: O=S(=O)(Cl)Cl
Reactant: CN1C(CCC(C)(C)Cl)C(=O)N(CSc2ccccc2)S1(=O)=O
Solvent: ClCCl
Product: CN1C(CCC(C)(C)Cl)C(=O)N(CCl)S1(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.4 %

Procedure:
To a solution of 2-phenylthiomethyl-4-(3-methyl-3-chlorobutyl)-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (1. 396 g, 3.82 mmol) in 30 ml of methylene chloride was added sulfuryl chloride (0.366 ml, 4.58 mmol) and the mixture was stirred for 2 hours at room temperature. The mixture was concentrated in vacuo and the residue was purified by silica column chromatography (10% ethyl acetate in hexane) to afford 410 mg (35.4%) of 2-chloromethyl-4-(3-methyl-3-chlorobutyl)-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula II: R1 =H; R2 =(CH2)2C(Cl) (CH3)2 ; R3 =CH3 ; X'=Cl).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O.[Br-].[CH2:24]([O:26][C:27]1[CH:52]=[CH:51][CH:50]=[C:49]([O:53][CH2:54][CH3:55])[C:28]=1[CH2:29][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:25].CC(C)([O-])C.[K+]>C1COCC1>[CH2:54]([O:53][C:49]1[CH:50]=[CH:51][CH:52]=[C:27]([O:26][CH2:24][CH3:25])[C:28]=1/[CH:29]=[CH:18]/[C:17]1[CH:16]=[C:15]([CH2:14][CH2:13][CH2:12][N:3]2[C:4](=[O:11])[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2]2=[O:1])[CH:22]=[CH:21][CH:20]=1)[CH3:55]
Reactant: CCOc1cccc(OCC)c1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cccc(CCCN2C(=O)c3ccccc3C2=O)c1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOc1cccc(OCC)c1/C=C/c1cccc(CCCN2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an ice-cold mixture of phthalimide 29 (0.440 g, 1.5 mmol) in THF (25 mL) was added (2,6-diethoxybenzyl)triphenylphosphonium bromide (0.860 g, 1.65 mmol) and potassium tert-butoxide (0.336 g, 3.0 mmol) portionwise. The reaction was allowed to warm to room temperature and stirred for 2 h. The mixture was then quenched with water and extracted with EtOAc. The combined organics were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (7% EtOAc-hexanes) gave (E)-2-(3-(3-(2,6-diethoxystyryl)phenyl)propyl)isoindoline-1,3-dione as a brown oil. Yield (0.055 g, 8%): 1H NMR (400 MHz, CDCl3) δ 7.80-7.83 (m, 2H), 7.67-7.70 (m, 2H), 7.62 (d, J=16.8 Hz, 1H), 7.45 (d, J=16.8 Hz, 1H), 7.29-7.31 (m, 1H), 7.22 (t, J=7.6 Hz, 1H), 7.17 (d, J=6.4 Hz, 1H), 7.11 (t, J=8.4 Hz, 1H), 7.06 (d, J=7.2 Hz, 1H), 6.60 (d, J=8.4 Hz, 2H), 4.11 (dt, J=7.2, 6.8 Hz, 4H), 3.78 (t, J=7.2 Hz, 2H), 2.71 (t, J=7.6 Hz, 2H), 2.03-2.11 (m, 2H), 1.50 (t, J=7.2 Hz, 6H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11]C(=O)C)=[C:7]([N+:15]([O-:17])=[O:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+]>CO>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([N+:15]([O-:17])=[O:16])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)Nc1ccc(C(C)(C)C)cc1[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1ccc(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.2 %

Procedure:
A reactor was charged with methanol (13.5 L) and N-(4-tert-butyl-2-nitrophenyl) acetamide (Preparation 109, 7.0 kg, 29.6 mol). The mixture was stirred for ten minutes then a solution of 30% sodium methoxide in methanol (6.49 L, 35.5 mol) was added slowly at room temperature. The mixture was heated slowly to reflux and held at that temperature for two hours. The methanol was distilled to dryness under vacuum at 50-55° C. and the solids cooled to room temperature. The residue was stirred in water (35 L) for one hour and the solids collected by filtration, washed with water (14 L), and dried at 45-50° C. to provide 5.3 kg of the title compound.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][CH:11]=[C:12]([CH2:14][N:15]3[CH:19]=[CH:18][N:17]=[N:16]3)[N:13]=2)=[CH:5][CH:4]=1.N>Br>[N:15]1([CH2:14][C:12]2[N:13]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=3)[S:10][CH:11]=2)[CH:19]=[CH:18][N:17]=[N:16]1
Reactant: COc1ccc(-c2nc(Cn3ccnn3)cs2)cc1
Agent: Br
Agent: N
Product: Oc1ccc(-c2nc(Cn3ccnn3)cs2)cc1
Yield: 22.2 %

Procedure:
A solution of 1.36 g (5.0 mmol) 1-[2-(4-methoxy-phenyl)-thiazol-4-ylmethyl]-1H-[1,2,3]triazole in 100 ml 47% aqueous hydrobromic acid was stirred at 70° C. for 6 h. The reaction mixture was poured on ice, made basic with concentrated ammonia and extracted with ethyl acetate to yield 0.87 g raw product. This was purified on silica. Elution with ethyl acetate/heptane 1:1 furnished 287 mg (22%) 4-(4-[1,2,3]triazol-1-ylmethyl-thiazol-2-yl) -phenol as white crystals, melting at 164-166° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[O:7][C@@H:6]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][C@@H:4]([CH2:16][O:17]C(C)=O)[O:3]1.C(=O)([O-])[O-].[K+].[K+]>CO>[OH:17][CH2:16][C@H:4]1[O:3][C:2]([CH3:1])([CH3:21])[O:7][C@@H:6]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5]1
Reactant: CC(=O)OC[C@@H]1C[C@H](CC(=O)OC(C)(C)C)OC(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CO)OC(C)(C)O1
Yield: 99.8 %

Procedure:
In 100 mL of methanol was dissolved 10 g (33.1 mmol) of tert-butyl 2-{(4R,6S)-2,2-dimethyl-6-[(methylcarbonyloxy)methyl]-1,3-dioxan-4-yl}acetate [synthesized by the process described in Example 8], and under ice-cooling and stirring, 0.46 g (3.3 mmol) of potassium carbonate was added. The mixture was further stirred under ice-cooling for 4 hours. From this reaction mixture, the reaction solvent was distilled off by heating under reduced pressure, and the residue was diluted with 50 mL of water and neutralized with 0.1 N-hydrochloric acid. This solution was extracted with ethyl acetate and the resulting organic layer was washed with water and dehydrated over anhydrous sodium sulfate. The solvent was then distilled off by heating under reduced pressure. The oily residue was decompressed to 1 Torr or less with a vacuum pump to remove the solvent almost thoroughly. As a result, 8.6 g of tert-butyl 2-[(4R,6S)-6-(hydroxymethyl)-2,2-dimethyl-1,3-dioxan-4-yl]acetate (colorless oil) was obtained in a yield of 100%.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([NH2:12])[C:7]1[O:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C(Cl)Cl.C(OCC)(=O)C>[O:11]1[CH:10]=[CH:9][CH:8]=[C:7]1[CH2:6][NH:12][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: NCc1ccco1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CS(=O)(=O)NCc1ccco1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
Methanesulfonyl chloride (3.2 mL, 42 mmol) was slowly added to a stirring solution of furfurylamine (4.2 g, 43.2 mmol) and triethylamine (6 mL, 43 mmol) in anhydrous methylene chloride (110 mL). The reaction was stirred overnight at ambient temperature and then diluted with ethyl acetate. The organic solution was successively washed with 1N aqueous hydrochloric acid three times, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride solutions, dried (anhydrous sodium sulfate), and filtered. The solution was concentrated under reduced pressure to give the desired product as a tan liquid (6.6 g, 89%). 1H NMR (CDCl3, 300 MHz) δ 7.39-7.38 (m, 1H), 6.33-6.31 (m, 2H), 5.02 (br s, 1H), 4.33-4.31 (d, 2H, J=6 Hz).
Reaction SMILES: [OH-].[Na+].[C:3]([NH:22][C:23]1[CH:33]=[CH:32][CH:31]=[CH:30][C:24]=1[C:25]([O:27]CC)=[O:26])(=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>C(O)C>[C:3]([NH:22][C:23]1[CH:33]=[CH:32][CH:31]=[CH:30][C:24]=1[C:25]([OH:27])=[O:26])(=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Nc1ccccc1C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCC(=O)Nc1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.9 %

Procedure:
A sodium hydroxide solution (NaOH 0.14 g / water 2 ml) was added to a solution of ethyl 2-(octadecanoylamino)benzoate (1.00 g) in ethanol (10 ml). After being stirred for 4 hours at room temperature, the reaction mixture was concentrated. The residue, with ethyl acetate added thereto, was washed with diluted hydrochloric acid, water and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. The residue was recrystallized from hexane-ethyl acetate mixed solution, thereby yielding 0.85 g of the aimed compound as colorless crystals.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:7][CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]1=[O:17])[C:4]([OH:6])=[O:5].C1(N=C=NC2CCCCC2)CCCCC1.[Cl:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][CH:35]=1.CCOCC>O1CCOCC1.C(Cl)(Cl)Cl>[Cl:33][C:34]1[CH:42]=[CH:41][C:37]([C:38]([NH:2][CH:3]([CH2:7][CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]2=[O:17])[C:4]([OH:6])=[O:5])=[O:39])=[CH:36][CH:35]=1
Reactant: NC(CC1C(=O)Nc2ccccc21)C(=O)O
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: O=C(NC(CC1C(=O)Nc2ccccc21)C(=O)O)c1ccc(Cl)cc1
Reaction time: 5 h

Procedure:
1.14 Grams of 2-amino-3-(oxindol-3-yl)propionic acid hydrochloride prepared in Reference Example 1, 1.3 g of dicyclohexylcarbodiimide (DCC) and 1.0 g of p-chlorobenzoic acid were suspended in 10 ml of dioxane, then the suspension was stirred at 60°-70° C. for 5 hours. After the reaction was completed, the solvent was removed by evaporation, to the residue thus obtained was added ether, and the crystals formed were removed by filtration. The filtrate obtained was concentrated, then the residue thus obtained was dissolved by adding chloroform, the chloroform solution was washed with water and a saturated sodium chloride aqueous solution. The chloroform solution was dried with anhydrous sodium sulfate, and the solvent was removed by evaporation. The residue was recrystallized from methanol-water to obtain 290 mg of 2-(4-chlorobenzoylamino)-3-(oxindol-3-yl)propionic acid 1/4-hydrate in the form of colorless powdery substance. Melting
Reaction SMILES: [CH:1]1([CH2:4][NH:5][CH2:6][C:7]2[NH:8][C:9](=[O:17])[C:10]3[CH2:16][O:15][CH2:14][CH2:13][C:11]=3[N:12]=2)[CH2:3][CH2:2]1.[CH2:18]([O:25][C:26]1[CH:43]=[CH:42][C:29]([C:30]([CH:32]2[CH2:37][CH2:36][N:35]([CH2:38][C:39](O)=[O:40])[CH2:34][CH2:33]2)=[O:31])=[CH:28][CH:27]=1)[C:19]1C=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH:1]1([CH2:4][N:5]([CH2:6][C:7]2[NH:8][C:9](=[O:17])[C:10]3[CH2:16][O:15][CH2:14][CH2:13][C:11]=3[N:12]=2)[C:39](=[O:40])[CH2:38][N:35]2[CH2:34][CH2:33][CH:32]([C:30](=[O:31])[C:29]3[CH:28]=[CH:27][C:26]([O:25][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:43][CH:42]=3)[CH2:37][CH2:36]2)[CH2:3][CH2:2]1
Reactant: O=c1[nH]c(CNCC2CC2)nc2c1COCC2
Reactant: O=C(O)CN1CCC(C(=O)c2ccc(OCc3ccccc3)cc2)CC1
Product: O=C(c1ccc(Oc2ccccc2)cc1)C1CCN(CC(=O)N(Cc2nc3c(c(=O)[nH]2)COCC3)CC2CC2)CC1
Yield: 17.4 %

Procedure:
The title compound (30 mg) was prepared according to the general procedure of Example 1 from 2-[(cyclopropylmethyl-amino)-methyl]-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one (73 mg, 0.31 mmol) and [4-(4-benzyloxy-benzoyl)-piperidin-1-yl]-acetic acid (110 mg, 0.31 mmol). 1H NMR (400 MHz, MeOD) δ: 8.01 (d, J=9.1 Hz, 2H), 7.44 (d, J=7.1 Hz, 2H), 7.38 (t, J=7.1 Hz, 2H), 7.33 (d, J=7.1 Hz, 1H), 7.12 (d, J=9.1 Hz, 2H), 4.66 (s, 1H), 4.57 (s, 2H), 4.38 (s, 2H), 3.91 (t, J=5.6 Hz, 2H), 3.78-3.66 (m, 4H), 3.36 (d, J=7.1 Hz, 2H), 3.33-3.29 (m, 5H), 2.68-2.58 (m, 2H), 2.18-2.02 (m 4H), 1.11-0.87 (m, 1H), 0.65-0.43 (m, 2H), 0.32-0.21 (m, 2H). HRMS calculated for C33H38N4O5=571.2920. found (ESI, [M+H]+), 571.2949. LRMS m/z: ES+=571.1 (M+H), retention time 1.49.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([Br:9])=[CH:4][N:3]=1.[CH:10]1[C:18]2[C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[O:15][C:14]=2[C:13](B(O)O)=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+].C(COC)OC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Br:9][C:5]1[C:6]([CH3:8])=[CH:7][C:2]([C:22]2[C:16]3[O:15][C:14]4[CH:13]=[CH:12][CH:11]=[CH:10][C:18]=4[C:17]=3[CH:19]=[CH:20][CH:21]=2)=[N:3][CH:4]=1
Reactant: OB(O)c1cccc2c1oc1ccccc12
Reactant: Cc1cc(Br)ncc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1cc(-c2cccc3c2oc2ccccc23)ncc1Br
Temperature: 25 °C
Yield: 72.2 %

Procedure:
2,5-Dibromo-4-methylpyridine (30 g, 118 mmol), dibenzo[b,d]furan-4-ylboronic acid (25 g, 118 mmol), Pd(PPh3)4 (1.4 g, 1.18 mmol), and K2CO3 (49 g, 354 mmol) were added to a flask with dimethoxyethane (450 mL) and water (100 mL) and degassed with nitrogen. The reaction mixture was heated to reflux for 15 h before cooling to room temperature. EtOAc and water were added, the organic layer separated and the aqueous layer was extracted with 3×50 mL dichloromethane and dried over sodium sulfate. After removing the solvent under reduced pressure, the crude product was chromatographed on silica gel with dichloromethane and 29.7 g of crude product was obtained. The product was crystallized from hexane to give 28.8 g (72%) of pure product. The product was confirmed by NMR and HPLC (99.3% pure)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[C:8]([F:10])[C:7]([CH2:11][NH:12][CH:13]=[O:14])=[N:6][C:5]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([Si](C)(C)C)=[CH:18][C:17]=1[F:26].C1C(=O)N([Br:35])C(=O)C1>ClCCl>[CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[C:8]([F:10])[C:7]([CH2:11][NH:12][CH:13]=[O:14])=[N:6][C:5]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([Br:35])=[CH:18][C:17]=1[F:26]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(F)c(CNC=O)nc1Nc1ccc([Si](C)(C)C)cc1F
Solvent: ClCCl
Product: COC(=O)c1cc(F)c(CNC=O)nc1Nc1ccc(Br)cc1F
Temperature: -30 °C
Reaction time: 1.5 h
Yield: 94.3 %

Procedure:
To a solution of 5-fluoro-2-(2-fluoro-4-trimethylsilanyl-phenylamino)-6-formylaminomethyl-nicotinic acid methyl ester (2.6 g, 6.6 mmol) in dichloromethane (65 mL) at −30° C. was added NBS (1.2 g, 6.6 mmol). The reaction mixture was stirred at −30° C. for 1.5 hours, and then concentrated under reduced pressure The resultant residue was taken up in ethyl acetate and this organic solution was washed with a saturated aqueous solution of sodium bicarbonate, followed by brine, dried (Na2SO4), filtered and evaporated in vacuo to afford the title compound as a brown solid (2.49 g, 95%). LCMS (method B): RT=3.79 min, [M+H]+=400/402.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:22])=[C:6]([CH:21]=1)[CH2:7][N:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([O:19]C)=[O:18])=[CH:13][N:12]=1)[CH2:9][CH3:10].[OH-].[Na+]>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:22])=[C:6]([CH:21]=1)[CH2:7][N:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][N:12]=1)[CH2:9][CH3:10]
Reactant: CCN(Cc1cc(Br)ccc1O)c1ccc(C(=O)OC)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCN(Cc1cc(Br)ccc1O)c1ccc(C(=O)O)cn1
Temperature: 40 °C
Yield: 88 %

Procedure:
A solution of methyl 2-[N-(5-bromo-2-hydroxybenzyl)-N-ethylamino]pyridine-5-carboxylate (see reference example 7) (10.2 g, 0.55 mmol) in THF (3 ml) and methanol (5 ml) was treated with 1N aqueous sodium hydroxide solution (2.7 ml) and was heated to 40° C. for 24 hours. The solvents were evaporated at reduced pressure, the residue treated with 1N acetic acid (2.7 ml) and the precipitate filtered, washed with water and air dried to give the title compound (0.17 g, 92%).
Reaction SMILES: [C:1]([O:13]C)(=O)[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH3:15][C:16]([CH3:18])=[O:17].[H-].[Na+].Cl>C1(C)C=CC=CC=1.C(COC)OC.C1(C)C=CC=CC=1.O>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([C:1](=[O:13])[CH2:15][C:16](=[O:17])[CH3:18])=[CH:11][CH:10]=1
Reactant: CC(C)=O
Reactant: COC(=O)c1ccc(C(=O)OC)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1ccc(C(=O)CC(C)=O)cc1
Temperature: 100 °C
Yield: 24.5 %

Procedure:
A solution of dimethyl terephthalate (10 g, 51.5 mmole) and acetone (4.15 mL, 56.6 mmole) in a mixture of toluene/dimethoxyethane (75 mL/25 mL) was added to a suspension of NaH 60% (2.68 g, 66.9 mmole) in dry toluene (25 mL) under argon. The mixture was heated at 100° C. for 4 hours. The reaction mixture was cooled to rt and 25 mL of water were added. The pH was adjusted to 3-4 with HCl 2N and the mixture was poured into water (300 mL). The aqueous mixture was extracted with ethyl acetate (3×150 mL), dried over sodium sulphate and evaporated to afford a yellow solid which was purified by column cromatography (n-Hex/EtOAc 9:1 to 7:3) to afford the title compound (2.78 g, 25% yield) as a yellow solid.