Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]12[CH2:15][C:6]1([C:7]([O:9]CC(Cl)(Cl)Cl)=[O:8])[N:5]1[C:16](=[O:28])[CH:17]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:4]1[S:3]2>CN(C)C=O.C(O)(=O)C.[Zn]>[CH3:1][C:2]12[CH2:15][C:6]1([C:7]([OH:9])=[O:8])[N:5]1[C:16](=[O:28])[CH:17]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C@H:4]1[S:3]2
Reactant: CC12CC1(C(=O)OCC(Cl)(Cl)Cl)N1C(=O)C(NC(=O)Cc3ccccc3)[C@H]1S2
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC12CC1(C(=O)O)N1C(=O)C(NC(=O)Cc3ccccc3)[C@H]1S2
Yield: 83.7 %

Procedure:
To a solution of 2,2,2-trichloroethyl 2-methyl-2,3-methylene-6-(2-phenylacetamido)penam-3-carboxylate (517 mg.) in a mixture of dimethylformamide (3 ml.) and acetic acid (1 ml.) was added zinc powder (0.7 g.) under ice-cooling. After stirring for 1 hour at the same temperature, zinc powder was filtered off and washed twice with dimethylformamide (2 ml.). The filtrate was combined with the washings and the combined solution was poured into a mixed cooled solution of ethyl acetate and water, extracted with ethyl acetate, after which the extract was washed with water and dried over magnesium sulfate. Crystalline material (390 mg.) obtained by distilling off the solvent under reduced pressure was washed with ether and dried to give colorless crystals of 2-methyl-2,3-methylene-6-(2-phenylacetamido)penam-3-carboxylic acid (310 mg.) mp 112° to 118°C (dec.).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:9][CH2:10][C:11]([NH-:13])=[O:12]>>[C:2]1([C:10](=[CH2:9])[C:11]([NH2:13])=[O:12])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: [NH-]C(=O)CCCl
Product: C=C(C(N)=O)c1ccccc1

Procedure:
Phenyl acrylamide was synthesized via the acylation reaction of aniline followed by the β-elimination of the 3-chloropropionyl amide intermediate product (intermediate product 1).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[Cl-].[NH4+].[O:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1>CCCCCC>[CH2:11]([CH2:10][C:9](=[O:8])[CH3:1])[CH3:12].[CH3:4][CH2:3][CH2:2][CH2:1][CH2:9][CH3:10]
Reactant: [Li]CCCC
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Product: CCCC(C)=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 10 %

Procedure:
Combine 1-((2-trimethylsilyl)ethoxymethyl)-1 H-benzimidazole (91.2 g, 367 mmol) and tetrahydrofuran (500 mL). Cool to −78° C. using a dry-ice/acetone bath. Add a solution of n-butyl]ithium (146 mL, 2.5 M in hexane, 367 mmol) at such a rate that the temperature of the reaction mixture remains at about −70° C. After the addition of n-butyllithium is complete allow to stir for 30 minutes at −78° C. Add a solution of 1-(t-butoxycarbonyl)-piperidine-4-(N-methyl-O-methyl)-hydroxamic acid (99.9 g, 367 mmol) in tetrahydrofuran (100 mL). Warm to ambient temperature. After 18 hours, add dropwise a saturated aqueous ammonium chloride solution (100 mL). Add water (300 mL) and extract with diethyl ether. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with 10% ethyl acetone/hexane to give a residue. Recrystallize the residue from methanol/water to give (1-(t-butoxycarbonyl)-4-(1-((2-trimethylsilyl)ethoxymethyl)-1 H-benzoimidazole-2-carbonyl)-piperidine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@@H:8]([C@@H:16]1[CH2:18][O:17]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[NH:20]1[CH:24]=[CH:23][N:22]=[N:21]1>>[C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C@@H:16]([OH:17])[CH2:18][N:20]1[CH:24]=[CH:23][N:22]=[N:21]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: c1c[nH]nn1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H]1CO1
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H](O)Cn1ccnn1

Procedure:
Using general procedure 4 and purification method E with [(1R)-1-{(2R)-oxiran-2-yl}-2-phenyl-ethyl]carbamic acid tert-butylester (0.15 g, 0.57 mmol) and 1,2,3-triazole (0.037 mL, 0.63 mmol) gives the title compound.
Reaction SMILES: [N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]([C:10]2[S:14][C:13]([C:15]([O:17]C)=O)=[C:12]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)[CH:11]=2)[CH:2]=1.[NH3:31]>CO>[N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]([C:10]2[S:14][C:13]([C:15]([NH2:31])=[O:17])=[C:12]([O:19][CH2:20][C:21]3[CH:22]=[CH:23][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:25][CH:26]=3)[CH:11]=2)[CH:2]=1
Reactant: COC(=O)c1sc(-n2cnc3ccncc32)cc1OCc1ccc(C(F)(F)F)cc1
Reactant: N
Solvent: CO
Product: NC(=O)c1sc(-n2cnc3ccncc32)cc1OCc1ccc(C(F)(F)F)cc1
Temperature: 125 °C
Reaction time: 4 h

Procedure:
A mixture of 41 mg of methyl 5-(3H-imidazo[4,5-c]pyridin-3-yl)-3-{[4-(trifluoromethyl)benzyl]oxy}thiophene-2-carboxylate and 5 ml of a saturated solution of ammonia in methanol is stirred in a microwave vial at 125° C. for 4 h in the microwave cavity. The reaction mixture is concentrated to dryness, the resulting residue is dissolved in 5 ml dichloromethane and purified by flash chromatography (dichloromethane/methanol, 95/5 (v/v)) to yield the title compound.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.CC1(C)C(C)(C)OB([C:47]2[CH:55]=[CH:54][CH:53]=[C:52]3[C:48]=2[CH:49]=[CH:50][NH:51]3)O1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH:51]1[C:52]2[C:48](=[C:47]([C:2]3[C:10]4[C:9]([NH:11][C@H:12]([C:14]5[N:19]([C:20]6[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=6)[C:18](=[O:26])[C:17]6=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]6[N:15]=5)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=4[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=3)[CH:55]=[CH:54][CH:53]=2)[CH:49]=[CH:50]1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cccc5[nH]ccc35)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 69.9 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (100 mg, 0.17 mmol) was treated with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (196 mg, 0.81 mmol), sodium carbonate (86 mg, 0.81 mmols) and bis(triphenylphosphine)palladium(II) dichloride (24 mg, 0.03 mmol) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 30%, dichloromethane-ethyl acetate) to give 75 mg (65% yield) of the title compound. Purity 89%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH3:26])[C:5]2[N:11]3[C:12]([CH2:15]Br)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[CH:19][CH:18]=3)[C:6]=2[CH:25]=1.[CH3:27][NH:28][CH3:29].[I-].[Na+]>>[CH3:27][N:28]([CH2:15][C:12]1[N:11]2[C:5]3[C:4]([CH3:26])=[CH:3][C:2]([CH3:1])=[CH:25][C:6]=3[C:7]([C:17]3[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[CH:19][CH:18]=3)=[N:8][CH2:9][C:10]2=[N:14][N:13]=1)[CH3:29]
Reactant: CNC
Reactant: CSc1ccc(C2=NCc3nnc(CBr)n3-c3c(C)cc(C)cc32)cc1
Agent: [I-]
Agent: [Na+]
Product: CSc1ccc(C2=NCc3nnc(CN(C)C)n3-c3c(C)cc(C)cc32)cc1

Procedure:
In the manner given in Example 1, 8,10-dimethyl-1-(bromomethyl)-6-[p-(methylthio)phenyl]-4H-s-triazolo[4,3-a]-[1,4]benzodiazepine was reacted with dimethylamine in the presence of sodium iodide to give 1-[(dimethylamino)methyl]-8,10-dimethyl-6-[p-(methylthio)phenyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [Li+].[OH-].[CH3:3][N:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([O:12]C)=[O:11])[C:5]1=[O:14].Cl>C1COCC1.CO>[CH3:3][N:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([OH:12])=[O:11])[C:5]1=[O:14]
Reactant: COC(=O)c1cccn(C)c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1cccc(C(=O)O)c1=O
Reaction time: 2 h
Yield: 44.2 %

Procedure:
LiOH (1.3 mL, 1.3 mmol, 1.0 M) was added to a solution of methyl 1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate (0.11 g, 0.65 mmol) in a mixture of THF-MeOH (3:1 ratio, 8 mL) at room temperature. After stirring for 2 hours, 1 N HCl (1.3 mL) was added. The reaction mixture was extracted with EtOAc, dried over MgSO4, and concentrated to give the desired product (0.044 g, 44% for 2 step process). 1H NMR (400 MHz, CD3OD) δ 8.45 (dd, 1H), 8.06 (dd, 1H), 6.66 (t, 1H), 3.71 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[C:10]2[O:11][CH2:12][C:13]([CH3:15])([CH3:14])[C:9]=2[CH:8]=[C:7]([C:16](=[N:18][OH:19])[NH2:17])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:20](Cl)(=O)[CH3:21]>N1C=CC=CC=1>[C:1]([C:5]1[C:10]2[O:11][CH2:12][C:13]([CH3:14])([CH3:15])[C:9]=2[CH:8]=[C:7]([C:16]2[N:17]=[C:20]([CH3:21])[O:19][N:18]=2)[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(C(N)=NO)cc2c1OCC2(C)C
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: Cc1nc(-c2cc(C(C)(C)C)c3c(c2)C(C)(C)CO3)no1
Temperature: 95 °C
Yield: 52.4 %

Procedure:
To a solution of 7-tert-butyl-2,3-dihydro-3,3-dimethyl-5-benzo-[b]furancarboxamide oxime (1.05 g, 4.0 mmol) in 20 mL of pyridine is added acetyl chloride (0.43 mL, 6.0 mmol). The reaction mixture is heated at 95 ° C. for 22 h and cooled to room temperature. Pyridine is removed in vacuo at 50 ° C.; the residue is partitioned between water and ethyl acetate. The organic layer is washed with water and with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give 1.33 g of the crude product. Purification by flash column chromatography on silica gel (10% ethyl acetate-hexane) produces about 0.60 g (52%) of the title compound as a colorless solid: mp 81°-82° C.
Reaction SMILES: [CH:1]([CH:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:2].[OH:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([O-:18])=[O:17])=[CH:14][CH:13]=1.[Na+].CS(C)=O>O>[OH:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([O:18][CH:3]([CH:1]=[CH2:2])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:17])=[CH:14][CH:13]=1
Reactant: C=CC(Cl)c1ccccc1
Reactant: O=C([O-])c1ccc(O)cc1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: C=CC(OC(=O)c1ccc(O)cc1)c1ccccc1
Yield: 92.3 %

Procedure:
71.5 g of vinylbenzyl chloride and 75.0 g of sodium p-hydroxybenzoate were added to 250 ml of dimethylsulfoxide and stirred and reacted at 40° C. for 4 days. Then 1,000 ml of water was added thereto, and the resulting mixture was extracted with 200 ml of ethyl acetate. After distilling off ethyl acetate, recrystallization of the residue from benzene-hexane mixture solvent yielded 110 g of vinylbenzyl p-hydroxybenzoate (m.p. 83°-85° C.).
Reaction SMILES: [CH3:1][N:2](C)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][S:8][C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]1=2.ClC(OC(Cl)=O)C.C(Cl)Cl>C(Cl)CCl>[CH3:1][NH:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][S:8][C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]1=2
Reactant: CN(C)CCN1CCSc2cc([N+](=O)[O-])ccc21
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: CNCCN1CCSc2cc([N+](=O)[O-])ccc21
Temperature: 88 °C
Yield: 62.7 %

Procedure:
A solution of N,N-dimethyl-2-(7-nitro-2H-benzo[b][1,4]thiazin-4(3H)-yl)ethanamine (1.65 g, 6.17 mmol) in ClCH2CH2Cl (20 mL) was cooled to 0° C. (ice/water bath) then treated with alpha chloroethylchoroformate (1.009 mL, 9.26 mmol) dropwise. The resulting suspension was heated at 88° C. for 1.5 hours then concentrated to dryness. The residue was dissolved in MeOH (50 mL) and heated at reflux for 2 hours. The dark mixture was concentrated and partitioned between saturated sodium bicarbonate solution (50 mL) and CH2Cl2 (200 mL). The mixture was transferred to a separatory funnel and extracted. After extraction, the organic layer was separated, dried (Na2SO4), filtered, and concentrated to give a brown residue. This residue was subjected to flash chromatography on silica gel using 5:95 (2M NH3 in MeOH):CH2Cl2 as the eluent to give a yellow residue (980 mg, 62.7%). 1H-NMR (CDCl3) δ 7.97 (d, J=2.7 Hz, 1H), 7.87 (d, J=2.7, 9.3 Hz, 1H), 6.68 (d, J=9.3 Hz, 1H), 3.86-3.82 (m, 2H), 3.55 (t, J=6.6 Hz, 2H), 3.04-3.01 (m, 2H), 2.87 (t, J=6.6 Hz, 2H), 2.49 (s, 3H), 1.32 (brs, 1H).
Reaction SMILES: [C:1]([N:4]([CH2:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1)[CH2:5][C:6]1[N:7]=[N:8][N:9]([CH3:11])[CH:10]=1)(=[O:3])[CH3:2].CC([N:26]([C:30]1[CH:35]=[CH:34][C:33]([C:36]2[S:37][CH:38]=[CH:39][CH:40]=2)=[CH:32][C:31]=1[NH:41]C(C1C=CC(CCl)=CC=1)=O)C(=O)[O-])(C)C.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(Cl)Cl.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>CCOC(C)=O.CN(C=O)C>[C:1]([N:4]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([NH:41][C:31]2[CH:32]=[C:33]([C:36]3[S:37][CH:38]=[CH:39][CH:40]=3)[CH:34]=[CH:35][C:30]=2[NH2:26])=[O:19])=[CH:20][CH:21]=1)[CH2:5][C:6]1[N:7]=[N:8][N:9]([CH3:11])[CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)N(C(=O)[O-])c1ccc(-c2cccs2)cc1NC(=O)c1ccc(CCl)cc1
Reactant: CC(=O)N(Cc1ccc(C(=O)O)cc1)Cc1cn(C)nn1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)N(Cc1ccc(C(=O)Nc2cc(-c3cccs3)ccc2N)cc1)Cc1cn(C)nn1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
4-({Acetyl[(1-methyl-1H-1,2,3-triazol-4-yl)methyl]amino}methyl)benzoic acid (17.7 mg, 0.061 mmol), 1,1-dimethylethyl[2-({[4-(chloromethyl)phenyl]carbonyl}amino)-4-(2-thienyl)phenyl]carbamate (22 mg, 0.074 mmol), HOBT (11 mg, 0.074 mmol) and EDC (12 mg, 0.074 mmol) were taken into DMF (409 ul) and stirred at 60° C. overnight. The reaction was diluted with EtOAc and washed with ½ saturated NaHCO3 3×, brine, dried (MgSO4) and concentrated to afford a residue taken into ca 1 mL DCM:TFA (2:1) and stirred for 2 h. This solution was concentrated and purified via HPLC (20-100% MeCN in water with 0.025% TFA) to afford fractions poured into sat. aq. NaHCO3 and extracted with EtOAc 2×. The combined organic layers were washed with brine, dried (MgSO4) and concentrated to afford the requisite material as a dark tan solid. 1H NMR (d6-DMSO, 600 MHz, 90° C.) δ 9.46 (br s, 1H), 8.00-7.90 (m, 3H), 7.50 (d, J=2.1 Hz, 1H), 7.32 (d, J=8.2 Hz, 2H), 7.29 (dd, J=5.3, 1.2 Hz, 1H), 7.24 (dd, J=8.5, 2.3 Hz, 1H), 7.17 (dd, J=3.5, 1.2 Hz, 1H), 7.01 (dd, J=5.0, 3.5 Hz, 1H), 6.81 (d, J=8.2 Hz, 1H), 4.94 (br s, 2H), 4.66-4.54 (m, 3H), 4.50 (s, 2H), 3.98 (s, 2H), 2.24-2.00 (m, 3H). MS: cal'd 461 (MH+), exp 461 (MH+).
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: NC(=O)c1ccccc1O
Reactant: O=C(O)c1ccc(-n2nc(-c3ccccc3O)nc2-c2ccccc2O)cc1
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][N:2]([CH3:28])[C:3]([C:5]1[N:22]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[CH:29]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)([CH3:31])[CH3:30]>>[CH3:28][N:2]([CH3:1])[C:3]([C:5]1[N:22]([CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][N:35]4[CH2:36][CH2:37][N:32]([CH:29]([CH3:31])[CH3:30])[CH2:33][CH2:34]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CC(C)N1CCNCC1
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C=O)cn3)nc2n1C1CCCC1
Product: CC(C)N1CCN(Cc2ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc2)CC1
Yield: 53 %

Procedure:
Following General Procedure B, 7-cyclopentyl-2-(5-formyl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (150 mg, 0.396 mmol) and N-isopropylpiperazine (56 mg, 0.436 mmol) gave 7-cyclopentyl-2-[5-(4-isopropyl-piperazin-1-ylmethyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (103 mg, 53%) [following SiO2 chromatography, eluting with 0-10% (2M NH3 in MeOH)/dichloromethane]. MS (ESI) m/z 491.3 (M+H)+ (method A).
Reaction SMILES: [CH:1]12[O:6][CH:5]1[CH2:4][CH2:3][CH2:2]2.[OH:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]=1[O:18][CH3:19].B(F)(F)F.CCOCC>C1C=CC=CC=1.C(OCC)(=O)C>[OH:6][C@@H:1]1[CH2:2][CH2:3][CH2:4][C@H:5]1[O:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]=1[O:18][CH3:19]
Reactant: COC(=O)c1ccc(O)c(OC)c1
Reactant: C1CC2OC2C1
Agent: FB(F)F
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: c1ccccc1
Product: COC(=O)c1ccc(O[C@@H]2CCC[C@H]2O)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-Oxabicyclo[3.1.0]hexane (2.43 g, 2.50 mL, 28.9 mmol) was added dropwise to a stirred solution of methyl 4-hydroxy-3-methoxy-benzoate (5.26 g, 28.9 mmol) and BF3.OEt2 (410 mg, 369 μL, 2.89 mmol) in benzene (10 mL) at ambient temperature. The mixture was stirred at room temperature overnight before it was diluted with ethyl acetate and was washed with 1N NaOH. The organic layer was dried over sodium sulfate, filtered and evaporated. The residue was purified by column chromatography eluting with 0-100% EtOAc in hexanes to give methyl 4-((1R,2R)-2-hydroxycyclopentyloxy)-3-methoxybenzoate. ESI-MS m/z talc. 266.1, found 267.1 (M+1)+; Retention time: 1.16 minutes (3 min run).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.CCN(C(C)C)C(C)C.[C:33]([O:37][C:38]([N:40]1[CH2:45][CH2:44][CH:43]([C:46]2[CH:51]=[CH:50][C:49]([NH:52][C:53]3N=[C:57]([CH2:59][CH2:60][C:61]4[CH:66]=[CH:65][C:64]([C:67]([F:70])([F:69])[F:68])=[CH:63][C:62]=4[CH2:71][C:72](O)=[O:73])[C:56]([C:75]([F:78])([F:77])[F:76])=[CH:55][N:54]=3)=[CH:48][CH:47]=2)[CH2:42][CH2:41]1)=[O:39])([CH3:36])([CH3:35])[CH3:34].C(=O)([O-])[O-].[NH4+:83].[NH4+:84]>CN(C=O)C.C1COCC1.CCOC(C)=O>[NH2:83][C:72](=[O:73])[CH2:71][C:62]1[CH:63]=[C:64]([C:67]([F:68])([F:69])[F:70])[CH:65]=[CH:66][C:61]=1[CH2:60][CH2:59][C:57]1[C:56]([C:75]([F:78])([F:76])[F:77])=[CH:55][N:54]=[C:53]([NH:52][C:49]2[CH:48]=[CH:47][C:46]([CH:43]3[CH2:42][CH2:41][N:40]([C:38]([O:37][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:39])[CH2:45][CH2:44]3)=[CH:51][CH:50]=2)[N:84]=1
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccc(C(F)(F)F)cc4CC(=O)O)n3)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccc(C(F)(F)F)cc4CC(N)=O)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
HOBt (0.042 g, 0.31 mmol), EDCl.HCl (0.049 g, 0.31 mmol) and DIPEA (0.204 mL, 1.20 mmol) were added to a solution of 2-(2-(2-(2-((4-(1-(tert-butoxycarbonyl)piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)-5-(trifluoromethyl)phenyl)acetic acid (A108) (0.157 g, 0.240 mmol) in dry DMF (5 mL) and dry THF (5 mL). Ammonium carbonate (113 mg, 1.20 mmol) was then added and the resulting mixture was stirred at room temperature for 3 days. The mixture was diluted with EtOAc and washed with 10% aqueous NaHCO3. The organic layer was dried (MgSO4) and the volatiles removed under reduced pressure. The residue was adsorbed onto silica gel and purified by silica gel column chromatography (SiO2, 0-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound A109 as a colourless solid (0.121 g, 77%); 1H NMR (400 MHz, d4-MeOH) δ 8.56 (s, 1H), 7.60 (m, 3H), 7.55-7.48 (m, 1H), 7.42 (m, 1H), 7.22 (d, J=8.5 Hz, 2H), 4.23 (d, J=13.3 Hz, 2H), 3.76 (s, 2H), 3.26 (m, 2H), 3.14 (m, 2H), 2.95-2.81 (m, 2H), 2.77-2.64 (m, 1H), 1.83 (m, 2H), 1.70-1.54 (m, 2H), 1.50 (s, 9H). LCMS-A: rt 6.671 min; m/z 652.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:12])[CH3:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(N)cc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: COc1ccc(NC(C)=O)cc1
Yield: 95.3 %

Procedure:
To a stirring suspension of p-anisidine (6.036 g, 49 mmol) in dichloromethane (20 ml) was added acetic anhydride (5 ml, 53 mmol, 1.1 equ) over one hour. The reaction was stirred for a further hour then poured onto hexane (60 ml) and stirred for another hour. The solid was collected and washed with hexane to give N-(4-methoxy-phenyl)-acetamide 51 (7.717 g, 95%) as a pale grey solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12](=O)[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:15]([NH2:17])[CH3:16].C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([NH:17][CH2:15][CH3:16])[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCN
Reactant: COc1ccc(CC(C)=O)cc1OC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCNC(C)Cc1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 92 %

Procedure:
A solution of 10 g (51.4 mmol) of 3,4-dimethoxyphenylacetone in 50 mL of methanol was cooled to 0° C. and was treated with 50 mL of 2M solution of ethylamine in methanol. To the reaction mixture 11.5 g (0.183 mmol) of sodium cyanoborohydride was added, and the pH of the reaction mixture was adjusted to 6.5-7 by adding glacial acetic acid. The mixture was allowed to stir at room temperature for 4 days. This was concentrated under reduced pressure, and 150 mL of water was added. The pH of the resulting solution was adjusted to 1 using 6 N HCl. This was extracted with 4×150 mL of ether and the organic layers were discarded. The pH of the aqueous layer was adjusted to 14, and the solution was extracted with 6×100 mL of chloroform. The organic layers were combined, dried (Na2SO4) and concentrated to dryness to give 10.6 g (47.4 mmol, 92%) of 2A as a pale yellow oil (M+H, 224).