Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:15]([CH2:25][O:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[O:14][C@@H:11]([O:12][CH3:13])[C@@H:10]1[OH:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.[Si:44](OS(C(F)(F)F)(=O)=O)([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45]>C(Cl)Cl>[CH2:1]([O:8][C@H:9]1[C@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:15]([CH2:25][O:26][CH2:27][C:28]2[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=2)[O:14][C@@H:11]([O:12][CH3:13])[C@@H:10]1[O:35][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CO[C@@H]1O[C@H](COCc2ccc(Cl)cc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1O
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CO[C@@H]1O[C@H](COCc2ccc(Cl)cc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.3 %

Procedure:
Methyl 3,4-di-O-benzyl-6-O-(4-chlorobenzyl)-β-D-glucopyranoside (0.258 g, 0.517 mmol) was dissolved in 3 mL CH2Cl2. 2,6-lutidine (240 μL, 2.06 mmol) and tert-butyldimethylsilyltrifluoromethane sulfonate (0.284 mL, 1.24 mmol) were added and the reaction mixture was stirred at room temperature for 30 min. The solution was filtered through silica, eluted with EtOAc and concentrated. Purification by flash column chromatography on silica gel (10% EtOAc/Hexanes) gave 283 mg (89%) of 22 as a colorless oil. [α]24D: −9.2° (c 2.01, CH2Cl2); IR (thin film) 2928, 2855, 1492, 1069 cm−1; 1H-NMR (CDCl3) δ 7.41–7.29 (m, 12H), 7.16–7.13 (m, 2H), 4.97 (d, J=11.3 Hz, 1H), 4.90 (d, J=11.3 Hz, 1H), 4.82 (d, J=11.0 Hz, 1H), 4.61 (d, J=12.5 Hz, 1H), 4.56–4.53 (m, 2H), 4.17 (d, J=7.3 Hz, 1H), 3.78–3.76 (m, 1H), 3.71 (dd, J=4.6, 10.7 Hz, 1H), 3.63–3.53 (m, 6H), 0.95 (s, 9H), 0.17 (s, 3H), 0.13 (s, 3H); 13C-NMR (CDCl3) δ 138.8, 138.1, 136.8, 133.5, 129.2, 128.6, 128.5, 128.4, 128.3, 128.0, 127.9, 127.5, 104.9, 86.0, 78.3, 75.8, 75.4, 75.1, 74.9, 72.8, 69.1, 57.9, 26.1, 18.4, −4.1, −4.2; FAB MS m/z (M+Na)+: calcd 635.2572, obsd 635.2574.
Reaction SMILES: [CH3:1][NH:2][C:3](=[NH:8])[O:4][N+:5]([O-:7])=[O:6].Cl.[CH3:10]N.Cl>>[CH3:1][NH:2][C:3](=[N:8][CH3:10])[O:4][N+:5]([O-:7])=[O:6]
Reactant: CNC(=N)O[N+](=O)[O-]
Reactant: CN
Agent: Cl
Product: CN=C(NC)O[N+](=O)[O-]
Reaction time: 3 h
Yield: 71.6 %

Procedure:
To a suspension of 1-methyl-2-nitroisourea (1.0 g) in a buffer solution of a tris(hydroxymethyl)aminomethanehydrochloric acid (tris-hydrochloric acid buffer solution, 1.0 M, pH: 7.5, 10 ml), methylamine hydrochloride (0.6 g) was added at room temperature. After stirring for 3 hours, an aqueous hydrochloric acid (4 M) was added, and then the solution was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and it was then concentrated under reduced pressure. The residual oil was purified with silica gel column chromatography (hexane/ethyl acetate: 2/1) and then recrystallized (ethyl acetate-hexane), to obtain the desired compound (0.8 g) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([N+:17]([O-])=O)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[N:6][CH:7]=1.CC1C=CC(N2C=C3C(C=CC([N+]([O-])=O)=C3)=N2)=NC=1>CCO.[Pd]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=3)[CH2:10][NH:9]2)=[N:6][CH:7]=1
Reactant: Cc1ccc(-n2ncc3cc([N+](=O)[O-])ccc32)nc1
Agent: [Pd]
Agent: Cc1ccc(-n2cc3cc([N+](=O)[O-])ccc3n2)nc1
Solvent: CCO
Product: Cc1ccc(N2NCc3cc(N)ccc32)nc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The mixture of 1-(5-methylpyridin-2-yl)-5-nitro-1H-indazole and 2-(5-methylpyridin-2-yl)-5-nitro-2H-indazole was dissolved in EtOH (20 mL), and 10% Pd/C (250 mg) was added. Under H2 atmosphere, the mixture was stirred at room temperature for 12 h, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with AcOEt/Hexane to give the title compound (61 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:18]=[C:19]([NH:24][C:25](=[O:35])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([N:32]([CH3:34])[CH3:33])[CH:27]=2)[CH:20]=[CH:21][C:22]=1[CH3:23]>C(O)(C)C>[CH3:23][C:22]1[CH:21]=[CH:20][C:19]([NH:24][C:25](=[O:35])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([N:32]([CH3:34])[CH3:33])[CH:27]=2)=[CH:18][C:17]=1[NH:16][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1N
Solvent: CC(C)O
Product: COc1cc2nccc(Nc3cc(NC(=O)c4cccc(N(C)C)c4)ccc3C)c2cc1OC
Temperature: 85 °C

Procedure:
4-Chloro-6,7-dimethoxyquinoline (WO 98/13350 A1) (150 mg) and N-(3-amino-4-methylphenyl)-3-dimethylaminobenzamide (199 mg) were stirred in isopropanol (5 ml) and heated to 85° C. for 18 hours. After cooling to room temperature the precipitated solid was isolated and washed with isohexane. Filtered solid was impure and so was purified by eluting through a silica column with 10% methanol in methylene chloride. The title compound was obtained as a solid (35 mg); NMR: 2.14 (s, 3H), 2.94 (s, 6H), 3.89 (s, 3H), 3.93 (s, 3H), 6.05 (m, 1H), 6.90 (m, 1H), 7.18 (m, 1H), 7.22 (m, 1H), 7.3 (m, 1H), 7.61 (m, 1H), 7.73 (s, 1H), 7.78 (m, 1H), 8.18 (d, 1H), 8.47 (s, 1H), 10.1 (s, 1H); m/s: M+H+ 457.
Reaction SMILES: [OH:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.C1CCC(N=C=NC2CCCCC2)CC1.C([NH:62][C@H:63]([C:68](O)=[O:69])[CH2:64][CH:65]([CH3:67])[CH3:66])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O>CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[NH2:62][C@H:63]([C:68]([O:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](=[O:26])[NH2:27])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:69])[CH2:64][CH:65]([CH3:67])[CH3:66]
Reactant: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: NC(=O)c1ccc(C[C@@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@H]2O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](N)C(=O)O[C@@H]1c2ccccc2C[C@@]1(Cc1ccc(C(N)=O)cc1)C1=Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 85.5 %

Procedure:
To a solution of 4-{[(1′S,2′S)-1′-hydroxy-1′,3′-dihydro-1H,2′H-2,2′-biinden-2′-yl]methyl}benzamide (20, 150 mg, 0.26 mmol), DCC (64 mg, 0.31 mmol) and DMAP (3 mg, 0.026 mmol) in ethyl acetate (10 mL), was added Fmoc leucine (91 mg, 0.26 mmol) and then stirred at room temperature for 12 h. The solids were filtered, washed with ethyl acetate (25 ml) and the combined filtrate was washed with 1.5 N HCl (25 mL), water (25 mL), brine (10 mL), dried over anhydrous Na2SO4. The organic layer was evaporated under reduced pressure and the residue 1 (180 mg) was dissolved in dry THF (5 mL) and cooled to 0° C. Dimethylamine (5 mL, 20% in THF) was added drop wise and the reaction mixture was slowly allowed to stir at room temperature for 1 h. The reaction mixture was evaporated under reduced pressure and the residue was purified by CombiFlash using 10% methanol in chloroform as an eluent to yield 110 mg (86%) of the title compound as an off white solid.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH3:23][O:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH3:23][O:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][N:30]([C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:5]=[N:1][NH:2][CH:3]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:20])[CH2:29][CH2:28]1
Reactant: COCCN1CCNCC1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: COCCN1CCN(C(=O)c2nc3c(s2)CCOc2cc(-c4cn[nH]c4)ccc2-3)CC1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with 1-(2-methoxyethyl)piperazine (1.2 equiv) to give 185 (21.8 mg, M+1 440.1)
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C@@H:9]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10][CH2:11][S:12]2)=[CH:7][C:6]=1[O:23][CH3:24])=[O:4].C(=O)([O-])[O-].[K+].[K+]>>[C:19]([O:18][C:16]([NH:15][C@@H:9]1[C:8]2[C:13](=[CH:14][C:5]([C:3]([OH:4])=[O:2])=[C:6]([O:23][CH3:24])[CH:7]=2)[S:12][CH2:11][CH2:10]1)=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: COC(=O)c1cc2c(cc1OC)[C@@H](NC(=O)OC(C)(C)C)CCS2
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc2c(cc1C(=O)O)SCC[C@@H]2NC(=O)OC(C)(C)C
Yield: 95.6 %

Procedure:
By a similar reaction operation as in Starting Material Synthetic Example 6 using (S)-4-(tert-butoxycarbonylamino)-6-methoxythiochromane-7-carboxylic acid methyl ester (1.10 g) and potassium carbonate (861 mg), the objective (S)-4-(tert-butoxycarbonylamino)-6-methoxythiochromane-7-carboxylic acid (1.01 g) was obtained as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C:12]2[CH:30]=[CH:29][C:15]3[N:16]([C:20](=[O:28])[CH2:21][CH2:22][C:23]([O:25]CC)=[O:24])[CH2:17][CH2:18][O:19][C:14]=3[CH:13]=2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+]>CO>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C:12]2[CH:30]=[CH:29][C:15]3[N:16]([C:20](=[O:28])[CH2:21][CH2:22][C:23]([OH:25])=[O:24])[CH2:17][CH2:18][O:19][C:14]=3[CH:13]=2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)CCC(=O)N1CCOc2cc(NC(=O)c3nc(Cl)c(CC)[nH]3)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CCc1[nH]c(C(=O)Nc2ccc3c(c2)OCCN3C(=O)CCC(=O)O)nc1Cl
Yield: 25.6 %

Procedure:
The same operation as in Example (91d) was performed using ethyl 4-(7-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-4-oxobutanoate obtained in Example (95d) (45 mg, 0.10 mmol), 2 N lithium hydroxide (3 mL, 6 mmol) and methanol (5 mL), to obtain 10.4 mg of the title compound as a colorless solid (25%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[O:19])[CH2:13][CH2:12]2)[C:5]([Cl:26])=[CH:4][N:3]=1.[CH:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)C>[Cl:26][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[O:19])[CH2:13][CH2:12]2)=[C:7]2[N:8]=[C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1ncc(Cl)c(N2CCN(CC(=O)Nc3nccs3)CC2)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C(CN1CCN(c2c(Cl)cnc3[nH]c(-c4ccccc4)nc23)CC1)Nc1nccs1
Temperature: 70 °C

Procedure:
To a mixture of 2-[4-(2-amino-5-chloro-3-nitro-pyridin-4-yl)-piperazin-1-yl]-N-thiazol-2-yl-acetamide (0.040 g, 0.10 mmol), ethanol (3 ml), and benzaldehyde (0.015 g, 0.14 mmol) was added a freshly prepared aqueous solution of sodium dithionite (Na2S2O4) (1M; 0.4 ml, 0.4 mmol). The reaction mixture was heated at 70° C. for 6 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column which was eluted with 70% dichloromethane in ethyl acetate and then 2% methanol in ethyl acetate/dichloromethane (v/v; 1:1). The title compound was obtained as an off white solid after trituration with diethyl ether (0.011 g, 24%); 1H-NMR (500 MHz, DMSO-d6) 2.73 (br s, 4H, piperazine N(CH2)2), 3.40 (s, 2H, CH2CO), 3.75 (br s, 4H, piperazine N(CH2)2), 7.23 (d, J=3.46 Hz, 1H) and 7.49 (d, J=3.46 Hz, 1H) (thiazole 4-H, 5-H), 8.12 (s, 1H, imidazo[4,5-b]pyridine 5-H), 7.60 (m, 3H) and 8.19 (d, J=7.00 Hz, 2H) (ArH), 11.92 (s, 1H, CONH), 13.49 (s, 1H, imidazo[4,5-b]pyridine N—H); LC-MS (ESI, m/z) Rt=6.16 min—454, 456 [(M+H)+, Cl isotopic pattern]. ESI-HRMS: Found: 454.1230, calculated for C21H21N7OSCl (M+H)+: 454.1217.
Reaction SMILES: N#N.[C:3]([CH2:22][CH2:23][S:24][CH2:25][CH2:26][NH2:27])([C:6]([C:9]([C:12]([C:15]([C:18]([F:21])([F:20])[F:19])([F:17])[F:16])([F:14])[F:13])([F:11])[F:10])([F:8])[F:7])([F:5])[F:4].CN(C)C.Cl[C:33](OCC)=[O:34].C[Si](Cl)(Cl)Cl>C1(C)C=CC=CC=1.C(N(CC)CC)C>[C:3]([CH2:22][CH2:23][S:24][CH2:25][CH2:26][N:27]=[C:33]=[O:34])([C:6]([C:9]([C:12]([C:15]([C:18]([F:19])([F:20])[F:21])([F:16])[F:17])([F:14])[F:13])([F:11])[F:10])([F:8])[F:7])([F:5])[F:4]
Reactant: CCOC(=O)Cl
Reactant: NCCSCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: CN(C)C
Agent: C[Si](Cl)(Cl)Cl
Agent: N#N
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C=NCCSCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 0 °C
Yield: 95 %

Procedure:
In a 500 mL three neck flask (with mechanical stirrer, temperature probe, dropping funnel —N2), containing dry toluene (350 mL), one equivalent of each of the C6F13C2H4SCH2CH2NH2 (0.1 mol) and trimethyl amine (0.1 mol) were added. The mixture was cooled to 0° C. Ethyl chloroformate (0.11 mol) was added dropwise within 20 min. The mixture was allowed to warm to room temperature while stirring was continued. A second equivalent of triethyl amine was added followed by the dropwise addition of methyl trichlorosilane (0.12 mol) at 30-40° C. (addition time about 20-30 min). The dropping funnel was replaced with a reflux condenser. The mixture was heated to 100° C. for 1 h (less than the reflux temperature of toluene). After the mixture was cooled to ambient temperature the precipitated ammonium salts were filtered into a flask using a glass frit. Under steady N2 flow, both toluene and generated ethoxy methyl dichlorosilane were distilled off at 200 mm Hg (266.6×102 Pa). The collected organic by-product was treated with dilute aqueous bicarbonate solution to quench the silane. The residue was dried at 2 mm Hg (2.67×102 Pa) using a dry-ice cooled trap to furnish C6F13C2H4SCH2CH2NCO in 95% yield as a light red-brown liquid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O.O.[OH-].[K+]>[Pd].P(=O)(O)(O)O>[NH2:1][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[CH:10]([OH:12])[CH3:11]
Reactant: CC(=O)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Agent: O=P(O)(O)O
Agent: [K+]
Solvent: O
Product: CC(O)c1cccc(N)c1
Yield: 86 %

Procedure:
m-Nitroacetophenone (82.3 g., 0.50 mole), water containing 0.85 mole of phosphoric acid (300 ml.), and 5% palladium on carbon (1.5 g.) were charged and hydrogenated as in Example II. The resulting hydrogenate was neutralized with 45% potassium hydroxide (1.70 mole) and stirred in a cooling bath until precipitation of solids was complete. m-Amino-α-methylbenzyl alcohol was obtained in 86% yield and contained 97.8% pure product with 2.2% m-ethylaniline.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:26]([OH:28])=O)[C:5]2[C:10](/[CH:11]=[CH:12]/[C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)=[N:9][N:8]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][O:21]3)[C:6]=2[N:7]=1.[C:29]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C(=O)C.O1CCCC1>[C:32]([O:31][C:29]([N:36]1[CH2:41][CH2:40][N:39]([C:26]([C:4]2[C:5]3[C:10](/[CH:11]=[CH:12]/[C:13]4[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=4)=[N:9][N:8]([CH:20]4[CH2:25][CH2:24][CH2:23][CH2:22][O:21]4)[C:6]=3[N:7]=[C:2]([Cl:1])[CH:3]=2)=[O:28])[CH2:38][CH2:37]1)=[O:30])([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)c1cc(Cl)nc2c1c(/C=C/c1ccc(Cl)cc1)nn2C1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(Cl)nc3c2c(/C=C/c2ccc(Cl)cc2)nn3C2CCCCO2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 53.7 %

Procedure:
To a solution of 6-chloro-3-[(E)-2-(4-chloro-phenyl)-vinyl]-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (2 g, 4.79 mmol) in a mixture of anhydrous tetrahydrofuran (42 ml) and N,N-dimethylacetamide (10 ml) were added 1-boc-piperazine (0.98 g, 5.27 mmol), 1-hydroxybenzotriazole (0.06 g, 0.48 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.91 g, 4.79 mmol). The reaction mixture was stirred at room temperature for 4 hours, tetrahydrofuran was evaporated under reduced pressure, water and dichloromethane were then added. The organic phase was separated, dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The crude residue was purified on a silica gel column chromatography using a gradient of ethyl acetate (0-45%) in cyclohexane to yield the title compound as a yellow foam (1.51 g, 54%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:23][CH2:24][CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Co](Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:23][CH2:24][CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)C=CC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCc1cccnc1
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCc1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3.27 g (7 mmol) of methyl 8-(p-chlorophenylsulfonamido)-4-[3-(3-pyridyl)propyl]-oct-2-enoate (example 3) in 32 ml methanol, 0.446 g (1.87 mmol) cobalt (II) chloride hexahydrate is added. The solution is cooled in an ice bath and 0.573 g (15 mmol) sodium borohydride is added in small portions. Vigorous gas evolution and formation of a black precipitate is observed during the addition of sodium borohydride. After completion of the addition, the ice bath is removed and the mixture stirred at room temperature for 1 h. The black precipitate is filtered off and washed with methanol. The combined filtrate is evaporated and the residue suspended in a mixture of 30 ml methylene chloride and 150 ml ether. The organic layer is washed with water. The aqueous phase is extracted with ether (2×50 ml). The combined organic extract is dried (MgSO4), filtered and the solvent evaporated. The residue is subjected to flash chromatography on silica using 3:2 ethyl acetate/hexane as the eluent to give methyl 8-(p-chlorophenylsulfonamido)-4-[3-(3-pyridyl)propyl]-octanoate, m.p. 81°-82°.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](/[CH:12]=[C:13](/[C:16](=O)[CH3:17])\[C:14]#[N:15])[CH:10]=2)[NH:5][N:4]=1.[O:19]1[C:23]([NH2:24])=[CH:22][CH:21]=[N:20]1>>[CH3:1][O:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]3[C:13]([C:14]#[N:15])=[C:16]([CH3:17])[NH:24][C:23]4[O:19][N:20]=[CH:21][C:22]3=4)[CH:10]=2)[NH:5][N:4]=1
Reactant: Nc1ccno1
Reactant: COc1n[nH]c2ccc(/C=C(\C#N)C(C)=O)cc12
Product: COc1n[nH]c2ccc(C3C(C#N)=C(C)Nc4oncc43)cc12

Procedure:
43 mg (0.178 mmol) (2E)-2-[(3-methoxy-1H-indazol-5-yl)methylidene]-3-oxobutanenitrile (Example 8A) were treated with 1,2-oxazol-5-amine following the procedure described in Example 2. The crude material was purified by preparative RP-HPLC (acetonitrile/water gradient) to yield 3 mg (5% of th.) of the racemic title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[C:9]1(B2OC(C)(C)C(C)(C)O2)[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C>[C:9]1([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[CH:7]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]=1
Reactant: Nc1cc(Cl)ccn1
Reactant: CC1(C)OB(C2=CCCCC2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1cc(C2=CCCCC2)ccn1
Yield: 14.3 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 33a by using 2-amino-4-chloropyridine (927 mg, 7.21 mmol), 2-cyclohex-1-en-1-yl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.50 g, 7.21 mmol), tetrakis(triphenylphosphine)palladium (0) (416 mg, 0.360 mmol), potassium carbonate (3.98 g, 14.5 mmol) and DMF (13 mL), to yield the title compound (180 mg, 14%) as a colorless solid.
Reaction SMILES: C(=O)([O-])[O-:2].[K+].[K+].[C:7]([N:10]1[C:19]2[C:14](=[CH:15][C:16]([C:22]3[CH:23]=[N:24][N:25]([CH:27]4[CH2:29][CH2:28]4)[CH:26]=3)=[C:17]([C:20]#[N:21])[CH:18]=2)[N:13]([C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])[CH2:12][C@@H:11]1[CH3:36])(=[O:9])[CH3:8].OO>CS(C)=O>[C:7]([N:10]1[C:19]2[C:14](=[CH:15][C:16]([C:22]3[CH:23]=[N:24][N:25]([CH:27]4[CH2:28][CH2:29]4)[CH:26]=3)=[C:17]([C:20](=[O:2])[NH2:21])[CH:18]=2)[N:13]([C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])[CH2:12][C@@H:11]1[CH3:36])(=[O:9])[CH3:8]
Reactant: CC(=O)N1c2cc(C#N)c(-c3cnn(C4CC4)c3)cc2N(C(=O)OC(C)C)C[C@@H]1C
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: CC(=O)N1c2cc(C(N)=O)c(-c3cnn(C4CC4)c3)cc2N(C(=O)OC(C)C)C[C@@H]1C
Temperature: 25 °C

Procedure:
Potassium carbonate (0.002 g, 0.014 mmol) was added to a solution of isopropyl (S)-4-acetyl-6-cyano-7-(1-cyclopropyl-1H-pyrazol-4-yl)-3-methyl-3,4-dihydroquinoxaline-1 (2H)-carboxylate (0.010 g, 0.025 mmol) in dimethyl sulfoxide (2004), and the mixture was cooled in an ice bath. Hydrogen peroxide (30 wt %, 100 μL, 0.979 mmol) was added dropwise, the ice bath removed after 1 minute, and the reaction was allowed to warm to room temperature. Water was added, and the resulting precipitate was filtered and dried. The solid was purified by mass triggered preparatory HPLC. The product-containing fractions were combined and concentrated in a Genevac to afford isopropyl (S)-4-acetyl-6-carbamoyl-7-(1-cyclopropyl-1H-pyrazol-4-yl)-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate. MS (ESI, pos. ion) m/z 426 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH:26]=[C:12]2[C:13]([NH:17][C:18]3[CH:23]=[C:22]([CH3:24])[N:21]=[C:20](C)[N:19]=3)=[N:14][CH:15]=[CH:16][C:11]2=[N:10]1.[Cl:27]C1C2=CN(C3C(Cl)=CC=CC=3Cl)N=C2C=CN=1.ClC1N=C(N)C=C(C)N=1>>[Cl:27][C:20]1[N:19]=[C:18]([NH:17][C:13]2[C:12]3=[CH:26][N:9]([C:3]4[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[N:10]=[C:11]3[CH:16]=[CH:15][N:14]=2)[CH:23]=[C:22]([CH3:24])[N:21]=1
Reactant: Cc1cc(Nc2nccc3nn(-c4c(Cl)cccc4Cl)cc23)nc(C)n1
Reactant: Clc1cccc(Cl)c1-n1cc2c(Cl)nccc2n1
Agent: Cc1cc(N)nc(Cl)n1
Product: Cc1cc(Nc2nccc3nn(-c4c(Cl)cccc4Cl)cc23)nc(Cl)n1
Yield: 57 %

Procedure:
Following the procedure described above for [2-(2,6-dichlorophenyl)-2H-pyrazolo[4,3-c]pyridine-4-yl]-(2,6-dimethylpyrimidin-4-yl)amine, 4-chloro-2-(2,6-dichlorophenyl)-2H-pyrazolo[4,3-c]pyridine and 2-chloro-6-methylpyrimidin-4-ylamine were reacted to afford the title compound as a yellow solid (256 mg, 57% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.06 (s, 1H), 9.14 (s, 1H), 8.51 (s, 1H), 8.02 (d, J=6.4 Hz, 1H), 7.84-7.80 (m, 2H), 7.73-7.68 (m, 1H), 7.30 (d, J=6.4 Hz, 1H), 2.46 (s, 3H). LCMS (Method D): RT=2.50 min, m/z: 407 [M+H+].