Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](/[CH:7]=[N:8]/[CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[N:3][CH:2]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]([N+:40]#[C-:41])S(C2C=CC(C)=CC=2)(=O)=O)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].COC(C)(C)C>CN(C=O)C>[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:40]=[CH:41][N:8]([CH:9]3[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]3)[C:7]=2[C:4]2[CH:5]=[CH:6][N:1]=[CH:2][N:3]=2)=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC(/N=C/c2ccncn2)CC1
Reactant: [C-]#[N+]C(c1ccc(F)cc1)S(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2cnc(-c3ccc(F)cc3)c2-c2ccncn2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of tert-butyl 4-{[(1E)-pyrimidin-4-ylmethylene]amino}piperidine-1-carboxylate (C13) (57.66 g, 198.6 mmol), 1-fluoro-4-{isocyano[(4-methylphenyl)sulfonyl]methyl}benzene (C2) (38.30 g, 132.4 mmol) and potassium carbonate (36.59 g, 264.8 mmol) in DMF (575 mL) was stirred for 18 hours. The reaction was filtered, and the solids were washed with ethyl acetate and discarded. The combined filtrates were diluted with ethyl acetate (1 L) and washed with water (2×1 L), and the combined aqueous layers were extracted with ethyl acetate (500 mL). Concentration of the combined organic layers in vacuo provided a solid, which was heated at reflux with tert-butyl methyl ether (400 mL), then cooled to room temperature and granulated for 1 hour. The solid was collected by filtration and washed with additional tert-butyl methyl ether; this filtrate was concentrated under reduced pressure and treated in the same way, using 75 mL of tert-butyl methyl ether, to obtain a second crop. The combined solids provided the product as a white solid. Yield: 41.70 g, 98.47 mmol, 74%. 1H NMR (400 MHz, CDCl3) δ 1.49 (s, 9H), 1.81-1.92 (m, 2H), 2.16 (br d, J=12 Hz, 2H), 2.77-2.85 (m, 2H), 4.30 (br s, 2H), 4.90 (tt, J=12.0, 3.8 Hz, 1H), 7.04 (dd, J=8.7, 8.7 Hz, 2H), 7.17 (dd, J=5.3, 1.4 Hz, 1H), 7.41 (dd, J=8.9, 5.4 Hz, 2H), 7.79 (s, 1H), 8.57 (d, J=5.4 Hz, 1H), 9.29 (d, J=1.5 Hz, 1H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C(N(CC)CC)C.[C:18](OC(=O)C)(=[O:20])[CH3:19].ClCCCl>CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:18](=[O:20])[CH3:19])[CH:6]=[CH:5]2
Reactant: CC(=O)OC(C)=O
Reactant: Ic1ccc2[nH]ccc2c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CC(=O)n1ccc2cc(I)ccc21
Yield: 96.5 %

Procedure:
A solution of 5-iodo-1H-indole (530 mg, 2.18 mmol), DMAP (53 mg, 0.43 mmol), triethylamine (0.46 mL, 3.30 mmol), acetic anhydride (0.81 mL, 8.57 mmol), and 1,2-dichloroethane (5.5 mL) was heated at 60° C. overnight. The reaction mixture was diluted with ethyl acetate (100 mL), washed (50 mL saturated NH4Cl then 50 mL brine), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to yield the title compound as a white solid (600 mg, 96%). 1H NMR (300 MHz, DMSO-d6): δ 8.17 (d, 1H), 8.01 (d, 1H), 7.87 (d, 1H), 7.58 (dd, 1H), 6.70 (d, 1H), 2.64 (s, 3H).
Reaction SMILES: OCC[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N+:7]=1[O-].[OH:13][C:14]1[CH:15]=[CH:16][C:17]2[CH2:23][C@@H:22]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:21]3[CH:30]=[CH:31][CH:32]=[CH:33][C:20]=3[CH2:19][C:18]=2[CH:34]=1.O[C:36]1C=CC2C[C@H](CC(OCC)=O)C3C=CC=CC=3CC=2[CH:56]=1>>[CH3:4][NH:5][C:6]1[N:7]=[C:8]([CH2:36][CH2:56][O:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:23][C@@H:22]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:21]4[CH:30]=[CH:31][CH:32]=[CH:33][C:20]=4[CH2:19][C:18]=3[CH:34]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)C[C@H]1Cc2ccc(O)cc2Cc2ccccc21
Reactant: [O-][n+]1ccccc1NCCCO
Reactant: CCOC(=O)C[C@@H]1Cc2ccc(O)cc2Cc2ccccc21
Product: CCOC(=O)C[C@@H]1Cc2ccc(OCCc3cccc(NC)n3)cc2Cc2ccccc21

Procedure:
According to the procedure of Example 6 (a), except substituting 6-(methylamino)-2-pyridylethanol for the 2-[(3-hydroxy-1-propyl)amino]pyridine-N-oxide, and ethyl (S)-10,11-dihydro-3-hydroxy-5H-dibenzo[a,d]cycloheptene-10-acetate for ethyl (R)-10,11-dihydro-3-hydroxy-5H-dibenzo[a,d]cycloheptene-10-acetate, the title compound was obtained as colorless oil following silica gel chromatography (0.2-2% MeOH/CH2Cl2): MS (ES) 431.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[C:9]([C:17](Cl)=[O:18])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:17](=[O:18])[C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)nc1
Reactant: O=C(Cl)C(=O)c1ccccc1
Product: O=C(Nc1ccc(Cl)nc1)C(=O)c1ccccc1

Procedure:
In analogy to the procedure described for the synthesis example 41 (step 1), the title compound N-(6-chloro-pyridin-3-yl)-2-oxo-2-phenyl-acetamide (MS m/e: 261.0 [M+H]+) was prepared from 6-chloro-pyridin-3-ylamine and benzoylformic acid chloride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](I)=[N:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:15][C:16]1[C:21]([F:22])=[C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:19]=[CH:18][C:17]=1B(O)O.O>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>[F:15][C:16]1[C:21]([F:22])=[C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:19]=[CH:18][C:17]=1[C:5]1[N:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1
Reactant: CCCCCCCCOc1ccc(B(O)O)c(F)c1F
Reactant: Brc1cnc(I)nc1
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
Solvent: O
Product: CCCCCCCCOc1ccc(-c2ncc(Br)cn2)c(F)c1F
Yield: 55.5 %

Procedure:
--To a degassed mixture of 5-bromo-2-iodopyrimidine 2 (4.0 g, 14.0 mmol), tetrakis(triphenylphosphine)palladium (323 mg, 0.28 mmol), DME (30 ml), and aqueous 2M sodium carbonate (50 ml) was added 2,3-difluoro-4-octyloxyphenylboronic acid 3 (4.42 g, 15.4 mmol) dropwise in DME (10 ml) under an atmosphere of nitrogen. The mixture was heated under reflux overnight; water was added to the mixture and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (twice) and the combined organic solutions were washed with brine and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by flash chromatography (5% to 10% ethyl acetate-light petroleum; the crude material was preloaded onto silica in dichloromethane) to give the phenylpyrimidine 4 (3.1 g, 55%) (from methanol), m.p. 74.6° C.; νmax /cm-1 (KBr) 2920, 2850, 1625, 1475, 1420, 1310 and 1090; δ 0.91(1H, t, Me), 1.2-1.55(10H, m), 1.85 (2H, quint. OCH2CH2), 4.11 (2H, t, OCH2), 6.82 (1H, ddd, 5'-H), 7.83 (1H, ddd, 6'-H) and 8.86 (2H, s, 4- and 6-H); m/z 288 (M+ -C8H16), 286 (M+ -C8H16), 178 and 155.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:35]=[CH:34][C:17]3[C:18]4[N:22]([CH2:23][CH2:24][O:25][C:16]=3[CH:15]=2)[CH:21]=[C:20]([C:26]2[N:27]([CH:31]([CH3:33])[CH3:32])[N:28]=[CH:29][N:30]=2)[N:19]=4)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:36]>>[ClH:36].[CH:31]([N:27]1[C:26]([C:20]2[N:19]=[C:18]3[N:22]([CH2:23][CH2:24][O:25][C:16]4[CH:15]=[C:14]([CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)[CH:35]=[CH:34][C:17]=43)[CH:21]=2)=[N:30][CH:29]=[N:28]1)([CH3:33])[CH3:32]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3=CCN(C(=O)OC(C)(C)C)CC3)cc1OCC2
Agent: Cl
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCNCC3)cc1OCC2

Procedure:
4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester was treated with hydrochloric acid to give 2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene hydrochloride. 1H NMR 400 MHz (DMSO-d) δ: 9.08 (2 H, s), 8.37 (1 H, d, J=8.30 Hz), 8.18 (1 H, s), 8.07 (1 H, s), 7.06 (1 H, dd, J=8.35, 1.80 Hz), 6.91 (1 H, d, J=1.80 Hz), 5.85 (1 H, m), 4.53 (4 H, m), 3.35 (2 H, d, J=12.46 Hz), 2.98 (2 H, m), 2.87 (1 H, m), 1.93 (4 H, m), 1.50 (6 H, d, J=6.57 Hz)
Reaction SMILES: [CH:1]([C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:9]=2[C:10]#[N:11])=[CH:5][C:4]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=O.CN.[C:30]([BH3-])#[N:31].[Na+].[C:34]([OH:41])(=[O:40])/[CH:35]=[CH:36]/[C:37]([OH:39])=[O:38]>C(OCC)(=O)C.C(O)(=O)C.CO>[C:34]([OH:41])(=[O:40])/[CH:35]=[CH:36]/[C:37]([OH:39])=[O:38].[CH3:30][NH:31][CH2:1][C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:9]=2[C:10]#[N:11])=[CH:5][C:4]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: N#Cc1ccc(C(F)(F)F)cc1Oc1ccc(C=O)c(-c2ccccc2)c1
Reactant: [BH3-]C#N
Agent: CN
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CNCc1ccc(Oc2cc(C(F)(F)F)ccc2C#N)cc1-c1ccccc1
Yield: 53.7 %

Procedure:
2-(4-Formyl-3-phenyl-phenoxy)-4-trifluoromethyl-benzonitrile (0.117 g, 0.35 mmol), methylamine (2M in methanol, 0.233 mL, 1.05 mmol) and sodium cyanoborohydride (0.025 g, 0.39 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution for 20 h. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. Fumaric acid (0.032 g, 0.28 mmol) was added to the separated ethyl acetate layer and the solvent removed in vacuo. The residue was triturated with ethyl acetate overnight, filtered and dried to give 2-(4-methylaminomethyl-3-phenyl-phenoxy)-4-trifluoromethyl-benzonitrile fumarate (75 mg, 61%) as a white solid.
Reaction SMILES: [N:1]1([CH2:14][CH2:15][C:16]([O:18]CC)=O)[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.[CH2:21]([NH2:24])[CH2:22][CH3:23]>>[N:1]1([CH2:14][CH2:15][C:16]([NH:24][CH2:21][CH2:22][CH3:23])=[O:18])[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1
Reactant: CCOC(=O)CCn1cnc2cnc3ccccc3c21
Reactant: CCCN
Product: CCCNC(=O)CCn1cnc2cnc3ccccc3c21

Procedure:
Ethyl 3-(1H-imidazo[4,5-c]quinolin-1-yl)propanoate (3.75 g, 13.9 mmol, prepared as described in Part A of Example 20) was treated with n-propylamine (11.4 mL, 139 mmol) according to the method described in Part B of Example 20 to provide 3.9 g of 3-(1H-imidazo[4,5-c]quinolin-1-yl)-N-propylpropanamide.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.C(N=C=NC(C)C)(C)C.O.N1(O)C2C=CC=CC=2N=N1.[C:41]12([C:51](O)=[O:52])[CH2:50][CH:45]3[CH2:46][CH:47]([CH2:49][CH:43]([CH2:44]3)[CH2:42]1)[CH2:48]2>CN(C=O)C.CO>[C:41]12([C:51]([N:10]3[CH2:11][CH2:12][C:13]4[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=4)[C@H:9]3[C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:20])=[CH:8][CH:7]=3)=[O:52])[CH2:48][CH:47]3[CH2:46][CH:45]([CH2:44][CH:43]([CH2:49]3)[CH2:42]1)[CH2:50]2
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Reactant: FC(F)(F)c1ccc([C@H]2NCCc3ccccc32)cc1
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: O=C(N1CCc2ccccc2[C@H]1c1ccc(C(F)(F)F)cc1)C12CC3CC(CC(C3)C1)C2
Temperature: 65 °C

Procedure:
A solution of (R)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (0.05 g, 0.2 mmol) in DMF (1 mL) was treated with N-((isopropylimino)methyl-ene)propan-2-amine (0.07 mL, 0.5 mmol), 1H-benzo[d][1,2,3]triazol-1-ol hydrate (0.04 g, 0.2 mmol), and 1-adamantanecarboxylic acid (TCI, 0.04 g, 0.2 mmol). The resulting mixture was heated at 65° C. for 12 h. The reaction was cooled to RT and the filtrate was purified by preparative HPLC [gradient 10-90% MeCN (0.1% TFA)/H2O (0.1% TFA)] to give the pure product. It was dissolved in methanol (10 mL) and neutralized by passing the solution through a Polymer Lab-HCO3 Macroporous resin cartridge, and the filtrate was concentrated to give (1R)-2-(tricyclo[3.3.1.1˜3,7˜]dec-1-ylcarbonyl)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline as a colorless solid. MS (ESI, positive ion) m/z: 440 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[C:21]1([CH2:27][C:28](Cl)=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[O:19]=[C:13]1[CH:12]([N:5]2[C:4](=[O:20])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:28](=[O:29])[CH2:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Solvent: C1CCOC1
Product: O=C1CCC(N2C(=O)c3cccc(NC(=O)Cc4ccccc4)c3C2=O)C(=O)N1
Yield: 92 %

Procedure:
To a stirred suspension of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (0.55 g, 2.0 mmol) in THF (30 ml) was added 2-phenylacetyl chloride (0.62 g, 4.0 mmol). The mixture was heated to reflux for 18 hours. The solvent was evaporated in vacuo and the resulting solid was slurried in diethyl ether (20 ml) and filtered to give 0.72 g (92%) of product as an off-white solid: mp 217-218° C.; 1H NMR (DMSO-d6) δ 11.15 (s, 1H), 9.79 (s, 1H), 8.49 (d, J=8.4 Hz, 1H), 7.82 (t, J=7.9 Hz, 1H), 7.60 (t, J=7.3 Hz, 1H), 7.41-7.27 (m, 5H), 5.13 (dd, J=5.1 and 12.7 Hz, 1H), 3.85 (s, 2H), 2.98-2.83 (m, 1H), 2.64-2.44 (m, 2H), 2.08-2.04 (m, 1H); 13C NMR (DMSO-d6) δ 172.71, 170.07, 169.74, 167.60, 166.61, 136.38, 136.10, 134.70, 131.41, 129.41, 128.58, 126.97, 125.96, 118.39, 116.90, 48.89, 43.47, 30.90, 21.91; Anal. Calcd. For C21H17N3O5: C, 64.45; H, 4.38; N, 10.74. Found: C, 64.23; H, 4.34; N. 10.53.
Reaction SMILES: N[N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.O.[ClH:12].[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C:14]1=O>C(O)(C)C>[ClH:12].[CH:8]1[CH:7]=[CH:6][C:5]2[CH2:4][CH2:3][N:2]3[C:10]=2[C:9]=1[C:17]1[CH2:18][NH:13][CH2:14][CH2:15][C:16]=13
Reactant: NN1CCc2ccccc21
Reactant: O=C1CCCCN1
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: c1cc2c3c(c1)c1c(n3CC2)CCNC1
Yield: 72.9 %

Procedure:
A mixture of 1-amino-2,3-dihydroindole (1.0 g, 5.9 mmol), piperidone hydrochloride monohydrate (0.91 g, 5.9 mmol) and isopropanol (29 mL) was brought to reflux for 4 hours. The resulting brown solid was filtered and washed with cold diethylether (20 mL) and dried under vacuum, affording the title compound (1.01 g, 74%). 1H NMR (CD3OD, 300 MHz) δ 7.15 (d, 1H, J=7.7 Hz), 6.85–6.96 (m, 2H), 4.39–4.50 (m, 4H), 3.75 (t, 2H, J=7.3 Hz), 3.57 (t, 2H, J=6.2 Hz), 3.15 (t, 2H, J=6.2 Hz) ppm.
Reaction SMILES: NC1N=CC=CC=1C(O)=O.[C:11]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=O)[C:19]2=[O:26])([O:13][CH2:14][CH3:15])=[O:12].F[C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33]C(=O)[C:31]2=[O:38]>>[C:11]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]1[C:20](=[N:33][C:34]3[C:30]([C:31]1=[O:38])=[CH:29][CH:28]=[CH:36][CH:35]=3)[C:19]2=[O:26])([O:13][CH2:14][CH3:15])=[O:12]
Reactant: O=C1Nc2ccc(F)cc2C1=O
Reactant: CCOC(=O)c1ccc2c(c1)C(=O)C(=O)N2
Agent: Nc1ncccc1C(=O)O
Product: CCOC(=O)c1ccc2c(c1)C(=O)c1nc3ccccc3c(=O)n1-2
Yield: 30 %

Procedure:
Using the procedure in Example 56 and substituting 2-aminobenzoic acid for 2-aminonicotinic acid and 5-carboethoxyisatin for 5-fluoroisatin gave the title compound in 30% yield: mp 270.5°-272.7° C.; 1H NMR (300 MHz, CDCl3) δ 8.71 (d, 1H) 8.59 (s, 1H) 8.42-8.54 (m, 2H) 8.05 (d, 1H) 7.84-7.94 (m, 1H) 7.66-7.76 (m, 1H) 4.38-4.5 (m, 2H) 1.4-1.5 (m, 3H).
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][N:9]([CH:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[C:16]([CH3:26])[CH:15]=3)[CH3:13])[C:10](=[O:11])[C:6]=2[CH:5]=[CH:4][N:3]=1.[CH:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28]>>[CH3:26][C:16]1[CH:15]=[C:14]([CH:12]([N:9]2[C:10](=[O:11])[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:27]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:28])[C:7]=3[CH2:8]2)[CH3:13])[CH:19]=[CH:18][C:17]=1[O:20][CH2:21][C:22]([F:25])([F:24])[F:23]
Reactant: O=COc1ccccc1
Reactant: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)ccc1OCC(F)(F)F
Product: Cc1cc(C(C)N2Cc3c(ccnc3C(=O)Oc3ccccc3)C2=O)ccc1OCC(F)(F)F
Yield: 73 %

Procedure:
The title compound is prepared in 73% yield (90 mg, yellow oil) from 4-chloro-2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (100 mg, 0.26 mmol, Intermediate-42, single enantiomer) and phenyl formate (64 mg, 0.52 mmol) in a similar manner to Intermediate-91.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=O)=[C:4]([Cl:11])[C:3]=1C.[CH:13]([O-:18])([O-])[O:14][CH2:15][CH3:16].[ClH:19]>C(O)C>[Cl:11][C:4]1[C:5]([CH3:6])=[C:9]([CH:10]=[CH:2][C:3]=1[Cl:19])[C:13]([O:14][CH2:15][CH3:16])=[O:18]
Reactant: Cl
Reactant: Cc1c(Cl)ccc(C(=O)O)c1Cl
Reactant: CCOC([O-])[O-]
Solvent: CCO
Product: CCOC(=O)c1ccc(Cl)c(Cl)c1C

Procedure:
12.0 g. (0.058 mol.) of dichloro-3-methylbenzoic acid and 75 ml. of ethyl orthoformate in 100 ml. of ethanol was saturated with hydrogen chloride and refluxed to give ethyl 3,4-dichloro-2-methylbenzoate.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH3:8])[N:6]=[C:5]([C:9]([O:11]CC)=[O:10])[CH:4]=1)[CH3:2].[OH-].[Na+]>C(O)C.O>[CH2:1]([C:3]1[N:7]([CH3:8])[N:6]=[C:5]([C:9]([OH:11])=[O:10])[CH:4]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(CC)n(C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCc1cc(C(=O)O)nn1C

Procedure:
Ethyl 5-ethyl-1-methylpyrazole-3-carboxylate (6.86 g) in ethanol (70 ml) was treated with sodium hydroxide (1.58 g) in water (30 ml) and heated under reflux for 6 h. The solution was concentrated and the aqueous phase washed with ethyl acetate before adding dichloromethane (50 ml). The solution was acidified with 5M hydrochloric acid, and the mixture exhaustively extracted with dichloromethane. The remaining undissolved solid was filtered off suspended in water and the pH adjusted to 6 with saturated sodium hydrogen carbonate. The solution was again extracted with dichloromethane. The combined organic layers were dried over anhydrous magnesium sulphate and concentrated to give the title compound as a white solid. (2.72 g, 47%); (Found: M+, 154.0742. C7H10N2O2 requires M, 154.0742); nmax (CH2Cl2) 3689 and 1760 cm−1; dH(CDCl3) 1.30 (3H, t, J7.4 Hz), 2.64 (2H, q, J7.4 Hz), 3.88 (3H, s) and 6.65 (1H, s).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:37])=[C:9]([CH2:11][O:12][C:13]2[CH:34]=[CH:33][C:16]([CH2:17][O:18][C:19]3[C:23]([CH:24]=O)=[CH:22][N:21]([CH2:26][C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)[N:20]=3)=[CH:15][C:14]=2[O:35][CH3:36])[N:10]=1.[CH2:38](P(=O)(OCC)OCC)[P:39](=[O:46])([O:43][CH2:44][CH3:45])[O:40][CH2:41][CH3:42].CN(C)C=O.[H-].[Na+]>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:37])=[C:9]([CH2:11][O:12][C:13]2[CH:34]=[CH:33][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:38]/[P:39](=[O:46])([O:43][CH2:44][CH3:45])[O:40][CH2:41][CH3:42])=[CH:22][N:21]([CH2:26][C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)[N:20]=3)=[CH:15][C:14]=2[O:35][CH3:36])[N:10]=1
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Reactant: COc1cc(COc2nn(Cc3cccnc3)cc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(/C=C/c1cn(Cc2cccnc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1)OCC
Reaction time: 15 h
Yield: 88.1 %

Procedure:
To a mixture of 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-(pyridin-3-ylmethyl)-1H-pyrazole-4-carbaldehyde (0.17 g), tetraethyl methylenediphosphonate (0.11 g) and N,N-dimethylformamide (5 mL) was added sodium hydride (60% in oil, 0.015 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give diethyl (E)-2-[3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-(pyridin-3-ylmethyl)-1H-pyrazol-4-yl]ethenylphosphonate as a colorless oil (0.19 g, yield 86%) from a fraction eluted with ethyl acetate-hexane (4:1, v/v).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:34])[CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:33])[C:18]([CH3:32])([CH3:31])[CH2:19][NH:20][C:21](=[O:30])[C:22]2[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=2)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S.[N:36]1C=CC=CC=1>>[CH2:1]([O:8][C:9](=[O:34])[CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:33])[C:18]([CH3:31])([CH3:32])[CH2:19][NH:20][C:21](=[O:30])[C:22]2[CH:27]=[CH:26][C:25]([C:28](=[NH:36])[NH2:29])=[CH:24][CH:23]=2)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(CNC(=O)c1ccc(C#N)cc1)C(=O)N1CCC(CC(=O)OCc2ccccc2)CC1
Reactant: c1ccncc1
Agent: S
Product: CC(C)(CNC(=O)c1ccc(C(=N)N)cc1)C(=O)N1CCC(CC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 40 %

Procedure:
N-(N-4-Cyanobenzoyl-α,α-dimethyl-β-alanyl)-4-piperidineacetic acid benzyl ester (0.6 g) was dissolved in pyridine (15 ml) and hydrogen sulfide gas was introduced for 1 hour. The reaction container was sealed and the reaction mixture was stirred at a room temperature for 12 hours. The solvent was distilled off and methyl iodide (2 g) was added, followed by refluxing in acetone for 3 hours. After the solvent and excess methyl iodide were distilled off from the reaction solution, ammonium acetate (0.2 g) was added and the mixture was refluxed in methanol for 6 hours. After the solvent was distilled off, the residue was dissolved in a small amount of methylene chloride and reprecipitated from hexane to yield N-(N-4-amidinobenzoyl-α,α-dimethyl-β-alanyl)-4-piperidineacetic acid benzyl ester (0.25 g, 40.0%).
Reaction SMILES: [Br-].[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11](=[O:14])[CH2:12][NH3+:13])=[CH:3]1.C(N(C(C)C)C(C)C)C.[C:24]1([N:34]=[C:35]=[O:36])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1>C1COCC1>[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11](=[O:14])[CH2:12][NH:13][C:35]([NH:34][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26][CH:25]=2)=[O:36])=[CH:3]1
Reactant: [NH3+]CC(=O)c1c[nH]c2ccccc12
Reactant: O=C=Nc1cccc2ccccc12
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)c1c[nH]c2ccccc12)Nc1cccc2ccccc12
Reaction time: 1 h
Yield: 87 %

Procedure:
[2-(3-indolyl)-2-oxoethyl]ammonium bromide (2.00 g, 7.84) was suspended in dry THF (20 ml). Ethyldiisopropylamine (1.40 ml, 7.84 mmol) was added followed by 1-naphthyl-isocyanate (1.13 ml, 7.84 ml). After stirring for 1 hour the formed precipitate was removed by filtration and washed with THF followed by water to give the sub-title product (2.33 g, 87%) as a white solid after drying.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[OH:12].[Cl-].Cl[C:15](Cl)=[N+:16]([CH3:18])[CH3:17]>C(Cl)Cl>[CH3:15][N:16]([CH3:18])[C:17]1[O:12][C:3]2[CH:4]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=[CH:11][C:2]=2[N:1]=1
Reactant: C[N+](C)=C(Cl)Cl
Reactant: COC(=O)c1ccc(N)c(O)c1
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)c1ccc2nc(N(C)C)oc2c1
Yield: 102 %

Procedure:
To a solution of methyl 4-amino-3-hydroxybenzoate (1.63 g, 9.8 mmol) in CH2Cl2 (30 mL) was added N-(dichloromethylene)-N-methylmethanaminium chloride (1.63 g, 10.0 mmol, 1.0 eq). The mixture was heated to reflux for 3 h. The reaction was quenched with H2O then extracted with CH2Cl2 (3×30 mL). Solvent was removed under reduced pressure to afford the title compound (2.2 g, ca. 10.0 mmol) which was used in next step without further purification.