Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:28])[C:10]=1[C:11]([C:13]1[C:21]2[C:16](=[C:17]([NH:22][C:23]([CH:25]3[CH2:27][CH2:26]3)=[O:24])[N:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1)=[O:12])[C:5]([OH:7])=O.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[NH2:50][CH2:51][CH:52]([OH:55])[CH2:53][OH:54].C(=O)(O)[O-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:28])[C:10]=1[C:11]([C:13]1[C:21]2[C:16](=[C:17]([NH:22][C:23]([CH:25]3[CH2:26][CH2:27]3)=[O:24])[N:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1)=[O:12])[C:5]([NH:50][CH2:51][CH:52]([OH:55])[CH2:53][OH:54])=[O:7]
Reactant: NCC(O)CO
Reactant: O=C(O)c1cc(Cl)c(C(=O)c2c[nH]c3c(NC(=O)C4CC4)nccc23)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(NCC(O)CO)c1cc(Cl)c(C(=O)c2c[nH]c3c(NC(=O)C4CC4)nccc23)c(Cl)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 55.5 %

Procedure:
To a solution of 3,5-dichloro-4-({7-[(cyclopropylcarbonyl)amino]-1H-pyrrolo[2,3-c]pyridin-3-yl}carbonyl)benzoic acid (50 mg, 0.11 mmol) in dimethylformamide (3 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (27.4 mg, 0.14 mmol), 1-hydroxybenzotriazole (19.37 mg, 0.14 mmol) and 3-aminopropane-1,2-diol (13 mg, 0.14 mmol) were added in one lot at room temperature. The resulting reaction mixture was stirred at room temperature for about 5 hours. Saturated aquoues sodium bicarbonate solution (20 mL) was added to quench the reaction mass. The aquoues phase was extracted with ethyl acetate and the combined organic layer dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel (100-200) column chromatography using ethyl acetate and hexane gradient elution to afford 3,5-dichloro-4-({7-[(cyclopropylcarbonyl)amino]-1H-pyrrolo[2,3-c]pyridin-3-yl}carbonyl)-N-(2,3-dihydroxypropyl)benzamide (30 mg, 51.72%).
Reaction SMILES: C([Li])(C)(C)C.BrC1C(C)=CC(C)=CC=1C.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1.[CH:24]1[C:37]2[C:36]3([CH2:39][N:40]4[CH2:45][CH2:44][C:43](=[O:46])[CH2:42][CH2:41]4)[CH2:38][CH:29]([C:30]4[C:35]3=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:28]=2[CH:27]=[CH:26][CH:25]=1>O1CCCC1.N1C=CC=CC=1>[CH:34]1[C:35]2[C:36]3([CH2:39][N:40]4[CH2:45][CH2:44][C:43]([C:23]5[C:18]([O:17][CH3:16])=[N:19][CH:20]=[CH:21][CH:22]=5)([OH:46])[CH2:42][CH2:41]4)[CH2:38][CH:29]([C:28]4[C:37]3=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:30]=2[CH:31]=[CH:32][CH:33]=1
Reactant: O=C1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Reactant: COc1ccccn1
Agent: Cc1cc(C)c(Br)c(C)c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1ncccc1C1(O)CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Temperature: 25 °C
Yield: 72.7 %

Procedure:
To a cooled solution (-72° C.) of t-butyllithium (1.7M in pentane, 5.38 mL, 9.15 mmol, 2.8 eq) in tetrahydrofuran (24 mL) under nitrogen was added dropwise bromomesitylene (0.64 mL, 4.18 mmol, 1.3 eq). The metal-halogen exchange reaction was stirred for an additional hour during which time a white precipitate forms. 2-Methoxypyridine (0.50 g, 4.38 mmol, 1.4 eq) was added to this suspension and the resulting reaction was warmed to room temperature and stirred at that temperature for 4 h. The metallated pyridine solution was recooled to -72° C. and a solution of 1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidinone (described in example 5d) (1.00 g, 3.3 mmol) in tetrahydrofuran (3 mL) was added. The reaction was warmed to room temperature over 1.5 h. After stirring for 18 h, the reaction was quenched with the addition of water (10 mL). The aqueous phase was extracted with ethyl acetate (200 mL). The organic extract was washed with water (2×100 mL), dried with anhydrous sodium sulfate, filtered, and reduced to an oil. The product was purified by flash chromatography over silica gel (100 mL, eluent: 30% ethyl acetate in hexane) to yield 0.99 g (73%) of the title compound as a white solid. TLC analysis (Rf 0.23, 30% ethyl acetate in hexane). 1H NMR (CDCl3, 300 MHz) 8.05 (dd, J=4.9, 1.7 Hz, 1H), 7.49 (dd, J=7.5, 5.7 Hz, 1H), 7.22 (m, 4H), 6.92 (m, 5H), 4.27 (s, 1H), 4.02 (s, 3H), 3.78 (s, 1H), 3.48 (s, 2H), 2.83 (m, 4H), 2.61 (d, J=1.4 Hz, 2H), 2.00 (m, 4H) MS (CI, CH4) m/z 413 (M+1,100), 441 (M+29,13), 395 (24). The free base was dissolved in methylene chloride, diluted with ether and acidified with ethereal HCl. The resulting hydrochloride salt was filtered, rinsed with fresh ether, and dried in vacuo (50° C., 10 pascal, 18 h) to yield a white solid, mp 225°-228° C. (dec).
Reaction SMILES: ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[OH:23][CH2:24][C:25]1[CH:26]=[CH:27][C:28]2[N:32]=[C:31]3[S:33][C:34]([C:36]([OH:38])=O)=[CH:35][N:30]3[C:29]=2[CH:39]=1.[O:40]1[CH2:44][CH2:43][O:42][CH:41]1[CH2:45][NH:46][CH3:47].[OH-].[Na+]>CN(C=O)C>[O:40]1[CH2:44][CH2:43][O:42][CH:41]1[CH2:45][N:46]([CH3:47])[C:36]([C:34]1[S:33][C:31]2=[N:32][C:28]3[CH:27]=[CH:26][C:25]([CH2:24][OH:23])=[CH:39][C:29]=3[N:30]2[CH:35]=1)=[O:38]
Reactant: O=C(O)c1cn2c(nc3ccc(CO)cc32)s1
Reactant: CNCC1OCCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CN(CC1OCCO1)C(=O)c1cn2c(nc3ccc(CO)cc32)s1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
1-Hydroxybenzotriazole (10.1 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (28.8 g) were added to a DMF (500 ml) suspension of 6-hydroxymethylthiazolo[3,2-a]benzimidazole-2-carboxylic acid (12.4 g), and the reaction mixture was stirred at room temperature for 1.5 hours. N-(1,3-Dioxolan-2-ylmethyl)-N-methylamine (17.1 ml) was added to the reaction mixture, and the resulting reaction mixture was stirred at the same temperature for 1 hour. After completion of the reaction, the reaction mixture was poured into 0.5 M sodium hydroxide aqueous solution (2 l). The insoluble matter was collected by filtration, washed with water and then with a mixed solvent of hexane and diethyl ether (mixing ratio; 3:1) and then dried by heating under a reduced pressure to obtain the title compound (8.62 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])O[C:6]([C:13]([OH:15])=[O:14])=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[NH2:22][CH2:23][C:24]1[CH:32]=[CH:31][C:27]2[O:28][CH2:29][CH2:30][C:26]=2[CH:25]=1.C(N(CC)CC)C>CO>[O:28]1[C:27]2[CH:31]=[CH:32][C:24]([CH2:23][N:22]3[C:6]([C:13]([OH:15])=[O:14])=[C:5]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=4)[C:8]3=[O:12])=[CH:25][C:26]=2[CH2:30][CH2:29]1
Reactant: O=C(O)c1oc(=O)c2ccc(F)cc2c1-c1ccccc1
Reactant: NCc1ccc2c(c1)CCO2
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(O)c1c(-c2ccccc2)c2cc(F)ccc2c(=O)n1Cc1ccc2c(c1)CCO2
Temperature: 50 °C
Reaction time: 36 h
Yield: 82.1 %

Procedure:
A mixture of 6-fluoro-1-oxo-4-phenyl-1H-isochromen-3-carboxylic acid (1 g), 5-aminomethyl-2,3-dihydrobenzo[b]furan (1.1 g), triethylamine (1 ml) and methanol (10 ml) was stirred at 50° C. for 36 hrs. The reaction mixture was concentrated, 1N-hydrochloric acid was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To the residue was added 4N-hydrochloric acid-ethyl acetate solution (5 ml) at room temperature and the mixture was stirred for 12 hrs. The reaction mixture was concentrated under reduced pressure and the residue was purified by recrystallization (ethyl acetate-hexane) to give the title compound (1.2 g).
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]2[CH2:6][CH2:7][CH:8]([NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.CS([C:24]1[N:29]=[CH:28][C:27]2=[CH:30][CH:31]=[C:32]([C:33]3[CH:38]=[CH:37][C:36]([S:39]([CH3:42])(=[O:41])=[O:40])=[CH:35][CH:34]=3)[N:26]2[N:25]=1)=O.[F-].[Cs+].C(N(CC)C(C)C)(C)C>C(O)(C)(C)C>[F:16][C:14]([F:17])([F:15])[C:13]([NH:12][CH:8]1[C:9](=[O:11])[NH:10][C:4]2[CH:3]=[C:2]([NH:1][C:24]3[N:29]=[CH:28][C:27]4=[CH:30][CH:31]=[C:32]([C:33]5[CH:34]=[CH:35][C:36]([S:39]([CH3:42])(=[O:41])=[O:40])=[CH:37][CH:38]=5)[N:26]4[N:25]=3)[CH:20]=[CH:19][C:5]=2[CH2:6][CH2:7]1)=[O:18]
Reactant: Nc1ccc2c(c1)NC(=O)C(NC(=O)C(F)(F)F)CC2
Reactant: CS(=O)c1ncc2ccc(-c3ccc(S(C)(=O)=O)cc3)n2n1
Agent: [Cs+]
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: CS(=O)(=O)c1ccc(-c2ccc3cnc(Nc4ccc5c(c4)NC(=O)C(NC(=O)C(F)(F)F)CC5)nn23)cc1
Temperature: 130 °C
Yield: 32.7 %

Procedure:
Into a 8-dram vial, N-(8-Amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl)-2,2,2-trifluoro-acetamide (39.4 mg, 0.137 mmol), 2-Methanesulfinyl-7-(4-methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (105 mg, 0.313 mmol), Cesium fluoride (41.7 mg, 0.274 mmol), tert-Butyl alcohol (0.80 mL) and N,N-Diisopropylethylamine (0.0478 mL, 0.274 mmol) were added. The reaction mixture was heated at 130° C. overnight. HPLC suggested no starting material. The solvent was evaporated. The reaction mixture was purified via HPLC reverse phase chromatography with 0.1% TFA in Water and 0.1% TFA in ACN. The collected fractions were lyophilized to give 2,2,2-Trifluoro-N-{8-[7-(4-methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl}-acetamide as a yellow solid (25 mg, 32%). LCMS (E/I+) 559.07 (M+H). NMR 1H (DMSO-d6)-9.96 (s, 1H0, 9.74 (s, 1H), 9.65 (bs, 1H), 9.08 (s, 1H), 8.46 (d, 2H, J=7.72 Hz), 8.04 (d, 2H, J=7.72 Hz), 7.59 (s, 1H), 7.54 (d, 1H, J=8.49 Hz), 7.35 (bs, 1H), 7.28 (d, 1H, J=7.72 Hz), 7.03 (d, 1H, J=4.62 Hz), 4.29 (bs, 1H), 3.22 (s, 3H), 2.63-2.72 (m, 2H), 2.24-2.35 (m, 2H).
Reaction SMILES: [H-].[K+].[C:3]([C:7]1[CH:19]=[CH:18][C:17]2[C:16]3[C:11](=[CH:12][C:13]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:14][CH:15]=3)[CH2:10][C:9]=2[CH:8]=1)([CH3:6])([CH3:5])[CH3:4].[CH2:24]([O:27][C:28]1[C:33]([C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:32][C:31]([CH3:38])=[CH:30][C:29]=1[Si:39](Cl)([CH2:42][CH3:43])[CH2:40][CH3:41])[CH:25]=[CH2:26].C(=O)([O-])O.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CCCCCC.C1COCC1.C1(C)C=CC=CC=1>[CH2:24]([O:27][C:28]1[C:33]([C:34]([CH3:35])([CH3:36])[CH3:37])=[CH:32][C:31]([CH3:38])=[CH:30][C:29]=1[Si:39]([CH:10]1[C:9]2[CH:8]=[C:7]([C:3]([CH3:6])([CH3:5])[CH3:4])[CH:19]=[CH:18][C:17]=2[C:16]2[C:11]1=[CH:12][C:13]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:14][CH:15]=2)([CH2:40][CH3:41])[CH2:42][CH3:43])[CH:25]=[CH2:26]
Reactant: C=CCOc1c(C(C)(C)C)cc(C)cc1[Si](Cl)(CC)CC
Reactant: CC(C)(C)c1ccc2c(c1)Cc1cc(C(C)(C)C)ccc1-2
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=CCOc1c(C(C)(C)C)cc(C)cc1[Si](CC)(CC)C1c2cc(C(C)(C)C)ccc2-c2ccc(C(C)(C)C)cc21
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
There was washed 3.00 g (22.45 mmol) of potassium hydride having a purity of 30% by weight with each 6 mL of hexane three times in an atmosphere of nitrogen, and 37 mL of THF was added thereto. To the obtained THF slurry of potassium hydride, 5.00 g (17.96 mml) of 2,7-di-tert-butylfluorene was added dropwise at 0° C. using 32 mL of a THF solution thereof. The obtained mixture was stirred for 2.5 hours at a room temperature, and then 5.84 g (17.96 mmol) of (2-allyloxy-3-tert-butyl-5-methylphenyl)chlorodiethylsilane was added dropwise at −78° C. using 7 mL of a toluene solution thereof. The temperature of the obtained liquid reaction mixture was raised up to a room temperature, and the mixture was stirred for 2.5 hours. The mixture was added dropwise at 0° C. to a mixture of 32 mL of a 10% aqueous solution of sodium hydrogen carbonate and 32 mL of a 10% aqueous solution of sodium carbonate, and the resultant mixture was extracted with 20 mL of toluene. The obtained extract was dried over sodium sulfate, and the solvent contained therein was distilled away under a reduced pressure, thereby obtaining quantitatively (2-allyloxy-3-tert-butyl-5-methylphenyl)(2,7-di-tert-butyl fluoren-9-yl)diethylsilane.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH2:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][N:24]1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:19])C1C=CC=CC=1>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH2:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][N:24]1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:19]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCCC1CONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2O
Reaction time: 3 h
Yield: 101 %

Procedure:
A mixture of tert-butyl 2-{[({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}piperidine-1-carboxylate 106 (0.40 g, 0.82 mmol) and Pd/C (0.13 g) in methanol (20 mL) was hydrogenated at 1 atm at room temperature for 3 h. The mixture was filtered through Celite pad and concentrated to give 107 (0.33 g, quantitative yield) as a white foam.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C@@H:10]([OH:13])[C:11]#[N:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].CCOC(C)=O.[OH-].[Na+]>CCOCC>[NH2:12][CH2:11][C@@H:10]([OH:13])[C@@H:9]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N#C[C@H](O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: NC[C@@H](O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 66 %

Procedure:
A solution of 3(S)-(dibenzylamino)-2(R)-hydroxy-4-phenylbutanenitrile [50.82 g, 143 mmol] described by M. T. Reetz et al., Tetrahedron Lett., 29, 3295 (1988)] in anhydrous Et2O (250 mL) was added dropwise over a period of 2 h to a stirred, cooled (0°) mixture of LiAlH4 (8.10 g, 213 mmol) and anhydrous Et2O (500 mL). The mixture was allowed to warm to room temperature while being stirred for 4.5 h. The mixture was cooled again to 0°. EtOAc (100 mL) was added slowly over 15 min. Stirring was continued for 15 min at 0°. A cold (0°) solution of 2N NaOH (250 mL) was added dropwise to the reaction mixture giving a white suspension/emulsion. The cloudy organic supernatant was separated and the remainder of the suspension/emulsion was passed through a 45 μm filter. The filtrate was extracted with EtOAc and the extract was combined with the first organic phase. After drying over NaCl/Na2SO4, the solution was concentrated to a volume of ca 100 mL and allowed to stand at 5° for 18 h. The precipitated material was separated, triturated with hexane (300 mL), collected by filtration, and dried under reduced pressure to give the title compound as a white solid (34 g, 66% yield). Mp: 72°-76°. [α]D24 -1.9° (c=1, MeOH). [α]Hg36524 -24.0° (c=1, MeOH). 1H NMR (CDCl3, 400 MHz) δ 2.68 (dd, J=12.6, 7.6, 7.2 Hz, 1H), 2.81 (dd, J=12.6, 3.8, 3.5 Hz, 1H), 2.86-3.00 (m, 2H), 3.08 (dd, J=14.1, 7.6, 7.3 Hz, 1H), 3.59 (d, J=13.7 Hz, 2H), 3.69 (m, 1H), 3.71 (d, J=13.7 Hz, 2H), 7.16-7.35 (m, 15H). FAB-MS (m/z): 361 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([Br:16])[CH:14]=2)[NH:9][N:8]=1)=[O:6].[CH3:17]I>C1COCC1>[CH3:3][O:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([Br:16])[CH:14]=2)[N:9]([CH3:17])[N:8]=1)=[O:6]
Reactant: CI
Reactant: COC(=O)c1n[nH]c2ncc(Br)cc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1nn(C)c2ncc(Br)cc12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Sodium hydride (47 mg, 60% in mineral oil, 1.18 mmol) was added in portions to a solution of 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid methyl ester Compound 1b (0.3 g, 1.17 mmol) in dry THF (20 mL) at 0° C. The mixture was stirred at 0° C. for 15 minutes then methyl iodide (80 μl, 1.29 mmol) was added. The reaction was warmed to room temperature gradually and stirred overnight. the solvent was removed and the residue was purified by silica gel chromatography (10% to 50% of ethyl acetate in hexanes) to yield 5-bromo-1-methyl-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid methyl ester Compound 11a (0.31 g, 97% yield) as a white powder. 1H NMR (400 MHz, CDCl3) δ 9.89 (s, 2H), 4.51 (s, 3H), 3.37 (s, 3H); MS (ESI) m/z: 271 (M+H+).
Reaction SMILES: [C:1]([O-])(O)=O.[Na+].C([O:8][CH:9]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:10][CH2:11][C:12]1[NH:13][C:14]([CH3:36])=[C:15]([C:32]([O:34][CH3:35])=[O:33])[CH:16]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=2)[C:17]=1[C:18]([O:20][CH2:21]C)=[O:19])=O>CO>[C:37]1([CH:9]([OH:8])[CH2:10][CH2:11][C:12]2[NH:13][C:14]([CH3:36])=[C:15]([C:32]([O:34][CH2:35][CH3:1])=[O:33])[CH:16]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=3)[C:17]=2[C:18]([O:20][CH3:21])=[O:19])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CCOC(=O)C1=C(CCC(OC=O)c2ccccc2)NC(C)=C(C(=O)OC)C1c1cccc([N+](=O)[O-])c1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)C1=C(C)NC(CCC(O)c2ccccc2)=C(C(=O)OC)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
0.3 ml of 5% NaHCO3 aqueous solution are added to a solution of the most polar diastereoisomer of 2-[3-formyloxy-3-phenyl-propyl]-3-carboethoxy-5-carbomethoxy-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine (2.5 g) in methanol (20 ml). The mixture is refluxed for 30 minutes, then it is cooled to 25° C. and evaporated to a small volume (2 ml) under reduced pressure. The sticky mass is diluted with ethyl ether (70 ml) and water (30 ml) and the phases are separed. The organic phase is washed with water (2×30 ml) and dried on sodium sulphate. The solvent is evaporated under reduced pressure, obtaining 2.3 g of the most polar diastereoisomer of 2-(3-phenyl-3-hydroxy-propyl)-3-carbomethoxy-5-carboethoxy-6-methyl-4-(m-nitrophenyl)-1,4-dihydropyridine as yellow foam.
Reaction SMILES: CS(O[CH:6]1[CH2:9][N:8]([C:10]2[S:11][CH:12]=[C:13]([C:15](=[O:36])[NH:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=4)=[O:24])[CH2:19][CH2:18]3)[N:14]=2)[CH2:7]1)(=O)=O.[C:37]([O-:40])(=[S:39])[CH3:38].[K+]>CN(C)C=O>[C:37]([S:39][CH:6]1[CH2:7][N:8]([C:10]2[S:11][CH:12]=[C:13]([C:15](=[O:36])[NH:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=4)=[O:24])[CH2:19][CH2:18]3)[N:14]=2)[CH2:9]1)(=[O:40])[CH3:38]
Reactant: CC([O-])=S
Reactant: CS(=O)(=O)OC1CN(c2nc(C(=O)NC3CCN(C(=O)OCc4ccc([N+](=O)[O-])cc4)CC3)cs2)C1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CN(c2nc(C(=O)NC3CCN(C(=O)OCc4ccc([N+](=O)[O-])cc4)CC3)cs2)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 69.7 %

Procedure:
To a solution of 3-methanesulfonyloxy-1-{4-[1-(p-nitrobenzyloxycarbonyl)-piperidin-4-ylcarbamoyl]-1,3-thiazol-2-yl}azetidine (390 mg, 0.723 mmol) (obtained as described in Reference Example 51(7)) in dimethylformamide (20 ml) was added potassium thioacetate (496 mg, 4.34 mmol) at room temperature. The mixture was stirred in an oil bath (80° C.) overnight. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (1:2)→ethyl acetate as the eluant to afford 3-acetylthio-1-{4-[1-(p-nitrobenzyloxycarbonyl)-piperidin-4-ylcarbamoyl]-1,3-thiazol-2-yl}azetidine (262 mg, yield 70%) as a pale brown solid.
Reaction SMILES: C(C1C=CC([O-])=CC=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Na+].C(=O)=O.Cl.[C:32]([C:51]1[CH:59]=[C:55]([C:56]([O-:58])=[O:57])[C:54]([OH:60])=[CH:53][CH:52]=1)([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[Na+]>O>[C:32]([C:51]1[CH:59]=[C:55]([C:56]([OH:58])=[O:57])[C:54]([OH:60])=[CH:53][CH:52]=1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: O=C([O-])c1cc(C(c2ccccc2)(c2ccccc2)c2ccccc2)ccc1O
Agent: Cl
Agent: O=C=O
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc(C(c2ccccc2)(c2ccccc2)c2ccccc2)ccc1O
Temperature: 180 °C
Yield: 37 %

Procedure:
The beaker containing the dried phenolate salt and a magnetic stirrer was placed in a 473-mL stainless steel Parr reaction bomb model 452HC2. The bomb was charged with carbon dioxide to a pressure of 830 psi, sealed and then heated in a silicone oil bath over a stirrer-hot plate for 8 hr at 180° C. The pressure increased to 1400 psi during the reaction. After cooling to room temperature, excess CO2 was released, the solid was suspended in 100 mL water and then the mixture was acidified to pH 1 by addition of 5M hydrochloric acid. The mixture was alternately sonicated and stirred vigorously to allow protonation of the insoluble sodium 5-tritylsalicylate. The product was collected on a sintered glass funnel, washed with cold water and dried in vacuum. The solid was suspended in 200 mL 5% aqueous NaHCO3 with sonication and stirring to convert the insoluble 5-tritylsalicylic acid to the insoluble sodium 5-tritylsalicylate while keeping the contaminating 4-tritylphenol unconverted. The solid was collected on a sintered glass funnel, washed with water and dried in vacuum. The product was suspended in 150 mL toluene with stirring and sonication to extract the contaminating phenol. The product was collected on a sintered glass funnel and dried in vacuum. The product was acidified to the salicylic acid by suspending the solid with vigorous stirring and sonication in 150 mL 0.5M hydrochloric acid. TLC of the vacuum-dried product still showed presence of 4-tritylphenol, thus the bicarbonate, toluene, and hydrochloric acid treatment was repeated. The dried product was recrystallized from toluene-acetone to produce 2.1 g (37% yield) of pure 5-tritylsalicylic acid (needles). Mp 234°-237° C. NMR in CDCl3 δ6.80 (d, 1H), δ6.90 (s, 1H), δ7.3 (s, 15H), δ7.8 (d, 1H). IR KBr disk: 2800-3600, 2600 (sh), 1660, 1610, 1490, 1440, 1300, 1200, 750, 700 cm-1.
Reaction SMILES: [C:1]([CH2:4][CH2:5][S:6][CH:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][O:10][C:9]2[CH:18]=[CH:19][C:20]([O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)=[CH:21][C:8]1=2)([OH:3])=O.[NH2:34][C:35]1[NH:39][N:38]=[N:37][N:36]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[N:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:32]=[CH:33][C:24]=1[CH2:23][O:22][C:20]1[CH:19]=[CH:18][C:9]2[O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH:7]([S:6][CH2:5][CH2:4][C:1]([NH:34][C:35]3[NH:39][N:38]=[N:37][N:36]=3)=[O:3])[C:8]=2[CH:21]=1
Reactant: O=C(O)CCSC1c2ccccc2COc2ccc(OCc3ccc4ccccc4n3)cc21
Reactant: Nc1nnn[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(CCSC1c2ccccc2COc2ccc(OCc3ccc4ccccc4n3)cc21)Nc1nnn[nH]1
Temperature: 25 °C
Reaction time: 48 h
Yield: 47.4 %

Procedure:
0.92 g of 11-(2-carboxyethylthio)-2-(quinolin-2-yl)methoxy-6,11-dihydrodibenz[b,e]oxepine obtained in Example 11, 0.21 g of 5-aminotetrazole and 0.5 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 0.25 g of 4-dimethylaminopyridine dissolved in 20 ml of methylene chloride were stirred at room temperature for 2 days. After this reaction mixture was washed with 1N-hydrochloric acid and a saturated saline solution, the organic layer was dried over anhydrous sodium sulfate. The residue obtained by condensation was applied to silica gel column chromatography and the resulting solid was recrystallized from methanol to obtain 0.5 g of the title compound as slightly brown powder.