Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=3)=[CH:26][CH:25]=2)[N:12]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[CH:13]=1.[C:37]([N:44]1[CH2:49][CH2:48][CH:47](O)[CH2:46][CH2:45]1)([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[C:40]([O:39][C:37]([N:44]1[CH2:49][CH2:48][CH:47]([O:36][C:33]2[CH:34]=[CH:35][C:30]([C:27]3[CH:28]=[CH:29][C:24]([CH2:23][C:11]4[N:12]([C:14]5[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=5)[CH:13]=[C:9]([C:3]5[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=5[Cl:1])[N:10]=4)=[CH:25][CH:26]=3)=[CH:31][CH:32]=2)[CH2:46][CH2:45]1)=[O:38])([CH3:43])([CH3:41])[CH3:42]
Reactant: O=[N+]([O-])c1ccc(-n2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(-c3ccc(O)cc3)cc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(-c3ccc(Cc4nc(-c5ccc(Cl)cc5Cl)cn4-c4ccc([N+](=O)[O-])cc4)cc3)cc2)CC1

Procedure:
2-(4-Bromo-benzyl)-4-(2,4-dichlorophenyl)-1H-imidazole (3.27 g, 8.6 mmol) was treated as described in general procedure B using 4-fluoronitrobenzene to provide 2-(4-bromo-benzyl)-4-(2,4-dichloro-phenyl)-1-(4-nitro-phenyl)-1H-imidazole, which was treated with 4-hydroxyphenyl boronic acid according to general procedure G to provide 4′-[4-(2,4-dichloro-phenyl)-1-(4-nitro-phenyl)-1H-imidazol-2-ylmethyl]-biphenyl-4-ol (996 mg, 22% for two steps). To a solution of the phenol in THF (0.5 M) was added N-boc-4-hydroxypiperidine (2 eq) and triphenylphosphine (2 eq) under nitrogen, then while sonicating this mixture diisopropyl azodicarboxylate (2 eq) was added. After sonicating 1 hour the reaction mixture was evaporated in vacuo and the reside was purified by silica gel column chromatography to afford 4-{4′-[4-(2,4-dichloro-phenyl)-1-(4-nitro-phenyl)-1H-imidazol-2-ylmethyl]-biphenyl-4-yloxy}-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][CH:7]1[O:13][CH:12]2[N:9]([C:10](=[O:14])[CH2:11]2)[CH2:8]1)=[O:4].[N-:15]=[N+:16]=[N-:17].[Na+]>CS(C)=O.C(OCC)(=O)C>[N:15]([CH2:2][C:3]([NH:5][CH2:6][CH:7]1[O:13][CH:12]2[N:9]([C:10](=[O:14])[CH2:11]2)[CH2:8]1)=[O:4])=[N+:16]=[N-:17]
Reactant: O=C(CCl)NCC1CN2C(=O)CC2O1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: [N-]=[N+]=NCC(=O)NCC1CN2C(=O)CC2O1
Yield: 89 %

Procedure:
(3RS,5RS)-3-(N-Chloroacetylaminomethyl)-4-oxa-1-azabicyclo[3.2.0]heptan-7-one(500 mg), of example 8, and Sodium azide(297 mg) were stirred in Dimethyl sulfoxide(10 ml) at room temperature for 14 hrs. The reaction mixture was diluted with Ethyl acetate, washed with water, brine and dried over Magnesium sulfate. The residue, which obtained after removal of solvent in vacuo, was purified by silicagel column chromatography (Hexane+Ethyl acetate 1:2). The title compound was obtained as oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6](/[C:9](=N/OC)/[CH2:10][O:11][C:12]2[CH:25]=[CH:24][C:15]([CH2:16][CH:17]3[S:21][C:20](=[O:22])[NH:19][C:18]3=[O:23])=[CH:14][CH:13]=2)=[N:7][CH:8]=1)[CH3:2].C(O)(=O)C(C)=[O:31]>Cl>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9](=[O:31])[CH2:10][O:11][C:12]2[CH:25]=[CH:24][C:15]([CH2:16][CH:17]3[S:21][C:20](=[O:22])[NH:19][C:18]3=[O:23])=[CH:14][CH:13]=2)=[N:7][CH:8]=1)[CH3:2]
Reactant: CC(=O)C(=O)O
Reactant: CCc1ccc(/C(COc2ccc(CC3SC(=O)NC3=O)cc2)=N/OC)nc1
Agent: Cl
Product: CCc1ccc(C(=O)COc2ccc(CC3SC(=O)NC3=O)cc2)nc1
Reaction time: 2 h

Procedure:
A stirring solution of 5-(4-{[(2Z)-2-(5-ethylpyridin-2-yl)-2-(methoxyimino)ethyl]oxy}benzyl)-1,3-thiazolidine-2,4-dione (81 mg, 0.20 mmol; Supplier=Kalexsyn; Lot=1003-TTP-194) in 6M HCl (2 ml) and pyruvic acid (0.5 ml) was heated at 75° C. After 2 h at 75° C. HPLC showed reaction was complete. Neutralized with sat'd NaHCO3 and extracted with EtOAc. Extract dried (Na2SO4), filtered and evaporated in vacuo to give 45 mg (60%) pale yellow oil. 1H-NMR (DMSO-d6): δ12.02 (brs, 1H), 8.64 (s, 1H), 7.91 (m, 1H), 7.14 (d, J=8.5 Hz, 2H), 6.88 (d, J=8.5 Hz, 2H), 5.66 (s, 2H), 4.87 (dd, J=9.2, 4.3 Hz, 1H), 3.31 (m, 1H), 3.05 (dd, J=14.1, 9.1 Hz, 1H), 2.74 (q, J=7.7 Hz, 2H), 1.23 (t, J=7.7 Hz, 3H). HPLC (3.860 min., 100 area % @ 210 and 254 nm. MS (ESI—) for C19H18N2O4S m/z 371.3 (M+H)+: m/z 369.4 (M−H)−
Reaction SMILES: BrC[CH2:3][C:4]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7].[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[OH:22]>>[Cl:14][C:11]1[CH:12]=[CH:13][C:4]([CH2:3][O:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[F:15])=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cc(Cl)ccc1CCBr
Reactant: Oc1ccccc1F
Product: COC(=O)c1cc(Cl)ccc1COc1ccccc1F

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 1 from methyl 2-(bromoethyl)-5-chlorobenzoate and 2-fluorophenol: 1H-NMR (CDCl3)  8.02 (1H, d, J=2.4 Hz), 7.80-7.77 (1H, m), 7.57-7.53 (1H, m), 7.15-6.89 (4H, m), 5.52 (2H, s), 3.92 (3H, s).
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:25])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]([C:14]2[NH:18][C:17]3[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:16]=3[N:15]=2)[SH:13])=[CH:8][CH:7]=1.Cl>O.C1COCC1>[CH3:24][O:23][C:21]1[CH:20]=[CH:19][C:17]2[NH:18][C:14]([CH:12]([SH:13])[C:9]3[CH:10]=[CH:11][C:6]([C:5]([OH:25])=[O:4])=[CH:7][CH:8]=3)=[N:15][C:16]=2[CH:22]=1
Reactant: COC(=O)c1ccc(C(S)c2nc3cc(OC)ccc3[nH]2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2[nH]c(C(S)c3ccc(C(=O)O)cc3)nc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of LiOH.H20 (1.02 g, 24.4 mmol) in water (15 ml) was added to a suspension of 376a (3.99 g, 9.75 mmol of in THF (10 ml). The reaction mixture was stirred 16 h at room temperature. The reaction mixture was acidified with a solution of HCl 1 M to pH 4. The desired product was triturated 20 min. at 0° C. and then filtered and dried. Compound 376b was obtained as a white powder (100% yield, 3.05 g). 1H NMR: (DMSO) δ (ppm): 12.85 (bs, 1H), 7.86 (d, J=8.1 Hz, 2H), 7.53 (d, J=8.1 Hz, 2H), 7.35 (d, J=8.1 Hz, 1H), 6.97 (d, J=2.2 Hz, 1H), 6.76 (dd, J=8.8, 2.2 Hz, 1H), 4.60 (s, 2H), 3.82 (s, 3H). MS: (calc.) 314.1, (obt.), 315.1 (MH)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[N:14]1[CH2:19][CH2:18][CH2:17][C@@H:16]([OH:20])[CH2:15]1)([O-:3])=[O:2].N1C=CN=C1.[Si:26](Cl)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27].CCOCC>CN(C=O)C>[Si:26]([O:20][C@@H:16]1[CH2:17][CH2:18][CH2:19][N:14]([C:5]2[CH:6]=[CH:7][C:8]([C:10]([F:11])([F:12])[F:13])=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:15]1)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1N1CCC[C@@H](O)C1
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CCCN(c2ccc(C(F)(F)F)cc2[N+](=O)[O-])C1
Reaction time: 14 h

Procedure:
To a solution of (R)-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidin-3-ol (3.35 g, 11.5 mmol) and imidazole (1.02 g, 15.0 mmol) in DMF at ambient temperature under nitrogen was added tert-butyldimethylsilylchloride (1.91 g, 12.7 mmol). The reaction was allowed to stir for 24 h, at which point additional 0.3 g tert-butyldimethylsilylchloride was added. The reaction was allowed to stir for an additional 14 h, and was then poured into Et2O/saturated aqueous NaHCO3. The organic layer was washed 2×H2O, 1×brine, dried over anhydrous MgSO4, filtered and concentrated to a yellow oil. The crude material was treated with hexanes and adsorbed onto silica gel and passed through a Redi-Sep® pre-packed silica gel column (80 g) eluting with 0-20% EtOAc/hexane. The product-containing fractions were concentrated to afford (R)-3-(tert-butyldimethylsilyloxy)-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidine as a yellow oil. MS m/z=405 [M+H]+. Calc'd for C18H27F3N2O3Si: 404.
Reaction SMILES: [C:1]1([S:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH:24]4[CH2:28][CH2:27][NH:26][CH2:25]4)[CH:21]=3)[NH:16][N:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH:36]=O)=[CH:31][CH:30]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl>[C:1]1([S:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH:24]4[CH2:28][CH2:27][N:26]([CH2:36][CH2:35][C:32]5[CH:33]=[CH:34][CH:29]=[CH:30][CH:31]=5)[CH2:25]4)[CH:21]=3)[NH:16][N:15]=2)(=[O:12])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2ccc(OC3CCNC3)cc12
Reactant: O=CCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2ccc(OC3CCN(CCc4ccccc4)C3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.5 %

Procedure:
A suspension of 3-(1-naphthylsulfonyl)-5-(pyrrolidin-3-yloxy)-1H-indazole (51.8 mg, 0.132 mmol) in 1,2-dichloroethane was treated portionwise with phenacetaldehyde (0.2 mL, 0.2 mmol) and acetic acid (0.2 mL, 4 mmol), stirred for one hour at ambient temperature under nitrogen, treated with sodium triacetoxyborohydride (49.1 mg, 0.232 mmol), stirred for 2.5 hours, treated with sodium triacetoxyborohydride (37.5 mg, 0.177 mmol), stirred for 2.5 hours, poured into 1.0 N sodium hydroxide and extracted with chloroform. The extracts were combined, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resultant residue was purified by flash chromatography using 100% chloroform and 0.05-0.2% ammonium hydroxide/0.5-2.0% methanol in chloroform to yield 3-(1-naphthylsulfonyl)-5-{[1-(2-phenylethyl)pyrrolidin-3-yl]oxy}-1H-indazole as a light yellow semi-solid, 24.6 mg (36.5% yield). The semi-solid was dissolved in methanol and chloroform, treated with isopropanolic HCl and concentrated in vacuo at 82° C. for 12 hours to give the title product as a brown foam, 24.6 mg, Mass spectrum (+ES, [M+H]+) m/z 498. 1HNMR (500 MHz, DMSO-d6): δ14.24 (d, 1H, J=4.88 Hz), 10.59-10.90 (m*, 1H), 8.77-8.79 (m, 1H), 8.59-8.60 (m, 1H), 8.31 (d, 1H, J=8.24 Hz), 8.07 (d, 1H, J=8.09 Hz), 7.75-7.78 (m, 1H), 7.60-7.68 (m, 3H), 7.24-7.37 (m, 6H), 7.15-7.19 (m, 1H), 5.25-5.31 (m*, 1H), 3.74-4.02 (m*, 2H), 3.31-3.55 (m*, 4H), 3.01-3.04 (m, 2H), 2.08-2.63 ppm (m*, 2H). *Conformational isomers due to protonation of tertiary amine.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][C@H:6]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH:20]([CH3:22])[CH3:21])[N:12]=2)=[O:10])[CH2:5][N:4]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].[CH3:30][S:31](Cl)(=[O:33])=[O:32]>>[CH:20]([N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([C:9]([NH:8][C@@H:6]2[CH2:5][N:4]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[C@H:3]([CH2:2][NH:1][S:31]([CH3:30])(=[O:33])=[O:32])[CH2:7]2)=[O:10])=[N:12]1)([CH3:21])[CH3:22]
Reactant: CC(C)n1nc(C(=O)N[C@H]2C[C@@H](CN)N(C(=O)OC(C)(C)C)C2)c2ccccc21
Reactant: CS(=O)(=O)Cl
Product: CC(C)n1nc(C(=O)N[C@H]2C[C@@H](CNS(C)(=O)=O)N(C(=O)OC(C)(C)C)C2)c2ccccc21

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 17 from tert-butyl (2S,4S)-2-(aminomethyl)-4-{[(1-isopropyl-1H-indazol-3-yl)carbonyl]amino}pyrrolidine-1-carboxylate (step 2 of Example 17) and methanesulfonyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[N+](C1C=CC([O:30][C:31](=O)[NH:32][C:33]2[CH:38]=[CH:37][C:36]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[CH:35][CH:34]=2)=CC=1)([O-])=O>C(Cl)Cl.CO.N.C(Cl)Cl>[N:39]1([C:36]2[CH:35]=[CH:34][C:33]([NH:32][C:31]([N:18]3[CH2:19][CH2:20][CH:15]([C:6]4[C:5]5[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=5)[N:9]=[CH:8][N:7]=4)[CH2:16][CH2:17]3)=[O:30])=[CH:38][CH:37]=2)[CH2:40][CH2:41][O:42][CH2:43][CH2:44]1
Reactant: COc1cc2ncnc(C3CCNCC3)c2cc1OC
Reactant: O=C(Nc1ccc(N2CCOCC2)cc1)Oc1ccc([N+](=O)[O-])cc1
Agent: N
Solvent: ClCCl
Solvent: CO
Product: COc1cc2ncnc(C3CCN(C(=O)Nc4ccc(N5CCOCC5)cc4)CC3)c2cc1OC
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 85.8 %

Procedure:
A mixture of 6,7-dimethoxy-4-piperidin-4-yl-quinazoline (111.4 mg, 408 μmol), prepared as described in Example 1d, but with purification by silica flash chromatography (9:1 DCM/MeOH saturated with NH3), (4-morpholin-4-yl-phenyl)-carbamic acid 4-nitro-phenyl ester (147 mg, 429 μmol), prepared as described in the previous step, and DCM (700 μL) was treated with TEA (63 μL, 449 μmol) in one portion at rt. The homogeneous amber solution was stirred at rt for 3.5 h, diluted with DCM (1.3 mL), and washed with 2 M K2CO3 (2 mL). The aqueous layer was extracted with DCM (2×2 mL), the organic layers were combined, dried (Na2SO4), and concentrated, and the residue was purified with silica flash chromatography (1:1 DCM/acetone) to afford the title compound (167.1 mg, 86%). 1H-NMR (300 MHz, CDCl3): δ 9.08 (s, 1H), 7.34 (s, 1H), 7.31-7.24 (m, 3H), 6.88 (m, 2H), 6.31 (br s, 1H), 4.32-4.22 (m, 2H), 4.07 (s, 3H), 4.06 (s, 3H), 3.86 (m, 4H), 3.59 (m, 1H), 3.23-3.07 (m, 6H), 2.24-2.07 (m, 2H), 2.05-1.93 (m, 2H). LC/MS (ESI): calcd mass 477.2, found 478.3 (MH+). Select fractions of this material were combined (112.5 mg) and submitted for combustion analysis: Anal. Calcd for C26H31N5O4: C, 65.39; H, 6.54; N, 14.67. Found: C, 65.26; H, 6.58; N, 14.51.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:7]=1[C:13]1[N:14]([CH3:18])[N:15]=[CH:16][CH:17]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([N:28]=[C:29]=[O:30])[CH:25]=[CH:26][CH:27]=1>>[CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:29]([NH:28][C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([O:21][CH3:20])[CH:23]=2)=[O:30])=[CH:8][C:7]=1[C:13]1[N:14]([CH3:18])[N:15]=[CH:16][CH:17]=1
Reactant: CN(C)CCOc1ccc(N)cc1-c1ccnn1C
Reactant: COc1cccc(N=C=O)c1
Product: COc1cccc(NC(=O)Nc2ccc(OCCN(C)C)c(-c3ccnn3C)c2)c1
Yield: 71.1 %

Procedure:
4-(2-Dimethylamino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (26.0 mg, 0.1 mmol) was treated with 3-methoxyphenyl isocyanate (13.8 μL, 0.105 mmol) in a similar manner as described in Example 1.2 to afford Compound 146 as a colorless waxy solid in 71.1% yield. LCMS m/z (%)=410 (M+H, 100). 1H NMR (400 MHz, DMSO-d6) δ: 8.70 (s, 1H), 8.63 (s, 1H), 7.45-7.42 (m, 2H), 7.37 (d, J=2.7 Hz, 1H), 7.18-7.10 (m, 3H), 6.91 (dd, J=8.02 Hz, 1.2 Hz, 1H), 6.53 (dd, J=7.71 Hz, 2.05 Hz, 1H), 6.24 (d, J=1.83 Hz, 1H), 4.03 (t, J=5.80 Hz, 2H), 3.72 (s, 3H), 3.67 (s, 3H), 2.52 (t, J=5.80 Hz, 2H), 2.12 (s, 6H).
Reaction SMILES: N[C@@H:2]([C@H:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:7])[C:3]([OH:5])=[O:4].N([O-])=[O:17].[Na+].[OH-].[Na+].C(OCC)(=O)C>S(=O)(=O)(O)O.O>[CH2:9]([O:8][C@H:6]([CH3:7])[C@H:2]([OH:17])[C:3]([OH:5])=[O:4])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=N[O-]
Reactant: C[C@@H](OCc1ccccc1)[C@H](N)C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@@H](OCc1ccccc1)[C@H](O)C(=O)O
Temperature: -5 °C
Reaction time: 6 h

Procedure:
To a solution of (2S,3R)-2-amino-3-benzyloxy-butyric acid (1.1 g) in 2M sulfuric acid (6.31 mL) was added dropwise over 2 h a solution of sodium nitrite (0.65 g) in water (6 mL), keeping the internal temperature of the reaction below 0° C. The reaction mixture was stirred at −5° C. for 6 h then allowed to warm to room temperature overnight. The mixture was adjusted to pH 4 with 50% aqueous sodium hydroxide then ethyl acetate was added. The mixture was stirred vigorously and acidified to pH 2 with concentrated sulfuric acid. The layers were separated and the aqueous layer extracted with further ethyl acetate (×2). The combined organic extracts were washed with saturated aqueous sodium chloride, dried (MgSO4), filtered and evaporated to give the subtitle compound as a yellow crystalline solid which was used without further purification. Yield: 0.84 g.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH2:12][C:13]([OH:16])([CH3:15])[CH3:14])[CH2:5]2.[H-].[Na+].[CH3:19]I.O>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH2:12][C:13]([OH:16])([CH3:14])[CH3:15])[CH:5]2[CH3:19]
Reactant: CI
Reactant: CC(C)(O)CN1Cc2cc(Br)ccc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC1c2cc(Br)ccc2C(=O)N1CC(C)(C)O
Temperature: 25 °C

Procedure:
Under nitrogen atmosphere, 100 mg of 5-bromo-2-(2-hydroxy-2-methyl-propyl)-1-oxo-isoindoline obtained in Example 177-1) was dissolved in tetrahydrofuran, 40 mg of sodium hydride, 0.4 ml of methyl iodide were added and the mixture was heated under reflux for 2 hours. The reaction solution was cooled down to room temperature, water was added, and the products were extracted with ethyl acetate. Ethyl acetate layer was washed with saturated saline solution and dried with anhydrous sodium sulfate. The solvents were distilled outunder reduced pressure, and the residues were separated and purified by thin-layer silicagel column chromatography (ethyl acetate) to obtain 7 mg of the above compound as a white solid.
Reaction SMILES: [C:1]1([C:6]2[C:7]3[CH:14]=[CH:13][NH:12][C:8]=3[N:9]=[CH:10][N:11]=2)[CH2:5][CH2:4][CH2:3][CH:2]=1>CCOC(C)=O.[Pd]>[CH:1]1([C:6]2[C:7]3[CH:14]=[CH:13][NH:12][C:8]=3[N:9]=[CH:10][N:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C1=C(c2ncnc3[nH]ccc23)CCC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: c1nc(C2CCCC2)c2cc[nH]c2n1
Reaction time: 5 h
Yield: 89 %

Procedure:
A mixture of 4-cyclopentenyl-7H-pyrrolo[2,3-d]pyrimidine (11 mg, 0.060 mmol) and Pd-C (10% on carbon, 22 mg) in EtOAc (1 mL) was stirred under H2 atmosphere (balloon) for 5 h. The mixture was filtered and concentrated to provide the title compound (10 mg) as a white solid.
Reaction SMILES: C(O)C.C1(C)C=CC=CC=1.[CH2:11]([C:14]1[CH:19]=[CH:18][C:17]([CH:20]=[CH:21][CH:22]2[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]2)=[CH:16][CH:15]=1)[CH2:12][CH3:13]>[H][H].[Pd]>[CH2:11]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH:22]2[CH2:23][CH2:24][C:25](=[O:28])[CH2:26][CH2:27]2)=[CH:16][CH:15]=1)[CH2:12][CH3:13]
Reactant: CCCc1ccc(C=CC2CCC(=O)CC2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCc1ccc(CCC2CCC(=O)CC2)cc1
Yield: 94 %

Procedure:
In a liquid mixture comprising 200 ml of ethanol and 200 ml of toluene was dissolved 42 g of the 4-(2-(4-n-propylphenyl)ethenyl)cyclohexanone mentioned above, 4 g of palladium/carbon (5%) was added as catalyst, and they were subjected to a catalytic reduction in hydrogen gas atmosphere. After finishing of the reaction, the catalyst was filtered off and the solvent was distilled off under a reduced pressure to obtain 39.8 g of 4-(2-(4-n-propylphenyl)ethyl)cyclohexanone.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:5][CH:4]([C:6]([C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=2)=O)[CH2:3]1.[N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]([NH2:30])[CH:21]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[BH4-].[Na+]>CO.C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:19])[CH2:5][CH:4]([CH:6]([NH:30][C:22]2[CH:21]=[N:20][C:29]3[C:24]([CH:23]=2)=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=2)[CH2:3]1
Reactant: Nc1cnc2ccccc2c1
Reactant: CCOC(=O)c1ccc(C(=O)C2CC(C)(C)C2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(C(Nc2cnc3ccccc3c2)C2CC(C)(C)C2)cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 3.1 %

Procedure:
A flask containing ethyl 4-(3,3-dimethylcyclobutanecarbonyl)benzoate (397 mg, 1.53 mmol) was charged with toluene (13.9 mL), quinolin-3-amine (200 mg, 1.39 mmol), and para-toluene sulfonic acid (26.8 mg, 0.139 mmol). The reaction was refluxed with a Dean-Stark for 24 h. The reaction was quenched with water and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give 508 mg of crude material. To this crude material was added anhydrous methanol (6.47 mL) and the solution was cooled to 0° C. Sodium borohydride (147 mg, 3.88 mmol) was then added. After 5 h, the reaction was partly concentrated and quenched with saturated aqueous ammonium chloride. The reaction mixture was extracted three times with ethyl acetate. The combined organic layers were then dried over sodium sulfate, filtered, and concentrated to give 560 mg of crude material. Purification by column chromatography (0-50% ethyl acetate in heptane) provided ethyl 4-((3,3-dimethylcyclobutyl)(quinolin-3-ylamino)methyl)benzoate (17.0 mg, 3.4% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ: 8.47 (d, J=2.9 Hz, 1H), 8.03-7.97 (m, 2H), 7.90-7.86 (m, 1H), 7.46-7.42 (m, 2H), 7.42-7.30 (m, 3H), 6.69 (d, J=2.7 Hz, 1H), 4.40-4.31 (m, 2H), 4.27 (dd, J=9.2, 4.3 Hz, 1H), 2.58-2.47 (m, 1H), 2.03 (ddd, J=11.2, 7.6, 4.2 Hz, 1H), 1.79-1.67 (m, 2H), 1.67-1.55 (m, 1H), 1.36 (t, J=7.1 Hz, 3H), 1.14 (s, 3H), 1.09 (s, 3H). MS (M+1): 389.3.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[N:12]=[C:11]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[N:10]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38]>CC(=O)CC>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([C:22]2[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=2)[N:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[N:14]=1
Reactant: CCOC(=O)CCl
Reactant: Cc1ccc(-c2nc(-c3ccc(C)cc3)nc(-c3ccc(O)cc3O)n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)COc1ccc(-c2nc(-c3ccc(C)cc3)nc(-c3ccc(C)cc3)n2)c(O)c1
Yield: 79 %

Procedure:
55.4 g (0.15 mol) of 2-(2,4-dihydroxyphenyl)-4,6-bis-(4-methylphenyl)-1,3,5-triazine are dissolved in refluxing 2-butanone (1 l) in the presence of 27.6 g (0.2 mol) of K2CO3. A catalytic amount (0.2 g) of KI is added, and 36.8 g (0.3 mol) of ethyl chloroacetate are added dropwise over 1 h30. After refluxing for 25 h, the reaction mixture is cooled in ice, the precipitate is filtered off, washed with water to neutrality and then with methanol. Drying in the oven yields the analytically pure 2-(2-hydroxy-4-ethoxycarbonylmethoxyphenyl)-4,6-bis-(4-methylphenyl)-1,3,5-triazine (54 g, m.p. 166-167° C.) (Compound No. 47).
Reaction SMILES: [CH3:1][O:2][N:3]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.C1C(=O)N([Br:23])C(=O)C1>C(Cl)Cl>[Br:23][C:11]1[CH:10]=[C:9]([C:6]2[CH2:5][CH2:4][N:3]([O:2][CH3:1])[CH2:8][CH:7]=2)[CH:14]=[CH:13][C:12]=1[NH2:15]
Reactant: CON1CCC(c2ccc(N)cc2)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CON1CC=C(c2ccc(N)c(Br)c2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 75.9 %

Procedure:
To a solution of 4-(1-methoxy-piperidin-4-yl)-phenylamine (as prepared above, 42 mg, 0.20 mmol) in DCM (2 mL) was added NBS (36.2 mg, 0.20 mmol) and the reaction mixture was stirred at RT for 12 h. The reaction mixture was diluted with DCM (10 mL) and washed with saturated aqueous NaHCO3 (10 mL) and water (10 mL). The organic layer was separated, dried (Na2SO4) and concentrated in vacuo to obtain 2-bromo-4-(1-methoxy-1,2,3,6-tetrahydro-pyridin-4-yl)-phenylamine (43 mg, 74.5%) which was used in the next step without purification.