Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH3:31])[C:9]1[C:10](OS(C(F)(F)F)(=O)=O)=[N:11][C:12]2[C:17]([N:18]=1)=[CH:16][C:15]([C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:40]2[CH:41]=[C:42]3[C:46](=[CH:47][CH:48]=2)[N:45]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[N:44]=[CH:43]3)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[CH2:1]([N:8]([CH3:31])[C:9]1[C:10]([C:40]2[CH:41]=[C:42]3[C:46](=[CH:47][CH:48]=2)[N:45]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[N:44]=[CH:43]3)=[N:11][C:12]2[C:17]([N:18]=1)=[CH:16][C:15]([C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)n1ncc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N(C)Cc3ccccc3)nc2c1
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: [Na+]
Solvent: COCCOC
Product: COC(=O)c1ccc2nc(-c3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c(N(C)Cc3ccccc3)nc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 43.2 %

Procedure:
To a solution of methyl 3-(benzyl(methyl)amino)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate (300 mg, crude) in ethylene glycol dimethyl ether (7 mL) was added tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole-1-carboxylate (181 mg, 0.53 mmol), sodium carbonate (93 mg, 0.88 mmol), and Pd(PPh3)4 (25 mg, 0.02 mmol). The resulting solution was stirred for 1 h at 90° C. under an inert atmosphere of nitrogen, quenched with water (100 mL) and extracted with dichloromethane (3×50 mL), dried over anhydrous magnesium sulfate, and concentrated under vacuum to give a residue, which was purified via silica gel chromatography (3% ethyl acetate in petroleum ether) to afford methyl 3-(benzyl(methyl)amino)-2-(1-(tert-butoxycarbonyl)-1H-indazol-5-yl)quinoxaline-6-carboxylate as a yellow solid (120 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][N:3]=1.Cl[S:9]([C:12]1[N:16]=[CH:15][N:14]([C:17](=[O:21])[N:18]([CH3:20])[CH3:19])[N:13]=1)(=[O:11])=[O:10].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([S:9]([C:12]2[N:16]=[CH:15][N:14]([C:17](=[O:21])[N:18]([CH3:19])[CH3:20])[N:13]=2)(=[O:10])=[O:11])[N:3]=1
Reactant: CN(C)C(=O)n1cnc(S(=O)(=O)Cl)n1
Reactant: Cc1cc(C)[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(C)n(S(=O)(=O)c2ncn(C(=O)N(C)C)n2)n1
Temperature: 50 °C
Reaction time: 2 h
Yield: 67.7 %

Procedure:
A mixture of 3,5-dimethylpyrazole (100 mg), 3-chlorosulfonyl-1-dimethylcarbamoyl-1H-1,2,4-triazole (Example 54-a) (480 mg), anhydrous potassium carbonate (280 mg), and acetonitrile (1.5 ml) was heated and stirred for 2 hours on an oil bath at 50° C. The reaction solution was extracted with ethyl acetate-water. The organic layer was washed with saturated aqueous sodium chloride solution, and concentrated. The residue was subjected to a silica-gel column chromatography with 20 to 30% (20% 2-propanol/ethyl acetate)/hexane, and the title compound (210 mg) was obtained by crystallization in ethyl acetate-hexane.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:12][C:13]2[N:23]=[C:22]3[C:16]([N:17]([CH3:30])[C:18](=[O:29])[CH2:19][CH2:20][N:21]3[CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:15][N:14]=2)=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].[NH2:31][CH:32]1[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:12][C:13]2[N:23]=[C:22]3[C:16]([N:17]([CH3:30])[C:18](=[O:29])[CH2:19][CH2:20][N:21]3[CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:15][N:14]=2)=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([NH:31][CH:32]1[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]1)=[O:8]
Reactant: CN1C(=O)CCN(C2CCCC2)c2nc(Nc3cc(F)c(C(=O)O)cc3Cl)ncc21
Reactant: CN1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(NC(=O)c2cc(Cl)c(Nc3ncc4c(n3)N(C3CCCC3)CCC(=O)N4C)cc2F)CC1
Temperature: 50 °C
Yield: 47.6 %

Procedure:
5-chloro-4-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-10-yl)amino]-2-fluoro-benzoic acid (Intermediate 219; 100 mg, 0.23 mmol), 4-amino-1-methylpiperidine (Fluorochem; 40 mg, 0.35 mmol) and HATU (132 mg, 0.35 mmol) were stirred in DMF (3 mL). N,N-diisopropylethylamine (121 μl, 0.69 mmol) was added and the mixture heated at 50° C. for 2 hours. The mixture was cooled and absorbed on to an SCX column, which was subsequently washed with methanol and eluted with ammonia in methanol. Product containing fractions were concentrated and the residue purified by base modified reverse phase preparative chromatography to yield the title compound as a white solid (58 mg, 48%)
Reaction SMILES: [CH:1]([N:4]1[C:9](=O)[CH2:8][O:7][CH:6]([C:11]([O:13][C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[CH2:19][CH2:18][CH2:17]3)=[O:12])[CH2:5]1)([CH3:3])[CH3:2].O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O>[OH:12][CH:11]([O:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[CH2:19][CH2:18][CH2:17]2)[CH:6]1[O:7][CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5]1
Reactant: CC(C)N1CC(C(=O)Oc2ccc3c(c2)CCC3)OCC1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)N1CCOC(C(O)Oc2ccc3c(c2)CCC3)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.7 %

Procedure:
After mixing 3.03 g, of 4-isopropyl-5-oxo-2-(1-oxo-5-indanyloxymethyl)morpholine, 100 ml. of tetrahydrofuran, and 2.0 g. of lithium aluminum hydride under ice-cooling, the mixture was stirred for 18 hours at room temperature. Then, 2.0 ml. of water, 2.0 ml. of 15% sodium hydroxide aqueous solution, and then 6 ml. of water were added to the mixture followed by stirring for 30 minutes. The mixture was then filtered and the filtrate was concentrated. The residue formed was adsorbed on a silica gel column prepared from 100 ml. of silica gel in chloroform and then eluted with ethyl acetate as the eluent. After removing the first 20 ml. of the ethyl acetate eluate emerging from the column, 300 ml. of the subsequent ethyl acetate eluate was collected and dried to provide 2.0 g. (yield 68.7%) of oily 2-(1-hydroxy-5-indanyloxymethyl)-4-isopropylmorpholine.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[C:8](=O)[O:9][C:10](=[O:11])[C:5]2=[CH:4][CH:3]=1.[BH4-].[Na+].C(O)(=O)C>C1COCC1>[CH3:1][C:2]1[N:7]=[C:6]2[CH2:8][O:9][C:10](=[O:11])[C:5]2=[CH:4][CH:3]=1
Reactant: Cc1ccc2c(n1)C(=O)OC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1ccc2c(n1)COC2=O
Temperature: 15 °C
Reaction time: 4 h
Yield: 65.8 %

Procedure:
A suspension of 2-methyl-furo[3,4-b]pyridine-5,7-dione (15 g, 92 mmol) in THF (100 mL) is treated with sodium borohydride (3.75 g, 99 mmol) at 15° C. under an argon atmosphere. The reaction mixture is then treated dropwise with acetic acid (12 g, 200 mmol) at 15° C. During this addition gas evolution is observed. The reaction mixture is stirred at 15° C. for 4 h and is then concentrated. The residue is treated with acetic acid (40 mL) and acetic anhydride (40 mL). The resulting solution is stirred at 100° C. for 3 h. The brown solution is cooled to room temperature and concentrated. The residue is treated with a 20% aqueous NaCl solution and extracted with chloroform. The organic extract is washed with saturated aqueous NaCl solution, dried over Na2SO4 and concentrated. The residue is purified by chromatography (silica gel, gradient elution, 5:1 hexane/ethyl acetate to 2:1 hexane/ethyl acetate). The product containing fractions are concentrated to give the title compound as a white solid (9.03 g, 44%).
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH2:12]([Sn](CCCC)(CCCC)CCCC)[CH:13]=[CH2:14].[K+].[Br-]>>[CH2:14]([C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1)[CH:13]=[CH2:12]
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Product: C=CCc1ccc(N)c([N+](=O)[O-])c1
Yield: 96 %

Procedure:
Prepared from 4-bromo-2-nitroaniline 17 (1.70 g, 7.84 mmol) and allyltributyltin (3.38 g, 10.2 mmol) as a yellow solid in 96% yield as described above for 5: mp 29°-31° C.; IR (KBr) 3490, 3374, 1638, 1518, 1341, 1253; 1H NMR δ7.90 (1H, d, J=2.0), 7.19 (1H, dd, J=8.5, 2.0), 6.77 (1H, d, J=8,5), 6.05 (NH, brs), 6.00-5.80 (1H, m), 5.11 (1H, dd, =1.4, 1.4), 5.04 (1H, ddd, J=6.6, 3.0, 1.5), 3.28 (1H, d, J=6.6); 13C NMR δ143.81, 137.13, 129.34, 125.59, 119.49, 116.95, 39.18; HRMS (EI) calcd for C9H10N2O2 178.0742, found 178.0746.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([NH2:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([C:26]2[O:30][C:29]([C:31](O)=[O:32])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1)([O-:19])=[O:18].C(OC(NC1C=CC(CC(O)=O)=CC=1)=O)(C)(C)C>>[C:1]([C:5]1[CH:10]=[C:9]([NH:11][C:31]([C:29]2[O:30][C:26]([C:23]3[CH:22]=[CH:21][C:20]([N+:17]([O-:19])=[O:18])=[CH:25][CH:24]=3)=[CH:27][CH:28]=2)=[O:32])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)c1ccc(-c2ccc([N+](=O)[O-])cc2)o1
Reactant: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1O
Agent: CC(C)(C)OC(=O)Nc1ccc(CC(=O)O)cc1
Product: CC(C)(C)c1cc(NC(=O)c2ccc(-c3ccc([N+](=O)[O-])cc3)o2)cc(C(C)(C)C)c1O
Yield: 56 %

Procedure:
The experimental protocol used is the same as that described for intermediate 40.1, 2,6-di-t-butyl-4-aminophenol and 5-(4-nitrophenyl)-2-furan carboxylic acid replacing thiazolidine and 4-(t-butoxycarbonylamino)-benzeneacetic acid respectively. The expected compound is obtained in the form of a colourless oil with a yield of 56%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([C:10]2[C:11]([F:27])=[C:12]([C@H:17]([NH:20][CH:21]([CH3:26])[CH2:22][C:23]([NH2:25])=[O:24])[CH2:18][CH3:19])[CH:13]=[CH:14][C:15]=2[Cl:16])=[O:9])=[CH:4][CH:3]=1.[C:28]([O:31][C:32](=[O:41])[C@H:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[OH:34])(=[O:30])[CH3:29]>CCO>[C:28]([O:31][C:32](=[O:41])[C@H:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[OH:34])(=[O:30])[CH3:29].[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([C:10]2[C:11]([F:27])=[C:12]([C@H:17]([NH:20][C@@H:21]([CH3:26])[CH2:22][C:23]([NH2:25])=[O:24])[CH2:18][CH3:19])[CH:13]=[CH:14][C:15]=2[Cl:16])=[O:9])=[CH:4][CH:3]=1
Reactant: CC[C@@H](NC(C)CC(N)=O)c1ccc(Cl)c(C(=O)c2ccc(N)nc2)c1F
Agent: CC(=O)OC(=O)[C@@H](O)c1ccccc1
Solvent: CCO
Product: CC[C@@H](N[C@@H](C)CC(N)=O)c1ccc(Cl)c(C(=O)c2ccc(N)nc2)c1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 58.2 %

Procedure:
Step 11—To a stirred solution of 3-{[(1R)-1-[3-(6-aminopyridine-3-carbonyl)-4-chloro-2-fluorophenyl]propyl]-amino}butanamide (237 g, 603 mmol) in EtOH (1900 mL) at 78° C. was added (+)-O-acetyl-L-mandelic acid (117 g, 603 mmol). The mixture was kept at 78° C. for 10 minutes then allowed to cool to room temperature (with stirring) providing a precipitate. After stirring overnight the solid was collected by filtration, washed with EtOH (1.25 Vol), then Et2O (1.7 Vol) and dried at 40° C. under vacuum providing (3S)-3-{[(1R)-1-[3-(6-aminopyridine-3-carbonyl)-4-chloro-2-fluorophenyl]propyl]-amino}butanamide (+)-O-acetyl-L-mandelic acid salt (206 g) diastereomer ratio of 97.5:2.5 in favour of the desired diastereomer. 1H NMR (400 MHz, DMSO-d6): 8.15 (1H, d), 7.78 (1H, dd), 7.64 (1H, t), 7.52-7.37 (6H, m), 7.31 (3H, d), 6.79 (1H, s), 6.54 (1H, d), 5.83-5.73 (1H, m), 4.01 (1H, t), 2.87-2.69 (1H, m), 2.62-2.52 (1H, m), 2.22-2.01 (2H, m), 2.12 (3H, s), 1.81-1.66 (1H, m), 1.66-1.50 (1H, m), 0.95 (3H, d), 0.78 (3H, t).
Reaction SMILES: [F:1][CH:2]([F:17])[O:3][C:4]1[CH:5]=[C:6]([CH2:14][CH2:15]O)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:38]>ClCCl>[Br:38][CH2:15][CH2:14][C:6]1[CH:7]=[CH:8][C:9]([O:10][CH:11]([F:13])[F:12])=[C:4]([O:3][CH:2]([F:17])[F:1])[CH:5]=1
Reactant: OCCc1ccc(OC(F)F)c(OC(F)F)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FC(F)Oc1ccc(CCBr)cc1OC(F)F
Temperature: 0 °C
Reaction time: 8 h

Procedure:
2-[3,4-Bis(difluoromethoxy)phenyl]ethanol (6 g, 0.024 mol; see step (iv) above) and triphenylphosphine (12.6 g, 0.048 mol) were taken up in dichloromethane (100 mL) and cooled to 0° C. CBr4 (15.9 g, 0.048 mol) in dichloromethane was added dropwise, and the mixture stirred at RT overnight under a nitrogen atmosphere. The reaction mixture was filtered, the filtrate concentrated under reduced pressure and the residue purified by column chromatography over silica gel (using 20% ethyl acetate in petroleum ether as eluent) to give the title compound as a yellow liquid. Yield 5.2 g.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:23])[C:10]([CH3:22])([CH3:21])[O:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.Cl[CH2:36][C:37]1[N:38]=[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][N:40]2[C:45]=1[CH3:46]>O>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[O:11][C:10]([CH3:21])([CH3:22])[C:9](=[O:23])[C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:36][C:37]3[N:38]=[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][N:40]4[C:45]=3[CH3:46])=[CH:7][CH:6]=2)=[CH:14][CH:15]=1
Reactant: Cc1c(CCl)nc2ccccn12
Reactant: COc1ccc(C2=C(c3ccc(O)cc3)C(=O)C(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C2=C(c3ccc(OCc4nc5ccccn5c4C)cc3)C(=O)C(C)(C)O2)cc1
Yield: 1925.1 %

Procedure:
4-(4-Hydroxyphenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (0.1 g, 0.32 mmol) was added to a mixture of cesium carbonate (0.52 g, 1.62 mmol) and DMF (20 mL) at RT under an atmosphere of nitrogen. The reaction mixture was stirred at RT for 30 min upon which 2-(chloromethyl)-3-methylimidazo[1,2-a]pyridine (87 mg, 0.48 mmol) was added. The mixture was heated at for 4 h (the reaction was monitored by TLC). The reaction mixture was diluted with water and extracted with EtOAc, the combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 20% ethyl acetate in n-hexane and silica gel (230-400 mesh) to afford 5-(4-methoxyphenyl)-2,2-dimethyl-4-(4-((3-methylimidazo[1,2-a]pyridin-2-yl)methoxy)phenyl)furan-3(2H)-one (2.8 g, 77%) as an off-white solid. 1H NMR, 500 MHz, DMSO-d6: δ 8.25 (d, 1H), 7.45 (d, 3H), 7.25 (t, 1H), 7.15-6.95 (Ar, 7H), 5.2 (s, 2H), 3.85 (s, 3H), 2.45 (s, 3H), 1.45 (s, 6H). MS: [M+H]+: m/z=455.3. HPLC: (96.3%, Condition-A).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.[Cu]I>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)=[CH:18][CH:19]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Reactant: COc1ccc(I)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: COc1ccc(Oc2ccc(N3CCN(Cc4ccccc4)CC3)cc2)cc1
Temperature: 90 °C
Reaction time: 24 h
Yield: 11.3 %

Procedure:
To a solution of the compound from step 1 (0.59 g, 2 mmol) and 1-iodo-4-methoxy-benzene (0.47 g, 2 mmol) in anhydrous dioxane (8 mL) were added cesium carbonate (1.26 g, 4 mmol), N,N-dimethylglycine. HCl (0.036 g, 0.25 mmol), and copper (I) iodide (0.015 g, 0.078 mmol) and the reaction mixture was stirred at 90° C. for 24 h under nitrogen. The mixture was filtered and partitioned between ethyl acetate (153 mL) and water (100 mL). The organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated to give a off-white oil, which was purified by silica gel flash chromatography to afford the title product (85 mg, 11.4%) as a light yellow solid: MS (ESI) m/z 359 (M+H). 1H NMR (400 MHz, CDCl3) δ 2.62 (t, J=4.8 Hz, 4H), 3.14 (t, J=4.8 Hz, 4H), 3.57 (s, 2H), 3.78 (s, 3H), 6.83-6.93 (m, 8H), 7.30-7.34 (m, 5H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:16]1(=O)[CH2:20][CH2:19][CH2:18][CH2:17]1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[CH:16]1([N:13]2[CH2:12][CH2:11][CH:10]([C:7]3[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[CH2:15][CH2:14]2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=C1CCCC1
Reactant: O=[N+]([O-])c1ccc(C2CCNCC2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=[N+]([O-])c1ccc(C2CCN(C3CCCC3)CC2)cc1
Reaction time: 1 h
Yield: 100 %

Procedure:
4-(4-Nitrophenyl)piperidine (5 g, 24 mmol) was dissolved in MeOH (240 mL). To the solution were added cyclopentanone (6.5 mL, 73 mmol) and acetic acid (3 mL). The mixture was stirred for 1 hour, and then NaBH3CN (6.1 g, 97 mmol) was added. The mixture was stirred at room temperature for 12 hours. The solvent was removed under reduced pressure, and the residue was suspended in EtOAc. The organic suspension was washed with 1N NaOH (aq), water and brine, dried, concentrated and purified by flash column chromatography (MeOH/DCM) to obtain 1-cyclopentyl-4-(4-nitrophenyl)piperidine (303) (6.5 g, 24 mmol, 100% yield).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][C@@H:20]2[CH3:25])[C:5]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][C:6]=2[N:7]=1.[CH2:26]([NH:28][C:29](=[O:46])[NH:30][C:31]1[CH:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][CH:32]=1)[CH3:27].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCO.O>[CH2:26]([NH:28][C:29](=[O:46])[NH:30][C:31]1[CH:36]=[CH:35][C:34]([C:2]2[N:3]=[C:4]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][C@@H:20]3[CH3:25])[C:5]3[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][C:6]=3[N:7]=2)=[CH:33][CH:32]=1)[CH3:27]
Reactant: CCNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1CCN(C(=O)OC(C)(C)C)C2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C(=O)OC(C)(C)C)C3)cc1
Temperature: 120 °C
Yield: 59.4 %

Procedure:
To a solution of (S)-tert-butyl 2-chloro-4-(3-methylmorpholino)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (intermediate 4) (576 mg, 1.56 mmol) and 4-(3-ethylureido)phenylboronic acid pinacol ester (498 mg, 1.72 mmol) in DME/EtOH/H2O (12/5/3) (15 mL) was added Pd(PPh3)2(Cl)2 (55 mg, 0.078 mmol) and Na2CO3 (496 mg, 4.68 mmol). The reaction mixture was then heated by microwave at 120° C. for 1 h. The crude reaction mixture was then partitioned between water and EtOAc, the phases separated and the organic layer washed with aqueous NaHCO3 and brine, dried over magnesium sulfate, filtered and the solvent removed in vacuo. The residue was purified by flash chromatography (20-50% EtOAc/Petroleum Ether 40-60) to yield a yellow solid (460 mg, 59%).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C@@H:8]2[CH2:10][C@H:9]2[C:11]([OH:13])=[O:12])=[O:7])=[CH:4][CH:3]=1.[CH3:16]OC(OC)(C)C.Cl>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C@@H:8]2[CH2:10][C@H:9]2[C:11]([O:13][CH3:16])=[O:12])=[O:7])=[CH:14][CH:15]=1
Reactant: COC(C)(C)OC
Reactant: O=C(O)[C@@H]1C[C@H]1C(=O)c1ccc(Br)cc1
Agent: Cl
Solvent: CO
Product: COC(=O)[C@@H]1C[C@H]1C(=O)c1ccc(Br)cc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 83.5 %

Procedure:
To a solution of trans-2-(4-bromobenzoyl)cyclopropanecarboxylic acid (9.43 g, 32.59 mmol) in MeOH (200 mL) was added 2,2-dimethoxypropane (10.18 g, 97.77 mmol) and HCl (4.0 M in dioxane, 4.0 mL). The resulting solution was stirred at 40° C. overnight, and then evaporated to dryness. The resulting residue was purified by flash chromatography (Biotage Flash 40M) using 15 to 25% ethyl acetate in hexanes to afford methyl trans-2-(4-bromobenzoyl)cyclopropanecarboxylate (7.7 g, 83%). 1H NMR (400 MHz, CD2Cl2) δ 1.68 (m, 2H), 2.37 (m, 1H), 3.21 (m, 1H), 3.65 (s, 3H), 7.68 (m, 2H), 7.90 (m, 2H).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14](OC)=[O:15])=[CH:13][C:8]=2[NH:7][C:6]1=[O:18].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([CH2:14][OH:15])=[CH:13][C:8]=2[NH:7][C:6]1=[O:18]
Reactant: COC(=O)c1ccc2c(c1)[nH]c(=O)n2CCN(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C)CCn1c(=O)[nH]c2cc(CO)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.5 %

Procedure:
To a solution of 0.37 g of 1,3-dihydro-1-(2dimethylaminoethyl)-5-methoxycarbonyl-2H-benzimidazol-2-one in 15 ml of tetrahydrofuran was added 0.10 g of lithium aluminum hydride. After being stirred for 1 hour at room temperature, the reaction was quenched by the addition of 3.0 g of sodium sulfate hydrate. The solid was removed by filtration and the solvent was evaporated in vacuo. The residue was chromatographed on silica gel using chloroform-methanol-ammonium hydroxide (40:10:1) to provide 0.20 g of 1,3-dihydro-1-(2-dimethylaminoethyl)-5-hydroxymethyl-2H-benzimidazol-2-one
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[F:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH:17]=[N:16][CH:15]=[CH:14]2>>[F:10][C:11]1[C:12]([N+:1]([O-:4])=[O:2])=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH:17]=[N:16][CH:15]=[CH:14]2
Reactant: Fc1ccc2cnccc2c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1c(F)ccc2cnccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under cooling 2.0 mL of concentrated nitric acid are added to 2.8 mL of sulphuric acid. Subsequently 350 mg of 6-fluoroisoquinoline (23) are added, the reaction is warmed up to room temperature and allowed to stir overnight. The reaction mixture is poured on ice, extracted with dichloromethane and adjusted to alkaline pH by addition of sodium hydroxide. The aqueous layer is extracted again with dichloromethane. The dichloromethane layer is dried over magnesium sulfate and evaporated to give 90 mg of 6-Fluoro-5-nitro-isoquinoline, which can be used without further purification. Rt=1.03 min (Method #1). Detected mass: 193.0 (M+H+).
Reaction SMILES: C(OC([N:8]1[C:12]2[N:13]=[CH:14][N:15]=[C:16]([N:17]3[CH2:24][C:21]4([CH2:23][CH2:22]4)[N:20]([S:25](=[O:36])(=[O:35])[NH:26][CH2:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:19][CH2:18]3)[C:11]=2[CH:10]=[CH:9]1)=O)(C)(C)C.[C:37]([O-])([O-])=O.[K+].[K+].IC.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O.CCCCCCC.O>[CH3:37][N:26]([CH2:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[S:25]([N:20]1[CH2:19][CH2:18][N:17]([C:16]2[C:11]3[CH:10]=[CH:9][NH:8][C:12]=3[N:13]=[CH:14][N:15]=2)[CH2:24][C:21]21[CH2:22][CH2:23]2)(=[O:35])=[O:36]
Reactant: CC(C)(C)OC(=O)n1ccc2c(N3CCN(S(=O)(=O)NCCc4ccccc4)C4(CC4)C3)ncnc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCCCCCC
Solvent: CI
Solvent: CCOC(C)=O
Product: CN(CCc1ccccc1)S(=O)(=O)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-(4-Phenethylsulfamoyl-4,7-diaza-spiro[2.5]oct-7-yl)-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid tert-butyl ester (intermediate 6) (0.78 mmol) was dissolved in dry DMF (5 mL) and added K2CO3 (1.56 mmol) and iodomethane (1.17 mmol). Stirred at rt for 3 h and then added H2O (20 mL). Extracted with EtOAc (3×20 mL) and the combined organic phases were concentrated in vacuo. Purified by flash chromatography on silica using EtOAc in heptane as eluent. The obtained compound was treated with TFA (2 mL) at rt for 1.5 h. The crude reaction mixture was added sat. Na2CO3 to pH=7 and the extracted with EtOAc (3×10 mL). The combined organic phases was washes with brine (10 mL), dried (Na2SO4), filtered and concentrated in vacuo. The pure compound was obtained by flash chromatography on silica using EtOAc in heptane as eluent.