Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20]CC)=[O:19])=[CH:13][CH:12]=3)[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[N+:23]([O-:25])=[O:24].Cl>C(O)(=O)C>[CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:15][CH:16]=3)[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[N+:23]([O-:25])=[O:24]
Reactant: CCOC(=O)Cc1ccc(-c2ccc3oc([N+](=O)[O-])c(C)c3c2)cc1
Agent: Cl
Solvent: CC(=O)O
Product: Cc1c([N+](=O)[O-])oc2ccc(-c3ccc(CC(=O)O)cc3)cc12
Temperature: 0 °C

Procedure:
A solution of 1.5 g. of the product of step C in 25 ml. of acetic acid and 10 ml. of 6 N hydrochloric acid is heated at its reflux temperature for 45 minutes then poured into ice water. The precipitate is collected and recrystallized from an ethanol-N,N-dimethylformamide mixture to provide 4-(3-methyl-2-nitrobenzofuran-5-yl)phenylacetic acid, m.p. 229°-230° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.Cl.[NH2:19][OH:20].C([O-])(=O)C.[Na+]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[N:19][OH:20])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)Cc2ccccc2)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(C(Cc2ccccc2)=NO)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 87.9 %

Procedure:
To a solution of the product of Step A, 1-(4-methoxy-phenyl)-2-phenyl-ethanone, (1011 g, 4468 mmoles) in absolute ethanol (2 gallons) is added hydroxylamine hydrochloride (373 g, 5362 mmoles) and sodium acetate (440 g, 5362 mmoles.) The reaction mixture is stirred at room temperature for two days. The mixture is diluted with water (8 L) and the resultant mixture is stirred at room temperature for one hour. The mixture is subsequently filtered to give a solid, which is rinsed with water (3×4 L.) The product is dried to afford the synthetic intermediate 1-(4-methoxy-phenyl)-2-phenyl-ethanone oxime (948 g.)
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][C@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.S(Cl)([Cl:12])=O.[CH3:14]O>>[ClH:12].[NH2:1][C@@H:2]1[CH2:6][CH2:5][C@H:4]([C:7]([O:9][CH3:14])=[O:8])[CH2:3]1
Reactant: CO
Reactant: N[C@@H]1CC[C@H](C(=O)O)C1
Reactant: O=S(Cl)Cl
Product: COC(=O)[C@H]1CC[C@@H](N)C1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(1S,3R)-3-aminocyclopentane-1-carboxylic acid (Acros; 952 mg, 7.37 mmol) was suspended in MeOH (15 ml) and cooled in an acetone/ice bath. Thionyl chloride (1.11 mL, 14.74 mmol) was added dropwise and the resulting pale yellow solution stirred in the acetone/ice bath for 30 minutes and then allowed to warm to room temperature, stirred at room temperature for 1 hr then heated at reflux for 1 hr. Solvents were evaporated to give the title compound as a cream solid after drying under high vacuum. (1.32 g 100%)
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([C:25]([OH:27])=[O:26])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:13][CH:12]=2)[C:8]([S:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)=[N:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[OH:37]O.Cl>C(O)(=O)C.O.CCOC(C)=O>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][CH:18]([C:25]([OH:27])=[O:26])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:15][CH:16]=2)[C:8]([S:28]([CH2:29][C:30]2[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=2)=[O:37])=[N:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: OO
Reactant: CCCCc1nnc(SCc2ccc(Cl)cc2)n1Cc1ccc(OC(C(=O)O)c2ccccc2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CCCCc1nnc(S(=O)Cc2ccc(Cl)cc2)n1Cc1ccc(OC(C(=O)O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 51 %

Procedure:
To a stirred solution of 60 mg (0.11 mmol) of 3-butyl-4-[[4-[1-carboxy-1-phenylmethoxy]phenyl]methyl]-5-(4-chlorobenzylthio) -4H-1,2,4-triazole from (Example 5) in 0.75 ml of glacial acetic acid was added gradually 0.75 ml of 30% hydrogen peroxide in H2O. The solution became turbid during the addition but largely clarified within a few minutes. After adding an additional 4 drops of acetic acid, the mixture was stirred at room temperature in a stoppered flask for 16 hours. It was then diluted with 50 ml of EtOAc and shaken with 50 ml of dilute HCl (pH 2.5). The aqueous phase was extracted with an additional 3 portions of EtOAc. The combined EtOAc fractions were washed once with dilute HCl (pH 2), then dried (MgSO4), filtered, and concentrated. Trituration of the residue with Et2O gave a gum. Upon decantation of the Et2O and drying in vacuo, 31 mg (51%) of the title compound was obtained as a stiff foam, mp 76°-78° C. dec.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=O)=[CH:4][CH:3]=1.C(NC(C)C)(C)C.C([Li])CCC.ClP(=O)(OCC)[O:31][CH2:32][CH3:33]>CCCCCC.C(N=CC)(C)(C)C.O1CCCC1>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[CH:33][CH:32]=[O:31])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: CCOP(=O)(Cl)OCC
Agent: CC=NC(C)(C)C
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=CC=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1

Procedure:
The compound was prepared according to the procedure described in Example 84. The following reagents were used: 4,4'-dichlorobenzophenone (25. lg), diisopropylamine (32.2 mL). 1.6M n-butyl lithium in hexane (144 mL), acetaldehyde N-tert-butylimine (14.75 mL), diethyl chlorophosphonate (16.6 mL) and tetrahydrofurane (200 mL). The usual work up furnished 23.8 g of essentially pure 3,3-bis(4-chlorophenyl)-2-propenal as an orange oil.
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[C:3]1=[O:21].C([O-])([O-])=O.[K+].[K+].[Br:28][C:29]1[C:34]([F:35])=[CH:33][C:32]([OH:36])=[C:31]([F:37])[CH:30]=1>CN(C=O)C.O.CCOC(C)=O>[Br:28][C:29]1[C:34]([F:35])=[CH:33][C:32]([O:36][CH:2]2[CH2:7][CH2:6][CH2:5][N:4]([CH:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]3)[C:3]2=[O:21])=[C:31]([F:37])[CH:30]=1
Reactant: Oc1cc(F)c(Br)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCCC(Br)C2=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(N2CCCC(Oc3cc(F)c(Br)cc3F)C2=O)CC1
Temperature: 60 °C
Yield: 72.5 %

Procedure:
To a solution of tert-butyl 3-bromo-2-oxo-1,4′-bipiperidine-1′carboxylate (723 mg, 2.00 mmol) in DMF (5 mL) was added K2CO3 (553 mg, 4.00 mmol) and 4-bromo-2,5-difluorophenol (460 mg, 2.20 mmol). The reaction was heated at 60° C. overnight. The reaction was cooled and diluted with water and EtOAc. The organic layer was separated and the aqueous washed with EtOAc. The combined organic layers were dried with MgSO4 and concentrated. The crude residue was purified over silica gel (2:1 hexanes/EtOAc) to give tert-butyl 3-(4-bromo-2,5-difluorophenoxy)-2-oxo-1,4′-bipiperidine-1′-carboxylate (710 mg, 73%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]2([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:7]1=[O:20].C([Li])CCC.Br[CH2:30][CH2:31][O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]>C1COCC1>[Si:33]([O:32][CH2:31][CH2:30][CH:5]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]2([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:7]1=[O:20])[C:4]1[CH:21]=[CH:22][CH:23]=[C:2]([F:1])[CH:3]=1)([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: O=C1N(Cc2cccc(F)c2)c2ccccc2C12CCCCC2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCC(c1cccc(F)c1)N1C(=O)C2(CCCCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.3 %

Procedure:
1′-(3-fluorobenzyl)spiro[cyclohexane-1,3′-indol]-2′(1′H)-one (0.61 g, 1.97 mmol) was dissolved in THF and cooled to −78° C. n-Butyl lithium (2.5 M in hexane, 0.87 mL, 2.2 mmol) was added dropwise and the mixture was warmed to 0° C. (2-Bromoethoxy)-tert-butyldimethylsilane (0.65 mL, 3 mmol) was added and the mixture was allowed to warm to 25° C. The mixture was stirred for 16 hours then quenched with saturated aqueous ammonium chloride, diluted with ether, washed with water, and saturated brine. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified via Isco chromatography (Redisep, silica, gradient 0-10% ethyl acetate in hexane) to afford 0.86 g (92%) 1′-[3-{[tert-butyl(dimethyl)silyl]oxy}-1-(3-fluorophenyl)propyl]spiro[cyclohexane-1,3′-indol]-2′(1′H)-one.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].Cl.[F:9][C:10]([F:25])([S:21]([O-:24])(=[O:23])=[O:22])[C:11]([F:20])([F:19])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14].[Na+].ClCCl>O.C(OCC)C>[F:25][C:10]([F:9])([S:21]([O-:24])(=[O:23])=[O:22])[C:11]([F:19])([F:20])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14].[CH2:1]([NH+:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2]
Reactant: CCN(CC)CC
Agent: Cl
Agent: O=S(=O)([O-])C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: O
Product: CC[NH+](CC)CC

Procedure:
Triethylamine was dissolved in cold water, and hydrochloric acid was added thereto to adjust the pH of the reaction liquid to fall within a range of 1 to 3. Then sodium perfluorobutylsulfonate and dichloromethane were added thereto and stirred. The separated organic layer was washed with water, and dichloromethane was removed under reduced pressure from the washed organic layer. To the residue thus obtained, diethyl ether was added for recrystallization. The resultant was filtrated and dried to obtain a desired product at a yield of 75%. The structure of the obtained product was identified using 1H-NMR, IR and TOFMS spectra.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:29]3[CH2:34][CH2:33][CH:32]([N:35]4[CH2:40][CH2:39][CH:38]([CH3:41])[CH2:37][CH2:36]4)[CH2:31][CH2:30]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22](O)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:42].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[F:74][C:75]([F:79])([F:78])[CH2:76][NH2:77]>CN(C=O)C>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:29]3[CH2:30][CH2:31][CH:32]([N:35]4[CH2:36][CH2:37][CH:38]([CH3:41])[CH2:39][CH2:40]4)[CH2:33][CH2:34]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([NH:77][CH2:76][C:75]([F:79])([F:78])[F:74])=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:42]
Reactant: NCC(F)(F)F
Reactant: Cc1ccc(C(=O)O)cc1-c1nc(N2CCC(N3CCC(C)CC3)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NCC(F)(F)F)cc1-c1nc(N2CCC(N3CCC(C)CC3)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.3 %

Procedure:
To the compound 3-[8-(2,6-difluorophenyl)-2-(4-methyl-1,4′-bipiperidin-1′-yl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (31.6 mg, 0.055 mmol) in DMF (0.5 mL) were added HBTU (25 mg, 0.066 mmol), triethylamine (15.5 uL, 0.11 mmol) and 2,2,2-trifluoroethanamine (6.56 uL, 0.0825 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (24.6 mg, 68%). LC-MS m/z 655 (M+H)+.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.[CH2:21]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35][CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[CH:42]1([C:48](Cl)=[O:49])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1>O1CCCC1.CCCCCC>[CH2:21]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35][CH2:36][CH:37]([C:48]([CH:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1)=[O:49])[C:38]([O:40][CH3:41])=[O:39])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(Cl)C1CCCCC1
Reactant: COC(=O)CCCc1ccccc1OCc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: COC(=O)C(CCc1ccccc1OCc1ccccc1)C(=O)C1CCCCC1
Reaction time: 0.5 h
Yield: 48.2 %

Procedure:
To a dry ice-acetone bath cooled solution of lithium diisopropylamide, prepared from diisopropylamine (222 mg) and 1.61M hexane solution of n-butyllithium (1.24 ml) in tetrahydrofuran (5.6 ml), was added methyl 4-(2-benzyloxyphenyl)butyrate (284 mg) and the mixture was stirred for 30 minutes at the same temperature. Cyclohexanecarbonyl chloride (176 mg) was added. After being stirred for 30 minutes the reaction mixture was quenched by 1N hydrochloric acid solution and the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with aqueous sodium bicarbonate solution and brine, and dried. The solvent was evaporated in vacuo and the residue was purified by preparative thin layer chromatography [silica gel, ether - n-hexane (1:4)] to afford methyl 4-(2-benzyloxyphenyl)-2-(cyclohexylcarbonyl)butyrate (190 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([C:24]([OH:26])=O)=[CH:12][N:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(P(C#N)(CC)=O)C.[CH3:35][O:36][CH2:37][CH2:38][NH2:39]>>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([C:24](=[O:26])[NH:39][CH2:38][CH2:37][O:36][CH3:35])=[CH:12][N:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2c(C(=O)O)cnc(CNC(=O)OC(C)(C)C)c2cc1OC
Reactant: COCCN
Agent: CCP(=O)(C#N)CC
Product: COCCNC(=O)c1cnc(CNC(=O)OC(C)(C)C)c2cc(OC)c(OC)cc12
Yield: 48.8 %

Procedure:
As described in example 1E, 1-(tert-butoxycarbonylamino-methyl)-6,7-dimethoxy-isoquinoline-4-carboxylic acid (80 mg, 0.22 mmol), diethylphosphoryl cyanide (54 mg, 0.33 mmol), and 2-methoxy ethylamine (25 mg, 0.33 mmol) were reacted to give [6,7-dimethoxy-4-(2-methoxy-ethylcarbamoyl)-isoquinolin-1-ylmethyl]-carbamic acid tert-butyl ester (45 mg, 49%): 1H NMR (CDCl3) δ 1.50 (s, 9H), 3.41 (s, 3H), 3.62-3.64 (m, 2H), 3.72-3.76 (m, 2H), 4.03 (s, 6H), 4.89 (d, 2H), 6.19 (s, 1H), 6.47 (s, 1H), 7.34 (s, 1H), 7.85 (s, 1H), 8.47 (s, 1H); MS (APCI) m/z 419.9 [M+1]+.
Reaction SMILES: O.[NH2:2][NH2:3].[F:4][C:5]1[CH:24]=[CH:23][C:8](/[CH:9]=[C:10]2\[O:11][C:12](=O)[C:13]3[C:18]\2=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][CH:14]=3)=[CH:7][C:6]=1[C:25]([N:27]1[CH2:32][CH2:31][CH:30]([O:33][CH3:34])[CH2:29][CH2:28]1)=[O:26].CN(C)C=O>O>[F:4][C:5]1[CH:24]=[CH:23][C:8]([CH2:9][C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[N+:19]([O-:21])=[O:20])[C:12](=[O:11])[NH:3][N:2]=2)=[CH:7][C:6]=1[C:25]([N:27]1[CH2:32][CH2:31][CH:30]([O:33][CH3:34])[CH2:29][CH2:28]1)=[O:26]
Reactant: COC1CCN(C(=O)c2cc(/C=C3\OC(=O)c4cccc([N+](=O)[O-])c43)ccc2F)CC1
Reactant: NN
Solvent: CN(C)C=O
Solvent: O
Product: COC1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4cccc([N+](=O)[O-])c34)ccc2F)CC1
Temperature: 100 °C
Reaction time: 18 h
Yield: 75.7 %

Procedure:
Hydrazine hydrate (0.046 mL, 0.94 mmol) was added in one portion to (Z)-3-(4-fluoro-3-(4-methoxypiperidine-1-carbonyl)benzylidene)-4-nitroisobenzofuran-1(3H)-one (44) (50 mg, 0.12 mmol) and N,N-Dimethylformamide (0.045 mL, 0.59 mmol) in water (2 mL) at 25° C. under air. The resulting mixture was stirred at 100° C. for 18 hours. The mixture was cooled to ambient temperature and the solvent evaporated to give crude desired product as a pale brown solid (40.0 mg, 77% yield); 1H NMR: (400.132 MHz, DMSO) δ 1.23-1.33 (1H, m), 1.36-1.50 (1H, m), 1.65-1.72 (1H, m), 1.79-1.92 (1H, m), 3.25-3.27 (4H, m), 3.33 (3H, s), 3.82-3.97 (1H, m), 4.10 (2H, s), 7.10-7.21 (3H, m), 7.99-8.03 (1H, m), 8.27 (1H, d), 8.59 (1H, d); m/z (LC-MS, ESI+), RT=1.85 (M+H 441.3).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)[CH2:4][CH2:3]1.[I:17][CH2:18][CH2:19][OH:20]>CN(C=O)C>[I-:17].[OH:20][CH2:19][CH2:18][N+:2]1([CH3:1])[CH2:3][CH2:4][N:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)[CH2:6][CH2:7]1
Reactant: OCCI
Reactant: CN1CCN(c2nc3ccccc3o2)CC1
Solvent: CN(C)C=O
Product: C[N+]1(CCO)CCN(c2nc3ccccc3o2)CC1
Product: [I-]
Reaction time: 1 h

Procedure:
A 435 mg portion of 2-(4-methyl-1-piperazinyl)-benzoxazole was dissolved in 3 ml of DMF. Under cooling with ice, 0.24 ml of 2-iodoethyl alcohol was added to the thus prepared solution, and the reaction was carried out for 1 hour at the same temperature and then for 17 hours at room temperature, followed by further addition of 0.48 ml 2 -iodoethyl alcohol and subsequent 21 hours of reaction at 50° C. The reaction mixture was concentrated under a reduced pressure, and 5 ml of acetone was added to the resulting residue. The precipitate thus formed was collected by filtration, washed with acetone and then dried to obtain 583 mg of the title compound.
Reaction SMILES: Cl.Cl.[NH:3]([C:7]1[S:8][CH:9]=[C:10]([CH2:12][S:13][CH2:14][CH2:15][NH2:16])[N:11]=1)[C:4]([NH2:6])=[NH:5].[NH:17]([C:21]1[S:22][CH:23]=[C:24]([CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:31]2[C:34](=O)[C:33](=[O:36])[C:32]=2[O:37]C)[N:25]=1)[C:18]([NH2:20])=[NH:19].C(N(CC)CC)C>CO>[NH:3]([C:7]1[S:8][CH:9]=[C:10]([CH2:12][S:13][CH2:14][CH2:15][NH:16][C:34]2[C:33](=[O:36])[C:32](=[O:37])[C:31]=2[NH:30][CH2:29][CH2:28][CH2:27][CH2:26][C:24]2[N:25]=[C:21]([NH:17][C:18]([NH2:20])=[NH:19])[S:22][CH:23]=2)[N:11]=1)[C:4]([NH2:6])=[NH:5]
Reactant: COc1c(NCCCCc2csc(NC(=N)N)n2)c(=O)c1=O
Reactant: N=C(N)Nc1nc(CSCCN)cs1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: N=C(N)Nc1nc(CCCCNc2c(NCCSCc3csc(NC(=N)N)n3)c(=O)c2=O)cs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.4 %

Procedure:
A mixture of 2-guanidino-4-[(2-aminoethyl)thiomethyl]thiazole dihydrochloride (0.024 g), 1-[4-(2-guanidinothiazol-4-yl)butylamino]-2-methoxycyclobutene-3,4-dione (0.032 g) and triethylamine (0.03 ml) in dry methanol (1 ml) was stirred for 18 hours at room temperature. The white solid was filtered off, washed with methanol and dried in vacuo to give 1-[2-(2-guanidinothiazol-4-ylmethylthio)ethylamino]-2-[4-(2-guanidinothiazol-4-yl)butylamino]cyclobuten-3,4-dione, (0.022 g), m.p. 208°-210°.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1CC(=O)C(O)=O.S([O-])([O-])(=O)=O.[NH4+].[NH4+].C1[N:24]=[C:25](N)[C:26]2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3O)C=2N=1.[C:67](=[O:70])([O-])[O-:68].[Na+].[Na+]>>[NH2:24][C@H:25]([C:67]([OH:68])=[O:70])[CH2:26][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: O=C(O)C(=O)Cc1cc2ccccc2[nH]1
Reactant: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Reactant: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Agent: [Na+]
Product: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
The substrate specificity of the purified amino acid dehydrogenase was investigated. The enzyme activity was measured by using each substrate in place of the phenylpyruvic acid substrate in the procedure previously described for measuring the enzyme activity. In the case of the enzyme activity for naphthylpyruvic acid, 100 μL of the appropriately diluted enzyme solution was added to 100 μL of 0.1 M sodium carbonate buffer (pH 9.0) that contained 1.0 mg naphthylpyruvic acid, 12.3 mg ammonium sulfate, and 6.1 mg NADH and the increment in the 2-naphthylalanine produced in 30 minutes at 30° C. was determined by quantitation by HPLC. The HPLC analysis was run using the following: column: COSMOSIL 5C18-ARII (4.6 mm×250 mm, Nacalai Tesque, Inc.), eluent: 10 mM potassium phosphate buffer (pH 2.0)/acetonitrile=5/1, flow rate: 1.0 mL/min, column temperature: 40° C., detection: 210 nm. Here, 1 unit is defined as the quantity of enzyme that produces 1 μmol 2-naphthylalanine in 1 minute. In the case of the enzyme activity for indolepyruvic acid, 100 μL of the appropriately diluted enzyme solution was added to 100 μL of 0.1 M sodium carbonate buffer (pH 9.0) that contained 2.0 mg indolepyruvic acid, 26.0 mg ammonium sulfate, and 7.6 mg NADH and the increment in the L-tryptophan produced in 30 minutes at 30° C. was determined by quantitation by HPLC. The HPLC analysis was run using the following: column: CROWNPAK CR—(4.6 mm×150 mm, Daicel Chemical Industries, Ltd.), eluent: aqueous HClO4 (pH 2.0), flow rate: 1.0 mL/min, column temperature: 30° C., detection: 210 nm. Here, 1 unit is defined as the quantity of enzyme that produces 1 μmol L-tryptophan in 1 minute. The relative activity values, assigning 100% to the activity for phenylpyruvic acid, are shown in Table 1.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])N(C2C=CC(C(O)=O)=CC=2)N=1.C(N)(=O)C1C(=CC=CC=1)[OH:32].C(Cl)(=O)C1C(=CC=CC=1)O>>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:19][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:11](=[O:32])[N:12]=1
Reactant: O=C(O)c1ccc(-n2nc(-c3ccccc3O)nc2-c2ccccc2O)cc1
Reactant: NC(=O)c1ccccc1O
Agent: O=C(Cl)c1ccccc1O
Product: O=c1nc(-c2ccccc2O)oc2ccccc12
Temperature: 170 °C

Procedure:
U.S. Pat. No. 6,465,504 discloses substituted 3,5-diphenyl-1,2,4-triazoles and their use as pharmaceutical metal chelators. This patent describes a process for the preparation of 4-[3,5-Bis(2-hydroxyphenyl)-1H-1,2,4-triazol-1-yl]benzoic acid (deferasirox) (1) that involves the condensation of salicylamide (2) with salicyloyl chloride (3) by heating at 170° C. yielding 2-(2-hydroxyphenyl)-benz[e][1,3]oxazin-4-one (5), which reacts with 4-hydrazinobenzoic acid (6) in refluxing ethanol to give (1) (Scheme 1):
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:12]=[CH:11][C:7]([C:8]([O-:10])=O)=[CH:6][CH:5]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:26][C:27]([CH3:31])([CH3:30])[CH2:28][OH:29].CCCCCCC>ClCCl.CCOC(C)=O>[OH:29][CH2:28][C:27]([NH:26][C:8]([C:7]1[CH:6]=[CH:5][C:4]([C:3]([O:2][CH3:1])=[O:13])=[CH:12][CH:11]=1)=[O:10])([CH3:31])[CH3:30]
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1
Reactant: CC(C)(N)CO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCCC
Product: COC(=O)c1ccc(C(=O)NC(C)(C)CO)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 19.9 %

Procedure:
To a suspension of mono-methylterephtalate (360 mg, 2.0 mmol) in dichloromethane (10 mL) under N2 was added 1,1′-carbonyldiimidazole (422 mg, 2.6 mmol) in one portion. The mixture was stirred at RT for 18 h. 2-Amino-2-methyl-1-propanol (232 mg, 2.6 mmol) was added as a solution in dichloromethane (1 mL) and stirring was continued for another 3 h. The reaction was quenched by pouring onto saturated aqueous NaHCO3 (50 mL). After extraction with dichloromethane (3×50 mL), the combined organic extracts were washed with brine (50 mL), dried (MgSO4), filtered and concentrated at reduced pressure. Purification by silica FCC (using a gradient of eluents; 7:3 to 1:1 heptane:EtOAc) gave the title compound (100 mg, 20% yield) as white solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[Cl:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:29]=1[F:30]>>[Cl:23][C:24]1[CH:25]=[C:26]([C:2]2[CH:3]=[C:4]([C:9]3[N:13]4[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:20])[CH3:21])=[C:17]([F:18])[C:12]4=[N:11][CH:10]=3)[CH:5]=[CH:6][C:7]=2[F:8])[CH:27]=[CH:28][C:29]=1[F:30]
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Reactant: OB(O)c1ccc(F)c(Cl)c1
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4ccc(F)c(Cl)c4)c3)cnc2c1F
Yield: 6 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol and 3-chloro-4-fluorobenzeneboronic acid were coupled in the same way as in Example 30 to give 2-[3-(3′-chloro-2,4′-difluorobiphenyl-5-yl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]propan-2-ol as an off-white solid (8 mg, 6%): m/z (ES+) 417 [MH+].