Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[O:2].[CH2:3]([N:5]([CH2:16][CH3:17])[C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([F:14])[CH:8]=1)[CH3:4].CN(CCN(C)C)C.[Li]C(CC)C>C1COCC1>[CH2:16]([N:5]([CH2:3][CH3:4])[C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([F:14])[C:8]=1[CH2:1][OH:2])[CH3:17]
Reactant: C=O
Reactant: CCN(CC)C(=O)c1ccc(F)c(F)c1
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1ccc(F)c(F)c1CO
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A flask is charged with 3,4-difluorobenzoic acid (2.40 g, 14.88 mmol) and dichloromethane (50 mL) is added. Upon complete dissolution, the mixture is cooled to 0° C. and DMF (0.022 g, 0.298 mmol) and oxalyl chloride (3.85 g, 29.75 mmol) are added. The cooling bath is removed. After 2 h, the mixture is concentrated, taken up in dichloromethane (50 mL) and diethylamine (5.50 g, 74.38 mmol) is added. After 30 min, dichloromethane (500 mL) is added and the mixture is washed with 1M aqueous HCl, saturated aqueous sodium bicarbonate and brine. The organic phase is dried over magnesium sulfate and concentrated in vacuo to afford N,N-diethyl-3,4-difluorobenzamide as a brown oil, which is redissolved in anhydrous THF (60 mL). A 2 neck-flask is charged with paraformaldehyde (2.40 g, 76.22 mmol) and connected via a small length of tubing to another two-neck flask fitted with a pipette using an appropriate adapter. The second flask is charged with THF (60 mL) and cooled to −78° C. The paraformaldehyde is cracked with a heatgun and bubbled into the cold THF through the pipette. A clear solution is formed. To the solution of N,N-diethyl-3,4-difluorobenzamide in THF, is added TMEDA (2.98 g, 25.41 mmol) and the flask is cooled to −78° C. sec-BuLi (1.4M in cyclohexane, 18.1 mL, 25.4 mmol) is added and after 30 min, the cold solution of formaldehyde is added via cannula. After 2 h, the cooling bath is removed. Upon reaching room temperature, the reaction is quenched with 1M aqueous sodium bisulfate. After dilution with ethyl acetate, the organic phase is washed with saturated aqueous sodium bicarbonate and brine. The organic phase is dried over magnesium sulfate and concentrated in vacuo. The residue is purified by silica gel flash chromatography (ethyl acetate-heptane, 3:7 to 2:3 to 1:1) to yield N,N-diethyl-3,4-difluoro-2-hydroxymethyl-benzamide as an orange oil; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.12 (t, J=7.1 Hz, 3 H), 1.28 (t, J=7.1 Hz, 3 H), 3.26 (q, J=7.1 Hz, 2 H), 3.58 (q, J=7.1 Hz, 2H), 4.62 (br. s., 2 H), 7.00 (ddd, J=8.4, 4.6, 1.6 Hz, 1 H), 7.09-7.19 (m, 1 H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH2:11]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)Cl.O>[CH2:11]([N:18]1[CH2:23][CH2:22][N:21]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:20][CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Temperature: 80 °C

Procedure:
A mixture of 1-bromo-4-nitrobenzene (5 g, 24.8 mmol) and 1-benzylpiperazine (8.6 ml, 49.5 mmol, 2 equiv) is heated to 80° C. for 17 h. The reaction mixture is allowed to cool to RT, and is diluted with DCM/H2O. The layers are separated and the aqueous phase is extracted with DCM. The combined organic phase is washed with brine, dried (Na2SO4), filtered and concentrated. Purification of the residue by silica gel column chromatography (Hex/EtOAc, 1:1) affords the title compound as a yellow solid: ESI-MS: 298.3 [MH]+; tR=3.25 min (purity: 100%, system 1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:18]([O:20][CH3:21])=[O:19])[C:5]2[NH:6][C:7]3[CH:8]=[C:9]([N+:15]([O-])=O)[CH:10]=[CH:11][C:12]=3[C:13]=2[N:14]=1>[Ni].C1COCC1>[NH2:15][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:14]=[C:2]([Br:1])[CH:3]=[C:4]([C:18]([O:20][CH3:21])=[O:19])[C:5]=3[NH:6][C:7]=2[CH:8]=1
Reactant: COC(=O)c1cc(Br)nc2c1[nH]c1cc([N+](=O)[O-])ccc12
Agent: [Ni]
Solvent: C1CCOC1
Product: COC(=O)c1cc(Br)nc2c1[nH]c1cc(N)ccc12
Yield: 72.7 %

Procedure:
A suspension of methyl 2-bromo-7-nitro-5H-pyrido[3,2-b]indole-4-carboxylate (1.00 g, 2.86 mmol) and Raney nickel (1.0 g, 17 mmol, 2800 nickel slurry in water) was stirred in THF (50 mL) under H2 (balloon) for 1.5 hr. This was filtered and the filter cake was washed with warn THF (100 mL). Removal of the solvent left methyl 7-amino-2-bromo-5H-pyrido[3,2-b]indole-4-carboxylate (700 mg, 2.08 mmol, 73% yield) as a solid. MS (ESI) m/z 321.94 (M+H). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.27 (1H, br. s.), 7.78 (1H, d), 7.62 (1H, s), 6.79 (1H, br. s.), 6.60 (1H, d, J=8.5), 5 84 (2H, br. s.), 4.00 (3H, s).
Reaction SMILES: [CH2:1]([O:3]C1C=CC(N)=C([N+]([O-])=O)C=1)[CH3:2].[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[C:24]2[CH:25]=[CH:26][C:27](C(F)(F)F)=[CH:28][C:23]=2[N:22]=[C:21]1/[CH:33]=[CH:34]/[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[C:41]([OH:46])(=[O:45])[C:42]([OH:44])=[O:43]>C(OCC)(=O)C>[C:41]([OH:46])(=[O:45])[C:42]([OH:44])=[O:43].[O:3]([C:27]1[CH:26]=[CH:25][C:24]2[N:20]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=3)[C:21](/[CH:33]=[CH:34]/[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[N:22][C:23]=2[CH:28]=1)[CH2:1][CH3:2]
Reactant: CCOc1ccc(N)c([N+](=O)[O-])c1
Reactant: FC(F)(F)c1ccc2c(c1)nc(/C=C/c1ccccc1)n2-c1ccccn1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Product: CCOc1ccc2c(c1)nc(/C=C/c1ccccc1)n2-c1ccccn1

Procedure:
Free base of the titled compound was prepared from 4-ethoxy-2-nitroaniline according to the preparation of (E)-1-(2-pyridyl)-2-styryl-5-trifluoromethyl-1H-benzimidazole (Example 57). The free base and oxalic acid were dissolved into ethyl acetate. Concentration and recrystallization from ethyl acetate/n-hexane yielded the titled compound.
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][N:6]=1)=[O:4].[Mg+2].[Cl-].[Cl-].[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.Cl>C1COCC1.C(OCC)(=O)C>[Cl:11][C:9]1[CH:8]=[CH:7][N:6]=[C:5]([C:3]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:4])[CH:10]=1
Reactant: C1CCNC1
Reactant: COC(=O)c1cc(Cl)ccn1
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(c1cc(Cl)ccn1)N1CCCC1
Reaction time: 0.08 h

Procedure:
4-Chloro-pyridine-2-carboxylic acid methylester (200 mg, 1.17 mmol) and MgCl2 (555 mg, 0.58 mmol) are suspended in THF (5 mL) at rt. The mixture is stirred for 5 min and then pyrrolidine (193 μL, 2.33 mmol) is added and the mixture stirred for an additional 15 min. It is worked up by addition of aqueous HCl solution (1M, 1.2 mL) and extraction with ethyl acetate. The combined organic extracts are washed with brine dried over MgSO4. The volatiles are removed under reduced pressure to give the title compound as a yellow oil: C10H11ClN2O: M+=211.3; 1H-NMR (DMSO-d6): 8.55 (d, 1H), 7.82 (s, 1H), 7.59 (d, 1H), 3.62-3.42 (m, 4H), 1.93-1.75 (m, 4H).
Reaction SMILES: [I-].[CH3:2][N+:3]1[C:16]2[C:7](=[CH:8][CH:9]=[C:10]3[C:15]=2[N:14]=[CH:13][CH:12]=[CH:11]3)[CH:6]=[CH:5][CH:4]=1.[OH-:17].[Na+]>[Fe-3](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[K+].[K+].[K+]>[CH3:2][N:3]1[C:16]2[C:7](=[CH:8][CH:9]=[C:10]3[C:15]=2[N:14]=[CH:13][CH:12]=[CH:11]3)[CH:6]=[CH:5][C:4]1=[O:17]
Reactant: C[n+]1cccc2ccc3cccnc3c21
Reactant: [OH-]
Agent: N#C[Fe-3](C#N)(C#N)(C#N)(C#N)C#N
Agent: [I-]
Agent: [K+]
Product: Cn1c(=O)ccc2ccc3cccnc3c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.4 %

Procedure:
To a stirred aqueous solution of potassium ferricyanide (92.2 g; 280 mmol) (1.12 L), compound (1) (37.6 g; 117 mmol) and an aqueous solution of sodium hydroxide (69.3 g; 1.73 mol) (200 mL) were alternately added in an ice bath (inner temperature of 10 to 15° C.) over 20 minutes. The resulting reaction mixture was stirred at room temperature for 3 hours. Crude crystals which precipitated out were filtered out and dried. The resulting crude crystals were dissolved in toluene (1.1 L) and benzene (450 mL), and insoluble matters were filtrated out. The filtrate was evaporated under reduced pressure, and the resulting residue was washed with isopropyl ether and ethyl acetate, and then dried to give 23.7 g (yield: 75%) of the title compound (2).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH2:10][C:9]2([CH2:15][CH2:14][CH:13]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:12][CH2:11]2)[O:8][N:7]=1)=[O:5])C.O.[OH-].[Li+]>CO.O>[C:16]([CH:13]1[CH2:14][CH2:15][C:9]2([O:8][N:7]=[C:6]([C:4]([OH:5])=[O:3])[CH2:10]2)[CH2:11][CH2:12]1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CCOC(=O)C1=NOC2(CCC(C(C)(C)C)CC2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)C1CCC2(CC1)CC(C(=O)O)=NO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 8-tert-butyl-1-oxa-2-azaspiro[4.5]dec-2-ene-3-carboxylic acid ethyl ester (2.4 g, 9 mmol) in MeOH (50 ml) and lithium hydroxide monohydrate (1 g, 13.5 mmol) in H2O (8 ml) was stirred overnight at RT. After removal of the solvent under vacuum, the residue was taken up in 10% aq. citric acid solution and EtOAc and the phases were separated. The aqueous phase was extracted several times with EtOAc, dried over magnesium sulphate and desolventised under vacuum. 2.17 g (100% of the theoretical amount) of the free acid 8-tert-butyl-1-oxa-2-azaspiro[4.5]dec-2-ene-3-carboxylic acid was obtained in the form of a colourless solid.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][CH:10]([C:13]([NH2:15])=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[C:1]1([N:7]2[CH2:8][CH2:9][CH:10]([CH2:13][NH2:15])[CH2:11][CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC(=O)C1CCN(c2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: NCC1CCN(c2ccccc2)CC1
Reaction time: 2 h
Yield: 82.3 %

Procedure:
1-Phenylpiperidine-4-carboxamide (1.5 g) was added portionwise to a stirring suspension of lithium aluminium hydride (0.5 g) in dry tetrahydrofuran (100 ml) under nitrogen. The resulting suspension was stirred at ambient termperature for 2 hours, then heated under reflux for 2 hours. The mixture was cooled, and water (0.5 ml), then concentrated sodium hydroxide solution (0.5 ml) were added. The resulting precipitate was removed by filtration (Celite). The filtrate was dried over magnesium sulphate, and the solvent removed in vacuo to yield 1-(1-phenylpiperid-4-yl)methylamine (1.15 g).
Reaction SMILES: C(O)(=O)C(O)=[O:3].[CH3:7][N:8]1[C@@H:24]2[CH2:25][C:13]3[CH:14]=[CH:15][C:16]([O:28][CH3:29])=[C:17]4[O:18][C@H:19]5[C:20]([O:26]C)=[CH:21][CH:22]=[C:23]2[C@:11]5([C:12]=34)[CH2:10][CH2:9]1.OO.P([O-])([O-])([O-])=O.[OH-].[K+]>O.C(O)=O>[CH3:7][N:8]1[C@@H:24]2[CH2:25][C:13]3[CH:14]=[CH:15][C:16]([O:28][CH3:29])=[C:17]4[O:18][CH:19]5[C:20]([CH:21]=[CH:22][C@:23]2([OH:3])[C@:11]5([C:12]=34)[CH2:10][CH2:9]1)=[O:26]
Reactant: O=C(O)C(=O)O
Reactant: COC1=CC=C2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Agent: O=P([O-])([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O=CO
Solvent: O
Product: COc1ccc2c3c1OC1C(=O)C=C[C@@]4(O)[C@@H](C2)N(C)CC[C@]314
Temperature: 5 °C
Yield: 117 %

Procedure:
18.66 kg of oxalic acid is dissolved in water, 84.8 kg of thebaine is added, and after it has dissolved, 19.50 kg of 88% formic acid and 42.4 kg of 30% hydrogen peroxide are added. The reaction mixture is stirred at 25° C. until total conversion of thebaine (determined by capillary electrophoresis; capillary 50 cm×0.05 mm, electrolyte 100 mM TRJS/phosphate, pH 2.7, 5 mM dimethoxy-β-cyclodextrin, temperature 25° C. 30 kV; thebaine migration time 5.6 min). The reaction mixture is cooled down to 5° C., 10% aqueous solution of KOH is added with stirring until pH of 9.2. Precipitated crystals of 14-hydroxycodeinone are centrifuged off, washed with water and dried. Ca. 76 kg of 14-hydroxycodeinone (89%) is obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4]OS(C1C=CC(C)=CC=1)(=O)=O.[CH-:16]1[CH:20]=[CH:19][CH:18]=[CH:17]1.[Na+]>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][C:16]1[CH2:20][CH:19]=[CH:18][CH:17]=1
Reactant: COCCOS(=O)(=O)c1ccc(C)cc1
Reactant: c1cc[cH-]c1
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCC1=CC=CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 44 %

Procedure:
To a solution of 19.7 g(85.7 mmol) 2-methoxyethyltosylate as prepared in step (a) in 200 ml THF cooled to 0° C. was added 55 ml of 2.0M (110 mmol) sodium cyclopentadienylide in THF. The reaction mixture was allowed to warm to room temperature and was stirred for 16 h. 100 ml concentrated aqueous saline solution was added and the product extracted with diethyl ether (3×75 ml). The combined organic fractions were dried over sodium sulphate for 16 hrs, filtered and the solvents removed under reduced pressure using a rotary evaporator to yield a brown oil. The crude product was distilled under reduced pressure (b.p. 40°-44° C. at 2-3 mm Hg) to give 4.5 g of a colourless oil (37.7 mmol, 44.0%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH2:10]1)=[O:8].[CH3:19][NH:20][CH3:21].[OH-].[K+]>C(O)CO>[CH3:19][N:20]([CH3:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH2:10]1)=[O:8]
Reactant: O=C(CCCCCBr)N1CCCc2ccccc21
Reactant: CNC
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Product: CN(C)CCCCCC(=O)N1CCCc2ccccc21

Procedure:
1-(6-bromohexanoyl)-1,2,3,4-tetrahydroquinoline, (4.9 g), prepared in a manner similar to that set forth in Preparation 1, was refluxed, using a dry ice condenser, in a saturated solution of dimethylamine in ethylene glycol (46 ml). After 45 minutes the solution was cooled and added to dilute aqueous potassium hydroxide. The resultant solution was extracted with ether, and the extract was washed, dried and evaporated to yield as an oil 1-(6-dimethylaminohexanoyl)-1,2,3,4-tetrahydroquinoline.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]([C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)([CH3:9])[CH3:8].[N+:17]([O-])([O-:19])=[O:18].[K+]>OS(O)(=O)=O>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]([C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][C:11]=1[N+:17]([O-:19])=[O:18])([CH3:9])[CH3:8]
Reactant: COCCOCC(C)(C)c1ccc(N)cc1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COCCOCC(C)(C)c1ccc(N)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 71.7 %

Procedure:
To a solution of 4-[2-(2-methoxy-ethoxy)-1,1-dimethyl-ethyl]-phenylamine (5.8 g, 26 mmol) in H2SO4 (20 mL) was added KNO3 (2.63 g, 26 mmol) at 0° C. After addition was complete, the mixture was stirred at this temperature for 20 min and then poured into ice-water. The mixture was extracted with EtOAc (50 mL×3). The combined organic layers were washed with water and brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography (petroleum ether-EtOAc, 100:1) to give 4-[2-(2-methoxy-ethoxy)-1,1-dimethyl-ethyl]-3-nitro-phenylamine (5 g, 71%).
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[CH2:3][C@H:2]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].C(N(C(C)C)CC)(C)C.[C:29]1([CH3:44])[CH:34]=[CH:33][C:32]([S:35]([O:38][C@H:39]([CH3:43])[C:40](Cl)=[O:41])(=[O:37])=[O:36])=[CH:31][CH:30]=1>ClCCl>[C:29]1([CH3:44])[CH:30]=[CH:31][C:32]([S:35]([O:38][C@H:39]([CH3:43])[C:40]([N:1]2[C:9]3[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=3[CH2:3][C@H:2]2[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])=[O:41])(=[O:36])=[O:37])=[CH:33][CH:34]=1
Reactant: Cc1ccc(S(=O)(=O)O[C@H](C)C(=O)Cl)cc1
Reactant: O=C(OCc1ccccc1)[C@@H]1CC2=C(CCCC2)N1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)O[C@H](C)C(=O)N2C3=C(CCCC3)C[C@H]2C(=O)OCc2ccccc2)cc1
Reaction time: 1 h

Procedure:
Introduce into a reactor 200 g of benzyl (2S)-2,3,4,5,6,7-hexahydro-1H-indole-2-carboxylate and 1.5 litres of dichloromethane, and then bring the temperature of the reaction mixture to 0° C. and add 201 ml of diisopropylethylamine, followed by 202 g of (1R)-2-chloro-1-methyl-2-oxoethyl p-toluenesulphonate. Subsequently, bring the mixture to ambient temperature. After stirring for 1 hour at that temperature, wash the mixture with water. The solution of benzyl (2S)-1-[(2R)-2-{p-toluenesulphonyloxy}propionyl]-2,3,4,5,6,7-hexahydro-1H-indole-2-carboxylate so obtained is used as it is in the following Step.
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[C:10]([NH2:13])[NH:11][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=O)[CH2:23][C:24](OCC)=[O:25])=[CH:18][CH:17]=1>C(O)(=O)C>[CH2:1]([C:8]1[N:9]=[C:10]2[NH:13][C:22]([C:19]3[CH:18]=[CH:17][C:16]([O:15][CH3:14])=[CH:21][CH:20]=3)=[CH:23][C:24](=[O:25])[N:11]2[N:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1nc(Cc2ccccc2)n[nH]1
Reactant: CCOC(=O)CC(=O)c1ccc(OC)cc1
Solvent: CC(=O)O
Product: COc1ccc(-c2cc(=O)n3nc(Cc4ccccc4)nc3[nH]2)cc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 7.8 %

Procedure:
A mixture of 5-benzyl-2H-1,2,4-triazol-3-amine (174 mg, 1.00 mmol, 1.00 equiv), acetic acid (3 mL), and ethyl 3-(4-methoxyphenyl)-3-oxopropanoate (228 mg, 1.10 mmol, 1.10 equiv) was stirred overnight at 110° C. and then concentrated to dryness. The resulting solid was washed with 5 mL MeOH and collected by filtration. The solid was dissolved in 10 mL of NH4OH (aq.) and filtered. The filtrate was adjusted to pH 6 with HOAc. The resulting solid was collected by filtration and washed with water. The solid was dried to get 26 mg (8%) of 2-benzyl-5-(4-methoxyphenyl)-[1,2,4]triazolo[1,5-α]pyrimidin-7(4H)-one as a white solid.
Reaction SMILES: [Mg].BrCC.Br[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1.CON(C)[C:23]([C:25]1[O:29][N:28]=[C:27]([CH3:30])[CH:26]=1)=[O:24]>O.C1COCC1>[CH3:30][C:27]1[CH:26]=[C:25]([C:23]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:12][O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)=[O:24])[O:29][N:28]=1
Reactant: CON(C)C(=O)c1cc(C)no1
Reactant: Brc1ccccc1COC1CCCCO1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCBr
Solvent: O
Product: Cc1cc(C(=O)c2ccccc2COC2CCCCO2)on1
Temperature: 55 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
Magnesium (0.73 g, 0.03 mol) and bromoethane (0.2 ml) were added to a mixture of 1-bromo-2-(2-tetrahydro-pyranyloxymethyl)benzene (5.42 g, 0.02 mol) and THF (50 ml) under an atmosphere of nitrogen gas, and the resulting mixture was stirred at 50 to 60° C. for 1 hour to prepare Grignard reagent. The Grignard reagent was added dropwise to a mixture of N-methoxy-3, N-dimethyl-5-isoxazolcarboxamide (3.40 g, 0.02 mol) and THF (40 ml). The mixture was stirred at −60° C. to room temperature for 1 hour, water (200 ml) was added, and the mixture was extracted with ether (200 ml). The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-(2-tetrahydropyranyloxymethyl)phenyl 3-methylisoxazol-5-yl ketone (4.09 g, yield: 67.9%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[NH:6][S:5](=[O:8])(=[O:7])[N:4]([C:9]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:10]=2[C:11]#[N:12])[CH2:3]1.[H-].[Na+].I[CH3:22]>CN(C=O)C.O>[F:17][C:15]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[C:9]([N:4]2[CH2:3][C:2]([CH3:18])([CH3:1])[N:6]([CH3:22])[S:5]2(=[O:8])=[O:7])[CH:16]=1
Reactant: CI
Reactant: CC1(C)CN(c2cc(F)ccc2C#N)S(=O)(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(C)(C)CN(c2cc(F)ccc2C#N)S1(=O)=O
Reaction time: 0.08 h
Yield: 100.1 %

Procedure:
To a solution of 2-(4,4-dimethyl-1,1-dioxido-1,2,5-thiadiazolidin-2-yl)-4-fluorobenzonitrile (3.18 g, 11.81 mmol) in DMF (40 mL) was added NaH (0.312 g, 12.99 mmol) and the mixture stirred for 5 min. Iodomethane (1.477 mL, 23.62 mmol) was added and the mixture stirred at 90° C. for 2 h then at room temperature for 16 h. The mixture was diluted with H2O and extracted with ethyl acetate. The organic phase was washed two times with H2O followed by brine, dried (Na2SO4), filtered and concentrated to give the title compound as a white solid (3.35 g, 100% yield). LCMS (M+H) calcd for C12H15FN3O2S: 284.08; found: 284.14. 1H NMR (300 MHz, CDCl3) δ: 7.70-7.61 (2H, m), 7.11-7.05 (1H, m), 3.80 (2H, s), 2.73 (3H, s), 1.42 (6H, s).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([NH2:13])=[O:12])=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.CN(C)/[CH:16]=[CH:17]/[N+:18]([O-:20])=[O:19]>C(O)(C(F)(F)F)=O>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([NH2:13])=[O:12])=[C:7]2[C:3]=1[C:4]([CH:16]=[CH:17][N+:18]([O-:20])=[O:19])=[CH:5][NH:6]2
Reactant: NC(=O)c1ccc(Br)c2cc[nH]c12
Reactant: CN(C)/C=C/[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1ccc(Br)c2c(C=C[N+](=O)[O-])c[nH]c12
Reaction time: 16 h

Procedure:
A dark red-brown solution of 4-bromo-1H-indole-7-carboxamide (0.79 g, 3.30 mmol) and (E)-N,N-dimethyl-2-nitroethenamine (0.422 g, 3.63 mmol) in TFA (9.44 mL) was stirred at room temperature overnight. After 16 h, LCMS indicated residual starting materials in addition to desired product. Additional (E)-N,N-dimethyl-2-nitroethenamine (77 mg) was added and the mixture was stirred at room temperature for 6 h. The mixture was partitioned between 1 M NaOH (pH was adjusted to ca. 4) and EtOAc. The organic phase was washed with NaHCO3 (aq) and brine, dried and concentrated to afford a bright orange-red solid. The crude product was suspended in EtOAc and the desired product was collected by filtration, washed with EtOAc and air dried to provide a solid (0.89 g, 87% yield). LCMS (M+H)+ m/z 309.7, 311.7.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]2[CH2:19][CH2:20][O:21][C:22]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=4)=[CH:25][C:23]=3[CH:24]=2)=[O:17])=[CH:11][CH:10]=1)=[O:8].CI.[CH:38](N(C(C)C)CC)(C)C>ClCCl>[CH3:38][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16]([C:18]2[CH2:19][CH2:20][O:21][C:22]3[CH:28]=[CH:27][C:26]([C:29]4[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=4)=[CH:25][C:23]=3[CH:24]=2)=[O:17])=[CH:13][CH:14]=1)=[O:8]
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(=O)C4CCCCN4)cc2)CCO3)cc1
Reactant: CCN(C(C)C)C(C)C
Solvent: CI
Solvent: ClCCl
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(=O)C4CCCCN4C)cc2)CCO3)cc1
Temperature: 25 °C

Procedure:
In dichloromethane (35 ml) was dissolved N-(4-(piperidin-2-ylcarbonyl)phenyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (0.3 g), and to the solution were added methyl iodide (0.08 ml) and diisopropylethylamine (0.17 ml). The mixture was stirred at room temperature over night. The solvent was evaporated, and to the residue was added water. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column (ethyl acetate/methanol/triethylamine) to give crude crystals, which were recrystallized from ethyl acetate-hexane to give N-(4-(1-methylpiperidin-2-ylcarbonyl)phenyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 157) (0.17 g) as colorless crystals.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH3:28])[C:10]=1[C:11](=[O:27])[NH:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([N:19]=[C:20]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[N:21]=2)[CH:18]=1)=[O:5])C.CN1C(C(=O)NC2C=CC3N(N=C(N4CCOCC4)N=3)C=2)=C(C(O)=O)C=N1>>[CH3:28][N:9]1[C:10]([C:11](=[O:27])[NH:12][C:13]2[CH:14]=[CH:15][C:16]3[N:17]([N:19]=[C:20]([N:22]4[CH2:23][CH2:24][CH2:25][CH2:26]4)[N:21]=3)[CH:18]=2)=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]1
Reactant: CCOC(=O)c1cnn(C)c1C(=O)Nc1ccc2nc(N3CCCC3)nn2c1
Agent: Cn1ncc(C(=O)O)c1C(=O)Nc1ccc2nc(N3CCOCC3)nn2c1
Product: Cn1ncc(C(=O)O)c1C(=O)Nc1ccc2nc(N3CCCC3)nn2c1

Procedure:
Using 1-Methyl-5-(2-pyrrolidin-1-yl-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid ethyl ester, this compound was prepared following the same method as for the synthesis of 1-Methyl-5-(2-morpholino-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid. White solid (430 mg, 93%). MS: m/z=356 (M+H+).