Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C@H:10]2[O:19][C@H:13]3[O:14][C:15]([CH3:18])([CH3:17])[O:16][C@H:12]3[C@H:11]2[CH2:20][CH2:21][N:22]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]2=[O:32])=[CH:4][CH:3]=1.[CH3:33][O:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][N:36]=1.C(=O)([O-])[O-].[K+].[K+]>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>[CH3:33][O:34][C:35]1[N:36]=[CH:37][C:38]([C:2]2[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C@H:10]3[O:19][C@H:13]4[O:14][C:15]([CH3:17])([CH3:18])[O:16][C@H:12]4[C@H:11]3[CH2:20][CH2:21][N:22]3[C:23](=[O:32])[C:24]4[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:30]3=[O:31])=[CH:6][CH:7]=2)=[CH:39][CH:40]=1
Reactant: CC1(C)O[C@@H]2O[C@H](/C=C/c3ccc(Br)cc3)[C@H](CCN3C(=O)c4ccccc4C3=O)[C@@H]2O1
Reactant: COc1ccc(B(O)O)cn1
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+]
Product: COc1ccc(-c2ccc(/C=C/[C@H]3O[C@H]4OC(C)(C)O[C@H]4[C@H]3CCN3C(=O)c4ccccc4C3=O)cc2)cn1
Temperature: 120 °C

Procedure:
A mixture of the compound obtained from step d above (1 g), 2-methoxy-5-pyridine boronic acid (0.614 g), tetrakistriphenylphosphinepalladium (0) (0.115 g), and potassium carbonate (0.832 g) was dried under high vacuum for 10 minutes, and dry dimethylformamide (8 mL) was added at room temperature. The reaction mixture was heated at 120° C. for 2 hours, and then quenched with water and extracted with ethyl acetate. The organic layer was washed with water and brine solution, and dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure to obtain a residue which was purified by column chromatography over silica gel using 30% ethyl acetate in hexane as eluant to afford the title compound (0.62 g).
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]1C[O:18][CH2:17][CH2:16]1.[Li][CH2:21]CCC>O>[CH2:1]([O:8][CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[C:11]1[CH:17]([OH:18])[CH:16]([CH3:15])[CH3:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [Li]CCCC
Reactant: C1CCOC1
Reactant: c1ccc(COCn2ccnc2)cc1
Solvent: O
Product: CC(C)C(O)c1nccn1COCc1ccccc1
Temperature: -40 °C
Reaction time: 0.25 h
Yield: 69 %

Procedure:
1-benzyloxymethylimidazole prepared according to the procedure of Ngochindo, R., J. Chem. Res. (S), 58 (1990)) (3.76 g, 20 mmol), and THF (40 mL) at -40° C., was treated dropwise with n-BuLi (8.4 mL, 21 mmol, 2.5M in hexane). The resulting solution was stirred at -40° C. for 15 min, and i-butyraldehyde (2.0 mL, 22 mmol) was added dropwise. The reaction was stirred at -40° C. for 1.5 h, 0° C. for 1 h, warmed to 23° C., poured into H2O, and extracted with EtOAc. The combined ekhracts were washed with brine, dried (Na2 SO4) and concentrated in vacuo. Trituration of the residue with Et2O/hexane gave a white solid which was dried in vacuo overnight to afford of the title compound (3.57 g, 69%). 1H NMR(CDCl3, 400 MHz) δ 7.28 (m, 5H), 6.97 (s, 1H), 6.92 (s, 1H), 5.23 (d, 1H, J=12 Hz), 5.42 (d, 1H, J=12 Hz), 4.48 (s, 2H), 4.44 (d, 1H, J=9 Hz), 2.21 (m, 1H), 1.02 (d, 3H, J=7 Hz), 0.83 (d, 3H, J=7 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[C:13]([F:15])([F:14])[C:12]([CH3:17])([CH3:16])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[F:21][CH:22]([F:34])[CH2:23][O:24][C:25]1[CH:26]=[CH:27][C:28]([C:31](O)=[O:32])=[N:29][CH:30]=1>>[NH2:18][C:10]1[O:11][C:12]([CH3:16])([CH3:17])[C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:31]([C:28]3[CH:27]=[CH:26][C:25]([O:24][CH2:23][CH:22]([F:34])[F:21])=[CH:30][N:29]=3)=[O:32])[CH:3]=[CH:4][C:5]=2[F:20])([CH3:19])[N:9]=1
Reactant: CC1(C)OC(N)=N[C@](C)(c2cc(N)ccc2F)C1(F)F
Reactant: O=C(O)c1ccc(OCC(F)F)cn1
Product: CC1(C)OC(N)=N[C@](C)(c2cc(NC(=O)c3ccc(OCC(F)F)cn3)ccc2F)C1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-2) and 5-(2,2-difluoro-ethoxy)-pyridine-2-carboxylic acid (CAS1097730-45-4, WO2009091016) following procedure I yielded the title compound as a white solid. MS (ISP): m/z=473.1 [M+H]+.
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:10]2[CH:11]=[C:12]([C:16]([O:18]C)=[O:17])[S:13][C:14]=2[CH3:15])[N:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[N:5]2.C1COCC1.[OH-].[K+]>CO>[N:1]1[CH:2]=[C:3]([C:10]2[CH:11]=[C:12]([C:16]([OH:18])=[O:17])[S:13][C:14]=2[CH3:15])[N:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[N:5]2
Reactant: COC(=O)c1cc(-c2cnc3cccnn23)c(C)s1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1sc(C(=O)O)cc1-c1cnc2cccnn12
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Methyl 4-(imidazo[1,2-b]pyridazin-3-yl)-5-methylthiophene-2-carboxylate (0.54 g, 1.98 mmol) was dissolved in methanol (9.88 mL) and THF (9.88 mL) and a solution of KOH in methanol was added (1 M, 5.93 mL, 5.93 mmol). The reaction mixture was left to stir overnight at 60° C. The reaction mixture was then cooled to room temperature, concentrated, and acidified with aqueous 1N HCl. The aqueous layer was extracted three times with ethyl acetate, then extracted one time with a 3:1 CHCl3:isopropanol mixture. The combined organics were dried with magnesium sulfate, filtered, and concentrated to afford the title compound. 1H NMR (500 MHz, CD3SOCD3) δ 8.77 (d, 1H); 8.34 (d, 1H); 8.25 (s, 1H); 8.11 (s, 1H); 7.51 (dd, 1H); 2.56 (s, 3H). LRMS (APCI) calc'd for (C12H9N3O2S) [M+H]+, 260.0. found 260.0.
Reaction SMILES: [CH3:1][C:2]([CH3:17])([CH2:15][OH:16])[CH:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)[OH:4].C(N(CC)CC)C.[P:25](Cl)(Cl)([Cl:27])=[O:26].O>ClCCl>[Cl:27][P:25]1(=[O:26])[O:4][CH:3]([C:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7][CH:6]=2)[C:2]([CH3:17])([CH3:1])[CH2:15][O:16]1
Reactant: CC(C)(CO)C(O)c1cccc2ccccc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC1(C)COP(=O)(Cl)OC1c1cccc2ccccc12
Temperature: 3 °C
Reaction time: 1.5 h
Yield: 67.8 %

Procedure:
2,2-Dimethyl-1-(1-naphthyl)-1,3-propanediol (83.6 g, 0.363 mol) and triethylamine (103.0 g, 1.018 mol) were dissolved in dichloromethane (300 ml). Phosphorus oxychloride (55.4 g, 0.361 mol) dissolved in dichloromethane (80 ml) was added dropwise to the solution above under cooling (2 to 4° C.) and with stirring for 1.5 hr. The solution was stirred at the same temperature for 1 hr, and water (150 ml) was added thereto to partition. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. To the obtained dark brown oil was added diethylether (100 ml) and diisopropylether (100 ml) and the mixture was stirred thoroughly and then ice-cooled for 1 hr. The upper layer containing a large amount of unreacted 1-naphthoaldehyde was removed by decantation and the under layer was concentrated to give the title compound as a black tar (76.1 g, yield 67.8%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C@H:14]3[O:18][C:17]([CH3:20])([CH3:19])[N:16]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@@H:15]3[CH2:28][F:29])=[CH:10][CH:9]=2)[O:5][N:4]=1.[S:30](Cl)([CH3:33])(=[O:32])=[O:31].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:29][CH2:28][C@@H:15]1[C@@H:14]([C:11]2[CH:10]=[CH:9][C:8]([C:6]3[O:5][N:4]=[C:3]([CH2:2][NH:1][S:30]([CH3:33])(=[O:32])=[O:31])[CH:7]=3)=[CH:13][CH:12]=2)[O:18][C:17]([CH3:19])([CH3:20])[N:16]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]
Reactant: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(-c3cc(CN)no3)cc2)OC1(C)C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(-c3cc(CNS(C)(=O)=O)no3)cc2)OC1(C)C
Temperature: 0 °C
Yield: 97.1 %

Procedure:
To a methylene chloride (10 ml) solution of (4S,5R)-tert-butyl 5-(4-(3-(aminomethyl)isoxazol-5-yl)phenyl)-4-(fluoromethyl)-2,2-dimethyloxazolidine-3-carboxylate (270 mg, 0.66 mmol) that had been cooled to 0° C. is added mesyl chloride (83 mg, 0.73 mmol) and diisopropylethylamine (94 mg, 0.73 mmol) sequentially. The reaction is stirred at 0° C. for thirty minutes then quenched with water (2 ml). The quenched reaction is stirred for thirty minutes at room temperature. The organic phase is dried over sodium sulfate and concentrated to give the title compound (310 mg): m/z (CI) 484 ([M+H]+.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[C:14]1(=O)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.[C-:21]#[N:22].[K+]>O>[C:21]([C:1]1([N:7]2[CH2:12][CH2:11][N:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)#[N:22]
Reactant: [C-]#N
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=C1CCCCC1
Agent: Cl
Agent: [K+]
Solvent: O
Product: N#CC1(N2CCN(c3ccccc3)CC2)CCCCC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 71.8 %

Procedure:
1-Phenylpiperazine (11.3 mL, 12 g, 75 mmol) was suspended in 100 mL water. The pH was adjusted to 3 using 10% HCl. Cyclohexanone (7.8 mL, 7.4 g, 75 mmol) was added followed by KCN (5 g, 75 mmol). The mixture was stirred 15 hours at room temperature during which time the product solidified. The product was collected by filtration, washed with water, then recrystallized from ethanol to give 14.5 g of 1-Cyano-1-(4-phenylpiperazin-1-yl)-cyclohexane as a white solid (73% yield), mp=133-135° C.
Reaction SMILES: C1N2CN3CN(C2)CN1C3.[CH3:11][O:12][C:13]1[CH:30]=[CH:29][CH:28]=[CH:27][C:14]=1[CH2:15][NH:16][C:17](=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25].FC(F)(F)[C:33](O)=[O:34]>>[CH:33]([C:28]1[CH:29]=[CH:30][C:13]([O:12][CH3:11])=[C:14]([CH:27]=1)[CH2:15][NH:16][C:17](=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25])=[O:34]
Reactant: COc1ccccc1CNC(=O)c1ccc(Cl)cc1Cl
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Product: COc1ccc(C=O)cc1CNC(=O)c1ccc(Cl)cc1Cl
Temperature: 50 °C
Reaction time: 23 h

Procedure:
9.04 g of hexamethylene tetramine was added to a solution of 10.0 g N1-(2-methoxybenzyl)-2,4-dichlorobenzamide in trifluoroacetic acid (200 mL), followed by stirring at 50° C. for 23 hours. The reaction solution was left and cooled to room temperature and then concentrated. The residue was diluted with ice-water and adjusted to pH 11 to 12 with 1N aqueous sodium hydroxide solution. The solution was extracted with ethyl acetate. The organic layer was washed with 1 N aqueous sodium hydroxide solution (×3), 1 N hydrochloric acid (×2) and brine, dried over anhydrous sodium sulfate and filtered thorough 100 g silica gel. After concentrating the filtrate, the residue was suspended in ethyl acetate. The solid was collected by filtration and washed with ethyl acetate, to give 7.15 g of N1-(5-formyl-2-methoxybenzyl)-2,4-dichlorobenzamide as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=[O:9].Cl.[C:12]1(C)C=CC(S(Cl)(=O)=O)=C[CH:13]=1>C(O)C>[CH2:12]([O:9][C:8]([C:7]1[CH:6]=[CH:5][N:4]=[N:3][C:2]=1[NH2:1])=[O:10])[CH3:13]
Reactant: Nc1nnccc1C(=O)O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1ccnnc1N
Yield: 1163.3 %

Procedure:
3-Aminopyridazine-4-carboxylic acid (1.68 g, prepared as in JOC, (1985), 50, 346) was refluxed in ethanol (170 ml) with concentrated hydrochloric acid (2 ml) and p-toluene-sulphonyl chloride (0.1 g) for 55 hours. The solvent was evaporated and ice water added to the residue, which was then neutralised with solid sodium bicarbonate. The mixture was extracted with chloroform, insoluble material filtered, the organic extract dried over magnesium sulphate and evaporated to give 3-aminopyridazine-4-carboxylic acid ethyl ester (1.02 g) as a white solid.
Reaction SMILES: [C:1]([NH:9][NH:10][C:11]([C:13]1[CH:25]=[CH:24][C:23]2[C:22]3[C:17](=[CH:18][C:19]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:20][CH:21]=3)[CH2:16][C:15]=2[CH:14]=1)=O)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:43])=CC=1.[OH-].[Na+]>O1CCCC1>[CH2:26]([C:19]1[CH:20]=[CH:21][C:22]2[C:23]3[C:15](=[CH:14][C:13]([C:11]4[S:43][C:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[N:9][N:10]=4)=[CH:25][CH:24]=3)[CH2:16][C:17]=2[CH:18]=1)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCCCCCCCc1ccc2c(c1)Cc1cc(C(=O)NNC(=O)CCCCCC)ccc1-2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCCCCCc1ccc2c(c1)Cc1cc(-c3nnc(CCCCCC)s3)ccc1-2
Temperature: 0 °C
Yield: 61.8 %

Procedure:
In a 30 ml-round-bottomed flask, 0.65 g (1.45 mM) of N-heptanoyl-N'-(7-octyl-2-fluorenecarbonyl)hydrazine, 0.62 g (1.53 mM) of Lawesson's reagent and 10 ml of tetrahydrofuran were placed, followed by heat-refluxing for 1.5 hours. After the reaction, the reaction mixture was poured into a solution of 0.45 g of sodium hydroxide in 100 ml of ice water to precipitate a crystal. The crystal was recovered by filtration, washed with water and dissolved in toluene, followed by washing with water, drying with anhydrous sodium sulfate and distilling-off of the solvent. The residue was purified by silica gel column chromatography (eluent: toluene) and recrystallized two times from a mixture solvent of toluene-methanol to obtain 0.40 g of 2-octyl-7-(5-hexyl-1,3,4-thiadiazole-2-yl)fluorene (Yield: 61.8%). ##STR87##
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[OH:12][CH2:13][C:14]12[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][C:16]([CH2:24][OH:25])([CH2:17]3)[CH2:15]1)[CH2:21]2>C(Cl)Cl.C1COCC1.C(OCC)C>[C:14]12([CH:13]=[O:12])[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][C:16]([CH:24]=[O:25])([CH2:17]3)[CH2:15]1)[CH2:21]2
Reactant: OCC12CC3CC(C1)CC(CO)(C3)C2
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: ClCCl
Product: O=CC12CC3CC(C1)CC(C=O)(C3)C2
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a suspension of pyridinium chlorochromate (PCC, 0.850 g, 4.0 mmol) in CH2Cl2 (˜10 mL) was added a suspension of 1,3-bis(hydroxymethyl)adamantane (0.196 g, 1.0 mmol) in anhydrous THF (˜5 mL). The reaction mixture was stirred at room temperature for 2.5 hours, whereupon it was diluted with anhydrous diethyl ether (˜50 mL) and filtered through a plug of florisil. The filtrate was evaporated in vacuo to afford dicarbaldehyde (0.183 g, 95%). According to GC analysis (DB 210, 150° C.), product had a purity of over 95%. Since dialdehyde is unstable and decomposes on silica gel, the sample was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[NH:6][C:5]2[O:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:4]=2[CH:3]=1.N1C=CC=CC=1.[C:23](Cl)(=[O:25])[CH3:24]>C(Cl)(Cl)Cl>[C:23]([NH:1][C:2]1[C:7](=[O:8])[NH:6][C:5]2[O:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:4]=2[CH:3]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)Cl
Reactant: Nc1cc2c([nH]c1=O)OCc1ccccc1-2
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1cc2c([nH]c1=O)OCc1ccccc1-2

Procedure:
To 2.0 gm of 2-amino-4,6-dihydro-3H-[2]benzopyrano[3,4-b]pyridin-3-one, in 100 ml of chloroform containing 1 ml of pyridine, add 0.80 gm of acetyl chloride. Stir the reaction at room temperature for 5 hours. Filter and wash the solution with water. Remove the solvent by stripping to give the title compound.
Reaction SMILES: N[C:2](N)=[S:3].[CH3:5][O:6][C:7]1[CH:18]=[CH:17][C:10]([CH2:11][O:12][CH2:13][CH:14]2CO2)=[CH:9][CH:8]=1>CO>[CH3:5][O:6][C:7]1[CH:18]=[CH:17][C:10]([CH2:11][O:12][CH2:13][CH:14]2[CH2:2][S:3]2)=[CH:9][CH:8]=1
Reactant: NC(N)=S
Reactant: COc1ccc(COCC2CO2)cc1
Solvent: CO
Product: COc1ccc(COCC2CS2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Thiourea (0.935 g, 12.28 mmol) was added to a solution of 2-(((4-methoxybenzyl)oxy)methyl) oxirane (1.084 g, 5.58 mmol) in methanol (30 mL) and the mixture stirred at room temperature for 16 hours, then evaporated under vacuum. Purification by chromatography on silica, eluting with 0-10% EtOAc/hexane, afforded the title compound.
Reaction SMILES: [I-:1].[Na+].Cl[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=1>C(C(C)=O)C>[I:1][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=1
Reactant: CCOC(=O)C(C)c1ccc(CCl)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCOC(=O)C(C)c1ccc(CI)cc1
Reaction time: 8 h
Yield: 92.9 %

Procedure:
After a solution of 15 g of sodium iodide in 140 ml of methyl ethyl ketone was refluxed for 1 hour, 12.5 g of ethyl 2-(4-chloromethylphenyl)propionate was added and refluxing was continued for further 8 hours. After the reaction was completed, methyl ethyl ketone was removed by distillation from the reaction mixture under reduced pressure, the residue was poured into ice-water and extracted with ether. The extract was washed with water and an aqueous sodium thiosulfate solution, successively, dried, and the solvent was evaporated to give 16.3 g of the desired compound as an oily and slightly yellow substance.
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[OH:15])=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2)([O-])=O>[Pd].CCO.CO>[NH2:1][C:4]1[C:5]([CH:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[OH:15])=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2
Reactant: O=[N+]([O-])c1c(C(O)c2ccccc2)ccc2cccnc12
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: Nc1c(C(O)c2ccccc2)ccc2cccnc12
Reaction time: 1.5 h
Yield: 99.4 %

Procedure:
Palladium on Carbon (10%, 38 mg) was added to a solution of (8-nitro-quinolin-7-yl)-phenyl-methanol (Intermediate 214) (500 mg, 1.78 mmol) in EtOH (20 ml) and the mixture was stirred under an atmosphere of hydrogen for 1.5 h. The mixture was diluted with MeOH (40 ml), filtered through celite and the filtrate was concentrated in vacuo to give the title compound (443 mg, 99%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]2[C:16]([F:17])=[CH:15][C:14]([NH:18][C:19](=[O:24])[CH2:20][C:21]([OH:23])=O)=[C:13]([F:25])[CH:12]=2)[CH:7]=[CH:6][N:5]=1)(=[O:3])[NH2:2].[C:26]1([CH:32]([NH2:34])[CH3:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:17][C:16]1[CH:15]=[C:14]([NH:18][C:19](=[O:24])[CH2:20][C:21](=[O:23])[NH:34][CH:32]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH3:33])[C:13]([F:25])=[CH:12][C:11]=1[O:10][C:8]1[CH:7]=[CH:6][N:5]=[C:4]([C:1]([NH2:2])=[O:3])[CH:9]=1
Reactant: NC(=O)c1cc(Oc2cc(F)c(NC(=O)CC(=O)O)cc2F)ccn1
Reactant: CC(N)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)CC(=O)Nc1cc(F)c(Oc2ccnc(C(N)=O)c2)cc1F)c1ccccc1
Reaction time: 15 h
Yield: 37 %

Procedure:
To a homogeneous mixture of 3-(4-(2-carbamoylpyridin-4-yloxy)-2,5-difluorophenylamino)-3-oxopropanoic acid (89 mg, 0.25 mmol) and (±)-1-phenylethanamine (Aldrich, 0.05 mL, 0.38 mmol) in DMF (3 mL) was added DIPEA (0.07 mL, 0.38 mmol) and O-benzotriazol-1-yl-N,N,N′,N′-bis(tetramethylene)uranium hexafluorophosphate (TBTU) (121 mg, 0.38 mmol). The resulting solution was stirred for 15 hours before being quenched with 10% LiCl (aq). The mixture was partitioned between EtOAc and 10% LiCl (aq), the layers separated, and the aqueous layer extracted with EtOAc. The combined organic layers were washed twice with 10% LiCl (aq), then concentrated in vacuo. The residue was purified by silica gel chromatography (eluting with 1:3 hexane/EtOAc) and the appropriate fractions were concentrated in vacuo to afford the title compound (42 mg, 37%). HRMS(ESI+), 455.1532 (M+H)+ calcd., 455.1528 (M+H)+ found.
Reaction SMILES: C(OC([NH:11][CH:12]([CH2:23][CH2:24][P:25]([O:34][CH:35]([C:38](=[O:51])[NH:39][CH2:40][C:41]([O:43]CC1C=CC=CC=1)=[O:42])[CH2:36][CH3:37])([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26])[C:13]([O:15]CC1C=CC=CC=1)=[O:14])=O)C1C=CC=CC=1.[H][H]>CO.O.[C].[Pd]>[NH2:11][CH:12]([CH2:23][CH2:24][P:25]([O:34][CH:35]([C:38](=[O:51])[NH:39][CH2:40][C:41]([OH:43])=[O:42])[CH2:36][CH3:37])([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26])[C:13]([OH:15])=[O:14]
Reactant: CCC(OP(=O)(CCC(NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)Oc1ccccc1)C(=O)NCC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: CO
Product: CCC(OP(=O)(CCC(N)C(=O)O)Oc1ccccc1)C(=O)NCC(=O)O
Yield: 177.5 %

Procedure:
Next, 0.25 g (0.35 mmol) of benzyl 2-(N-benzyloxycarbonylamino)-4-[1-[N-(benzyloxycarbonylmethyl)carbamoyl]propyl(phenyl)phosphono]butanoate was dissolved in 30 mL of a solvent mixture of methanol and water at 20:1 and mixed with 200 mg of 5% palladium-carbon and hydrogen gas was introduced for 45 minutes. The palladium-carbon was removed by Celite filtration and the filtrate was vacuum-concentrated. The residue was purified by medium pressure reversed-phase column chromatography ODS-S-50B. The column was eluted with a linear gradient of 30 to 60% methanol at a flow rate of 6 mL/min and the fractions containing the compound eluted at 60% methanol were collected. The elution and purity of the compound were confirmed by TLC (BuOH/AcOH/H2O=5:2:2, ninhydrin coloration). After vacuum concentration, freeze drying was carried out to obtain 2-amino-4-[1-[N-(carboxymethyl)carbamoyl]propyl(phenyl)phosphono]butanoic acid (250 mg, yield 18%) as a colorless solid.
Reaction SMILES: [Li]CCCC.Br[C:7]1[C:15]2[C:14]([Cl:16])=[N:13][CH:12]=[N:11][C:10]=2[N:9]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:8]=1.[N+:22]([C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](Cl)=[O:29])([O-:24])=[O:23]>C1COCC1>[Cl:16][C:14]1[C:15]2[C:7]([C:28]([C:27]3[CH:31]=[CH:32][CH:33]=[C:25]([N+:22]([O-:24])=[O:23])[CH:26]=3)=[O:29])=[CH:8][N:9]([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[C:10]=2[N:11]=[CH:12][N:13]=1
Reactant: Clc1ncnc2c1c(Br)cn2C1CCCC1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(c1cccc([N+](=O)[O-])c1)c1cn(C2CCCC2)c2ncnc(Cl)c12
Temperature: 25 °C
Yield: 65 %

Procedure:
n-BuLi (22 mL, 2.5 M in Hexane, 55.0 mmol) was added dropwise to a solution of 5-Bromo-4-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine (15.0 g, 50.0 mmol) in THF (200 mL) at −78° C. After 1 h the resulting solution was added via cannula to a solution of 3-Nitrobenzoyl Chloride in THF (100 mL) at −78° C. After 30 min the reaction was quenched with saturated aqueous NH4Cl and warmed to room temperature. The layers were separated and the aqueous layer was extracted with EtOAc (1×200 mL). The THF was concentrated off under reduced pressure and the resulting organic layer was diluted with EtOAc. The organic layer was washed with 1N NaOH (2×) and water (1×) then dried over Na2SO4 and concentrated. Recrystallization from EtOAc afforded the title compound as a white solid (12.1 g, 65%). MS: 371.2/373.1 (MH+); HPLC Rf: 6.59 min. (HPLC method 4).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][CH3:32].[CH3:33][C:34]([CH3:36])=O>C1(C)C=CC=CC=1>[CH2:30]([O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:33][CH2:34][CH3:36])=[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:31][CH3:32]
Reactant: CCCBr
Reactant: CCOC(=O)c1c(C(=O)OCC)c(O)c2ccccc2c1O
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCCOc1c(C(=O)OCC)c(C(=O)OCC)c(OCCC)c2ccccc12
Temperature: 60 °C

Procedure:
Diethyl 1,4-dihydroxy-2,3-naphthalenedicarboxylate* (11 g, 36.1 mmol) was dissolved in acetone (180 ml) and potassium carbonate (24.9 g, 180.5 mmol) added and stirred. 1-Bromopropane (13.1 ml, 144.4 mmol) was added and the reaction mixture was heated at reflux (60° C.) overnight under argon. The reaction was cooled to room temperature and the inorganic solid filtered off. The solvent was evaporated to give an orange brown oil. The residue was taken up in toluene and washed with 5% potassium hydroxide solution, brine and dried over magnesium sulphate. Solvent was removed under vacuum to give a brown oil which was purified by chromatography on silica gel eluting with, 10% ethyl acetate in hexane. The clean fractions were evaporated to give the title compound as yellow oil (11.45 g, 29.5 mmol).