Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)C.[Cl-].[NH4+].[CH3:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[N:14]1[CH2:19][CH2:18][N:17]([C:20]([C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][C:23]=2[CH3:31])=[O:21])[CH2:16][CH2:15]1>[Fe].O>[NH2:28][C:25]1[CH:26]=[CH:27][C:22]([C:20]([N:17]2[CH2:16][CH2:15][N:14]([C:8]3[CH:9]=[CH:10][C:11]([CH3:13])=[CH:12][C:7]=3[CH3:6])[CH2:19][CH2:18]2)=[O:21])=[C:23]([CH3:31])[CH:24]=1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc([N+](=O)[O-])cc3C)CC2)c(C)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N)cc3C)CC2)c(C)c1
Yield: 118.1 %

Procedure:
2-Methyl-4-nitrobenzoic acid (500 mg), 1-(2,4-dimethylphenyl)piperazine (523 mg) and 1-hydroxybenzotriazole 1 hydrate (373 mg) were dissolved in N,N-dimethylformamide (13 mL), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (531 mg) was added, and the mixture was stirred at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (chloroform:methanol) to give [4-(2,4-dimethylphenyl)piperazin-1-yl](2-methyl-4-nitrophenyl)methanone (771 mg). Then, to a mixed solution of ethanol (11 mL) and water (3 mL) were added ammonium chloride (660 mg) and iron (480 mg), and the obtained [4-(2,4-dimethylphenyl)piperazin-1-yl](2-methyl-4-nitrophenyl)methanone (771 mg) was added while stirring at 60° C.-70° C. After completion of the reaction, the insoluble material was collected by filtration, and the filtrate was concentrated. To the obtained residue was added aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The solvent was evaporated from the organic layer to give the title compound (833 mg).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:37]([O:38][C:39](=[O:41])[CH3:40])[C@H:36]([O:42][C:43](=[O:45])[CH3:44])[C@@H:35]([CH2:46][O:47][C:48](=[O:50])[CH3:49])[O:34][C@H:6]1[O:7][C:8]1[CH:13]=[C:12]([NH:14]C(OCC2C=CC=CC=2)=O)[CH:11]=[CH:10][C:9]=1[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH3:33])=[CH:28][CH:27]=1)(=[O:3])[CH3:2]>O1CCCC1.[C].[Pd]>[C:1]([O:4][C@@H:5]1[C@@H:37]([O:38][C:39](=[O:41])[CH3:40])[C@H:36]([O:42][C:43](=[O:45])[CH3:44])[C@@H:35]([CH2:46][O:47][C:48](=[O:50])[CH3:49])[O:34][C@H:6]1[O:7][C:8]1[CH:13]=[C:12]([NH2:14])[CH:11]=[CH:10][C:9]=1[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH3:33])=[CH:28][CH:27]=1)(=[O:3])[CH3:2]
Reactant: CCc1ccc(Cc2ccc(NC(=O)OCc3ccccc3)cc2O[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCc1ccc(Cc2ccc(N)cc2O[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
To a solution of 5-benzyloxycarbonylamino-2-(4-ethylbenzyl)phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (0.35 g) in tetrahydrofuran (4 mL) was added 10% palladium-carbon powder (0.07 g), and the mixture was stirred under a hydrogen atmosphere at room temperature for 8 hours. Insoluble materials were removed by filtration, and the solvent of the filtrate was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=2/3-dichloromethane/ethyl acetate=1/1) to give 5-amino-2-(4-ethylbenzyl)phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (0.19 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([Cl:11])[C:3]=1[OH:12].N12CCN(CC1)CC2.[CH3:21][N:22]([CH3:26])[C:23](Cl)=[S:24]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([Cl:11])[C:3]=1[O:12][C:23](=[S:24])[N:22]([CH3:26])[CH3:21]
Reactant: O=[N+]([O-])c1cc(Cl)c(O)c(Cl)c1
Reactant: CN(C)C(=S)Cl
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)C(=S)Oc1c(Cl)cc([N+](=O)[O-])cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.3 %

Procedure:
A solution of 2,6-dichloro-4-nitro-phenol (3.0 g, 14.4 mmol) in N,N-dimethylformamide (70 mL) at 25° C. was treated with 1,4-diazabicyclo[2.2.2]octane (3.16 mL, 28.8 mmol) and dimethylthiocarbamoyl chloride (2.85 g, 23.04 mmol). The reaction was stirred at 25° C. for 18 h. At this time, the reaction was diluted with ethyl acetate (250 mL) and was then washed with a 1N aqueous hydrochloric acid solution (1×125 mL), water (1×125 mL), and a saturated aqueous sodium chloride solution (1×125 mL), dried with magnesium sulfate, filtered and concentrated under vacuum. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 80:20 petroleum ether/ethyl acetate) afforded dimethyl-thiocarbamic acid O-(2,6-dichloro-4-nitro-phenyl)ester (79) (3.2 g, 75%) as a white solid; EL-LRMS for C9H8Cl2N2O3S (M−Cl)+ at m/z=259. Exact Mass=293.9633; Molecular weight=295.15
Reaction SMILES: C(=O)(O)[O-].[Na+].[CH3:6][C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([CH3:16])[CH:15]=1)[C:10](Cl)=[O:11].FC(F)(F)C(O)=O.[CH2:24]([C@@H:31]1[CH2:36][CH:35]([NH:37][C:38](=[O:43])[C:39]([F:42])([F:41])[F:40])[CH2:34][CH2:33][NH:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1(C)C=CC=CC=1.O>[CH2:24]([C@@H:31]1[CH2:36][CH:35]([NH:37][C:38](=[O:43])[C:39]([F:42])([F:40])[F:41])[CH2:34][CH2:33][N:32]1[C:10](=[O:11])[C:9]1[CH:8]=[C:7]([CH3:6])[CH:15]=[C:14]([CH3:16])[CH:13]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(NC1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Reactant: Cc1cc(C)cc(C(=O)Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: Cc1cc(C)cc(C(=O)N2CCC(NC(=O)C(F)(F)F)C[C@H]2Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
710 mg of solid sodium bicarbonate and 712 mg of 3,5-dimethylbenzoyl chloride are added to a stirred mixture of 1.39 g (3.44 mmol) of (2R,4RS)-N-(2-benzyl-4-piperidyl)trifluoroacetamide trifluoroacetate and 10 ml of toluene/water (1:1) cooled in ice-water. The reaction mixture is then allowed to warm to room temperature, subsequently stirred for 2 hours and partitioned between toluene and 1N sodium bicarbonate solution. The organic phases are washed with water, dried over magnesium sulfate and evaporated to dryness. The colourless oil is chromatographed on silica gel with ethyl acetate/hexane 1:2, resulting in the title compound. This is used further without further purification.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[NH2:5][C:6]1[N:14]=[C:13]2[C:9]([NH:10][CH:11]=[N:12]2)=[C:8](Cl)[N:7]=1>O.CS(C)=O>[NH2:5][C:6]1[N:14]=[C:13]2[C:9]([NH:10][CH:11]=[N:12]2)=[C:8]([N:1]=[N+:2]=[N-:3])[N:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: [N-]=[N+]=Nc1nc(N)nc2nc[nH]c12
Yield: 89.3 %

Procedure:
A solution of sodium azide (14.08 g, 0.216 mol) in water (35 mL) was added to a solution of 2-amino-6-chloropurine (28.27 g, 0.166 mol) in dimethyl sulfoxide (DMSO, 280 mL). The mixture was heated at 100°-110° C. for 24 h, then the resulting suspension was cooled and poured into 1.3 L of water. The precipitate was collected by filtration, washed with water and dried to afford 26.11 g of 2-amino-6-azidopurine, mp>260° C.; IR (KBr) 3313, 3146, 1678, 1641, 1551 cm-1 ; 1H NMR (DMSO-d6, 360 MHz) δ8.18 (s, 1H), 8.25 (bs, 2H), 13 (vbs, 1H); 13C NMR (DMSO-d6, 90 MHz), 110.8, 138.7, 143.4, 145.7 , 146.1 ppm.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8]([I:11])=[N:9][NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[H-].[Na+].[C:14](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CN(C=O)C>[Cl:1][C:2]1[C:7]2[C:8]([I:11])=[N:9][N:10]([C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Clc1nccc2[nH]nc(I)c12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1nccc2c1c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
To a solution of 4-chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine (1.0 g) obtained in Step C of Example 305 in DMF (10 mL) was added sodium hydride (60%, 130 mg) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added trityl chloride (1.1 g) at room temperature, and the mixture was stirred for 15 hr. To the reaction mixture was added water, and the resulting solid was collected by filtration, and dried to give the title compound (1.7 g).
Reaction SMILES: C([CH:3]([CH2:21][CH2:22][CH2:23]C)[CH2:4]/[C:5](/C([O-])=O)=[C:6](\[CH2:10][CH:11]([CH2:16][CH3:17])[CH2:12][CH2:13][CH2:14][CH3:15])/[C:7]([O-:9])=[O:8])C.S(OS([O-])=O)([O-])=O.[Na+:32].[Na+].S([O-])([O-])=O.[S:38]([CH:42](CC([O-])=O)[C:43]([O-:45])=[O:44])([OH:41])(=[O:40])=[O:39].[CH2:50](O)[CH3:51]>O>[CH2:50]([CH:4]([CH2:3][CH2:21][CH2:22][CH3:23])[CH2:5][C:6]([CH2:10][CH:11]([CH2:16][CH3:17])[CH2:12][CH2:13][CH2:14][CH3:15])([C:7]([O-:9])=[O:8])[CH:42]([S:38]([OH:41])(=[O:40])=[O:39])[C:43]([O-:45])=[O:44])[CH3:51].[Na+:32].[Na+:32]
Reactant: CCO
Reactant: O=C([O-])CC(C(=O)[O-])S(=O)(=O)O
Reactant: CCCCC(CC)C/C(C(=O)[O-])=C(\CC(CC)CCCC)C(=O)[O-]
Agent: O=S([O-])OS(=O)[O-]
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCCCC(CC)CC(CC(CC)CCCC)(C(=O)[O-])C(C(=O)[O-])S(=O)(=O)O
Temperature: 104 °C
Reaction time: 0.17 h

Procedure:
556 g (1.63 mol) di-(2-ethylhexyl)-maleate, 40 g Hydropalat 875, 160 g (0.84 mol) sodium disulfite and 194 g deionized water were introduced into a 1-liter four-necked flask equipped with a mechanical stirrer, heating system, reflux condenser and nitrogen inlet and were heated under reflux at 104° C. in a gentle stream of nitrogen until a clear solution was obtained (ca. 3 hours). After stirring for 10 minutes, no more sulfite could be detected in the product. On cooling, the product gelled/solidified which could be avoided by addition of a co-solvent: to this end, 50 g ethanol was added at ca. 80° C. The solution thus obtained contained 75% by weight sulfosuccinate and had the following characteristic data: Epton: 16.39%; dry residue: 74.29%.
Reaction SMILES: ClCCl.[OH:4][C@H:5]1[CH2:9][CH2:8][NH:7][CH2:6]1.C(N(CC)CC)C.[C:17]([N:21]=[C:22]=[O:23])([CH3:20])([CH3:19])[CH3:18]>C(OCC)C>[C:17]([NH:21][C:22]([N:7]1[CH2:8][CH2:9][C@H:5]([OH:4])[CH2:6]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)N=C=O
Reactant: O[C@H]1CCNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)NC(=O)N1CC[C@H](O)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a dichloromethane (200 mL) and diethyl ether (200 mL) solution of (S)-3-hydroxypyrrolidine (19.8 mL, 244 mmol) and triethylamine (45.0 mL, 323 mmol) at 0° C. was added tert-butyl isocyanate (28.0 mL, 245 mmol). The reaction mixture was stirred for 1 hour at 0° C., filtered, and concentrated in vacuo to afford the title compound as a white solid. This crude product was used in the subsequent step without further purification. 1H NMR (500 MHz, CDCl3) δ 4.50-4.45 (m, 1H), 3.50-3.34 (m, 4H), 2.08-1.93 (m, 2H), 1.35 (s, 9H); LC-MS: m/z 187.3 (M+H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([C@H:17]([NH2:19])[CH3:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.[Cl:20][CH2:21][CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=1.Cl>C(#N)C.C1(C)C=CC=CC=1.O>[ClH:20].[C:7]1([C@H:17]([NH:19][CH2:21][CH:22]=[CH:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[CH:25]=2)[CH3:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: FC(F)(F)c1cccc(C=CCCl)c1
Reactant: C[C@@H](N)c1cccc2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@@H](NCC=Cc1cccc(C(F)(F)F)c1)c1cccc2ccccc12
Reaction time: 0.29 h

Procedure:
Anhydrous potassium carbonate (64.0 g) and (R)-1-(1-naphthyl)ethylamine (39.0 g) was added to a solution of 1-[3-chloroprop-1-en-1-yl]-3-(trifluoromethyl)benzene (Example 6; 50 g) in acetonitrile (500 mL) at room temperature. The reaction mixture was refluxed for 12 hours at 80° C. to 85° C. After completion of the reaction, the mixture was quenched with de-ionized water (250 mL). The organic layer was separated and completely distilled off to remove acetonitrile to obtain oil. The oil obtained was dissolved in toluene (500 mL) and added to de-ionized water (250 mL). The pH of this mixture was adjusted to 0.1-0.5 by adding solution of hydrochloric acid (6 N; 100 mL). The mixture was stirred at 50° C. to 60° C. for 15-20 minutes, followed by the layer separation. The organic layer was acidified with hydrochloric acid (6N; 50 mL) and stirred at 50° C. to 60° C. for 15-20 minutes. The organic layer was completely distilled off to obtain N-[(1R)-1-(naphthalen-1-yl)ethyl]-3-[3-(trifluoromethyl)phenyl]prop-2-en-1-amine hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[C:4]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.[C:18](N1C=CN=C1)(N1C=CN=C1)=[O:19].O>CN(C)C=O>[CH:15]1[CH:14]=[CH:13][C:12]([CH2:11][O:10][C:4]2[C:5]3[NH:9][C:18]([NH:8][C:6]=3[N:7]=[C:2]([NH2:1])[N:3]=2)=[O:19])=[CH:17][CH:16]=1
Reactant: Nc1nc(N)c(N)c(OCc2ccccc2)n1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc(OCc2ccccc2)c2[nH]c(=O)[nH]c2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,4,5-Triamino-6-benzyloxypyrimidine (Pfleiderer et al., Chem. Ber., 94, 12-18 (1961)) (1.85 g, 8 mmol) and 1,1′-carbonyldiimidazole (1.30 g, 8 mmol) were dissolved in anhydrous N,N-dimethylformamide (5 mL) under argon. The solution was stirred at room temperature overnight and was mixed with water (200 mL) to precipitate a white solid. The solid was collected by filtration, and dissolved in 250 mL of aqueous 2 N NaOH solution. Undissolved material was removed by filtration, and the filtrate was neutralized with glacial acetic acid to precipitate a white solid. The solid was collected by filtration, was washed with water, and was recrystallized from 50% aqueous ethanol to afford analytically pure 1c: yield, 1.63 g (79%); mp 256-257° C. dec.; UV (pH 1) 1max 243 nm (e=0.717×104), 306 (1.499×104); (pH 6.9) 243 (0.915×104), 290 (1.108×104); (pH 13) 249 (sh) (0.443×104), 293 (1.368×104); 1H NMR d 5.41 (s, 2 H, ArCH2), 6.13 (s, 2 H, NH2, exchange with D2O), 7.33-7.51 (m, 5 H, ArH), 10.46 (s, 1 H, exchanges with D2O), 11.04 (s, 1 H, exchanges with D2O); MS (EI) Calcd. m/z for C12H11N5O2: 257.0912. Found: 257.0914. Anal. (C12H11N5O2. 1/2 H2O) C, N, H.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11](Cl)=[O:12])[C:6]=1[CH3:14])(=[O:3])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CC(C)=O>Cl[Pd]Cl.O>[C:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11](=[O:12])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:6]=1[CH3:14])(=[O:3])[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CC(=O)Oc1cccc(C(=O)Cl)c1C
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)Oc1cccc(C(=O)c2ccccc2)c1C
Yield: 64.3 %

Procedure:
A mixture of 3-(chlorocarbonyl)-2-methylphenyl acetate (10.0 g, 47.0 mmole), PdCl2 (83.4 mg, 0.470 mmole), Na2CO3 (8.13 g, 76.7 mmole) and phenyl boronic acid (6.02 g, 49.4 mmole) in a 3:1 acetone:H2O mixture (300 mL) was stirred at room temperature for 5 days. The acetone was removed in vacuo and the aqueous mixture was extracted with EtOAc (2×200 mL). The combined extracts were washed with brine (100 mL), dried over MgSO4, filtered and concentrated in vacuo to give 7.68 g (64% yield) of the product as a white crystalline solid: E1HRMS m/z 254.0939 (M+, C16H14O3, Calc'd 254.0943).
Reaction SMILES: [CH2:1]([C:3]1[N:8]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[C:7](=[O:16])[C:6]([C:17]#N)=[CH:5][CH:4]=1)[CH3:2].[OH2:19].[OH-:20].[Na+]>S(=O)(=O)(O)O>[CH2:1]([C:3]1[N:8]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[C:7](=[O:16])[C:6]([C:17]([OH:20])=[O:19])=[CH:5][CH:4]=1)[CH3:2]
Reactant: [OH-]
Reactant: O
Reactant: CCc1ccc(C#N)c(=O)n1-c1ccc(F)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCc1ccc(C(=O)O)c(=O)n1-c1ccc(F)cc1
Temperature: 25 °C
Yield: 78 %

Procedure:
A solution of 6-ethyl-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile (410 mg, 1.69 mmol) in conc. sulfuric acid (2 mL)/water (2 mL) was stirred at 120° C. for 17 hr. The reaction solution was allowed to cool to room temperature, 6N aqueous sodium hydroxide solution was added, and the aqueous layer was washed with ethyl acetate. 1N Hydrochloric acid was added to the aqueous layer, and the precipitate was collected by filtration and washed with water to give the title compound (345 mg, 78%) as a white solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:9]([C:10]2[CH:15]=[C:14]([S:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:13]([CH3:22])=[CH:12][C:11]=2[F:23])[N:8]=[C:7]([OH:24])[CH:6]=1)(=[O:3])[CH3:2].N1C=CC=CC=1.FC(F)(F)S([O-])(=O)=O.[F:39][C:40]([I+]C1C=CC=CC=1)([F:54])[C:41]([F:53])([F:52])[C:42]([F:51])([F:50])[C:43]([F:49])([F:48])[C:44]([F:47])([F:46])[F:45]>ClCCl>[C:1]([NH:4][C:5]1[N:9]([C:10]2[CH:15]=[C:14]([S:16][CH2:17][C:18]([F:19])([F:20])[F:21])[C:13]([CH3:22])=[CH:12][C:11]=2[F:23])[N:8]=[C:7]([O:24][C:40]([F:54])([F:39])[C:41]([F:52])([F:53])[C:42]([F:50])([F:51])[C:43]([F:48])([F:49])[C:44]([F:47])([F:46])[F:45])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)[I+]c1ccccc1
Reactant: CC(=O)Nc1cc(O)nn1-c1cc(SCC(F)(F)F)c(C)cc1F
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1cc(OC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)nn1-c1cc(SCC(F)(F)F)c(C)cc1F

Procedure:
2.0 g of 5-acetylamino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-hydroxypyrazole was dissolved in 30 mL of dichloromethane, 2.18 g of pyridine was added, and the above prepared crude (perfluoropentyl)phenyliodonium trifluoromethanesulfonate was added at room temperature until 5-acetylamino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-hydroxypyrazole disappeared (disappearance was confirmed by thin layer chromatography). Then, the solvent was distilled off under reduced pressure, a saturated salt solution was added, extraction with ethyl acetate was carried out, the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:3) to obtain 0.64 g of 5-acetylamino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-(1,1,2,2,3,3,4,4,5,5,5-undecafluoropentyloxy)pyrazole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]([OH:18])=O)[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.[NH2:21][CH2:22][C:23]1[NH:32][C:31](=[O:33])[C:30]2[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=2[N:24]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([CH:9]2[CH2:10][CH2:11][N:12]([CH2:15][C:16]([NH:21][CH2:22][C:23]3[NH:32][C:31](=[O:33])[C:30]4[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=4[N:24]=3)=[O:18])[CH2:13][CH2:14]2)=[O:8])=[CH:19][CH:20]=1
Reactant: NCc1nc2c(c(=O)[nH]1)CCCC2
Reactant: COc1ccc(C(=O)C2CCN(CC(=O)O)CC2)cc1
Product: COc1ccc(C(=O)C2CCN(CC(=O)NCc3nc4c(c(=O)[nH]3)CCCC4)CC2)cc1
Yield: 34 %

Procedure:
The title compound (100 mg) was prepared following the general procedure of Example 1 from 2-(4-(4-methoxybenzoyl)piperidin-1-yl)acetic acid (265 mg, 0.67 mmol, 70% purity) and 2-(aminomethyl)-5,6,7,8-tetrahydroquinazolin-4(3H)-one (120 mg, 0.67 mmol). 1H NMR (400 MHz, CDC3) δ 10.91 (br. s., 1H), 7.91 (br. s., 1H), 7.82-7.89 (m, 2H), 6.85-6.91 (m, J=8.6 Hz, 2H), 4.29 (d, J=6.1 Hz, 2H), 3.81 (s, 3H), 3.17 (d, J=6.6 Hz, 1H), 3.07 (br. s., 2H), 2.90 (br. s., 2H), 2.52 (t, J=6.1 Hz, 2H), 2.42 (t, J=6.1 Hz, 4H), 1.80 (br. s., 4H), 1.48-1.77 (m, 4H). HRMS calculated for C24H30N4O4 439.2345. found (ESI, [M+H]+), 439.2352. Retention time=2.84 min.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[C:17]([O-:20])([O-:19])=O.[K+].[K+].Br[CH2:24][CH2:25][CH:26]1[O:31][CH2:30][CH2:29][CH2:28][O:27]1>C(#N)C>[C:26]([OH:31])(=[O:27])/[CH:25]=[CH:24]/[C:17]([OH:20])=[O:19].[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][CH2:25][CH:26]4[O:31][CH2:30][CH2:29][CH2:28][O:27]4)[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: O=C([O-])[O-]
Reactant: BrCCC1OCCCO1
Agent: [K+]
Solvent: CC#N
Product: Fc1ccc2c(C3CCN(CCC4OCCCO4)CC3)noc2c1
Product: O=C(O)/C=C/C(=O)O

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.0 g, 9.1 mmol), K2CO3 (1.5 g, 10.9 mmol) and bromoethyl-1,3-dioxane (2.1 g, 10.7 mmol) in acetonitrile (50 ml) was heated at reflux for 3 hours. At the end, the insolubles were filtered and rinsed with DCM and the filtrate was evaporated down. The crude mixture was purified by flash chromatography over a silica gel column (Sorbsil C-30, 25 g; eluted with DCM and MEOH (1-3%) in DCM). The fractions containing the pure product with DCM and MEOH (1-3%) in DCM). The fractions containing the pure product fumaric acid (1.0 g) ethanol solution. The crystals were collected: 3.98 g (77%), m.p.=161-162° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[O:24][C:23]([NH:25][CH2:26][C@@H:27]3[C@H:32]([CH3:33])[CH2:31][CH2:30][CH2:29][NH:28]3)=[N:22][C:21]=2[CH:34]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[O:24][C:23]([NH:25][CH2:26][C@@H:27]3[C@H:32]([CH3:33])[CH2:31][CH2:30][CH2:29][N:28]3[C:7]([C:6]3[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=3[C:11]3[S:12][CH:13]=[CH:14][N:15]=3)=[O:9])=[N:22][C:21]=2[CH:34]=1
Reactant: Cc1ccc(-c2nccs2)c(C(=O)O)c1
Reactant: C[C@@H]1CCCN[C@@H]1CNc1nc2cc(Cl)ccc2o1
Product: Cc1ccc(-c2nccs2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2nc3cc(Cl)ccc3o2)c1

Procedure:
The title compound was prepared following the same general protocol as described in Example A1, using 5-methyl-2-(thiazol-2-yl)benzoic acid and 5-chloro-N-(((2S,3R)-3-methylpiperidin-2-yl)methyl)benzo[d]oxazol-2-amine. ESI-MS (m/z): 481 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([N:6]([CH3:8])[CH3:7])=[C:4]([F:11])[CH:3]=1.C(B(CC)[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)C>>[F:11][C:4]1[CH:3]=[C:2]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[CH:10]=[CH:9][C:5]=1[N:6]([CH3:8])[CH3:7]
Reactant: CCB(CC)c1ccncc1
Reactant: CN(C)c1ccc(Br)cc1F
Product: CN(C)c1ccc(-c2ccncc2)cc1F
Yield: 44 %

Procedure:
4-Bromo-2-fluoroaniline was methylated by treating it with dimethylsulphate to give a 26% yield of 4-Bromo-2-fluoro-N,N-dimethylaniline (XI) as a red oil. The resultant 4-Bromo-2-fluoro-N,N-dimethylaniline was coupled to diethyl (4-pyridyl)borane (I) using a tetrakis triphenyl phosphine palladium (0) catalyst to give 2-Fluoro-N,N-dimethyl-4-(pyridin-4-yl)aniline (XII) in a 44% yield. This was methylated by refluxing it in acetonitrile in the presence of methyl iodide and the product 4-(4-(dimethylamino)-3-fluorophenyl)-1-methylpyridinium iodide (XIII) IDT330 was obtained in a 21% yield.
Reaction SMILES: [CH3:1][C:2]1[C:3]([OH:10])=[CH:4][C:5](=O)[O:6][C:7]=1[CH3:8].[NH3:11]>O1CCOCC1>[OH:6][C:5]1[CH:4]=[C:3]([OH:10])[C:2]([CH3:1])=[C:7]([CH3:8])[N:11]=1
Reactant: N
Reactant: Cc1oc(=O)cc(O)c1C
Solvent: C1COCCO1
Product: Cc1nc(O)cc(O)c1C

Procedure:
5,6-Dimethyl-4-hydroxy-2-oxo-2H-pyran (11.92 g) (see J.C.P.Perkin Trans. 1, 1980, 2272) was dissolved in 1,4-dioxane (80 ml), aqueous 35% ammonia solution (40 ml) was added and the mixture was heated under reflux for 90 minutes. The solution was left to cool overnight, the precipitate filtered off and dried under reduced pressure at 90° C. for 24 hours to yield 2,4-dihydroxy-5,6-dimethylpyridine (3.47 g) as a white solid.