Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:4][CH2:5][C:6]1([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)([CH3:3])[CH3:2].C=O.[CH:29](O)=O.O>C(OCC)(=O)C>[CH:1]([N:4]([CH3:29])[CH2:5][C:6]1([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:22]3[CH2:23][CH2:24][CH2:25][CH2:26]3)=[CH:16][CH:17]=2)[CH2:7][CH2:8][O:9][CH2:10][CH2:11]1)([CH3:3])[CH3:2]
Reactant: CC(C)NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: O=CO
Agent: C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)N(C)CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Temperature: 60 °C
Yield: 65 %

Procedure:
To isopropyl-{4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-ylmethyl}-amine (258 mg, 0.71 mmol) was added formaldehyde (37% w/w solution in H2O, 1 mL) and formic acid (1.5 mL). The resulting mixture was heated to 60° C. overnight. After cooling, H2O and ethyl acetate were added. The aqueous layer was separated, basified with 30% NaOH and extracted 3 times with ethyl acetate. The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo to give the title compound as an oil (170 mg, 65%). 1H NMR (400 MHz, CDCl3) δ 7.19 (d, 2H), 6.86 (d, 2H), 4.02 (t, 2H), 3.76 (m, 2H), 3.50 (m, 2H), 2.63 (t, 2H), 2.53 (m, 4H), 2.44 (m, 1H), 2.38 (s, 2H), 2.08 (m, 2H), 2.01 (m, 2H), 1.89 (m, 2H), 1.85 (s, 3H), 1.79 (m, 4H), 0.84 (d, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH2:12][C:13]([OH:15])=O)[N:8]=[CH:7][CH:6]=[CH:5]2.[Br:16][C:17]1[C:18]([C:23]2[NH:27][N:26]=[CH:25][N:24]=2)=[C:19]([NH2:22])[S:20][CH:21]=1>>[Br:16][C:17]1[C:18]([C:23]2[NH:27][N:26]=[CH:25][N:24]=2)=[C:19]([NH:22][C:13](=[O:15])[CH2:12][C:11]2[CH:10]=[C:9]3[C:4]([CH:5]=[CH:6][CH:7]=[N:8]3)=[CH:3][C:2]=2[F:1])[S:20][CH:21]=1
Reactant: Nc1scc(Br)c1-c1ncn[nH]1
Reactant: O=C(O)Cc1cc2ncccc2cc1F
Product: O=C(Cc1cc2ncccc2cc1F)Nc1scc(Br)c1-c1ncn[nH]1

Procedure:
N-(4-Bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(6-fluoroquinolin-7-yl)acetamide was prepared from 2-(6-fluoroquinolin-7-yl)acetic acid (42 mg, 0.203 mmol) and 4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-amine (25 mg, 0.102 mmol) according to protocol A. Retention time (min)=2.338, method [7], MS (ESI) 432.0 (M+H); 1H NMR (300 MHz, CD3OD) δ 9.02 (d, J=4.2 Hz, 1H), 8.73 (d, J=8.0 Hz, 1H), 8.24 (d, J=7.2 Hz, 1H), 7.93 (s, 1H), 7.88 (d, J=10.0 Hz, 1H), 7.82 (dd, J=9.0, 4.2 Hz, 1H), 7.09 (s, 1H), 4.42 (s, 2H).
Reaction SMILES: C([N:8](C(C1C=CC=CC=1)C)[CH:9]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH2:10][C:11]([NH:13][CH2:14][CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:12])C1C=CC=CC=1.CO.[H][H]>C(OCC)(=O)C.C(O)C.[Pd]>[NH2:8][CH:9]([CH:20]1[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1)[CH2:10][C:11]([NH:13][CH2:14][CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:12]
Reactant: CC(c1ccccc1)N(Cc1ccccc1)C(CC(=O)NCCC(C)(C)C)C1CCCCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)CCNC(=O)CC(N)C1CCCCC1
Reaction time: 3 h

Procedure:
In a Parr bottle 10% Pd/C (0.8 g) was cooled to −78° C., followed by addition of a solution of 3-[benzyl-(1-phenyl-ethyl)-amino]-3-cyclohexyl-N-(3,3-dimethyl-butyl)-propionamide (0.8 g, 1.78 mmol) in ethyl acetate (10 mL), ethanol (100 mL), and methanol (20 mL). The resulting mixture was subjected to hydrogen atmosphere and shaken for 3 h. The hydrogen was purged with nitrogen, the reaction mixture was filtered (glass fiber filter paper) and the solvent was evaporated under reduced pressure to yield a residue.
Reaction SMILES: C([Li])(C)(C)C.BrC1C(C)=CC(C)=CC=1C.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1.CN([CH:27]=[O:28])C>C1COCC1>[CH3:16][O:17][C:18]1[C:23]([CH:27]=[O:28])=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: CN(C)C=O
Reactant: COc1ccccn1
Agent: Cc1cc(C)c(Br)c(C)c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1ncccc1C=O
Reaction time: 1 h
Yield: 74.7 %

Procedure:
To a stirred solution of 1.7M t-butyl lithium in THF (35.0 mL, 59.6 mmol, 2.60 equiv.) with THF (150 mL) at −78 degrees was added dropwise 2-bromomesitylene (4.56 mL, 29.8 mmol, 1.30 equiv.). After stirring for 1 h, 2-methoxy-pyridine (2.5 g, 22.9 mmol) was added dropwise. This solution was warmed to −23 degrees and stirred for 3 h and then cooled to −78 degrees again. DMF (2.66 mL, 34.4 mmol, 1.5 equiv.) was added, the solution was stirred at −78 degrees for 1 h. The reaction was quenched at this temperature with brine (150 mL) and extracted with ether. The combined ether was dried over K2CO3 and evaporated on vacuo. The residue was chromatographed with 50%-80% EtOAc/Hexanes to give 2-methoxy-pyridine-3-carbaldehyde (2.34 g, 17.1 mmol, 74.5%) as a yellow solid.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24])(OCC)=O.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH2:1]([N:8]1[C:18](=[O:19])[C:17]2[C:16](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C1c2ccccc2C(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.2 %

Procedure:
Benzylamine (manufactured by Tokyo Kasei Kogyo Co., Ltd.) (1.00 g) was dissolved in purified water (20 ml) and then added with N-carbethoxyphthalimide (manufactured by Tokyo Kasei Kogyo Co., Ltd.) (3.06 g) and sodium carbonate (2.47 g), followed by stirring at room temperature for 3 hours. After completion of the reaction, the solution was filtered and the residue was washed with purified water and then dried under vacuum at 60° C., thereby obtaining the subject compound (1.82 g) as a white solid.
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](O)=[O:29].[CH3:47][O:48][CH:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1.C(N(CC)CC)C>CC(N(C)C)=O.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:52]1[CH2:53][CH2:54][CH:49]([O:48][CH3:47])[CH2:50][CH2:51]1)=[O:29]
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: COC1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: COC1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)CC1
Temperature: 20 °C
Reaction time: 21 h
Yield: 61.6 %

Procedure:
O-Benzotriazol-1-yl-tetramethyluronium hexafluorophosphate (45.5 g, 119.86 mmol) was added portionwise to a solution of 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1) (27.5 g, 92.20 mmol), 4-methoxypiperidine (11.68 g, 101.42 mmol) and triethylamine (30.8 mL, 221.28 mmol) in DMA (450 mL) at 20° C. under nitrogen. The resulting solution was stirred at 20° C. for 21 hours. The solution was poured into water (2.5 liters) and extracted with EtOAc (×3), the combined extracts washed with brine (×3), dried (MgSO4), filtered and evaporated to a gum. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in isohexane. Pure fractions were evaporated to dryness and slurried with EtOAc to afford 4-(4-fluoro-3-(4-methoxypiperidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (2b) (22.45 g, 61.6%) as a white solid after filtration and vacuum drying.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:10]=[CH:11][C:12]2[N:13]([C:15]([C:18]([F:21])([F:20])[F:19])=[N:16][N:17]=2)[N:14]=1.[F:22][C:23]([F:33])([F:32])[C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1>>[F:19][C:18]([F:20])([F:21])[C:15]1[N:13]2[N:14]=[C:9]([N:2]3[CH2:3][CH:4]4[CH2:8][N:7]([CH2:28][C:27]5[CH:26]=[CH:25][C:24]([C:23]([F:22])([F:32])[F:33])=[CH:31][CH:30]=5)[CH2:6][CH:5]4[CH2:1]3)[CH:10]=[CH:11][C:12]2=[N:17][N:16]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CC4CNCC4C3)nn12
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Product: FC(F)(F)c1ccc(CN2CC3CN(c4ccc5nnc(C(F)(F)F)n5n4)CC3C2)cc1

Procedure:
Reductive amination of 6-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-(trifluoromethyl)benzaldehyde was carried out according to General Synthetic Method 10. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 3-(trifluoromethyl)-6-[2-[[4-(trifluoromethyl)phenyl]methyl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl]-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:8]([CH2:9][NH:10][C:11](=[O:22])[C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:7][C:6]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[Cl:30])=[C:5]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[N:4]=1.[CH3:38][O:39][CH2:40][C:41](Cl)=[O:42]>>[Cl:37][C:34]1[CH:33]=[CH:32][C:31]([C:5]2[N:4]=[C:3]([CH2:2][NH:1][C:41](=[O:42])[CH2:40][O:39][CH3:38])[C:8]([CH2:9][NH:10][C:11](=[O:22])[C:12]3[CH:13]=[CH:14][C:15]([C:18]([F:20])([F:21])[F:19])=[CH:16][CH:17]=3)=[CH:7][C:6]=2[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[Cl:30])=[CH:36][CH:35]=1
Reactant: NCc1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)cc1CNC(=O)c1ccc(C(F)(F)F)cc1
Reactant: COCC(=O)Cl
Product: COCC(=O)NCc1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)cc1CNC(=O)c1ccc(C(F)(F)F)cc1
Yield: 77.6 %

Procedure:
0.35 g of N-{[6-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-2-{[(methoxyacetyl)amino]methyl}pyrid-3-yl]methyl}-4-(trifluoromethyl)benzamide is prepared from 0.40 g of N-{[2-(aminomethyl)-6-(4-chlorophenyl)-5-(2,4-dichlorophenyl)pyrid-3-yl]methyl}-4-(trifluoromethyl)benzamide and 0.084 g of methoxyacetyl chloride, using a procedure similar to that of step E) of Example 2.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@:5]2([C:19]3[C:14](=[N:15][CH:16]=[C:17](Br)[CH:18]=3)[O:13][C:12]3[C:7]2=[CH:8][C:9]([OH:21])=[CH:10][CH:11]=3)[N:6]=1.C(=O)([O-])[O-].[K+].[K+].[O:28]1[CH2:33][CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH2:30][CH2:29]1.CN(C=O)C>O>[NH2:1][C:2]1[O:3][CH2:4][C@:5]2([C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:31]4[CH2:32][CH2:33][O:28][CH2:29][CH:30]=4)[CH:18]=3)[O:13][C:12]3[C:7]2=[CH:8][C:9]([OH:21])=[CH:10][CH:11]=3)[N:6]=1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: NC1=N[C@@]2(CO1)c1cc(O)ccc1Oc1ncc(Br)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: NC1=N[C@@]2(CO1)c1cc(O)ccc1Oc1ncc(C3=CCOCC3)cc12

Procedure:
A vial was charged with (S)-2′-amino-3-bromo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-7-ol (380 mg, 1.091 mmol), potassium carbonate (754 mg, 5.46 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (688 mg, 3.27 mmol), pd(ph3p)4 (126 mg, 0.109 mmol), DMF (5457 μL), and water (2.5 mL). The vial was sealed, placed in 80° C. and heated overnight. The mixture was diluted with water (35 mL) and extracted with EtOAc (3×15 mL). The combined organic extract was dried over sodium sulfate, filtered, and evaporated. The residue was purified by chromatography on a 80-g Redi-Sep column, eluting with 0-100% of a 90:10:1 mix of DCM/MeOH/NH4OH in DCM to give (S)-2′-amino-3-(3,6-dihydro-2H-pyran-4-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-7-ol as an orange solid.
Reaction SMILES: [OH:1][C:2]1([C:31](O)=[O:32])[CH2:7][CH2:6][CH:5]([N:8]2[C:16]([NH:17][C:18]3[C:23]([F:24])=[CH:22][C:21]([F:25])=[CH:20][C:19]=3[F:26])=[N:15][C:14]3[C:9]2=[N:10][C:11]([NH:27][CH:28]([CH3:30])[CH3:29])=[N:12][CH:13]=3)[CH2:4][CH2:3]1.[CH:34]1([NH2:39])[CH2:38][CH2:37][CH2:36][CH2:35]1.C(NC(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C1COCC1>[CH:34]1([NH:39][C:31]([C:2]2([OH:1])[CH2:7][CH2:6][CH:5]([N:8]3[C:16]([NH:17][C:18]4[C:23]([F:24])=[CH:22][C:21]([F:25])=[CH:20][C:19]=4[F:26])=[N:15][C:14]4[C:9]3=[N:10][C:11]([NH:27][CH:28]([CH3:30])[CH3:29])=[N:12][CH:13]=4)[CH2:4][CH2:3]2)=[O:32])[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: NC1CCCC1
Reactant: CC(C)Nc1ncc2nc(Nc3c(F)cc(F)cc3F)n(C3CCC(O)(C(=O)O)CC3)c2n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)Nc1ncc2nc(Nc3c(F)cc(F)cc3F)n(C3CCC(O)(C(=O)NC4CCCC4)CC3)c2n1
Reaction time: 0.17 h
Yield: 66 %

Procedure:
1-Hydroxy-4-{2-[(methylethyl)amino]-8-[(2,4,6-trifluorophenyl)amino]purin-9-yl}cyclohexanecarboxylic acid (0.200 g, 0.4 mmol) was dissolved in 4 mL of dry THF. Cyclopentyl amine (0.079 mL, 0.8 mmol) was added neat followed by di-isopropyl amine (0.105 mL, 0.6 mmol). Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) was added last, as a solid in one portion at room temperature (0.177 g, 0.4 mmol). The reaction was complete within 10 min as confirmed by LC-MS. DMF was removed under reduced pressure. The residue was triturated in saturated aqueous sodium bicarbonate. The resulting beige solid was collected by filtration and washed with water. The crude product was re-crystallized from hot methanol-water. The crystals were dried in vacuum oven. (141 mg, 66% yield) M+1: 532.
Reaction SMILES: [C:1]([C:3]1[N:7]([CH3:8])[C:6]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=NC#N)[C:12]23[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:5][CH:4]=1)#[N:2].C(NCC)C>C1COCC1>[C:1]([C:3]1[N:7]([CH3:8])[C:6]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]=[CH:13][C:12]23[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: Cn1c(C#N)ccc1-c1ccc2c(c1)C1(CCCCC1)C(=NC#N)N2
Solvent: CCNCC
Solvent: C1CCOC1
Product: Cn1c(C#N)ccc1-c1ccc2c(c1)C1(C=N2)CCCCC1
Temperature: 25 °C
Yield: 69.5 %

Procedure:
Crude 5′-(5-cyano-1-methyl-1H-pyrrol-2-yl)spiro[cyclohexane-1,3′-[3H]indol]-2′-ylidenecyanamide (95.0 g; purity 78% HPLC area) in THF (250 mL) was treated with diethylamine (105 g) and refluxed with a concomitant addition of THF (3.35 L) until dissolved. The solvent was distilled off (2.5 L) during which a precipitate was formed. The flask was cooled to ambient temperature and the white precipitate was filtered, washed with ether and dried to give 58.0 g (61% yield) of purified 5′-(5-cyano-1-methyl-1H-pyrrol-2-yl)spiro[cyclohexane-1,3′-[3H]indol])-2′-ylidenecyanamide (purity >99% HPLC area).
Reaction SMILES: C1COCC1.[F:6][C:7]1[CH:12]=[CH:11][C:10]([Mg]Br)=[CH:9][CH:8]=1.[CH2:15]([C:19]1[CH:24]=[CH:23][C:22](Cl)=[CH:21][CH:20]=1)[CH2:16][CH2:17][CH3:18].[Cl-].C(C1C=CC=C(C(C)C)C=1[NH+]1CCN(C2C(C(C)C)=CC=CC=2C(C)C)C1)(C)C>CCCCC>[CH2:15]([C:19]1[CH:24]=[CH:23][C:22]([C:10]2[CH:11]=[CH:12][C:7]([F:6])=[CH:8][CH:9]=2)=[CH:21][CH:20]=1)[CH2:16][CH2:17][CH3:18]
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: CCCCc1ccc(Cl)cc1
Agent: CC(C)c1cccc(C(C)C)c1N1CC[NH+](c2c(C(C)C)cccc2C(C)C)C1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCCCc1ccc(-c2ccc(F)cc2)cc1
Reaction time: 24 h
Yield: 87 %

Procedure:
Using a THF solution of 4-fluorophenylmagnesium bromide (1.46 mL, 1.03 M, 1.5 mmol), 4-butylchlorobenzene (168.7 mg, 1.0 mmol), FeF3.3H2O (6.68 mg, 0.04 mmol) and 1,3-bis(2,6-diisopropylphenyl)imidazolinium chloride (51.2 mg, 0.12 mmol) as starting materials, the reaction was performed at a scale of 1.0 mmol at 60° C. for 24 hours in the same manner as in Example 2. After performing silica gel column chromatography (pentane), the above compound was obtained as a white solid (0.199 g, yield=87%, purity=>97% (GC analysis)).
Reaction SMILES: ClC(Cl)C.[NH2:5][CH2:6][CH2:7][CH2:8][C:9]1[C:10](=[O:29])[N:11]([CH2:27][CH3:28])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1)=[CH:16][CH:15]=[C:14]([CH3:26])[N:13]=2.[CH3:30][S:31](Cl)(=[O:33])=[O:32].C(N(CC)CC)C>C(OCC)(=O)C>[Cl:25][C:21]1[CH:20]=[C:19]([C:18]2[C:17]3[C:12](=[N:13][C:14]([CH3:26])=[CH:15][CH:16]=3)[N:11]([CH2:27][CH3:28])[C:10](=[O:29])[C:9]=2[CH2:8][CH2:7][CH2:6][NH:5][S:31]([CH3:30])(=[O:33])=[O:32])[CH:24]=[CH:23][CH:22]=1
Reactant: CCn1c(=O)c(CCCN)c(-c2cccc(Cl)c2)c2ccc(C)nc21
Reactant: CS(=O)(=O)Cl
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCn1c(=O)c(CCCNS(C)(=O)=O)c(-c2cccc(Cl)c2)c2ccc(C)nc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.6 %

Procedure:
To a 10 ml dichloroethane solution containing 630 mg of 3-(3-aminopropyl)-4-(3-chlorophenyl)-l-ethyl-7-methyl-1,8-naphthyridin-2(1H)-one were added 243 mg of methanesulfonyl chloride and 0.30 ml of triethylamine under ice cooling, followed by stirring for 1 hour with warming to room temperature. The reaction mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate aqueous solution and saturated brine. The solvent was evaporated from the organic layer and the resulting residue was purified by a silica gel column chromatography (hexane-ethyl acetate) and then recrystallized from ethanol-water to obtain 204 mg of N-{3-[4-(3-chlorophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl]propyl}methanesulfonamide as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[O:11][CH:10]2[C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:15]([NH:22][CH2:23][CH2:24][OH:25])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CO.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>C1COCC1>[CH2:15]([N:22]([CH2:23][CH2:24][OH:25])[C:12]([CH:10]1[CH:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[O:11]1)=[O:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)C1OC1c1ccc(Cl)c(Cl)c1
Reactant: OCCNCc1ccccc1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(C1OC1c1ccc(Cl)c(Cl)c1)N(CCO)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.7 %

Procedure:
To a mixed solution of (2RS,3SR)-3-(3,4-dichlorophenyl)oxirane-2-carboxylic acid (50.0 g) and 2-(benzylamino)ethanol (38.9 g) in THF (700 mL)-methanol (100 mL) was added 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (71.2 g), and the mixture was stirred at room temperature overnight. The reaction solution was concentrated, the residue was diluted with ethyl acetate, and the mixture was washed with saturated aqueous sodium hydrogen carbonate, water and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (42.2 g).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][CH2:10][C:9](=O)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:14][OH:15].O>C(O)C.CCOC(C)=O>[C:1]1([CH:7]2[CH2:12][CH2:11][CH2:10][C:9](=[N:14][OH:15])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCCC(c2ccccc2)C1
Reactant: NO
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: ON=C1CCCC(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.07 %

Procedure:
To a solution of 3-phenylcyclohexanone (0.060 g, 0.3444 mmol) in 95% ethanol (2 ml) was added 50% hydroxylamine in water (0.2110 ml, 3.444 mmol), and the reaction was stirred at ambient temperature overnight. The reaction was diluted with EtOAc and washed with water and saturated sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to yield 60 mg of the title compound (92.07% yield).
Reaction SMILES: [O:1]1[CH2:5][C:4](=O)[CH2:3][C:2]1=[O:7].[CH3:8][C:9]1([NH:15][C:16]([NH2:18])=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>>[CH3:8][C:9]1([NH:15][C:16]([NH:18][C:4]2[CH2:5][O:1][C:2](=[O:7])[CH:3]=2)=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=C1COC(=O)C1
Reactant: CC1(NC(N)=O)CCCCC1
Product: CC1(NC(=O)NC2=CC(=O)OC2)CCCCC1
Yield: 38.2 %

Procedure:
Using the procedure described in Example 2 using 5 g of 2,4-furandione and 6 g of 1-methylcyclohexylurea there is obtained 3.5 g 1-(1-methylcyclohexyl)-3-(2,5-dihydro-5-oxo-3-furyl)urea, m.p. 183° C. (decomposition).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([N+:14]([O-:16])=[O:15])[CH:13]=1)[C:8](O)=[O:9])=[O:4].O=S(Cl)[Cl:19]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([N+:14]([O-:16])=[O:15])[CH:13]=1)[C:8]([Cl:19])=[O:9])=[O:4]
Reactant: COC(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(C(=O)Cl)cc([N+](=O)[O-])c1

Procedure:
Heat 3-methoxycarbonyl-5-nitrobenzoic acid (2.0 g=8.9 mmol) with SOCl2 (2.1 g=18 mmol) in toluene at reflux 1 hr. Concentrate to obtain 3-methoxycarbonyl-5-nitrobenzoyl chloride, m.p. 66°-8° C.
Reaction SMILES: C([BH3-])#N.[Na+].[CH2:5]([O:8][C:9]([C:11]1[N:12]([NH2:16])[CH:13]=[CH:14][CH:15]=1)=[O:10])[CH:6]=[CH2:7].[Cl:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[F:26])[CH:21]=O.C(O)(=O)C>CO>[CH2:5]([O:8][C:9]([C:11]1[N:12]([NH:16][CH2:21][C:20]2[CH:23]=[CH:24][C:25]([F:26])=[C:18]([Cl:17])[CH:19]=2)[CH:13]=[CH:14][CH:15]=1)=[O:10])[CH:6]=[CH2:7]
Reactant: C=CCOC(=O)c1cccn1N
Reactant: O=Cc1ccc(F)c(Cl)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: C=CCOC(=O)c1cccn1NCc1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.4 %

Procedure:
Sodium cyanoborohydride (1.11 g, 16.8 mmol) was added to a solution of 1-amino-1H-pyrrole-2-carboxylic acid allyl ester (Example 1b, 1.12 g, 6.74 mmol), 3-chloro-4-fluorobenzaldehyde (1.32 g, 8.08 mmol) and acetic acid (1.2 mL), in methanol (50 mL) at 25° C. The reaction mixture was stirred at 25° C. for 18 h, quenched with saturated aqueous sodium bicarbonate solution and was extracted with ethyl acetate (2×50 mL). The organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. Purification of the residue by flash column chromatography (Teledyne Isco RediSep 40 g, 0→40% ethyl acetate in hexanes) afforded the desired product, 1-(3-chloro-4-fluoro-benzylamino)-1H-pyrrole-2-carboxylic acid allyl ester (1.36 g, 4.41 mmol, 65% yield) as an off-white oil. 1H NMR (400 MHz, CDCl3) δ 4.06 (2H, d, J=5.5 Hz), 4.76 (2H, d, J=5.3 Hz), 5.29 (1H, d, J=11.0 Hz), 5.40 (1H, d, J=16.4 Hz), 5.96-6.05 (2H, m), 6.58 (1H, t, J=5.5 Hz), 6.76 1H, (t, J=1.9 Hz), 6.91 (1H, dd, J1=4.3 Hz, J2=1.8 Hz), 7.06 (1H, t, J=8.6 Hz), 7.10-7.14 (1H, m), 7.33 (1H, dd, J1=7.1 Hz, J2=1.4 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4]([O:6][CH2:7][N:8]1[N:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]([C:18](=[O:32])[C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[CH:21][C:20]=2[N+:29]([O-])=O)=[N:9]1)=[O:5])[CH3:2].[H][H]>C(OCC)(=O)C.[OH-].[Pd+2].[OH-]>[NH2:29][C:20]1[CH:21]=[C:22]([O:27][CH3:28])[C:23]([O:25][CH3:26])=[CH:24][C:19]=1[C:18]([C:10]1[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:12][N:8]([CH2:7][O:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:9]=1)=[O:32]
Reactant: [H][H]
Reactant: CCOC(=O)OCn1nc(C(=O)OCC)c(C(=O)c2cc(OC)c(OC)cc2[N+](=O)[O-])n1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CCOC(=O)OCn1nc(C(=O)OCC)c(C(=O)c2cc(OC)c(OC)cc2N)n1
Yield: 95.2 %

Procedure:
Ethyl 2-(ethoxycarbonyloxymethyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate (45 mg) prepared in step (3a) was dissolved in ethyl acetate (1 ml). Palladium hydroxide (15 mg) was added to the solution. The mixture was stirred in a hydrogen atmosphere at room temperature for 15 hr. The reaction solution was filtered through Celite. The filtrate was concentrated under reduced pressure to give ethyl 5-(2-amino-4,5-dimethoxybenzoyl)-2-(ethoxycarbonyloxymethyl)-2H-1,2,3-triazole-4-carboxylate as a yellow oil (40 mg, 95%).