Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].Cl[C:13]([O:15][CH3:16])=[O:14].[OH-].[Na+]>O>[CH3:16][O:15][C:13]([O:11][C:10]1[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=1[F:1])=[O:14]
Reactant: COC(=O)Cl
Reactant: O=C(O)c1ccc(O)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)Oc1ccc(C(=O)O)cc1F
Temperature: -20 °C
Reaction time: 4 h

Procedure:
4-methoxycarbonyloxy-3-fluorobenzoic acid (VI) was synthesized from 3-fluoro-4-hydroxybenzoic acid (V) by reaction of the latter with methyl chloroformate. NaOH (90 mmol) and 3-fluoro-4-hydroxybenzoic acid (30 mmol) were dissolved in water (80 ml) and cooled to -20° C. Methyl chloroformate (45 mmol) was added dropwise to the mixture. The mixture was then stirred with a magnetic stir bar at 5° C. for four hours and left overnight in the refrigerator. The mixture was then acidified to pH 5 to precipitate 4-methoxycarbonyloxy-3-fluorobenzoic acid. The precipitates were filtered and crystallized from acetonitrile to afford the clean product, 4-methoxycarbonyloxy-3-fluorobenzoic acid (VI), in a 77% yield.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2=[CH:15][N:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)[N:17]=[C:11]2[CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].O=C(N1C=CN=C1)N1C=CN=C1.C1(C)C=CC=CC=1.O[NH:47]/[C:48](=[N:50]\[H])/[CH3:49]>ClCCl>[CH3:49][C:48]1[N:50]=[C:22]([C:21]2[CH:20]=[CH:19][C:18]([N:16]3[CH:15]=[C:12]4[C:11]([CH2:10][CH2:9][N:8]([C:6]([O:5][C:2]([CH3:3])([CH3:4])[CH3:1])=[O:7])[CH2:14][CH2:13]4)=[N:17]3)=[CH:26][CH:25]=2)[O:24][N:47]=1
Reactant: [H]/N=C(/C)NO
Reactant: CC(C)(C)OC(=O)N1CCc2cn(-c3ccc(C(=O)O)cc3)nc2CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1noc(-c2ccc(-n3cc4c(n3)CCN(C(=O)OC(C)(C)C)CC4)cc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 4-[6-{[(1,1-dimethylethyl)oxy]carbonyl}-5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl]benzoic acid (may be prepared as described in Description 23) (185 mg, 0.52 mmol) in dichloromethane (10 ml) was added 1,1′-(oxomethanediyl)bis-1H-imidazole (168 mg, 1.04 mmol) and the reaction stirred at room temperature, under argon, overnight. The solvent was evaporated in vacuo. Toluene (5 ml) and then (1Z)-N-hydroxyethanimidamide (may be prepared as described in Description 30) (116 mg, 1.56 mmol) were added and the reaction mixture heated, under argon, at reflux overnight. A further 2 eq. of 1,1′-(oxomethanediyl)bis-1H-imidazole was added and stirring continued for a further 40 minutes. A further 3 eq. of (1Z)-N-hydroxyethanimidamide was added and stirring continued for a further 3 hours. The reaction was cooled to room temperature and the solvent evaporated in vacuo. The resulting crude mixture was diluted with dichloromethane and water, and extracted into dichloromethane (×2). The combined organic fractions were washed with water (×1), dried over magnesium sulphate and solvent evaporated in vacuo to afford the title compound (D34). MS (ES+) m/e 340 [M-tBu]+.
Reaction SMILES: CC1(C)[O:6][C:5](=[CH:7][C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[O:9])[C:4](=[O:19])O1.[CH2:21]=[N:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>CO>[F:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][NH:10][C:8]([C:7]2[CH2:21][N:22]([CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[C:4](=[O:19])[C:5]=2[OH:6])=[O:9])=[CH:17][CH:16]=1
Reactant: CC1(C)OC(=O)C(=CC(=O)NCc2ccc(F)cc2)O1
Reactant: C=NCCN1CCOCC1
Solvent: CO
Product: O=C(NCc1ccc(F)cc1)C1=C(O)C(=O)N(CCN2CCOCC2)C1
Temperature: 25 °C
Yield: 32 %

Procedure:
A mixture of 2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-benzyl)-acetamide (77 mg, 0.275 mmol) and a 0.2 mmol solution of methylene-(2-morpholin-4-yl-ethyl)-amine in methanol (1.5 mL, 0. mmol) was heated at 70° C. for 1 h. The reaction mixture was cooled to room temperature and purified by preparative HPLC using methanol/water (0.1% TFA) as the eluent. The fractions containing the product were combined and concentrated to give the title compound as a pale yellow powder (42 mg, 32% yield). 1H NMR (500 MHz, DMSO) δ: 11.92 (1H, br s), 9.48 (1H, br s), 7.95 (1H, t, J=4.9 Hz), 7.34–7.31 (2H, m), 7.17–7.13 (2H, m), 4.42 (2H, d, J=4.9 Hz), 4.04 (2H, s), 4.01–3.95 (2H, m), 3.80–3.77 (2H, m), 3.66–3.39 (6H, m), 3.15–3.06 (2H, m). HRMS calcd for C18H21FN3O4 (M+H): 362.1516. found: 362.1505.
Reaction SMILES: C1(N[C:5](=[O:25])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][C:17]([OH:23])=[CH:18][CH:19]=4)[C:14]3=[O:24])[CH:7]=2)CC1.C(OCC)(=[O:28])C>Br>[OH:23][C:17]1[CH:16]=[C:15]2[C:20]([CH:21]=[CH:22][N:13]([C:8]3[CH:7]=[C:6]([CH:11]=[CH:10][C:9]=3[CH3:12])[C:5]([OH:28])=[O:25])[C:14]2=[O:24])=[CH:19][CH:18]=1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccc2ccc(O)cc2c1=O
Reactant: CCOC(C)=O
Agent: Br
Product: Cc1ccc(C(=O)O)cc1-n1ccc2ccc(O)cc2c1=O
Temperature: 150 °C

Procedure:
N-Cyclopropyl-3-(7-hydroxy-1-oxoisoquinolin-2(1H)-yl)-4-methylbenzamide (0.5 g) was stirred in 48% hydrobromic acid (7 mL) and heated under microwave irradiation conditions (Personal Chemistry Emrys Optimizer with 300 W magnetron) at 150° C. for 1 hour. The reaction mixture was diluted with ethyl acetate, washed water (×3), brine, dried (magnesium sulfate) and concentrated to a brown solid. The solid was triturated with diethyl ether to yield 3-(7-hydroxy-1-oxoisoquinolin-2(1H)-yl)-4-methylbenzoic acid as a brown solid (0.32 g); NMR Spectrum: (DMSOd6) 2.11 (s, 3H), 6.65 (d, 1H), 7.12 (d, 1H), 7.27 (d, 1H), 7.54 (d, 1H), 7.60 (s, 1H), 7.61 (d, 1H), 7.78 (s, 1H), 7.95 (d, 1H), 10.09 (s, 1H), 13.05 (s, 1H); Mass Spectrum: M+H+ 296.
Reaction SMILES: [O:1]=[C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:3]P(=O)(OCC)OCC.[H-].[Na+].[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([CH:33]=O)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>C1COCC1>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([CH:33]=[CH:3][C:2](=[O:1])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CCOP(=O)(CC(=O)c1ccccc1)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C=CC(=O)c2ccccc2)CC1
Reaction time: 0.25 h
Yield: 76.8 %

Procedure:
Diethyl (2-oxo-2-phenylethyl)phosphonate (0.255 mL, 301 mg, 1.17 mmol) was added in one portion to a stirred suspension of sodium hydride (60% oil dispersion, 45 mg, 1.13 mmol) in THF (7 mL) at rt. After 15 min, a portion (1.8 mL) of the clear solution was removed and discarded, and the remainder cooled in an ice bath. 1-(tert-Butoxycarbonyl)-4-piperidinecarboxaldehyde (177 mg, 0.830 mmol, from Step B) was added in THF (1.0 mL) with additional THF (2×1.0 mL) for rinsing. After 16 h at rt, the mixture was then partitioned between ether (40 mL) and 2.5 N aq. NaOH (20 mL). The organic layer was washed with sat'd NaCl (20 mL), dried (Na2SO4), decanted, and evaporated. The crude product was purified by flash column chromatography on silica gel, eluting with 10% EtOAc in hexane, to give 201 mg of 1-(tert-butoxycarbonyl)-4-(3-oxo-3-phenylprop-1-enyl)piperidine as a colorless oil. Hydrogenation of this material using 5% Pd/C in 95% ethanol at atmospheric pressure yielded the title compound as a white crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([F:11])[C:3]=1[OH:12].NC1C=CC(O)=CC=1F>>[NH2:8][C:6]1[CH:5]=[C:4]([F:11])[C:3]([OH:12])=[C:2]([Cl:1])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(F)c(O)c(Cl)c1
Agent: Nc1ccc(O)cc1F
Product: Nc1cc(F)c(O)c(Cl)c1
Yield: 31 %

Procedure:
This compound was prepared from 2-chloro-6-fluoro-4-nitrophenol (1.3 g, 6.79 mmol) in the manner described for 4-amino-3-fluorophenol, affording 0.34 g (40%) of 4-amino-2-chloro-6-fluorophenol. 1H-NMR (DMSO-d6) δ 4.99 (s, 2H), 6.29-6.36 (m, 2H), 8.85 (s, 1H).
Reaction SMILES: [C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21](/[C:23](/[CH:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:24]\[C:25]([NH2:27])=[O:26])[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[H][H]>CO>[C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21]([C@@H:23]([CH:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)[CH2:24][C:25]([NH2:27])=[O:26])[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:4])([CH3:5])[CH3:3]
Reactant: CC(C)(C)C(=O)OCn1ccc2c(-c3cnn(/C(=C\C(N)=O)C4CCCC4)c3)ncnc21
Reactant: [H][H]
Solvent: CO
Product: CC(C)(C)C(=O)OCn1ccc2c(-c3cnn([C@H](CC(N)=O)C4CCCC4)c3)ncnc21
Temperature: 30 °C
Reaction time: 21 h

Procedure:
A solution of (4-{1-[(1Z)-3-amino-1-cyclopentyl-3-oxoprop-1-en-1-yl]-1H-pyrazol-4-yl}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate, (10, 500 mg) in methanol (MeOH, 8.0 mL) in a pressure glass tube was treated with the catalyst Ru(COD) (SL-A153-1) (CF3CO2)2 (6.6 mg) under nitrogen before the reaction mixture was pressurized with hydrogen gas to 50 bar pressure. The reaction mixture was stirred at 30° C. under this hydrogen pressure for 21 h. When HPLC analysis showed that the substrate was completely consumed, the reaction mixture was cooled down to room temperature. The enantiomeric excess of the reaction mixture was determined to be 98% ee (99% of the second peak, (R)-11; 1% of the first peak, (S)-11) by chiral HPLC analysis. The reaction mixture was then filtered through a thin silica gel pad and the pad was washed with methanol (5 mL). The filtrate was then concentrated under reduced pressure to dryness. The resultant foamy solid (470 mg) was analyzed by chiral HPLC analysis and result showed a 98.0% of enantiomeric excess favoring the second peak (99.0% of the second peak, (R)-11; 1.0% of the first peak, (S)-11).
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([NH:7][C:8]2[N:9]=[N:10][NH:11][C:12]=2[C:13]([OH:15])=O)=[CH:3][CH:2]=1>CCO.CN(C=O)C.O>[CH3:16][C:1]1[CH:2]=[CH:3][C:4]2[NH:7][C:8]3[N:9]=[N:10][NH:11][C:12]=3[C:13](=[O:15])[C:5]=2[CH:6]=1
Reactant: Cc1ccc(Nc2nn[nH]c2C(=O)O)cc1
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2[nH]c3nn[nH]c3c(=O)c2c1
Yield: 71.9 %

Procedure:
Cyclisation of 4-(p-tolylamino)-1,2,3-triazole-5-carboxylic acid (1 g) with 85% polyphosphoric acid (12 g) at 100° C. over 2 hrs. gave 0.66 g (72%) of the title compound of mp (EtOH-DMF-H2O) 310° C.; νmax (mull) 2720 (br.) 1655, 1600 cm-1, Δ (DMSO) 2.42 (3H, s); 7.58 (2H, s); 8.10 (1H,s), 1 low fieled broad (exchangeable). (Found; C, 59.89; H, 4.37; N, 28.09; C10H8N4O2 requires; C, 59.99 H, 4.03; N, 27.99%).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:25]=[CH:26][C:27]([C@@H:35]4[CH2:40][CH2:39][C@H:38]([C:41]([O:43]CC)=[O:42])[CH2:37][CH2:36]4)=[C:28]4[C:32]=3[C:31](=[O:33])[N:30]([CH3:34])[CH2:29]4)[C:20]([C:46]([F:49])([F:48])[F:47])=[CH:19][N:18]=2)=[C:12]([O:50][CH2:51][CH3:52])[CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C1COCC1.CO.O.[OH-].[Li+].O>>[CH2:7]([O:6][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:25]=[CH:26][C:27]([C@@H:35]4[CH2:40][CH2:39][C@H:38]([C:41]([OH:43])=[O:42])[CH2:37][CH2:36]4)=[C:28]4[C:32]=3[C:31](=[O:33])[N:30]([CH3:34])[CH2:29]4)[C:20]([C:46]([F:47])([F:49])[F:48])=[CH:19][N:18]=2)=[C:12]([O:50][CH2:51][CH3:52])[CH:11]=1)([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOc1cc(CP(=O)(OCC)OCC)ccc1Nc1ncc(C(F)(F)F)c(Nc2ccc([C@H]3CC[C@@H](C(=O)OCC)CC3)c3c2C(=O)N(C)C3)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCOc1cc(CP(=O)(OCC)OCC)ccc1Nc1ncc(C(F)(F)F)c(Nc2ccc([C@H]3CC[C@@H](C(=O)O)CC3)c3c2C(=O)N(C)C3)n1
Temperature: 25 °C
Reaction time: 30 h

Procedure:
Ethyl cis-4-(7-{[2-({4-[(diethoxyphosphoryl)methyl]-2-ethoxyphenyl}amino)-5-(trifluoromethyl)pyrimidin-4-yl]amino}-2-methyl-1-oxo-2,3-dihydro-1H-isoindol-4-yl)cyclohexanecarboxylate (Example 244, 72.0 mg, 0.096 mmol) was taken up in THF (0.13 mL, 1.60 mmol) and MeOH (0.13 mL, 3.20 mmol). This was treated with a solution of lithium hydroxide, monohydrate (20.2 mg, 0.48 mmol) in H2O (0.13 mL, 7.2 mmol) and was allowed to stir at rt for 30 hrs. The reaction was concentrated in vacuo to a solid and was purified by CombiFlash®Rf 4X Organic Purification System [24 g RediSep® Normal-phase GOLD Silica Flash Column, dried loaded, elution gradient: 0→5% MeOH in DCM] to afford 68.6 mg (99%) of the desired product. 1H NMR (400 MHz, MeOD) δ ppm 8.43 (d, J=9.09 Hz, 1H), 8.34 (s, 1H), 7.88 (d, J=8.34 Hz, 1H), 7.26 (d, J=8.84 Hz, 1H), 7.03 (t, J=2.02 Hz, 1H), 6.90 (dt, J=8.21, 2.21 Hz, 1H), 4.51 (s, 2H), 4.03-4.17 (m, 6H), 3.27 (s, 2H), 3.18 (s, 3H), 2.74 (br. s., 1H), 2.61-2.70 (m, 1H), 2.30 (d, J=12.38 Hz, 2H), 1.66-1.82 (m, 6H), 1.41 (t, J=6.95 Hz, 3H), 1.28 (t, J=7.07 Hz, 6H). MS (ES+): m/z 720.22/721.26 (100/98) [MH+]. HPLC: tR=1.62 min (Micromass TOF: polar—3 min).
Reaction SMILES: ClOC(C)(C)C.[Na].[C:8]([NH:20][NH2:21])(=[O:19])[C:9]1[C:10](=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:11](NN)=[O:12]>CC(C)=O>[C:8]1(=[O:19])[C:9]2[C:10](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:11](=[O:12])[N:21]=[N:20]1
Reactant: NNC(=O)c1ccccc1C(=O)NN
Agent: CC(C)(C)OCl
Agent: [Na]
Solvent: CC(C)=O
Product: O=C1N=NC(=O)c2ccccc21
Reaction time: 2.5 h

Procedure:
To a solution of t-butyl hypochlorite (3.8 g., 0.038 m.) in acetone (200 ml.), which was cooled to -60°, is added the sodium salt of phthalhydrazide (4.8 g., 0.021 g.). After 2.5 hours at -60° to -50°, the resulting green reaction mixture is filtered to give a solution of 1,4-phthalazinedione. Cyclopentadiene (2.0 ml. ) is added to the cooled green solution (-50°) and white crystals precipitate almost immediately. After 10 minutes at -50°, the crude product (3.0 g.) is collected by filtration. Recrystallization from CH2Cl2 /Et2O affords white microprisms of 1,4-methano-1,4-dihydropyridazino[1,2-b]phthalazine-6,11-dione (1.8 g., 64%), mp 206°-212° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([N:7]=[CH:8][C:9]2[O:10][C:11]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH2:21][CH2:22][N:23]([CH3:31])[CH2:24][C:25]4[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=4)[C:12]=3[C:13]=2[CH3:14])[CH:3]=1.[BH4-].[Na+]>CO>[CH3:1][C:2]1[O:6][N:5]=[C:4]([NH:7][CH2:8][C:9]2[O:10][C:11]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH2:21][CH2:22][N:23]([CH3:31])[CH2:24][C:25]4[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=4)[C:12]=3[C:13]=2[CH3:14])[CH:3]=1
Reactant: Cc1cc(N=Cc2oc3cccc(OCCCN(C)Cc4cccnc4)c3c2C)no1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(NCc2oc3cccc(OCCCN(C)Cc4cccnc4)c3c2C)no1
Yield: 60.6 %

Procedure:
To a solution of (5-methyl-isoxazol-3-yl)-{3-methyl-4-[3-(methyl-pyridin-3-ylmethyl-amino)-propoxy]-benzofuran-2-ylmethylene}-amine (46 mg) in methanol (2 ml) was added sodium borohydride (20 mg) at room temperature. After 1 hour the mixture was concentrated in vacuo and purified by silica gel column chromatography developed by dichloromethane and methanol to give the titled compound as white solids (28 mg). ESI-MS: m/z 421 (MH+); 1H-NMR (CDCl3): δ 1.97-2.06 (2H, m), 2.25 (3H, s), 2.27 (3H, s), 2.28 (3H, s), 2.59 (2H, t, J=6.9 Hz), 3.52 (2H, s), 4.09 (2H, t, J=5.94 Hz), 4.41 (2H, s), 5.53 (1H, s), 6.58 (1H, d, J=7.6 Hz), 7.00 (1H, d, J=7.6 Hz), 7.05-7.15 (2H, m), 7.59-7.63 (1H, m), 8.39 (1H, dd, J=1.7 Hz, 4.9 Hz), 8.49 (1H, d, J=2.0 Hz).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:11]2[C:7](=[N:8]S[N:10]=2)[CH:6]=[CH:5][CH:4]=1>[Ni]>[NH2:10][C:11]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:2][OH:1]
Reactant: OCc1cccc2nsnc12
Agent: [Ni]
Product: Nc1cccc(CO)c1N

Procedure:
A procedure for preparing a BBZ ligand and its related metal complex is shown in FIG. 2. The precursor, 4-hydroxymethyl-2,1,3-benzothiadiazole 1,56 was reduced with Raney nickel to yield 2,3-diaminobenzyl alcohol 2. Using the copper acetate coupling conditions,55 the phenylbenzimidazole backbone was formed from reaction of the 2,3-diaminobenzyl alcohol 2 with 2-nitrophenyl-1-carboxaldehyde in 82% yield. The benzyl alcohol group of 3 was oxidized to the corresponding aldehyde by manganese dioxide and then protected as the acetal 5. With both the aldehyde protected as the acetal and the amine protected as the nitro group, substitution at the benzimidazole nitrogen position can be achieved fairly easily. For example, a methyl group can be added by treatment of 5 with methyl iodide in the presence of sodium hydride. Other substituents have also been added via similar procedures, providing for a wide range of bis-benzimidazole derivatives. Reduction of the nitro group of 6 with hydrogen, catalyzed by Pd on carbon, followed by the addition of perchloric acid, unmasked both the amine and carboxaldehyde functionalities. Dimerization and cyclization of the resulting precursor gave the desired Me2BBZ ligand.
Reaction SMILES: C(O[C:4]([C:6]1[C:7](=[O:19])[O:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([CH3:17])[C:10]=2[CH3:18])=[O:5])C.[NH2:20][CH2:21][C:22]([O-:24])=[O:23].[Na+]>COC(O)C>[OH:16][C:15]1[C:14]2[C:9](=[C:10]([CH3:18])[C:11]([CH3:17])=[CH:12][CH:13]=2)[O:8][C:7](=[O:19])[C:6]=1[C:4]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[O:5]
Reactant: NCC(=O)[O-]
Reactant: CCOC(=O)c1c(O)c2ccc(C)c(C)c2oc1=O
Agent: COC(C)O
Agent: [Na+]
Product: Cc1ccc2c(O)c(C(=O)NCC(=O)O)c(=O)oc2c1C
Yield: 79.6 %

Procedure:
A mixture of 4-hydroxy-7,8-dimethyl-2-oxo-2H-chromene-3-carboxylic acid ethyl ester (18 mg, 0.069 mmol) and sodium glycinate (34 mg, 0.34 mmol) in methoxyethanol (5 mL) was refluxed for 16 h; then cooled, the solvent was removed, the residue was redissolved in water, acidified with 2 M HCl, the precipitates were collected and freeze dried to give the desired title product (16 mg). ESI (m/z): 292 (M+H)+.
Reaction SMILES: C1C=CN=C(NS(C2C=CC(N=N[C:19]3[CH:20]=[CH:21][C:22]([OH:28])=[C:23]([C:25]([OH:27])=[O:26])[CH:24]=3)=CC=2)(=O)=O)C=1.C1C([N:35]=NC2C=CC(O)=C(C(O)=O)C=2)=CC(C(O)=O)=C(O)C=1.C1C(C(NCCC(O)=O)=O)=CC=C(N=NC2C=CC(O)=C(C(O)=O)C=2)C=1>>[NH2:35][O:28][C:22]1[C:23](=[CH:24][CH:19]=[CH:20][CH:21]=1)[C:25]([OH:27])=[O:26]
Reactant: O=C(O)c1cc(N=Nc2ccc(O)c(C(=O)O)c2)ccc1O
Reactant: O=C(O)c1cc(N=Nc2ccc(S(=O)(=O)Nc3ccccn3)cc2)ccc1O
Agent: O=C(O)CCNC(=O)c1ccc(N=Nc2ccc(O)c(C(=O)O)c2)cc1
Product: NOc1ccccc1C(=O)O

Procedure:
sulfasalazine, mesalizine, olsalazine, balsalazide.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([CH3:15])[C:11]([O:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([C:24](=O)[C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:18]=1)=[C:10]([CH3:33])[CH:9]=2)=[O:5])[CH3:2].C([SiH](CC)CC)C.O.C(OCC)(=O)C>FC(F)(F)C(O)=O.C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([CH3:15])[C:11]([O:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[CH:18]=1)=[C:10]([CH3:33])[CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c(C)c(Oc3ccc(O)c(C(=O)c4ccc(F)cc4)c3)c(C)cc2[nH]1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2c(C)c(Oc3ccc(O)c(Cc4ccc(F)cc4)c3)c(C)cc2[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.3 %

Procedure:
To a solution of 5-[3-(4-Fluoro-benzoyl)-4-hydroxy-phenoxy]-4,6-dimethyl-1H-indole-2-carboxylic acid ethyl ester (25 mg, 0.056 mmol) in a mixture of trifluoroacetic acid (0.2 mL) and methylene chloride (0.25 mL) at room temperature was added triethylsilane (0.09 mL, 0.56 mmol), and the resulting solution was stirred at room temperature for 18 hours. The reaction solution was poured into water (10 mL) and ethyl acetate (15 mL) was added. The organic phase was washed with saturated aqueous NaHCO3 (2 times 10 mL), brine (10 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative thin layer chromatography (30% ethyl acetate in hexane) to afford the title compound (17.8 mg) as a white solid. 1H NMR (400 MHz, CDCl3) δ8.84 (s, 1H), 7.21 (s, 1H), 7.15-7.09(m, 3H), 6.94 (t, 2H), 6.63 (d, 1H), 6.58 (d, 1H), 6.45-6.42 (dd, 1H), 4.43-4.37 (q, 2H), 3.86 (s, 2H), 2.31 (s, 3H), 2.20 (s, 3H), 1.41 (t, 3H). MS (APCI−) Calc:433.2, Found: 432.1 (M−1).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[CH:13]1[CH2:18][CH:17]([C:19]([O:21][CH3:22])=[O:20])[CH2:16][CH2:15][NH:14]1.CCN(C(C)C)C(C)C.[C:32](Cl)(=[O:35])[O:33][CH3:34]>C(Cl)Cl>[F:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:6]=[CH:5][C:4]=1[CH:13]1[CH2:18][CH:17]([C:19]([O:21][CH3:22])=[O:20])[CH2:16][CH2:15][N:14]1[C:32]([O:33][CH3:34])=[O:35]
Reactant: COC(=O)Cl
Reactant: COC(=O)C1CCNC(c2ccc(C(F)(F)F)cc2F)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CCN(C(=O)OC)C(c2ccc(C(F)(F)F)cc2F)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.2 %

Procedure:
Methyl 2-(2-fluoro-4-(trifluoromethyl)phenyl)piperidine-4-carboxylate hydrochloride (5.50 g, 16.09 mmol) was dissolved in DCM (100 mL), then DIPEA (7.03 mL, 40.23 mmol) was added. Methyl carbonochloridate (1.774 mL, 22.53 mmol) was added dropwise to the solution. The mixture was stirred at room temperature for 4 h. The mixture was washed with 0.1 M HCl (100 mL) and satd NaHCO3 (100 mL), then dried through a phase-separator and evaporated yielding dimethyl 2-(2-fluoro-4-(trifluoromethyl)phenyl)piperidine-1,4-dicarboxylate (5.33 g, 91%) as a brown oil.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Si:21]([O:28][CH2:29][C@H:30]([C:32]1[CH:33]=[N:34][C:35]([CH3:38])=[N:36][CH:37]=1)[NH2:31])([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>C(#N)C.C(N(CC)C(C)C)(C)C>[Si:21]([O:28][CH2:29][C@@H:30]([NH:31][C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1)[C:32]1[CH:37]=[N:36][C:35]([CH3:38])=[N:34][CH:33]=1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: Cc1ccc(N2CCc3ncnc(Cl)c3C2)c(C#N)c1
Reactant: Cc1ncc([C@H](N)CO[Si](C)(C)C(C)(C)C)cn1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N2CCc3ncnc(N[C@H](CO[Si](C)(C)C(C)(C)C)c4cnc(C)nc4)c3C2)c(C#N)c1

Procedure:
A reaction mixture of 2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-methylbenzonitrile (420 mg, 1.48 mmol) and (S)-2-(tert-butyldimethylsilyloxy)-1-(2-methylpyrimidin-5-yl)ethanamine (742 mg, 2.78 mmol) in acetonitrile (8 mL) and N,N-diisopropylethylamine (1 mL) was subjected to microwave irradiation at 185° C. for 3 h. The reaction mixture was concentrated and the residue was purified by silica-gel column to yield the product as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6].[CH3:14]O>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([O:7][CH3:14])=[O:6]
Reactant: Cc1cc(C(=O)O)ccc1[N+](=O)[O-]
Reactant: CO
Product: COC(=O)c1ccc([N+](=O)[O-])c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 5-liter three-necked round-bottomed flask equipped with a reflux condenser, overhead stirrer and gas inlet, was placed 300 g of 3-methyl-4-nitrobenzoic acid and 3 l of methanol. To the resulting well-stirred solution was bubbled in 20.8 g of hydrogen chloride and the resulting mixture was refluxed for 3 hours. The reaction mixture was cooled to room temperature and allowed to stand overnight. The expected methyl 3-methyl-4-nitrobenzoate precipitated as light yellow crystals, which were collected by suction filtration yielding after drying 259.3 g. This solid was used as such in the next step.