Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[OH-].[Na+].Cl[C:7]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:8]>C(Cl)Cl>[CH2:1]([NH:3][C:7](=[O:8])[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:2]
Reactant: CCN
Reactant: O=C(Cl)Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCNC(=O)Oc1ccccc1
Reaction time: 1 h
Yield: 99.9 %

Procedure:
An aqueous solution of ethylamine (2.58g of 70% solution, 0.04 mole) and an aqueous sodium hydroxide solution (1.44g in 8 ml solution, 0.036 mole) were added dropwise simultaneously over a period of 15 minutes to a cool solution of phenyl chloroformate (6.0g, 0.038 mole) in methylene chloride (35 ml). The reaction mixture was stirred for one hour, then separated. The organic layer was dried over anhydrous magnesium sulfate, then filtered and stripped of solvent on a Rotovap. White crystals of phenyl N-ethylcarbamate weighing 6.27g were obtained having a melting point of 49°-50° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:21]=1[NH2:22]>>[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:21]=1[NH:22][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccncc2)n1
Reactant: COc1ccc(C)cc1N
Product: COc1ccc(C)cc1Nc1cc(C(F)(F)F)nc(-c2ccncc2)n1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 2-methoxy-5-methylaniline (40 mg, 0.290 mmol) similar to Example 115 and isolated as a white solid (48 mg, 69%). 1H NMR (CDCl3): 8.79 (dd, J=1.8, 4.5 Hz, 2H), 8.30 (dd, J=1.8, 4.5 Hz, 2H), 7.97 (s, 1H), 7.46 (s, 1H), 6.99 (dd, J=1.5, 8.1 Hz, 1H), 6.94 (s, 1H), 6.89 (d, J=8.4 Hz, 1H), 3.90 (s, 3H), 2.41 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:9]2)=[CH:4][CH:3]=1.[Br:17][CH2:18][CH2:19]O.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>ClCCl>[Br:17][CH2:18][CH2:19][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:9]2)=[CH:4][CH:3]=1
Reactant: OCCBr
Reactant: CCOC(=O)C1CCc2ccc(O)cc2O1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)C1CCc2ccc(OCCBr)cc2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.4 %

Procedure:
To a 60 ml dichloromethane solution of ethyl 7-hydroxychromane-2-carboxylate (1.32 g, 5.9 mmol), 2-bromoethanol (0.84 ml, 11.9 mmol), and triphenylphosphine (3.12 g, 11.9 mmol) was added diisopropyl azodicarboxylate (2.34 ml, 11.9 mmol) dropwise upon cooling in an ice-water bath. After stirring at rt overnight, the solvent was removed under reduced pressure, and the residue was chromatographed on silica gel eluting with 10% AcOEt/hexanes to give the title compound 1.27 g (65%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:16][C:17]([OH:19])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:23])=O>CN(C=O)C.ClCCl>[Cl:23][C:17](=[O:19])[CH2:16][C@@H:12]1[CH2:13][CH2:14][CH2:15][N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: O=C(O)C[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)C[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To an argon purged round bottom flask fitted with a magnetic stirbar was added (S)-2-(1-(benzyloxycarbonyl)pyrrolidin-2-yl)acetic acid (235 mg, 0.893 mmol) followed by anhydrous dichloromethane (5 mL). The reaction was treated with anhydrous DMF (2 drops ˜5 μL). The flow of argon was stopped, and the reaction vessel fitted with a balloon. Oxalyl chloride (0.12 mL, 1.38 mmol) was added in two portions, resulting in effervescence. The reaction was stirred at room temperature for 3 hours, before being concentrated to dryness under reduced pressure and dried overnight under high vacuum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][C:32]=1[O:33][CH2:34][C:35]1[CH:36]=[N:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=1)[CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([NH:22]C(=O)OC(C)(C)C)[CH2:18][CH2:17]3)=[CH:15][C:10]=2[N:9]=[CH:8]1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][C:32]=1[O:33][CH2:34][C:35]1[CH:36]=[N:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=1)[CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]3)=[CH:15][C:10]=2[N:9]=[CH:8]1
Reactant: COc1ccc(COc2ccc(Cn3cnc4cc(N5CCC(NC(=O)OC(C)(C)C)CC5)ccc43)cc2OC)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(COc2ccc(Cn3cnc4cc(N5CCC(N)CC5)ccc43)cc2OC)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.2 %

Procedure:
To a stirred solution of tert-butyl (1-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)piperidin-4-yl)carbamate (0.33 g, 0.58 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (5.0 mL. 64.90 mmol). The reaction mixture was allowed to stir at room temperature. After 2 h, the mixture was concentrated, and the residue partitioned between 3 M ammonium hydroxide solution and dichloromethane. The phases were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered, and concentrated. Chromatographic purification (Combi-Flash, 40 g SiO2 gold column, 1-15% methanol/dichloromethane elute) afforded 0.19 g (62%) of the product as a solid: 1H NMR (400 MHz, CDCl3) δ 8.18 (d, J=2.0 Hz, 1H), 7.83 (s, 1H), 7.65 (dd, J=8.5, 2.4 Hz, 1H), 7.36-7.26 (m, 1H), 7.15 (d, J=8.8 Hz, 1H), 7.01 (dd, J=8.8, 2.2 Hz, 1H), 6.89-6.82 (m, 1H), 6.78-6.67 (m, 3H), 5.21 (s, 2H), 5.01 (s, 2H), 3.93 (s, 3H), 3.76 (s, 3H), 3.60-3.52 (m, 2H), 2.85-2.72 (m, 3H), 1.98-1.90 (m, 2H), 1.80 (b, 2H), 1.62-1.50 (m, 2H) ppm; (M+1)=474.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.O[CH2:12][NH:13]C(=O)C(F)(F)F>>[CH:1]1[C:10]2[C:5](=[C:6]([NH:13][CH3:12])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: O=C(NCO)C(F)(F)F
Reactant: c1ccc2cnccc2c1
Product: CNc1cccc2cnccc12

Procedure:
Isoquinoline is reacted with N-(hydroxymethyl)trifluoroacetamide in acid followed by reduction to afford isoquinolin-5-yl-methylamine. Carbamylation using aminotetralin as described above, produces aminotetralin-derived ureas in which L=CH2 (methylene) (Scheme 7).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:13])[C:9](=[O:12])[N:10]([CH3:11])[C:5]2=[CH:4][CH:3]=1.[C:14]([N:21](C)[C@H:22]([C:24](O)=[O:25])[CH3:23])(OC(C)(C)C)=O.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[ClH:61]>>[ClH:61].[CH3:11][N:10]1[C:5]2[C:6](=[N:7][C:2]([NH:1][C:24](=[O:25])[C@@H:22]([NH:21][CH3:14])[CH3:23])=[CH:3][CH:4]=2)[N:8]([CH3:13])[C:9]1=[O:12]
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: Cn1c(=O)n(C)c2nc(N)ccc21
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Product: CN[C@@H](C)C(=O)Nc1ccc2c(n1)n(C)c(=O)n2C

Procedure:
5-Amino-1,3-dimethyl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one (Russian Journal of Organic Chemistry, 2007, 43, 11, 1706-1709) was treated with Boc-N-methyl-L-alanine according to the General procedure 4 (PyBop coupling) and the product of the reaction deprotected according to the General procedure 3 (HCl deprotection) to afford the title compound. 1H NMR (400 MHz, Me-d3-OD): 7.93 (1H, d), 7.48 (1H, d), 4.04 (1H, d), 3.45 (6H, s), 2.77 (3H, s), 1.64 (3H, d). MS: [M+H]+=264.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]([C:12]([N:14]3[CH2:19][CH2:18][CH:17]([CH:20]([F:22])[F:21])[CH2:16][CH2:15]3)=[O:13])[CH2:7][C:6]=2[CH:23]=1.CC1(C)C(C)(C)OB([C:32]2[CH:37]=[CH:36][C:35]([C:38]3[NH:39][CH:40]=[CH:41][N:42]=3)=[CH:34][CH:33]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[F:21][CH:20]([F:22])[CH:17]1[CH2:18][CH2:19][N:14]([C:12]([N:8]2[CH2:7][C:6]3[CH:23]=[C:2]([C:32]4[CH:37]=[CH:36][C:35]([C:38]5[NH:42][CH:41]=[CH:40][N:39]=5)=[CH:34][CH:33]=4)[CH:3]=[CH:4][C:5]=3[O:11][CH2:10][CH2:9]2)=[O:13])[CH2:15][CH2:16]1
Reactant: CC1(C)OB(c2ccc(-c3ncc[nH]3)cc2)OC1(C)C
Reactant: O=C(N1CCC(C(F)F)CC1)N1CCOc2ccc(Br)cc2C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(N1CCC(C(F)F)CC1)N1CCOc2ccc(-c3ccc(-c4ncc[nH]4)cc3)cc2C1
Temperature: 90 °C
Reaction time: 18 h
Yield: 4.4 %

Procedure:
A mixture of 7-bromo-4-{[4-(difluoromethyl)piperidine-1-yl]carbonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepine (78 mg, 0.20 mmol) (example 2, step 3), 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazole (0.20 mmol), cesium carbonate (325 mg, 1.00 mmol), and dichloro[1,1-bis(diphenylphosphino]ferrocenepalladium (II) dichloromethane adduct (16 mg, 0.02 mmol) in dioxane (5.0 mL) and water (0.5 mL) was degassed with nitrogen, and then stirred at 90° C. for 18 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and filtered through celite. The filtrate was washed with water (1×) and brine (1×), dried over sodium sulfate, filtered and concentrated. Purification by preparative reverse phase HPLC (0.1% aqueous trifluoroacetic acid-acetonitrile) provided the title compound (4 mg, 4% yield). 1H NMR (400 MHz, methanol-d4): 7.97 (d, 2H), 7.91 (d, 2H), 7.66 (s, 2H), 7.62 (d, 1H), 7.57 (dd, 1H), 7.08 (d, 1H), 5.72 (m, 1H), 4.53 (s, 2H), 4.24 (m, 2H), 3.72 (m, 4H), 2.84 (m, 2H), 2.00 (m, 1H), 1.76 (m, 2H), 1.49 (m, 2H); MS (EI) for C25H26F2N4O2: 453 (MH+).
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.Cl[CH:17]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([NH:28][C:29](=[O:31])[CH3:30])([CH3:27])[CH3:26])=[CH:21][CH:20]=1)[CH3:18]>>[F:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([NH:28][C:29](=[O:31])[CH3:30])([CH3:27])[CH3:26])=[CH:21][CH:20]=3)[CH3:18])[CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: CC(=O)NC(C)(C)c1ccc(C(C)Cl)cc1
Agent: Cl
Product: CC(=O)NC(C)(C)c1ccc(C(C)N2CCN(c3ccc(F)cc3)CC2)cc1

Procedure:
By similar reaction and treatment to that in Example 1(5) using 1-(4-fluorophenyl)piperazine dihydrochloride instead of phenylpiperazine and N-(1-(4-(1-chloroethyl)phenyl)-1-methylethyl)acetamide instead of N-(4-chloromethylphenylmethyl)acetamide, the title compound was obtained as white crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:16][CH:15]3[CH2:17][N:11]4[CH2:12][CH:13]([CH2:18][CH:9]2[CH2:10]4)[CH2:14]3)[CH:5]=[N:6][CH:7]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1B(O)O>>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[C:2]1[CH:3]=[C:4]([N:8]2[CH2:16][CH:15]3[CH2:17][N:11]4[CH2:12][CH:13]([CH2:18][CH:9]2[CH2:10]4)[CH2:14]3)[CH:5]=[N:6][CH:7]=1
Reactant: Brc1cncc(N2CC3CC4CC2CN(C4)C3)c1
Reactant: COc1ccc(OC)c(B(O)O)c1
Product: COc1ccc(OC)c(-c2cncc(N3CC4CC5CC3CN(C5)C4)c2)c1

Procedure:
The title compound was prepared from the product of Example 65A and 2,5-dimethoxyphenylboronic acid according to General Method B: LC-MS Method D (ESI+) m/z 366.0 (M+H)+, retention time 1.36 minutes.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[C:14]2[C:9](=[C:10]([N+:16]([O-:18])=[O:17])[C:11]([Cl:15])=[CH:12][CH:13]=2)[N:8]=[CH:7][CH:6]=1>CO>[Cl:15][C:11]1[C:10]([N+:16]([O-:18])=[O:17])=[C:9]2[C:14]([C:5]([O:2][CH3:1])=[CH:6][CH:7]=[N:8]2)=[CH:13][CH:12]=1
Reactant: O=[N+]([O-])c1c(Cl)ccc2c(Cl)ccnc12
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccnc2c([N+](=O)[O-])c(Cl)ccc12
Yield: 86.5 %

Procedure:
Sodium methoxide (2.0 g, 37.0 mmol) was added to a solution of 4,7-dichloro-8-nitro-quinoline (Intermediate 68) (3.0 g, 12.3 mmol) in MeOH (20 ml) and the reaction was heated under reflux for 24 h. The solvent was removed in vacuo. The residue was dissolved in EtOAc (150 ml) and washed with water, dried (MgSO4) and concentrated in vacuo. The crude residue was purified by column chromatography with EtOAc/heptane (4:1) to give the title compound (2.54 g, 83%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]2[C:13](=O)[CH2:14][CH2:15][CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17]1([NH2:20])[CH2:19][CH2:18]1.C(O)(=O)C.C([BH3-])#N>ClCCl>[CH2:1]([N:8]1[CH2:12][C@H:11]2[C@@H:13]([NH:20][CH:17]3[CH2:19][CH2:18]3)[CH2:14][CH2:15][C@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC2CN(Cc3ccccc3)CC12
Reactant: NC1CC1
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: ClCCl
Product: c1ccc(CN2C[C@@H]3CC[C@H](NC4CC4)[C@@H]3C2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Benzylhexahydrocyclopenta[c]pyrrol-4(5H)-one (0.578 g, 2.68 mmol), cyclopropylamine (0.189 mL, 2.68 mmol), and acetic acid (10 mL) were combined in dichloromethane (20 mL). PS-Cyanoborohydride (1.147 g, 2.68 mmol) was added. The reaction was stirred at room temperature for 2 hours, then filtered and the resin was washed with dichloromethane. The solvent was removed in vacuo, and the crude material was applied to a silica gel column and was eluted with 1-10% methanol(2 N ammonia)/dichloromethane to give the title compounds.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[CH2:21]([N:28]1[CH:32]=[C:31]([C:33](O)=[O:34])[N:30]=[N:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[Cl:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:33]([C:31]3[N:30]=[N:29][N:28]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:32]=3)=[O:34])=[CH:4][N:5]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][CH:9]=1
Reactant: O=C(O)c1cn(Cc2ccccc2)nn1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1cn(Cc2ccccc2)nn1

Procedure:
Benzyl-1H-[1,2,3]triazole-4-carboxylic acid (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide was prepared starting from intermediate D and 1-benzyl-1H-[1,2,3]triazole-4-carboxylic acid. MS calcd. for C26H21ClN5O2 [(M+H)+] 470.1, obsd. 469.9.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][CH:28]=O)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[NH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][CH2:28][NH:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CC=O)cn(C)c34)no2)cc1Cl
Reactant: CCOC(=O)CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)CNCCc1cn(C)c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Temperature: 20 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
To a stirred solution of [7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]acetaldehyde (D88) (20 mg), ethyl glycinate (10 mg) and acetic acid (0.1 mL) in DCM (10 mL) was added sodium triacetoxyborohydride (21 mg). The reaction was stirred at 20° C. for 1 h. The reaction mixture was partitioned between DCM (25 mL) and water (25 mL). The organic phase was evaporated to give ethyl N-{2-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]ethyl}glycinate (D89) as a brown oil (20 mg), which was used directly in the next hydrolysis step. MS (ES): C26H29ClN4O4 requires 496; found 497.2 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])/[CH:5]=[CH:6]/[C:7]1[CH:12]=[C:11]([F:13])[C:10]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]([F:22])[CH:8]=1)[CH3:2].[N+](=[CH2:26])=[N-].O>C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:3][C:4]([CH:5]1[CH2:26][CH:6]1[C:7]1[CH:12]=[C:11]([F:13])[C:10]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]([F:22])[CH:8]=1)=[O:23])[CH3:2]
Reactant: C=[N+]=[N-]
Reactant: CCOC(=O)/C=C/c1cc(F)c(OCc2ccccc2)c(F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C1CC1c1cc(F)c(OCc2ccccc2)c(F)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 87 %

Procedure:
After (E)-3-(4-benzyloxy-3,5-difluoro-phenyl)-acrylic acid ethyl ester (2.5 g, 7.85 mmol) obtained in Step C of Preparation Example 2 was dissolved in THF (10 mL), diazomethane solution (94 mL, 23.55 mmol, 0.25M ether) was added thereto. After the reactant was cooled to 0˜5° C., palladium(II) acetate (0.29 g, 1.30 mmol) was added slowly thereto, and the mixture was stirred at room temperature for 5 hours. After the termination of the reaction, the reactant was added with water and then extracted. The organic layer was concentrated under reduced pressure and the residue was purified by column chromatography (eluent EtOAc/Hex=1/10) to obtain the title compound (2.27 g, 87%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[NH:8][C:7]=1[CH2:17][CH2:18][NH2:19])[CH3:2].[OH-].[Na+].[Cl:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[NH:8][C:7]=1[CH2:17][CH2:18][NH:19][C:28](=[O:29])[C:27]1[CH:31]=[CH:32][C:24]([Cl:23])=[CH:25][CH:26]=1)[CH3:2]
Reactant: CCOC(=O)Cc1c(CCN)[nH]c2ccc(OC)cc12
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCOC(=O)Cc1c(CCNC(=O)c2ccc(Cl)cc2)[nH]c2ccc(OC)cc12

Procedure:
61.7 g (0.223 mol) of the 2-aminoethyl-5-methoxy-indole-3-acetic acid ethyl ester produced in (d) are dissolved in 600 ml of methylene chloride and the solution is covered with a layer of 150 ml of 2 N sodium hydroxide solution. A solution of 43 g (0.245 mol) of p-chlorobenzoyl chloride is added, at 0°-5°, in the course of 21/2 hours, while stirring vigorously, and extraction by stirring is then carried out for a further hour. The methylene chloride phase is then separated off, washed with water, dried over MgSO4 and concentrated to dryness by evaporation. The residue crystallises on being taken up in ether, to form colourless crystals of 2-[(p-chlorobenzoyl-amino)-ethyl]-5-methoxy-indole-3-acetic acid ethyl ester having a melting point of 136°-138°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[N:27]=[C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:29][C:30]=1[CH3:31])[CH2:6][O:7][C:8]1[CH:12]=[C:11]([CH:13]=O)[N:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]=1.C(OP([CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48])(OCC)=O)C.CN(C)C=O.[H-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[N:27]=[C:28]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[O:29][C:30]=1[CH3:31])[CH2:6][O:7][C:8]1[CH:12]=[C:11](/[CH:13]=[CH:46]/[C:47]([O:49][CH2:50][CH3:51])=[O:48])[N:10]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:9]=1
Reactant: COc1cc(COc2cc(C=O)n(-c3ccccc3)n2)ccc1OCc1nc(-c2ccccc2)oc1C
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)c(OC)c2)nn1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.1 %

Procedure:
To a mixture of 3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-phenyl-1H-pyrazole-5-carbaldehyde (600 mg), ethyl diethylphosphonoacetate (300 mg) and N,N-dimethylformamide (10 mL) was added sodium hydride (60% in oil, 52.0 mg) at 0° C., and the mixture was stirred overnight at room temperature. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with dilute hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give ethyl (E)-3-(3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-phenyl-1H-pyrazol5-yl)-2-propenoate (590 mg, yield 86%) as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:4, v/v). The crystals were recrystallized from ethyl acetate-hexane. melting point: 121-122° C.
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([OH:21])=O)=[C:15]([I:22])[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[N:23]1([CH2:30][CH2:31][OH:32])[CH2:29][CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:26]3[CH2:27][CH2:28][CH2:29][N:23]([CH2:30][CH2:31][OH:32])[CH2:24][CH2:25]3)=[O:21])=[C:15]([I:22])[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1cccc(-c2nc(I)c(C(=O)O)n2C)c1
Reactant: OCCN1CCCNCC1
Product: CCCCCCc1cccc(-c2nc(I)c(C(=O)N3CCCN(CCO)CC3)n2C)c1

Procedure:
In analogy to the procedure described for example 1, 2-(3-hexyl-phenyl)-5-iodo-3-methyl-3H-imidazole-4-carboxylic acid (intermediate 1) and 2-[1,4]diazepan-1-yl-ethanol gave the title compound as light yellow oil. MS: 539.3 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[N:17]=[C:16]([NH:18][CH3:19])[N:15]=[C:14](Cl)[N:13]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1.C(Cl)Cl.[K+].[Br-]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[N:17]=[C:16]([NH:18][CH3:19])[N:15]=[C:14]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[N:13]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: Nc1ccc(O)cc1
Reactant: CNc1nc(Cl)nc(Nc2cc(OC)cc(OC)c2)n1
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Product: CNc1nc(Nc2ccc(O)cc2)nc(Nc2cc(OC)cc(OC)c2)n1
Yield: 80 %

Procedure:
The title compound was synthesized from 2-(3,5-dimethoxyphenylamino)-4-methylamino-6-chloro-1,3,5-triazine and 4-aminophenol using a similar procedure to the one used in 7. Yield: 80%; Tg 81° C.; FTIR (CH2Cl2/KBr) 3401, 3288, 3133, 3003, 2958, 2915, 2840, 1587, 1507, 1481, 1450, 1427, 1400, 1360, 1294, 1264, 1234, 1205, 1177, 1153, 1106, 1082, 1065, 1014, 980, 927, 834, 808, 737, 703, 682, 661 cm−1; 1H NMR (300 MHz, DMSO-d6, 298 K): δ 9.02 (s, 1H), 8.95 (br s, 0.5H), 8.82 (br s, 1H), 8.64 (br s, 0.5H), 7.49 (br s, 2H), 7.09 (br d, 2H), 6.86 (br s, 1H), 6.66 (d, 3J=8.8 Hz, 2H), 6.08 (s, 1H), 3.69 (s, 6H), 2.81 (br s, 3H) ppm; 13C NMR (75 MHz, DMSO-d6): δ 166.0, 164.1, 163.8, 160.2, 152.4, 142.1, 131.6, 122.3, 114.7, 98.0, 93.7, 54.9, 27.3 ppm; HRMS (EI) calcd. for C18H20N6O3 (m/e): 368.1597. found: 368.1609.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([OH:11])=[CH:3][C:2]=1[OH:12].C(O)(=O)C.[N+:17]([O-])([OH:19])=[O:18]>O>[N+:17]([C:3]1[C:2]([OH:12])=[N:1][C:10]2[C:5]([C:4]=1[OH:11])=[CH:6][CH:7]=[CH:8][CH:9]=2)([O-:19])=[O:18]
Reactant: Oc1cc(O)c2ccccc2n1
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1c(O)nc2ccccc2c1O
Temperature: 105 °C
Reaction time: 0.17 h
Yield: 78.2 %

Procedure:
To a 50 mL round bottom flask were sequentially added quinoline-2,4-diol (2 g, 12.4 mmol), glacial acetic acid 12.5 mL, and concentrated nitric acid 3.25 mL, stirred for 30 min at room temperature, and then stirred for 10 min in an oil bath of 105° C., followed by cooling to room temperature. 25 mL water was added to form precipitates, which were filtrated through an air pump, washed sequentially with water and ethyl ether. The solid was dried under vacuum to afford 2 g titled product with a yield of 78.2%.