Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([NH:8][C:9](=[O:34])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([C:28]([O:30]C)=[O:29])[CH:26]=4)[N:21]=[CH:20][CH:19]=3)=[CH:13][C:12]=2[O:32][CH3:33])[CH:5]=[N:4]1)[CH3:2].[OH-].[Li+]>>[CH2:1]([N:3]1[CH:7]=[C:6]([NH:8][C:9](=[O:34])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([C:28]([OH:30])=[O:29])[CH:26]=4)[N:21]=[CH:20][CH:19]=3)=[CH:13][C:12]=2[O:32][CH3:33])[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1cc(NC(=O)Cc2ccc(Oc3ccnc4ccc(C(=O)OC)cc34)cc2OC)cn1
Agent: [Li+]
Agent: [OH-]
Product: CCn1cc(NC(=O)Cc2ccc(Oc3ccnc4ccc(C(=O)O)cc34)cc2OC)cn1
Yield: 82 %

Procedure:
Using an analogous procedure to that described in Example 8, N-(1-ethylpyrazol-4-yl)-2-[4-(6-methoxycarbonylquinolin-4-yloxy)-2-methoxyphenyl]acetamide was reacted with lithium hydroxide to give the title compound in 82% yield; 1H NMR: (DMSOd6) 1.33 (t, 3H), 3.61 (s, 2H), 3.78 (s, 3H), 4.07 (q, 2H), 6.73 (d, 1H), 6.88 (m, 1H), 7.04 (d, 1H), 7.36 (d, 1H), 7.42 (s, 1H), 7.88 (s, 1H), 8.11 (d, 1H), 8.28 (m, 1H), 8.81 (d, 1H), 8.96 (d, 1H), 10.05 (s, 1H), 13.34 (br s, 1H); Mass Spectrum: M+H+ 447.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[C:9]3[N:14]([C:6]=2[C:5]([CH3:15])=[N:4][N:3]=1)[CH:13]=[CH:12][CH:11]=[CH:10]3.[N:16]1([CH:22]=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[CH3:15][C:5]1[C:6]2[N:14]3[C:9]([CH:10]=[CH:11][CH:12]=[CH:13]3)=[CH:8][C:7]=2[C:2]([N:19]2[CH2:20][CH2:21][N:16]([CH:22]=[O:23])[CH2:17][CH2:18]2)=[N:3][N:4]=1
Reactant: O=CN1CCNCC1
Reactant: Cc1nnc(Cl)c2cc3ccccn3c12
Product: Cc1nnc(N2CCN(C=O)CC2)c2cc3ccccn3c12

Procedure:
Following the procedure of Example 1, reaction of one equivalent of 1-chloro-4-methylpyridazino[4,5-b]indolizine and 10 equivalents of piperazinecarboxaldehyde at 150° C. gave the title compound as the free base, which was purified by flash chromatography (silica gel, 1 to 20% methanol:ethyl acetate) and converted to the dihydrochloride salt (MeOH/etheral HCl/diethyl ether), mp 325° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH:3]=1.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([CH2:41][C:42]2[CH:43]=[C:44](B(O)O)[C:45]([F:48])=[N:46][CH:47]=2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29].C([O-])(=O)C.[K+]>C(O)C.O>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C:4]2[N:5]=[C:6]([CH3:8])[N:7]=[C:2]([C:44]3[CH:43]=[C:42]([CH2:41][N:38]4[CH2:39][CH2:40][N:35]([C:33]([O:32][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:34])[CH2:36][CH2:37]4)[CH:47]=[N:46][C:45]=3[F:48])[CH:3]=2)=[CH:12][CH:13]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(Cl)nc(C)n2)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cnc(F)c(B(O)O)c2)CC1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(-c3cc(CN4CCN(C(=O)OC(C)(C)C)CC4)cnc3F)nc(C)n2)cc1
Temperature: 100 °C
Yield: 42.4 %

Procedure:
6-Chloro-N,N-bis(4-methoxybenzyl)-2-methylpyrimidin-4-amine (214.0 mg, 0.557 mmol), 5-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)-2-fluoropyridin-3-ylboronic acid (Example 34, Step 3)(189 mg, 0.557 mmol), PdCl2 (AmPhos)2 (Aldrich, St. Louis, Mo.) (19.74 mg, 0.028 mmol), and potassium acetate (164 mg, 1.672 mmol) in a mixture of ethanol (3.0 mL) and water (0.300 mL) was sparged with argon and then heated (microwave) at 100° C. in a 20 mL microwave vial for 20 min. The reaction mixture was then concentrated onto silica gel and chromatographically purified (ISCO, 24 g, 0 to 100% EtOAc/Hexanes) to provide tert-butyl 4-((5-(6-(bis(4-methoxybenzyl)amino)-2-methylpyrimidin-4-yl)-6-fluoropyridin-3-yl)methyl)piperazine-1-carboxylate (152.0 mg, 0.236 mmol, 42.4% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.44 (dd, J=9.39, 2.15 Hz, 1H); 8.14 (s, 1H); 7.17 (d, J=7.82 Hz, 4H); 6.86 (d, J=8.61 Hz, 5H); 4.74 (br. s., 4H); 3.79 (s, 6H); 3.55 (s, 2H); 3.42 (t, J=4.69 Hz, 4H); 2.62 (s, 3H); 2.37-2.43 (m, 4H); 1.45 (s, 9H). 19F NMR (377 MHz, CDCl3) 6-71.01 (d, J=9.16 Hz, 1F). m/z (ESI, +ve ion) 643.2 (M+H)+.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.Cl.[N:12]1([C:18]2[CH:23]=[CH:22][N:21]=[C:20]3[NH:24][N:25]=[C:26]([O:27][CH2:28][CH2:29][OH:30])[C:19]=23)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[C:31]([O:35][C:36]([N:38]([CH:51]([CH3:53])[CH3:52])[CH2:39][C@H:40]([C:44]1[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][CH:45]=1)[C:41](O)=[O:42])=[O:37])([CH3:34])([CH3:33])[CH3:32].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[Cl:50][C:47]1[CH:48]=[CH:49][C:44]([C@H:40]([C:41]([N:15]2[CH2:16][CH2:17][N:12]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]4[NH:24][N:25]=[C:26]([O:27][CH2:28][CH2:29][OH:30])[C:19]=34)[CH2:13][CH2:14]2)=[O:42])[CH2:39][N:38]([CH:51]([CH3:52])[CH3:53])[C:36](=[O:37])[O:35][C:31]([CH3:33])([CH3:32])[CH3:34])=[CH:45][CH:46]=1
Reactant: CC(C)N(C[C@@H](C(=O)O)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Reactant: OCCOc1n[nH]c2nccc(N3CCNCC3)c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)N(C[C@@H](C(=O)N1CCN(c2ccnc3[nH]nc(OCCO)c23)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
DIEA (0.0815 mL, 0.468 mmol) was added to 2-(4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridin-3-yloxy)ethanol dihydrochloride (0.0472 g, 0.140 mmol), (S)-3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoic acid (0.234 mL, 0.117 mmol, see Example B) and TBTU (0.0451 g, 0.140 mmol) in DCM (1 mL) and stirred at room temperature for 1 hour. The reaction was concentrated to dryness. The resulting residue was dissolved in THF/MeOH (2 mL, 1:1). A LiOH solution (1 mL, 2M) was added and stirred for 10 minutes. Ether (20 mL) was added. The organic layer was separated, washed with brine (5 mL), and dried over sodium sulfate. After removal of the solvent, the resulting residue was purified by chromatography (ethyl acetate) to give (S)-tert-butyl 2-(4-chlorophenyl)-3-(4-(3-(2-hydroxyethoxy)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate as a solid. The solid was then dissolved in DCM (1 mL), and TFA (0.4 mL) was added. The mixture was stirred at room temperature for 1 hour and then concentrated to dryness. The resulting residue was dissolved in DCM (0.5 mL), and HCl in ether (1 mL, 2N) was added. The solvent was removed, and the resulting solid was dissolved in MeOH (2 mL). A LiOH solution (2 mL, 2M) was added and stirred for 10 minutes. DCM (20 mL) and water (10 mL) were added. The organic layer was separated, dried over sodium sulfate and concentrated to give (S)-2-(4-chlorophenyl)-1-(4-(3-(2-hydroxyethoxy)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one (0.018 g, 32%) as a solid. MS APCI (+) m/z 487.3 detected.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[C:11]([O:19][CH3:20])=[CH:10][C:5]=1[O:6][CH2:7][C:8]#[N:9])(=[O:3])C.C(O)(C)C.[N-:25]=[N+:26]=[N-:27].[Na+].Cl>O.C(OCC)(=O)C.[Br-].[Zn+2].[Br-].O1CCCC1>[CH3:20][O:19][C:11]1[C:12]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[CH:13][C:4]([CH:1]=[O:3])=[C:5]([O:6][CH2:7][C:8]2[NH:9][N:27]=[N:26][N:25]=2)[CH:10]=1
Reactant: COc1cc(OCC#N)c(C(C)=O)cc1-c1cccs1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: COc1cc(OCc2nnn[nH]2)c(C=O)cc1-c1cccs1
Reaction time: 24 h
Yield: 63.2 %

Procedure:
Ex-89B: (2-Acetyl-5-methoxy-4-thiophen-2-yl-phenoxy)-acetonitrile (Ex-89A, 0.30 g, 1.1 mmol) was slurried in a mixture of water:isopropanol (3 mL, 2:1) to obtain a well-dispersed solution. Sodium azide (0.079 g, 1.2 mmol) followed by zinc bromide (0.25 g, 1.1 mmol) were added and the reaction was heated to reflux and vigorously stirred for 24 h. Additional solvent (1 mL, 1:1 water:isopropanol) was added after 10 h at reflux due to evaporation. The reaction was diluted with an ethyl acetate:tetrahydrofuran mixture (25 mL, 2:1) and a 3 N HCl solution (10 mL) and vigorously stirred until a homogenous solution was obtained (1 h). The layers were separated and the aqueous was extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried over sodium sulfate and concentrated to a dark green solid. Silica gel chromatography (15% methanol/methylene chloride containing 1% acetic acid) gave 0.22 g (65%) of 4-methoxy-2-(1H-tetrazol-5-ylmethoxy)-5-thiophen-2-yl-benzaldehyde as a pale green solid. 1H-NMR (300 MHz, DMSO-d6) δ 10.33 (s, 1H), 7.97 (s, 1H), 7.52–7.56 (m, 2H), 7.10–7.12 (m, 2H), 5.81 (s, 2H), 4.05 (s, 3H). MS (ESI) m/z=317 ([M+H]+, 100%), HRMS (ESI) Calcd. for C27H25NO7S: 317.0708. Found: 317.0712.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:30])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([O:17][CH3:18])[C:11]=2[NH:19][C:20]([C:22]2[S:23][CH:24]=[C:25]([CH2:28]Cl)[C:26]=2[Cl:27])=[O:21])=[N:6][CH:7]=1.[F:31][C:32]([F:36])([F:35])[CH2:33][NH2:34]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:30])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([O:17][CH3:18])[C:11]=2[NH:19][C:20]([C:22]2[S:23][CH:24]=[C:25]([CH2:28][NH:34][CH2:33][C:32]([F:36])([F:35])[F:31])[C:26]=2[Cl:27])=[O:21])=[N:6][CH:7]=1
Reactant: NCC(F)(F)F
Reactant: COc1cc(Cl)cc(C(=O)Nc2ccc(Cl)cn2)c1NC(=O)c1scc(CCl)c1Cl
Solvent: CN(C)C=O
Product: COc1cc(Cl)cc(C(=O)Nc2ccc(Cl)cn2)c1NC(=O)c1scc(CNCC(F)(F)F)c1Cl
Temperature: 75 °C
Yield: 94.5 %

Procedure:
To a solution of N-(5-chloropyridin-2-yl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide (2.1 g, 4.1 mmol) in DMF (20 mL) was added a 2,2,2-trifluoroethylamine (3.2 mL, 41 mmol). The mixture was heated at 75° C. for 18 hours, then cooled to ambient temperature and concentrated in vacuo to remove excess 2,2,2-trifluoroethylamine. Water was added and the mixture was extracted with methylene chloride. The organic layer was dried over Na2SO4 and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 2.2 g (95% yield) of N-(5-chloropyridin-2-yl)-2-[((4-(((2,2,2-trifluoroethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide; NMR (DMSO-d6/TFA) 10.8 (s, 1) 9.4 (s, 1), 8.2 (d, 1), 8.1 (d, 1), 8.0 (s, 1), 7.8 (dd, 1), 7.2 (d, 2), 4.2 (s, 2), 4.1 (q, 2), 3.8 (s, 3) ppm.
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:14](Cl)[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1.CCOC(C)=O>[CH2:16]([O:15][CH2:14][N:11]1[CH:10]=[CH:9][N:8]=[C:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: ClCOCc1ccccc1
Reactant: c1ccc(-c2ncc[nH]2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: c1ccc(COCn2ccnc2-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 68.7 %

Procedure:
To 2-phenylimidazole (500 mg, 3.47 mmol) in 10 mL THF at 0° C., was added 60% NaH (146 mg, 3.64 mmol). The mixture was stirred at 0° C. for 15 min, then BOM-Cl (80%, 656 μL, 3.82 mmol) was added. The mixture was stirred at rt for 1 h, then was diluted with EtOAc. The organic phase was washed with H2O and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 100% EtOAc/hexanes gradient) to afford 630 mg of Intermediate 15.1 as a colorless oil.
Reaction SMILES: [CH:1]([N:5]=[C:6]=[S:7])([CH2:3][CH3:4])[CH3:2].[Cl:8][C:9]1[C:10]([CH3:17])=[C:11]([NH:15][NH2:16])[CH:12]=[CH:13][CH:14]=1>C1(C)C=CC=CC=1>[Cl:8][C:9]1[C:10]([CH3:17])=[C:11]([NH:15][NH:16][C:6]([NH:5][CH:1]([CH3:2])[CH2:3][CH3:4])=[S:7])[CH:12]=[CH:13][CH:14]=1
Reactant: Cc1c(Cl)cccc1NN
Reactant: CCC(C)N=C=S
Solvent: Cc1ccccc1
Product: CCC(C)NC(=S)NNc1cccc(Cl)c1C

Procedure:
1.44 g (10 mmole) of sec-butyl isothiocyanate were added to 1.56 g (10 mmole) of 3-chloro-2-methylphenyl hydrazine dissolved in 120 ml of toluene, and the mixture was refluxed for 2 hours and then evaporated. The remanence was stirred with a small amount of hexane, separated by filtration and dried.
Reaction SMILES: [H+].[B-](F)(F)(F)[F:3].N[C:8]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][N:14]2[C@@H:17]2[O:37][C@H:36]([CH2:38][O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C@@H:27]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C@@H:18]2[O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:10]([NH2:47])[N:9]=1.[OH-].[Na+]>C(Cl)(Cl)Cl.O>[CH2:20]([O:19][C@H:18]1[C@H:27]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@@H:36]([CH2:38][O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[O:37][C@H:17]1[N:14]1[CH:13]=[N:12][C:11]2[C:15]1=[N:16][C:8]([F:3])=[N:9][C:10]=2[NH2:47])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: F[B-](F)(F)F
Reactant: Nc1nc(N)c2ncn([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@@H]3OCc3ccccc3)c2n1
Agent: [H+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: Nc1nc(F)nc2c1ncn2[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reaction time: 8 h

Procedure:
HBF4 (48%) (150 ml) was added to a solution (5°) of 2-amino-9-(2,3,5-tri-O-benzyl-β-D-arabinofuranosyl)adenine (III, 4.6 g, 8.4 mmol) in CHCl3 (60 ml). The resulting mixture was cooled to -10° before a solution of N--NO2 (17 g, 25 mmol) in 4 ml of H2O was added dropwise with stirring. After the addition was complete, the mixture was stirred an additional 40 min. at -10° to -5° before it was diluted with CHCl3 (75 ml), cooled to -20°, and neutralized (pH 5-6) with 50% NaOH. The CHCl3 layer was separated, washed with H2O, dried (MgSO4), and evaporated to dryness in vacuo. The residue, primarily a mixture of II and 9-(2,3,5-tri-O-benzyl-β-D-arabinofuranosyl)-2,6-difluoropurine, identified by TLC (1:1 CHCl3 -EtOAc), was dissolved in absolute EtOH, and the solution was saturated at 5° with dry NH3. After refrigeration overnight, the reaction solution was evaporated to dryness in vacuo. The residue was dissolved in CHCl3 (25 ml), and the solution was filtered through dry Celite to remove inorganic salts. The filtrate was adsorbed on a silica gel column (2.6×35 cm, packed and equilibrated with CHCl3). The column was eluted with 1:1 CHCl3 -EtOAc. The fractions containing II were combined and evaporated to dryness in vacuo, and the residue was recrystallized from C6H6 (40 ml); yield 1.7 g (36%); mp 157°-159°; λmax (mμ), pH 1, 7, 13, and EtOH--261, 272 (sh); vmax (cm-1) 3350, 3320, 3150 (NH), 2940, 2920, 2910, 2860 (CH), 1665, 1610, 1575 (NH, C=C, C=N), 1110, 1100, 1085, 1060 (COC), 730 (phenyl).
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([CH3:28])=[C:9]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[C:10]([CH3:17])=[N:11]2.CO.[OH-].[Na+]>C(O)=O>[Cl:16][C:13]1[CH:14]=[CH:15][C:6]([O:5][CH2:4][C:3]([OH:29])=[O:2])=[C:7]2[C:12]=1[N:11]=[C:10]([CH3:17])[C:9]([S:18]([C:21]1[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=1)(=[O:19])=[O:20])=[C:8]2[CH3:28]
Reactant: COC(=O)COc1ccc(Cl)c2nc(C)c(S(=O)(=O)c3ccc(Cl)cc3)c(C)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O=CO
Product: Cc1nc2c(Cl)ccc(OCC(=O)O)c2c(C)c1S(=O)(=O)c1ccc(Cl)cc1

Procedure:
A solution of [8-chloro-3-(4-chlorobenzenesulfonyl)-2,4-dimethylquinolin-5-yloxy]acetic acid methyl ester (0.020 g), methanol (3.0 mL) and 1.0 M aqueous sodium hydroxide solution (0.22 mL) was stirred at room temperature for 3 hours. The pH of the solution was adjusted to 5 by the addition of formic acid and the solvent removed under reduced pressure. Purification of the residue by preparative reverse-phase HPLC using a gradient over 30 minutes of acetonitrile in water gave title compound as a pale yellow solid, 0.0025 g.
Reaction SMILES: CN(/[CH:4]=[N:5]/[C:6](=O)[C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([O:16][CH3:17])=[C:9]([O:18][CH3:19])[CH:8]=1)C.[C:21]([C:24]1[C:25]([C:31]([F:34])([F:33])[F:32])=[N+:26]([O-:30])[CH:27]=[CH:28][CH:29]=1)(=[NH:23])[NH2:22]>>[CH3:19][O:18][C:9]1[CH:8]=[C:7]([C:6]2[N:5]=[CH:4][N:22]=[C:21]([C:24]3[C:25]([C:31]([F:32])([F:34])[F:33])=[N+:26]([O-:30])[CH:27]=[CH:28][CH:29]=3)[N:23]=2)[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]=1[O:16][CH3:17]
Reactant: COc1cc(C(=O)/N=C/N(C)C)cc([N+](=O)[O-])c1OC
Reactant: N=C(N)c1ccc[n+]([O-])c1C(F)(F)F
Product: COc1cc(-c2ncnc(-c3ccc[n+]([O-])c3C(F)(F)F)n2)cc([N+](=O)[O-])c1OC
Temperature: 25 °C

Procedure:
To a solution of (E)-N-((dimethylamino)methylene)-3,4-dimethoxy-5-nitrobenzamide (1.12 g, 4 mmol) ethanol (30 mL) was added 3-carbamimidoyl-2-(trifluoromethyl)pyridine 1-oxide (0.82 g, 4 mmol). The reaction mixture was heated to reflux for 5 hours. It was cooled to room temperature and the solvent was removed by evaporation. The residue was then dissolved in dichloromethane/isopropanol mixture (50 mL, 70:30) and the organic phase was washed with water, dried over anhydrous magnesium sulphate, filtered and evaporated, The crude product was recrystallized from ethanol to give 3-(4-(3,4-dimethoxy-5-nitrophenyl)-1,3,5-triazin-2-yl)-2-(trifluoromethyl)pyridine 1-oxide, 1.27 g (75%).
Reaction SMILES: C(O[C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[F:27])=[CH:14][CH:15]=1)=[O:5])C.[NH2:28][C:29]1[N:34]=[CH:33][C:32]([CH2:35][N:36]([CH3:41])[CH2:37][C:38]([NH2:40])=[O:39])=[CH:31][CH:30]=1.C[Al](C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CO.C(Cl)Cl>[C:38]([CH2:37][N:36]([CH2:35][C:32]1[CH:31]=[CH:30][C:29]([NH:28][C:4]([C:6]2[C:7]3[N:8]=[CH:9][CH:10]=[N:11][C:12]=3[C:13]([C:16]3[C:17]([F:27])=[C:18]([O:25][CH3:26])[CH:19]=[C:20]([O:23][CH3:24])[C:21]=3[F:22])=[CH:14][CH:15]=2)=[O:5])=[N:34][CH:33]=1)[CH3:41])(=[O:39])[NH2:40]
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2F)c2nccnc12
Reactant: CN(CC(N)=O)Cc1ccc(N)nc1
Agent: C[Al](C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1cc(OC)c(F)c(-c2ccc(C(=O)Nc3ccc(CN(C)CC(N)=O)cn3)c3nccnc23)c1F
Temperature: 80 °C
Reaction time: 22 h

Procedure:
The title compound was prepared in analogy to the procedure described in Example 115 but using 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 124.1), 2-[(6-amino-pyridin-3-ylmethyl)-methyl-amino]-acetamide (Step 118.1), 2 equiv of trimethyl aluminum, stirring the reaction mixture for 22 h at 80° C. and pouring it onto a saturated aqueous solution of NaHCO3 and DCM. The title compound: ESI-MS: 523.1 [M+H]+; tR=3.53 min (System 1); TLC: Rf=0.16 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: [OH-].[Na+].Br[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]2[N:21](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:20]=[N:19][N:18]=2)=[CH:7][CH:6]=1.Cl.[CH2:42]([C:46]1[NH:50][C:49](=[O:51])[C:48]2([CH2:55][CH2:54][CH2:53][CH2:52]2)[N:47]=1)[CH2:43][CH2:44][CH3:45].[OH-].[K+]>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH3:45][CH2:44][CH2:43][CH2:42][C:46]1[N:50]([CH2:4][C:5]2[CH:6]=[CH:7][C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:17]3[N:18]=[N:19][NH:20][N:21]=3)=[CH:9][CH:10]=2)[C:49](=[O:51])[C:48]2([CH2:55][CH2:54][CH2:53][CH2:52]2)[N:47]=1
Reactant: CCCCC1=NC2(CCCC2)C(=O)N1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCC1=NC2(CCCC2)C(=O)N1Cc1ccc(-c2ccccc2-c2nn[nH]n2)cc1
Temperature: 85 °C
Yield: 92 %

Procedure:
16.4 g of sodium hydroxide dissolved in 240 ml of purified water was added to the mixture of 5-(4′-bromomethyl-biphenyl-2-yl)-1-trityl-1H-tetrazole (59.5 g) and 2n-butyl-1,3-diazaspiro (4,4) non-1-en-4-one HCl (25 g) and tetra butyl ammonium bromide (2.15 g) in toluene (250 ml). The mixture was heated to about 85° C. for about 2 hours. After reaction completion, the reaction mass was cooled to about 25° C. and the toluene layer separated. The aqueous phase was extracted with toluene (105 ml). The combined organic layer was evaporated. The residue was dissolved in acetone (208 ml) and 3N HCl was added (600 ml). The contents were stirred at room temperature until reaction completion (as monitored by TLC). After reaction completion, a solution of KOH (30.4 g) in water (208 ml) was slowly added and acetone was evaporated under reduced pressure. The precipitated trityl alcohol was filtered and washed with water (2×105 ml). The filtrate was washed with toluene and slowly acidified to pH 4 with 3 N HCl. The suspension was cooled to 0-4° C., stirred for an additional 30 minutes and filtered. The cake was washed with cold isopropanol (2×50 ml) and dried under reduced pressure at 50-60° C. to yield irbesartan free base (92.0%).
Reaction SMILES: [O:1]=[C:2]1[CH:6]2[CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10][N:5]2[CH2:4][CH2:3]1.[BH4-].[Na+]>CO>[OH:1][C@H:2]1[C@@H:6]2[CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10][N:5]2[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCN2CCC(=O)C2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN2CC[C@@H](O)[C@@H]2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
To a solution of Example 100C (46 g, 0.192 mol) in methanol (460 mL) was added NaBH4 (13 g, 0.345 mol) at approximately 0° C., and the mixture was stirred at ambient temperature for 1 hour. The reaction mixture was quenched with saturated ammonium chloride solution (100 mL), and the he volatiles were removed under reduced pressure. The residue obtained was partitioned between ethyl acetate (500 mL) and water (250 mL). The organic layer was separated, dried over Na2SO4, filtered and concentrated. The material obtained was purified by column chromatography over silica gel using 5-6% methanol in chloroform to get the first eluting product (Example 101A, 5.3 g) and second eluting product (Example 100D, 5.1 g) together with 20 g of a mixture of both diastereomers.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH:4]([C:5](O)=[O:6])[CH:3]1[C:8]([OH:10])=[O:9].FC(F)(F)C(OC(=O)C(F)(F)F)=O>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:11])[CH:4]2[C:5]([O:9][C:8](=[O:10])[CH:3]12)=[O:6]
Reactant: CC1(C)C(C(=O)O)C1C(=O)O
Solvent: Cc1ccccc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC1(C)C2C(=O)OC(=O)C21
Reaction time: 3 h

Procedure:
To a solution containing the product (caronic acid) of step 1 (10 g) in toluene (35 mL) was added trifluoroacetic anhydride (17.9 mL) over 10 min. The mixture was heated to reflux while simultaneously distilling out trifluoroacetic acid and excess trifluoroacetic anhydride. When the temperature reached 100-110° C., additional toluene (20 mL) was added and the reaction mixture was heated under reflux. After 3 h, the mixture was concentrated to about 30 mL. Toluene (70 mL) was added and the mixture once again concentrated to about 30 mL. This solution which contained the compound of formula II (assayed by 1H NMR using ρ-nitromethylbenzoate as an internal std) was used in the first step of Example 2 without further purification. Alternatively, the compound formula II can be purified by methods such as fractional distillation.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[CH:12]=[CH:11][NH:10][C:7]2=[N:8][CH:9]=1)([O-])=O>C1COCC1.[Pt]>[NH:10]1[C:7]2=[N:8][CH:9]=[C:4]([NH2:1])[CH:5]=[C:6]2[CH:12]=[CH:11]1
Reactant: O=[N+]([O-])c1cnc2[nH]ccc2c1
Agent: [Pt]
Solvent: C1CCOC1
Product: Nc1cnc2[nH]ccc2c1

Procedure:
2.675 g 5-Nitro-1H-pyrrolo[2,3-b]pyridine in 200 ml THF were hydrogenated over 1.0 g Platinum on carbon at atmospheric pressure for 3 hrs at RT (with thin layer chromatography (TLC) control). The catalyst was removed by filtration, the filtrate was evaporated and the residue purified by chromatography on silica in ethyl acetate/heptane mixtures.