Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][C:14]=2[O:22][CH3:23])[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12].[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>ClCCl>[CH:19]([C:16]1[CH:17]=[CH:18][C:13]([C:2]2([NH:1][C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:10](=[O:11])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:12])=[C:14]([O:22][CH3:23])[CH:15]=1)([CH3:21])[CH3:20]
Reactant: COc1cc(C(C)C)ccc1C1(N)C(=O)c2ccccc2C1=O
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C(C)C)ccc1C1(NC(=O)c2ccccc2)C(=O)c2ccccc2C1=O
Yield: 100.8 %

Procedure:
A solution of 2-amino-2-(4-isopropyl-2-methoxyphenyl)-2H-inden-1,3-dione (200 mg, 0.60 mmol) in dichloromethane (10 ml) was stirred overnight together with benzoyl chloride (0.09 mL, 0.77 mmol) and triethylamine (0.27 mL, 1.9 mmol) at room temperature. The reaction mixture was extracted with dichloromethane, and purified by silica gel column chromatography (30% ethylacetate in hexane) to afford the title compound (250 mg, 97%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][OH:11].[F:12][C:13]([F:24])([F:23])[C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1.C1(C2C3C(=C(Cl)C=CC=3)CCN=2)C=CC=CC=1>>[F:12][C:13]([F:23])([F:24])[C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH:1][CH2:2][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:10][OH:11])=[O:19])=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: NCCc1ccccc1CO
Agent: Clc1cccc2c1CCN=C2c1ccccc1
Product: O=C(NCCc1ccccc1CO)c1ccc(C(F)(F)F)cc1

Procedure:
1-Amino-2-(2-hydroxymethylphenyl)ethane and 4-trifluoromethylbenzoyl chloride were successively reacted in the same way as in steps (b) and (c) of Example 12 to afford 1-(4-trifluoromethylbenzoyl)amino-2-(2-hydroxymethylphenyl)ethane having a melting point of 145.8° to 146.3° C. The product was successively reacted in the same way as in steps (d), (e), (f) and (g) of Example 12 to afford 1-(4-trifluoromethylphenyl)isoquinoline-5-acetonitrile having a melting point of 121.9° to 122.6° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][CH:8]([SH:10])[CH3:9].Cl[C:12]1[N:16]([CH3:17])[N:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[C:13]=1[CH:22]=[O:23]>CN(C=O)C>[CH:8]([S:10][C:12]1[N:16]([CH3:17])[N:15]=[C:14]([C:18]([F:20])([F:19])[F:21])[C:13]=1[CH:22]=[O:23])([CH3:9])[CH3:7]
Reactant: Cn1nc(C(F)(F)F)c(C=O)c1Cl
Reactant: CC(C)S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Sc1c(C=O)c(C(F)(F)F)nn1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 102.4 %

Procedure:
Potassium carbonate (1.68 g, 12 mmol) was suspended in DMF (50 ml) and isopropylthiol (1 ml, 11 mmol) added. The suspension was stirred at room temperature for 15 minutes before a solution of 5-chloro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carbaldehyde (2.12 g, 10 mmol) in DMF (5 ml) was added. The reaction was stirred at room temperature for 16 hours. The reaction was partitioned between aqueous ammonium chloride solution and diethyl ether and the two phases were separated. The organic phase was washed with water and brine, dried over sodium sulfate and concentrated to give the product (2.584 g, 100% yield) which was used without further purification. 1H NMR (400 MHz, CDCl3): 1.29 (3H, s, Me), 1.31 (3H, s, Me), 3.52 (1H, heptet, CH), 4.02 (3H, s, Me), 10.03 (1H, s, CH).
Reaction SMILES: [CH3:1][C@H:2]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1.[H][H].C(OC(C)C)(C)C>[C].[Pd].C(O)(=O)C>[CH3:1][C@H:2]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:3][O:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1
Reactant: C[C@@H](COc1ccncc1)NC(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(C)OC(C)C
Solvent: CC(=O)O
Product: C[C@@H](COC1CCNCC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 107.1 %

Procedure:
tert-Butyl [(1S)-1-methyl-2-(pyridin-4-yloxy)ethyl]carbamate (30 g), acetic acid (300 mL) and 10% palladium-carbon (7.5 g) were charged into pressure-resistant reactor vessel, and the mixture was stirred at 80° C. for 6 hr at 0.8 MPa hydrogen pressure. The mixture was allowed to cool to room temperature, and the pressure was reduced to normal level. The insoluble material was removed by filtration, and the filtrate was concentrated. Ethyl acetate (300 mL) was added to the residue, and the mixture was extracted with 10% aqueous citric acid solution (300 mL). The ethyl acetate layer was extracted again with 10% aqueous citric acid solution (150 mL). The aqueous layers were combined, adjusted to pH 12 with 8M aqueous sodium hydroxide solution, and extracted twice with toluene (300 mL). The toluene layers were combined and concentrated. Methanol (30 mL), ethyl acetate (120 mL) and succinic acid (12.1 g) were added to the residue and the mixture was stirred to give crystals. After stirring for 1 hr, diisopropyl ether (150 mL) was added, and the mixture was stirred for 1 hr. The resulting crystals were collected by filtration, washed with diisopropyl ether (150 mL) and dried to give the title compound (32.9 g) as white crystals.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])=[NH:7])=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].Br[CH2:25][C:26](=O)[C:27]([O:29][CH2:30][CH3:31])=[O:28]>CCO>[CH2:30]([O:29][C:27]([C:26]1[N:7]=[C:6]([C:5]2[CH:17]=[CH:18][C:2]([Br:1])=[CH:3][CH:4]=2)[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[CH:25]=1)=[O:28])[CH3:31]
Reactant: CCOC(=O)C(=O)CBr
Reactant: N=C(NCc1ccccc1Cl)c1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cn(Cc2ccccc2Cl)c(-c2ccc(Br)cc2)n1
Temperature: 175 °C
Yield: 13.3 %

Procedure:
A mixture of 4-bromo-N-(2-chlorobenzyl)-benzamidine (1.4 g, 4.3 mmol), sodium bicarbonate (0.72 g, 8.6 mmol) and ethyl bromopyruvate (0.98 mL, 7.8 mmol) in EtOH (14 mL) was heated in a microwave unit (Biotage Initiator™) at 175° C. for 12 min. The resulting mixture was decanted and the solids rinsed with EtOAc. The combined filtrates were concentrated and purified by chromatography (silica, EtOAc/Hex, 0:100 to 40:60) to give the title compound (0.24 g, 13%) as a pale brown residue. 1H-NMR (DCM-d2): δ 7.58-7.62 (m, 3H), 7.43-7.49 (m, 3H), 7.34 (m, 1H), 7.28 (m, 1H), 6.96 (d, 1H), 5.30 (s, 2H), 4.32 (q, 2H), 1.35 (t, 3H); MS (ES): 419, 421 [M+H].
Reaction SMILES: [C:1]([O:9]CC)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:13][NH2:14]>C(O)C>[C:1]([NH:13][NH2:14])(=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: CCOC(=O)c1ccccc1
Solvent: O
Solvent: CCO
Product: NNC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 100 ml 3-neck flask were added 40 ml of ethanol and 6 g of ethyl benzoate, to which 12.5 g of 85% hydrazine hydrate was added slowly and dropwise with stirring. After the addition was completed, the mixture was heated under reflux for 8 hours and then cooled to room temperature. The solvent was distilled under reduced pressure and water was added. The solid was precipitated. The mixture was allowed to stand for 30 min until the solid was fully precipitated, which was filtrated and washed with water. Recrystallization with anhydrous ethanol gave benzoyl hydrazine.
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH2:20][CH3:21])[C:7]([CH2:9][CH2:10][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)=O)=[N:8][C:4]=2[CH:3]=1.[CH3:24][N:25]([CH:27]([N:31]([CH3:33])C)N(C)C)C.[CH3:34][NH:35]N>>[Br:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH2:20][CH3:21])[C:7]([CH2:9][C:10]3[C:11]([C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=4)=[N:35][N:25]([CH3:27])[CH:24]=3)=[N:8][C:4]=2[CH:3]=1.[Br:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH2:20][CH3:21])[C:7]([CH2:9][C:10]3[CH:34]=[N:35][N:31]([CH3:33])[C:11]=3[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: CN(C)C(N(C)C)N(C)C
Reactant: CCn1c(CCC(=O)c2cccc(F)c2)nc2cc(Br)ccc21
Reactant: CNN
Product: CCn1c(Cc2cn(C)nc2-c2cccc(F)c2)nc2cc(Br)ccc21
Product: CCn1c(Cc2cnn(C)c2-c2cccc(F)c2)nc2cc(Br)ccc21
Temperature: 60 °C

Procedure:
A mixture of 3-(5-Bromo-1-ethyl-1H-benzoimidazol-2-yl)-1-(3-fluoro-phenyl)-propan-1-one (0.1 g, 0.27 mmol) and tris(dimethylamino)methane (0.077 g, 0.54 mmol) is heated at 60° C. in a sealed tube for 6 hours. The volatile material is removed in vacuo. EtOR (5 mL) and methyl hydrazine (1.1 mmol) are added to the residue. The mixture is heated at 120° C. for 2 hours. The solvent is removed. NaHCO3 (aq.) (10 mL) and DCM (30 mL) are added to the residue. The organic layer is separated and the aqueous layer is extracted with DCM (2×15 mL). The combined organic layers are dried and the solvent removed. The crude is purified by PTLC (ethyl acetate/Hexanes 1:1) to give 5-bromo-1-ethyl-2-[3-(3-fluoro-phenyl)-1-methyl-1H-pyrazol-4-ylmethyl]-1H-benzoimidazole and 5-bromo-1-ethyl-2-[5-(3-fluoro-phenyl)-1-methyl-1H-pyrazol-4-ylmethyl]-1H-benzoimidazole. 5-bromo-1-ethyl-2-[3-(3-fluoro-phenyl)-1-methyl-1H-pyrazol-4-ylmethyl]-1H-benzoimidazole: 1H NMR (CDCl3) δ 7.88 (s, 1H), 7.27-7.42 (m, 4H), 7.00-7.20 (m, 3H), 4.21 (s, 2H), 3.95 (t, 2H), 3.83 (s, 3H), 1.15 (t, 3H). 5-bromo-1-ethyl-2-[5-(3-fluoro-phenyl)-1-methyl-1H-pyrazol-4-ylmethyl]-1H-benzoimidazole: 1H NMR (CDCl3) δ 7.81 (s, 1H), 7.38-7.45 (m, 2H), 7.32 (dd, 1H), 7.00-7.18 (m, 4H), 4.00 (s, 2H), 3.90 (q, 2H), 3.78 (s, 3H), 1.15 (t, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[F:23][C:24]([F:34])([F:33])[C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][NH2:29]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([NH:29][CH2:28][C:27]2[CH:30]=[CH:31][CH:32]=[C:25]([C:24]([F:23])([F:33])[F:34])[CH:26]=2)=[O:21])=[CH:16][CH:15]=1
Reactant: NCc1cccc(C(F)(F)F)c1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NCc4cccc(C(F)(F)F)c4)cc3)c2)o1

Procedure:
2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(3-trifluoromethylbenzyl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and 3-trifluoromethylbenzylamine using method N. NMR; δH [2H6]—DMSO 9.24,(1H, t), 8.00,(2H, d), 7.90,(1H, dd), 7.77,(1H, d), 7.69-7.52,(7H, m), 4.59,(2H, d), 2.56,(3H, s), 2.31,(3H, s). LCMS; retention time 3.59 min, MH+ 452.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.[CH3:23][S:24]([NH2:27])(=[O:26])=[O:25].O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:27][S:24]([CH3:23])(=[O:26])=[O:25])=[O:7])=[CH:4][CH:3]=1
Reactant: CS(N)(=O)=O
Reactant: Cc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(C(=O)NS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 22.1 %

Procedure:
To a solution of 4-methylbenzoic acid (1.07 g, 7.82 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (3.00 g, 15.6 mmol) and N,N-dimethylpyridin-4-amine (2.01 g, 15.6 mmol) in DCM (50 mL) was added methanesulphonamide (1.53 g, 15.6 mmol) and the resulting mixture stirred for 18 hours at room temperature under nitrogen. The reaction mixture was poured into water (100 mL) and extracted with DCM (2×75 mL). The combined organics were dried over magnesium sulphate and evaporated in vacuo, azeotroping with toluene (2×20 mL) to yield a crude solid (2.14 g). The solid was dissolved in DCM (100 mL) and washed with aqueous hydrochloric acid solution (2 M, 2×50 mL). The organic layer was extracted with saturated solution of sodium carbonate (2×50 mL) and the aqueous washed with DCM (50 mL). The basic aqueous layer was acidified to pH 2 with 2 M aqueous hydrochloric acid and extracted with DCM (2×50 mL). The combined organic extracts were washed with water (20 mL), dried over magnesium sulphate and evaporated in vacuo to yield the first crop of the title compound as a white solid (368 mg). All aqueous layers from the extraction process were then evaporated in vacuo to yield a white solid which was triturated with DCM (50 mL). The organics were dried over magnesium sulphate and evaporated in vacuo to yield a white solid, which was redissolved in DCM (50 mL), washed with hydrochloric acid (2 M, 20 mL) dried over magnesium sulphate and evaporated in vacuo to yield a second crop of the title compound as a white crystalline solid (578 mg, combined yield of 56%).
Reaction SMILES: [C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][OH:17])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Cl:26][C:27]1[N:31]2[N:32]=[C:33](Cl)[CH:34]=[CH:35][C:30]2=[N:29][C:28]=1[C:37]([CH3:44])([CH3:43])[C:38]([O:40][CH2:41][CH3:42])=[O:39]>CN(C)C=O>[ClH:26].[ClH:26].[Cl:26][C:27]1[N:31]2[N:32]=[C:33]([O:17][CH2:16][CH2:15][CH2:14][N:11]3[CH2:10][CH2:9][N:8]([CH:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH2:13][CH2:12]3)[CH:34]=[CH:35][C:30]2=[N:29][C:28]=1[C:37]([CH3:43])([CH3:44])[C:38]([O:40][CH2:41][CH3:42])=[O:39]
Reactant: OCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: CCOC(=O)C(C)(C)c1nc2ccc(Cl)nn2c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)c1nc2ccc(OCCCN3CCN(C(c4ccccc4)c4ccccc4)CC3)nn2c1Cl
Product: Cl
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 60.9 %

Procedure:
1.0 g of 4-(diphenylmethyl)-1-piperazinepropanol was dissolved in 10 ml of N,N-dimethylformamide; 142 mg of a 60% dispersion of sodium hydride in mineral oil was added, followed by stirring at room temperature under reduced pressure for 40 minutes. To the reaction mixture, 973 mg of ethyl 2-(3,6-dichloroimidazo[1,2-b]pyridazin-2-yl)-2-methylpropionate was added, followed by stirring at 0° C. for 2 hours. Ice water was added, followed by extraction with ethyl acetate; the extract was washed with saturated saline and dried with magnesium sulfate. The dry product was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography and eluted with hexane:ethyl acetate:triethylamine (50:50:1). The desired fraction was collected and concentrated under reduced pressure; the crystal precipitated was dissolved in 5 ml of ethyl acetate; 1.01 ml of a 4 N hydrogen chloride solution in ethyl acetate acid was added, followed by concentration again. The residue was recrystallized from methanol, collected by filtration, washed with ethyl acetate and dried to yield 424 mg of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:27]=[CH:26][C:7]([CH2:8][O:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][C:16]([S:18][C@H:19]2[NH:22][C:21](=[O:23])[C@@H:20]2[O:24][CH3:25])=[O:17])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+:28]([C:31]1[CH:45]=[CH:44][C:34]([CH2:35][O:36][C:37](=[O:43])[CH:38](OCC)[OH:39])=[CH:33][CH:32]=1)([O-:30])=[O:29].C(Cl)Cl>C1(C)C=CC=CC=1.CN(C)C=O>[N+:28]([C:31]1[CH:32]=[CH:33][C:34]([CH2:35][O:36][C:37](=[O:43])[CH:38]([N:22]2[C@H:19]([S:18][C:16](=[O:17])[CH2:15][CH2:14][CH2:13][NH:12][C:10]([O:9][CH2:8][C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:27][CH:26]=3)=[O:11])[C@@H:20]([O:24][CH3:25])[C:21]2=[O:23])[OH:39])=[CH:44][CH:45]=1)([O-:30])=[O:29]
Reactant: CCOC(O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CO[C@H]1C(=O)N[C@@H]1SC(=O)CCCNC(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CO[C@H]1C(=O)N(C(O)C(=O)OCc2ccc([N+](=O)[O-])cc2)[C@@H]1SC(=O)CCCNC(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
Analogously to Example 23, 400 mg of (3S,4R)-4-(4-p-nitrobenzyloxycarbonylaminobutyrylthio)-3-methoxy-2-oxoazetidine in 15 ml of absolute toluene and 3.7 ml of absolute dimethylformamide are reacted with 565 mg of 2-ethoxy-2-hydroxyacetic acid p-nitrobenzyl ester in the presence of freshly dried molecular sieves. After working up and chromatography over silica gel, the title compound with the following IR spectrum (CH2Cl2) is obtained:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([CH2:11][CH3:12])[NH:10][C:5]2=[C:4]([CH3:13])[CH:3]=1.[N+:14]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1)([O-:16])=[O:15].N#N>CN(C=O)C.C(Cl)Cl>[CH3:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:21][C:20]3[CH:23]=[CH:24][C:17]([N+:14]([O-:16])=[O:15])=[CH:18][CH:19]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:5]2=[C:4]([CH3:13])[CH:3]=1
Reactant: CCc1nc2nc(C)cc(C)c2[nH]1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: N#N
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc([N+](=O)[O-])cc1
Reaction time: 0.08 h
Yield: 76.7 %

Procedure:
To a solution of 5.0 g (1.0 eq, 28.6 mmol) 5,7-dimethyl-2-ethylimidazo[4,5-b]pyridine in 30 mL DMF under N2 at rt was added 1.37 g (1.2 eq, 34.3 mmol) of a 60% oil dispersion of NaB. After stirring for 5 minutes, 8.64 g (1.4 eq, 40.0 mmol) of p-nitrobenzyl bromide was added. The dark brown mixture was stirred for 2 hours under a blanket of N2 at rt. The mixture was diluted with 1 L CH2Cl2 and washed with 500 mL H2O and 500 mL saturated aqueous NaCl. The organic phase was dried over MgSO4 and concentrated to a yellow oil. The oil was flash chromatographed with 50% ethyl acetate/hexane. The product containing fractions were combined and concentrated to a yellow oil which crystallized on standing, yielding 6.81 g (76.8%) of the title compound.
Reaction SMILES: [F:1][C:2]1C(F)=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:9]1([NH:37][C:38]([NH:40][C:41](=[O:48])[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[S:39])[C@H:13]([CH2:14]O)[C@@H:12]([CH2:16][O:17][C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:11][CH2:10]1.N1C=CC=CC=1.F[C:56]([F:69])(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>C(Cl)Cl>[F:1][C:2]1[C:56]([F:69])=[CH:6][CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:10][O:11][C@H:12]([CH2:16][O:17][C:18]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:13]1[CH2:14][S:39][C:38]([NH:40][C:41](=[O:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[N:37]2
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=C(NC(=S)N[C@@]1(c2cccc(F)c2F)CO[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@H]1CO)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(NC1=N[C@@]2(c3cccc(F)c3F)CO[C@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)[C@H]2CS1)c1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
N-(((3S,4R,5S)-3-(2,3-difluorophenyl)-4-(hydroxymethyl)-5-((trityloxy)methyl)tetrahydrofuran-3-yl)carbamothioyl)benzamide, obtained in Preparation Example 1-(4), (19.06 g) was dissolved in DCM (75 mL). Pyridine (8.6 mL) was added, and the mixture cooled to 0° C. Trifluoromethanesulfonic anhydride (9.6 mL) was added dropwise and the reaction was allowed to stir at 0° C. After 90 min, the reaction was quenched by the careful addition of NaHCO3 (sat., aq., 250 mL) and extracted with EtOAc (3×250 mL). The combined organic extracts were dried over MgSO4, concentrated in vacuo and purified by silica gel column chromatography (0% to 30% EtOAc/hex) to obtain the title compound (14.52 g). 1H NMR (400 MHz, CDCl3) δ ppm 2.63-2.76 (m, 1H), 3.07-3.24 (m, 2H), 3.32-3.52 (m, 3H), 3.99-4.11 (m, 1H), 4.53-4.63 (m, 2H), 7.09-7.56 (m, 21H), 8.08-8.30 (m, 2H)
Reaction SMILES: [F:1][C:2]([F:17])([S:13](F)(=[O:15])=[O:14])[C:3]([F:12])([F:11])[C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6].[OH:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]=1[C:29]([O:31][CH3:32])=[O:30].C(N(CC)CC)C.C1(C)C=CC=CC=1>O1CCCC1>[F:1][C:2]([F:17])([S:13]([O:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]=1[C:29]([O:31][CH3:32])=[O:30])(=[O:15])=[O:14])[C:3]([F:12])([F:11])[C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: COC(=O)c1c(O)ccc2ccccc12
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1c(OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)ccc2ccccc12
Temperature: 0 °C
Reaction time: 64 h

Procedure:
Perfluoro-1-butanesulfonyl fluoride (19 mL, 106 mmol, 1 eq) was added to a solution of methyl 2-hydroxy-1-naphthoate (21.25 g, 105 mmol, 1 eq) and triethylamine (15 mL, 108 mmol, 1 eq) in tetrahydrofuran (150 mL) maintained at an internal temperature about 0° C., under nitrogen. Once the addition was complete, the mixture was allowed to warm to ambient temperature and stirred for 64 hours. Toluene (150 mL) was added causing some precipitation. The solids were removed by filtration through Celiteä and washed with toluene (20 mL). The organic solutions were combined and washed with 2 N HCl (aq) (2×50 mL), water (100 mL), saturated aqueous sodium carbonate solution (100 mL) and brine (100 mL). The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure. Yield 48.79 g, 95%
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[NH2:11][C:12]1[C:21](C2C=CC=CC=2OC)=[CH:20][C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1.[CH3:30][OH:31]>O>[CH3:30][O:31][C:2]1[CH:3]=[CH:4][CH:8]=[CH:9][C:10]=1[C:16]1[N:15]=[C:14]2[C:19]([CH:20]=[CH:21][C:12]([NH:11][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=3)=[N:13]2)=[CH:18][CH:17]=1
Reactant: CO
Reactant: COc1ccccc1-c1cc2cccnc2nc1N
Reactant: O=C(O)c1cccc(Br)c1
Solvent: O
Product: COc1ccccc1-c1ccc2ccc(NC(=O)c3cccc(Br)c3)nc2n1
Temperature: 4 °C

Procedure:
The procedure is analogous to that described in Example 11, but starting with 3-bromobenzoic acid (1.6 g), N,N'-carbonyldiimidazole (1.3 g) and 2-amino(2-methoxyphenyl)-1,8-naphthyridine (1.3 g). The product obtained by precipitation in water (1.5 g) is dissolved in boiling methanol (75 cc). After cooling for 2 hours at 4° C., the crystallized solid is separated by filtration, washed with methanol (3×3 cc) and dried at 35° C. under reduced pressure (0.07 kPa). N-[7-(2-Methoxyphenyl)-1,8-naphthyridin-2-yl]-3-bromobenzamide (0.6 g), m.p. 110° C., is obtained.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([CH2:18][CH2:19][CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)[S:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])(=O)=O.CN(C)C=O.[N-:32]=[N+:33]=[N-:34].[Na+]>O>[N:32]([CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([CH2:18][CH2:19][CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)[S:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N+:33]=[N-:34]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)CSC(CCCCOS(C)(=O)=O)CCCc1cccnc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CSC(CCCCN=[N+]=[N-])CCCc1cccnc1
Temperature: 60 °C

Procedure:
A mixture of 0.12 g (0.3 mmol) ethyl 8-methanesulfonyloxy-4-[3-(3-pyridyl)propyl]-3-thia-octanoate, 1.5 mL dimethylformamide and 0.062 g (0.95 mmol) sodium azide is heated at 60° C. for 18 hours. The mixture is then poured into water and extracted with ether. The organic phase is washed with water, saturated brine, dried, filtered and evaporated to give ethyl 8-azido-4-[3-(3-pyridyl)propyl]-3-thia-octanoate; IR (CH2Cl2) 2099, 1732 cm-1.
Reaction SMILES: OS(O)(=O)=O.[C:6]([OH:15])(=[O:14])[C:7]1[C:8](=[CH:10][CH:11]=[CH:12][CH:13]=1)[OH:9].[CH3:16][CH2:17]O>C(Cl)Cl>[OH:9][C:8]1[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=1[C:6]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: O=C(O)c1ccccc1O
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CCOC(=O)c1ccccc1O
Yield: 70 %

Procedure:
H2SO4 (1.5 mL, 28.14 mmol) was added to a solution of salicylic acid (1.50 g, 10.860 mmol) in EtOH (50 mL). The reaction mixture was refluxed for 2 days, allowed to reach r.t., and it was diluted with CH2Cl2 (200 mL). The organic layer was washed with Na2CO3 (1 M aqueous solution, 200 mL). It was dried over Na2SO4 (anhydrous), filtered and concentrated to furnish 1.26 g of ethyl 2-hydroxybenzoate (yellow-coloured oil, yield: 70%).