Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][C:5](=O)[CH:4]([CH2:9][C:10](=O)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:3]1.[NH2:18][C:19]1[S:20][CH:21]=[C:22]([C:24]([O:26]C)=[O:25])[N:23]=1>>[CH3:1][CH:2]1[CH2:7][CH2:6][C:5]2[N:18]([C:19]3[S:20][CH:21]=[C:22]([C:24]([OH:26])=[O:25])[N:23]=3)[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][C:4]=2[CH2:3]1
Reactant: CC1CCC(=O)C(CC(=O)c2ccccc2)C1
Reactant: COC(=O)c1csc(N)n1
Product: CC1CCc2c(cc(-c3ccccc3)n2-c2nc(C(=O)O)cs2)C1
Yield: 49 %

Procedure:
Following the general methods as outlined under Intermediate 13, starting from 4-methyl-2-(2-oxo-2-phenylethyl)cyclohexanone and methyl 2-amino-1,3-thiazole-4-carboxylate, the title compound was isolated in 49% yield (93% purity by HPLC). MS(ESI+): 339.5; MS(ESI−): 337.4.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]2[CH:10]([CH:11]2[CH2:14][N:15]([C:28]([C:30]2[N:31]=[CH:32][N:33]([CH3:35])[CH:34]=2)=[O:29])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:27])([F:26])[F:25])[CH:18]=2)[CH2:9]1)=O)(C)(C)C.[ClH:36]>CCOC(C)=O>[ClH:36].[CH:10]12[CH:11]([CH2:14][N:15]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:26])([F:27])[F:25])[CH:18]=3)[C:28]([C:30]3[N:31]=[CH:32][N:33]([CH3:35])[CH:34]=3)=[O:29])[CH:12]1[CH2:13][NH:8][CH2:9]2
Reactant: Cn1cnc(C(=O)N(Cc2cccc(OC(F)(F)F)c2)CC2C3CN(C(=O)OC(C)(C)C)CC32)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cn1cnc(C(=O)N(Cc2cccc(OC(F)(F)F)c2)CC2C3CNCC32)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 6-{[(1-Methyl-1H-imidazole-4-carbonyl)-(3-trifluoromethoxy-benzyl)-amino]-methyl}-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester prepared above (7.74 gm, 15.65 mmol) was added 5 mL of saturated HCl in EtOAc at room temperature. The reaction stirred at room temperature for 4 hours. The mixture was concentrated under reduced pressure to yield 6.63 gm of 1-Methyl-1H-imidazole-4-carboxylic acid (3-aza-bicyclo[3.1.0]hex-6-ylmethyl)-(3-trifluoromethoxy-benzyl)-amide Hydrochloride.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([NH:7][C:8]2[N:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:17][C:18]1[N:22]([CH3:23])[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]=1>CN(C)C=O>[CH3:23][N:22]1[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]=[C:18]1[CH2:17][N:7]([C:5]1[CH:6]=[CH:1][CH:2]=[CH:3][N:4]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][N:13]=1
Reactant: Cn1c(CCl)nc2ccccc21
Reactant: c1ccc(Nc2ccccn2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(CN(c2ccccn2)c2ccccn2)nc2ccccc21

Procedure:
To a flask were added 1.1 g of 2,2′-dipyridylamine and 25 ml of N,N-dimethylformamide. To this mixture were added 0.32 g of 60% sodium hydride in mineral oil in small portions, and after stirring at 10 C for ten minutes, 1.2 g of 2-(chloromethyl)-1-methyl-1H-benzimidazole in 5 ml of N,N-dimethylformamide were added. The reaction mixture was stirred at 22 C for several hours, and then quenched with 40 ml water. The product was extracted with 50 ml ethyl acetate, and then extracted with 30 ml of 1M hydrochloric acid, and basified with 3M sodium hydroxide. Following extraction with 20 ml ethyl acetate, the product was purified by silica gel chromatography using 33% ethyl acetate, 62% hexane, and 5% methanol, resulting in an oil which crystallized on standing. After drying, 0.6 g of a yellow solid remained.
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=1)#[CH:9].[C:17]([N:24]1[CH2:29][CH2:28][CH:27]([CH:30]=[O:31])[CH2:26][CH2:25]1)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>C1(C)C=CC=CC=1.O.FC(F)(F)S([O-])(=O)=O.[Zn+2].FC(F)(F)S([O-])(=O)=O>[OH:31][CH:30]([CH:27]1[CH2:28][CH2:29][N:24]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:25][CH2:26]1)[C:9]#[C:8][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: C#Cc1cccc(C)n1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Zn+2]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cccc(C#CC(O)C2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of zinc trifluoromethanesulfonate (0.07 g, 0.19 mmol) and triethylamine (0.065 mL, 0.47 mmol) in anhydrous toluene (5 mL) was stirred at room temperature under nitrogen atmosphere. After 1 h, 2-ethynyl-6-methyl-pyridine (0.13 g, 1.13 mmol) prepared as described in WO200544267 was added and after 15 min was dropped a solution of 1-Boc-4-piperidinecarboxaldehyde (0.2 g, 0.938 mmol) in toluene (1 mL): the resulting mixture was heated at 100° C. for 6 h. Afterwards, it was cooled to r.t., diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried on Na2SO4 and evaporated to dryness in vacuo to give a crude, which was purified twice by automated flash liquid chromatography (Horizon™-Biotage) eluting with CHCl3-MeOH 98-2 affording the title product (0.13 g) as a brown oil.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][O:7][C:8]2[CH:9]=[C:10]([C:17]([OH:19])=O)[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=O)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:35][CH2:36][C:37]([NH2:39])=[O:38].N1C=CC=CC=1>CN1CCCC1=O.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]2[CH:9]=[C:10]3[C:11](=[CH:15][CH:16]=2)[C:12](=[O:14])[N:35]([CH2:36][C:37]([NH2:39])=[O:38])[C:17]3=[O:19])=[CH:20][CH:21]=1
Reactant: O=C(O)c1ccc(OCc2ccc(F)cc2)cc1C(=O)O
Reactant: NCC(N)=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: c1ccncc1
Solvent: CN1CCCC1=O
Solvent: O
Product: NC(=O)CN1C(=O)c2ccc(OCc3ccc(F)cc3)cc2C1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69.5 %

Procedure:
A mixture of 4-(4-fluoro-benzyloxy)-phthalic acid (185 mg, 0.64 mmol) and carbonyldiimidazole (109 mg, 0.67 mmol) in 1-methyl-2-pyrrolidinone (4 mL) was stirred at room temperature for 10 min and then heated at 50° C. for 15 min. To this mixture was added glycinamide hydrochloride (78 mg, 0.71 mmol) and pyridine (50 mg, 0.63 mmol) and the resulting mixture heated at 175 or 200° C. with microwave radiation (Smith reactor) for 10 min. After cooling to room temperature, the mixture was diluted with water and the resulting precipitate was filtered off and purified by chromatography (SiO2, CH2Cl2:2N NH3/MeOH 9:1) to afford the title compound (146 mg, 69%) as a white solid. MS: m/e=329.3. (M+H+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[CH:10]=O)=[CH:3][CH:2]=1.[BH3-][C:16]#[N:17].[Na+].CN.Cl>CO>[CH3:16][NH:17][CH2:10][C:9]1[CH:12]=[CH:13][CH:14]=[C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH:8]=1
Reactant: O=Cc1cccc(-c2ccncc2)c1
Reactant: [BH3-]C#N
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CNCc1cccc(-c2ccncc2)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 46.2 %

Procedure:
Into a 250 mL round-bottom flask was placed a solution of 3-(pyridin-4-yl)benzaldehyde (10 g, 54.6 mmol, 1 equiv) in MeOH (200 mL), NaBH3CN (10.33 g, 164 mmol, 3 equiv) and CH3NH2.HCl (18.44 g, 273 mmol, 5 equiv). The mixture was stirred overnight at 60° C. The solvents were removed under reduced pressure. The residue was added to 100 mL of H2O and extracted with 5×200 mL of ethyl acetate. After removal of solvent, the crude product was purified by re-crystallization from ethyl acetate to give 5 g of N-methyl-(3-(pyridin-4-yl)phenyl)methylamine as a white solid.
Reaction SMILES: [C:1]([NH:4][CH:5]1[C:11](=[O:12])[N:10]2[CH:13]([C:17]([NH:19][CH:20]([C:29](=[O:42])[CH2:30][O:31][C:32](=[O:41])[C:33]3[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][C:34]=3[Cl:40])[CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])=[O:18])[CH2:14][CH2:15][CH2:16][N:9]2[C:8](=[O:43])[CH2:7][CH2:6]1)(=[O:3])[CH3:2].CO.[K+].[Br-]>O>[C:1]([NH:4][CH:5]1[C:11](=[O:12])[N:10]2[CH:13]([C:17]([NH:19][CH:20]([C:29](=[O:42])[CH2:30][O:31][C:32](=[O:41])[C:33]3[C:34]([Cl:40])=[CH:35][CH:36]=[CH:37][C:38]=3[Cl:39])[CH2:21][C:22]([OH:24])=[O:23])=[O:18])[CH2:14][CH2:15][CH2:16][N:9]2[C:8](=[O:43])[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC1CCC(=O)N2CCCC(C(=O)NC(CC(=O)OC(C)(C)C)C(=O)COC(=O)c3c(Cl)cccc3Cl)N2C1=O
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(=O)NC1CCC(=O)N2CCCC(C(=O)NC(CC(=O)O)C(=O)COC(=O)c3c(Cl)cccc3Cl)N2C1=O

Procedure:
was synthesized from 216c by the same method as compound 217e as a glassy white solid (166 mg, 66%): mp 85-175° C.; [α]D25 −156 (c 0.13, MeOH; IR (KBr) 3373, 2929, 1742, 1659, 1562, 1533, 1433, 1412, 1274, 1266, 1223, 1197, 1145, 1138, 1H NMR (CD3OD) δ7.38 (3H, s), 5.14-5.03 (1H, m), 4.49-4.32 (2H, m), 3.50-3.27 (1H, m), 3.11-2.92 (1H, m), 2.84-2.62 (2H, m), 2.46-2.11 (2H, m), 2.05-1.46 (5H, m), 1.92 (3H, s); Anal. Calcd for C24H26N4Cl2O9.H2O: C, 47.77; H, 4.68; N, 9.29. Found: C, 47.75; N, 4.59; N, 9.07. MS (ES+) 627/5/3 (M+K, 21%), 611/9/7 (M+Na, 87), 589/7/5 (M+ +1, 71), 266 (100); Accurate mass calculated for C24H27N4Cl2O9 (MH+): 585.1155. Found: 585.1134.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:25][C:26]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:39](=[O:46])[NH:38][N:37]=2)=[CH:31][C:27]=1[C:28]([OH:30])=O.C(N(CC)CC)C.Cl.[O:55]1[CH2:59][CH2:58][CH2:57][CH:56]1[CH2:60][O:61][CH:62]1[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1>CN(C)C=O>[F:25][C:26]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:39](=[O:46])[NH:38][N:37]=2)=[CH:31][C:27]=1[C:28]([N:65]1[CH2:66][CH2:67][CH:62]([O:61][CH2:60][CH:56]2[CH2:57][CH2:58][CH2:59][O:55]2)[CH2:63][CH2:64]1)=[O:30]
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: C1COC(COC2CCNCC2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCC(OCC2CCCO2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 76.3 %

Procedure:
O-Benzotriazol-1-yl-N,N,N′,N′-tetra-methyluronium hexafluorophosphate (509 mg, 1.34 mmol) was added, in one portion, to 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (200 mg, 0.67 mmol) and triethylamine (0.206 mL, 1.48 mmol) in N,N-dimethylformamide (2.5 mL), at 25° C. under an air atmosphere. The resulting solution was stirred at 25° C. for 10 minutes. A solution of 4-((tetrahydrofuran-2-yl)methoxy)piperidine hydrochloride (164 mg, 0.74 mmol) and triethylamine (0.206 mL, 1.48 mmol) in N,N-dimethylformamide (1 mL) was then added dropwise and the resulting solution stirred at 25° C. for 10 hours. The crude mixture was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired compound as a solid (238 mg, 76%); 1H NMR (400.132 MHz, DMSO) δ 1.01 (2H, dt), 1.31-1.37 (1H, m), 1.43-1.50 (1H, m), 1.51-1.58 (1H, m), 1.68-1.73 (1H, m), 1.74-1.93 (4H, m), 3.00-3.07 (1H, m), 3.17-3.18 (1H, m), 3.39 (2H, d), 3.53-3.59 (1H, m), 3.70-3.75 (1H, m), 3.90 (2H, ddd), 4.33 (2H, s), 7.21 (1H, t), 7.33-7.35 (1H, m), 7.39-7.43 (1H, m), 7.83 (1H, td), 7.89 (1H, td), 7.97 (1H, d), 8.27 (1H, dd), 12.56 (1H, s) m/z (LC-MS, ESI+), RT=1.71 (M+H 466.5).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[Cl:18])[N:14]([CH2:19][C:20]1[N:25]=[C:24]([C:26]([O:28][CH3:29])=[O:27])[CH:23]=[CH:22][CH:21]=1)[C:13]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[CH:12]2)C1C=CC=CC=1>FC(F)(F)C(O)=O.O.CSC>[Cl:18][C:17]1[CH:16]=[C:15]2[C:11]([CH:12]=[C:13]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:14]2[CH2:19][C:20]2[N:25]=[C:24]([C:26]([O:28][CH3:29])=[O:27])[CH:23]=[CH:22][CH:21]=2)=[CH:10][C:9]=1[OH:8]
Reactant: COC(=O)c1cccc(Cn2c(-c3ccccc3)cc3cc(OCc4ccccc4)c(Cl)cc32)n1
Solvent: CSC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COC(=O)c1cccc(Cn2c(-c3ccccc3)cc3cc(O)c(Cl)cc32)n1
Yield: 70.4 %

Procedure:
A solution of methyl 6-(5-benzyloxy-6-chloro-2-phenylindol-1-ylmethyl)pyridine-2-carboxylate (372 mg) in trifluoroacetic acid/water/dimethyl sulfide (95/5/10, 7.7 mL) was stirred at room temperature for 80 hours. The reaction mixture was concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution (20 mL) was added to the residue and this resulting mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was triturated in dichloromethane/hexane (2/1). The precipitate was collected by filtration, washed with dichloromethane/hexane (2/1), and air-dried to obtain the title compound (213 mg).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[CH2:7]2.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]=[C:30]=[O:31].C(N(CC)CC)C.Cl>CN(C)C=O>[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29][C:30]([NH:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[CH2:7]2)=[O:31]
Reactant: O=C=Nc1ccccc1Cl
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1CCC(N2Cc3cc(CNC(=O)Nc4ccccc4Cl)ccc3C2=O)C(=O)N1
Reaction time: 2 h
Yield: 93.7 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.50 g, 1.40 mmol) and 2-chlorophenylisocyanate (0.16 mL, 1.40 mmol) in N,N-dimethylformamide (10 mL), was added triethylamine (0.38 mL, 2.7 mmol) at room temperature under nitrogen. After 2 h, 1 N aq. HCl (40 mL) was added and the solids were isolated by filtration and washed with water (20 mL). The crude product was triturated in EtOAc (50 mL) for 0.5 h. The product was isolated by filtration and dried in vacuo to give 1-(2-chloro-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid (0.56 g, 97% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 6.35 min (98.37%); mp: 235-237° C.; 1H NMR (DMSO-d6) δ 1.77-2.14 (m, 1H, CHH), 2.23-2.47 (m, 1H, CHH), 2.60 (d, J=17.2 Hz, 1H, CHH), 2.77-3.04 (m, 1H, CHH), 4.32 (d, J=17.4 Hz, 1H, CHH), 4.39-4.61 (m, 3H, CHH, CH2), 5.11 (dd, J=4.9, 13.2 Hz, 1H, CH), 6.88-7.04 (m, 1H, Ar), 7.15-7.32 (m, 1H, Ar), 7.34-7.50 (m, 2H, Ar), 7.54 (s, 1H, NH), 7.58 (t, J=5.8 Hz, 1H, NH), 7.71 (d, J=7.7 Hz, 1H, Ar), 8.17 (d, J=6.0 Hz, 2H, Ar), 10.98 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.50, 31.21, 42.83, 47.14, 51.59, 120.86, 121.28, 122.01, 122.61, 123.03, 127.00, 127.45, 129.08, 130.44, 136.57, 142.48, 144.30, 154.83, 167.92, 171.00, 172.85; LCMS: MH=427/429; Anal Calcd for C21H19N4O4Cl: C, 59.09; H, 4.49; N, 13.13; Cl, 8.31. Found: C, 58.86; H, 4.26; N, 12.88; Cl, 8.32.
Reaction SMILES: [NH:1]([C:3]1[N:4]=[N:5][C:6]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)=[CH:7][N:8]=1)[NH2:2].[N:19]1[C:28]2[C:23](=[CH:24][C:25]([C:29]3([CH:32]=O)[CH2:31][CH2:30]3)=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C(O)C.C(O)(=O)C>[N:19]1[C:28]2[C:23](=[CH:24][C:25]([C:29]3([C:32]4[N:4]5[N:5]=[C:6]([C:9]6[CH:10]=[CH:11][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:17][CH:18]=6)[CH:7]=[N:8][C:3]5=[N:1][N:2]=4)[CH2:31][CH2:30]3)=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)c1ccc(-c2cnc(NN)nn2)cc1
Reactant: O=CC1(c2ccc3ncccc3c2)CC1
Solvent: Ic1ccccc1
Solvent: CCO
Solvent: CC(=O)O
Product: COC(=O)c1ccc(-c2cnc3nnc(C4(c5ccc6ncccc6c5)CC4)n3n2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 60.6 %

Procedure:
A mixture of methyl 4-(3-hydrazino-1,2,4-triazin-6-yl)benzoate (115 mg, 0.000469 mol) and 1-quinolin-6-ylcyclopropanecarbaldehyde (92 mg, 0.00047 mol) in ethanol (2 mL) and acetic acid (0.5 mL) was stirred at RT for 6 h. The volatiles were removed under reduced pressure. The residue was dried under high vacuum, and then dissolved in methylene chloride (6 mL). To the solution was added iodobenzene diacetate (180 mg, 0.00056 mol). The reaction mixture was stirred at RT overnight. The solvent was evaporated and the residue was flash chromatographed on a silica gel column to afford the desired product (120 mg, 60%). Analytical LCMS: (M+H)+=423.3.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH2:18][CH:19]1[CH2:21][CH2:20]1)[CH:11]=[CH:10]2.CN([CH:25]=[O:26])C>>[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH2:18][CH:19]1[CH2:20][CH2:21]1)[CH:11]=[C:10]2[CH:25]=[O:26]
Reactant: CN(C)C=O
Reactant: O=c1c2ccc(Br)cc2ccn1CC1CC1
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cn(CC2CC2)c(=O)c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
DMF (10 mL) was cooled in an ice bath and phosphorus oxychloride (0.40 mL) was added over 20 seconds. The solution was stirred for 10 minutes at room temperature and then the product of step i) (0.6 g) in DMF (2 mL) was added over 5 minutes. The mixture was heated at 80° C. overnight. The mixture was allowed to cool then poured onto ice/water and stirred for 20 minutes. The aqueous was extracted with ethyl acetate, the organics were combined and evaporated under reduced pressure. The residue was purified (SiO2, eluting with 1:4 ethyl acetate:isohexane) to give the sub-title compound (0.4 g).
Reaction SMILES: [NH2:1][CH:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]CCC)[CH3:3].NC(CCCCCCCCCCC)C>>[NH2:1][CH:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH3:3]
Reactant: CCCCCCCCCCC(C)N
Agent: CCCCCCCCCCCC(C)N
Product: CCCCCCCC(C)N

Procedure:
2-amino dodecane, 2-amino-tridecane;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[C:14]([OH:19])[CH:13]=[C:12]3[NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([C:30]3[S:34][C:33]([C:35]([O:37]C)=[O:36])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[CH2:23][CH2:22]2)=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:39]2[CH:40]=[CH:41][C:42]([Cl:45])=[CH:43][CH:44]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[C:14]([OH:19])[CH:13]=[C:12]3[NH:20][CH:21]2[CH2:22][CH2:23][N:24]([S:27]([C:30]3[S:34][C:33]([C:35]([OH:37])=[O:36])=[CH:32][CH:31]=3)(=[O:28])=[O:29])[CH2:25][CH2:26]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)N2CCC(Nc3cc(O)nc4ccc(C(c5ccc(Cl)cc5)c5ccc(Cl)cc5)cc34)CC2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(S(=O)(=O)N2CCC(Nc3cc(O)nc4ccc(C(c5ccc(Cl)cc5)c5ccc(Cl)cc5)cc34)CC2)s1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Into a 100-mL round-bottom flask, was placed methyl 5-[4-([6-[bis(4-chlorophenyl)methyl]-2-hydroxyquinolin-4-yl]amino)piperidine-1-sulfonyl]thiophene-2-carboxylate (100 mg, 0.15 mmol, 1.00 equip), methanol (20 mL), and 1M sodium hydroxide (20 mL). The resulting solution was stirred overnight at 50° C. The resulting mixture was concentrated under vacuum. The pH value of the solution was adjusted to 5-6 with 10% HCl. The solids were collected by filtration. The resulting residue was purified by Prep-HPLC with the following conditions: water with 0.05% TFA and MeOH (60% MeOH up to 85% in 10 min, hold 95% for 1 min, down to 60% in 1 min) to yield 5-[4-([6-[bis(4-chlorophenyl)methyl]-2-hydroxyquinolin-4-yl]amino)piperidine-1-sulfonyl]thiophene-2-carboxylic acid; trifluoroacetic acid salt as an off-white solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][C:10]1([CH3:14])[CH2:13][O:12][CH2:11]1.[OH:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:14][C:10]1([CH2:9][O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=2)[CH2:13][O:12][CH2:11]1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CC1(COCCCCCCBr)COC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(COCCCCCCOc2ccc(C(=O)O)cc2)COC1
Temperature: 90 °C
Reaction time: 4 h
Yield: 69.9 %

Procedure:
A solution comprising 20 g of 3-[(6-bromohexyloxy)methyl]-3-methyloxetane, 11.6 g of 4-hydroxybenzoic acid, 13 g of potassium carbonate and 150 ml of dimethylformamide was stirred at 90° C. for 4 hours. Water was added to the reaction liquid to terminate the reaction, and the liquid was extracted with ethyl acetate. The organic layer was washed with water, and the solvent was distilled off. A 5% sodium hydroxide aqueous solution was added to the resulting residue, and the solution was refluxed for 8 hours. Then, the solution was acidified with hydrochloric acid and extracted with ether, followed by drying on anhydrous magnesium sulfate. The solvent was distilled off to obtain 17 g of 4-[6-(3-methyloxetane-3-ylmethoxy)hexyloxy]benzoic acid. Melting point: 61° C.
Reaction SMILES: N[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:11]>CN(C)C=O>[OH:11][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)O
Reactant: Nc1ccc(C=O)cc1
Solvent: CN(C)C=O
Product: O=Cc1ccc(O)cc1
Yield: 23 %

Procedure:
The procedure of Example 1 was repeated except that the N,N-dimethylformamide was not added and p-aminobenzaldehyde was reacted with sulphuric acid in 40% aqueous solution at 40° C. for one hour, to obtain p-hydroxybenzaldehyde in a yield of 23%, based on the weight of p-nitrotoluene used.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[C-:14]#[N:15].[Na+]>CSC.O>[C:14]([CH2:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:15]
Reactant: CCOC(=O)c1cccc(CCl)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CSC
Product: CCOC(=O)c1cccc(CC#N)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 89.1 %

Procedure:
To a solution of ethyl 3-(chloromethyl)benzoate (5.0 g, 25.1 mmol) in dimethylsulfide (50 mL) was added sodium cyanide (1.85 g, 37.8 mmol), and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with water, extracted with ethyl acetate, and the extract was washed successively with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: silica gel, eluent: hexane-ethyl acetate) to give the title compound (4.23 g, 89%) as a colorless oil.
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:19]([C:21]1[CH:36]=[CH:35][C:24]([O:25][C:26]2[CH:34]=[CH:33][C:29]([C:30]([NH2:32])=[O:31])=[CH:28][N:27]=2)=[CH:23][CH:22]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl.CO.C(Cl)Cl>[C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:8][CH2:9][N:10]([CH2:19][C:21]3[CH:36]=[CH:35][C:24]([O:25][C:26]4[CH:34]=[CH:33][C:29]([C:30]([NH2:32])=[O:31])=[CH:28][N:27]=4)=[CH:23][CH:22]=3)[CH2:11][CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C2(c3ccccc3)CCNCC2)cc1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: ClCCCl
Product: NC(=O)c1ccc(Oc2ccc(CN3CCC(c4ccccc4)(c4ccccc4)CC3)cc2)nc1
Yield: 44.8 %

Procedure:
Using a method similar to Example 345, using 4,4-diphenyl-piperidine (0.100 g, 0.421 mmol), 6-(4-formyl-phenoxy)-nicotinamide (compound of example 332, step 1) (0.102 g, 0.419 mmol), sodium triacetoxyborohydride (0.133 g, 0.627 mmol), and acetic acid (0.038 mL, 0.664 mmol) in 1,2-dichloroethane (8.0 mL) provides, after silica gel chromatography (20:1 methylene chloride:methanol), 0.0871 g (45%) of the title compound as a white solid: high resolution mass spectrum (electrospray): m/z calc for C30H30N3O2 464.2338, found 464.2357; 1H NMR (methanol-d4): 8.67 (d, 1H, J=2.4 Hz), 8.29 (dd, 1H, J=2.0, 7.8 Hz), 7.43 (d, 2H, J=7.8 Hz), 7.38-7.27 (m, 8H), 7.19-7.11 (m, 4H), 7.02 (d, 1H, J=8.8 Hz), 3.55-3.50 (m, 2H), 2.71-2.51 (m, 8H).