Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].[CH3:12][N:13]([CH:22]1[CH2:27][CH2:26][N:25]([C:28](=[O:36])[C:29]2[CH:34]=[CH:33][C:32](Cl)=[N:31][CH:30]=2)[CH2:24][CH2:23]1)[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CS(C)=O>[CH3:12][N:13]([CH:22]1[CH2:27][CH2:26][N:25]([C:28](=[O:36])[C:29]2[CH:34]=[CH:33][C:32]([N:1]3[CH:5]=[N:4][CH:3]=[N:2]3)=[N:31][CH:30]=2)[CH2:24][CH2:23]1)[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: c1nc[nH]n1
Reactant: CN(CCc1ccccc1)C1CCN(C(=O)c2ccc(Cl)nc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CN(CCc1ccccc1)C1CCN(C(=O)c2ccc(-n3cncn3)nc2)CC1
Temperature: 100 °C
Reaction time: 4 h
Yield: 15.1 %

Procedure:
1.16 g of 1,2,4-triazole and 1.16 g of potassium carbonate were added to a solution of 2.00 g of 4-[N-methyl-N-(2-phenylethyl)amino]-1-(6-chloronicotinoyl)piperidine in 10 ml of dimethyl sulfoxide. The container inside was purged with nitrogen and the container contents were stirred at 100° C. for 4 hours. The reaction mixture was cooled and water was added thereto. The mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was purified by a silica gel column chromatography (eluant: methylene chloride/methanol=150/1). The product was subjected to crystallization from diethyl ether and then to recrystallization from ethyl acetate-diethyl ether to obtain 0.33 g of 4-[N-methyl-N-(2-phenylethyl)amino]-1-[6-(1,2,4-triazol-1-yl)nicotinoyl]piperidine as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:20])=[C:6]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10](N2CCOCC2)=[O:11])[CH:7]=1.[CH:21]([Li])([CH3:23])[CH3:22]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:20])=[C:6]([C:8]([CH3:18])([CH3:19])[CH2:9][C:10](=[O:11])[CH:21]([CH3:23])[CH3:22])[CH:7]=1
Reactant: Cc1ccc(F)cc1C(C)(C)CC(=O)N1CCOCC1
Reactant: [Li]C(C)C
Solvent: C1CCOC1
Product: Cc1ccc(F)cc1C(C)(C)CC(=O)C(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
A solution of 3-(5-fluoro-2-methylphenyl)-3-methyl-1-morpholin-4-ylbutan-1-one (200 mg, 0.716 mmol) in 2 mL of THF was treated with i-PrLi (0.7 M in pentane, 1.28 mL) at −78° C. The reaction mixture was stirred at −78° C. for 1 hour, allowed to warm to room temperature, quenched with 1 mL of methanol and 5 mL of saturated aqueous ammonium chloride solution, and extracted with three 50 mL portions of ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. Chromatography on SiO2 (100% hexanes to 25% ethyl acetate in hexanes, gradient) afforded 80.4 mg of the title product (48% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[O:13][CH3:14].C(N(CC)CC)C.Cl[C:23](Cl)([O:25]C(=O)OC(Cl)(Cl)Cl)Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[C:7]([F:9])[C:5]([N:6]=[C:23]=[O:25])=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[O:13][CH3:14]
Reactant: COc1c(Cl)cc(F)c(N)c1[N+](=O)[O-]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1c(Cl)cc(F)c(N=C=O)c1[N+](=O)[O-]

Procedure:
4-Chloro-6-fluoro-3-methoxy-2-nitroaniline (0.5 g, 2.27 mmol) was dissolved in anhydrous toluene (30 ml) and triethylamine (0.46 g, 4.54 mmol) was added. This solution was slowly added to a stirred solution of triphosgene (0.67 g, 2.27 mmol) in toluene (30 ml) and the solution refluxed for 2 hr. The solution was cooled and filtered. Clear filtrate was evaporated in vacuo to afford the title compound. 1H NMR (CDCl3, 3.00 MHz) 3.96 (3H, s), 7.38 (1H, d, J=8.8 Hz) ppm.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9](=O)[CH2:10][CH3:11])[CH:6]=[C:5]([CH2:13][CH3:14])[C:4]=1[OH:15])[CH3:2].Cl.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25]N)=[CH:21][CH:20]=1>>[CH2:13]([C:5]1[CH:6]=[C:7]([C:9]2[NH:25][C:22]3[C:23]([C:10]=2[CH3:11])=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=3)[CH:8]=[C:3]([CH2:1][CH3:2])[C:4]=1[OH:15])[CH3:14]
Reactant: CCC(=O)c1cc(CC)c(O)c(CC)c1
Reactant: COc1ccc(NN)cc1
Agent: Cl
Product: CCc1cc(-c2[nH]c3ccc(OC)cc3c2C)cc(CC)c1O

Procedure:
2,6-Diethyl-4-propionylphenol and 4-methoxyphenylhydrazine hydrochloride were treated in the same way as in Example 1 to give 2-(3,5-diethyl-4-hydroxyphenyl)-5-methoxy-3-methylindole.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH:6]=[CH:5]2.[CH2:20]([NH:24][C:25](=[O:34])[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:21][C:22]#[CH:23].C(N(CC)CC)C>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Si:13]([O:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([C:23]#[C:22][CH2:21][CH2:20][NH:24][C:25](=[O:34])[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH:11]=[CH:10]2)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: C#CCCNC(=O)OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2cc(Br)ccc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)Oc1ccc2cc(C#CCCNC(=O)OCc3ccccc3)ccc2c1
Temperature: 25 °C
Yield: 38.8 %

Procedure:
A solution of (6-bromonaphthalen-2-yloxy)(tert-butyl)dimethylsilane (81, 16.1 g, 47.7 mmol), benzyl but-3-ynylcarbamate (82, 9.0 g, 47.7 mmol), and triethylamine (95 mL) in anhydrous THF (100 mL) was cooled to −78° C. and degassed with argon. The mixture was warmed to room temperature and dichlorobis(triphenylphosphine)palladium(II) (3.3 g, 4.8 mmol) and CuI (1.8 g, 9.6 mmol) were added rapidly in one portion under argon. The mixture was heated at 50° C. for 12 h. The reaction mixture was filtered through a plug of diatomaceous earth and the filtrate was concentrated. The residue was purified by column chromatography (silical gel, 10:1 hexanes/EtOAc) to afford carbamate 83 (8.5 g, 38%) as a thick brown oil: 1H NMR (300 MHz, CDCl3) δ 7.83 (s, 1H), 7.65 (d, J=9.0 Hz, 1H), 7.60 (d, J=8.7 Hz, 1H), 7.39-7.29 (m, 6H), 7.13 (d, J=2.1 Hz, 1H), 7.07 (dd, J=8.7, 2.4 Hz, 1H), 5.17 (br s, 1H), 5.13 (s, 2H), 3.46 (q, J=6.3 Hz, 2H), 2.67 (t, J=6.3 Hz, 2H), 1.01 (s, 9H), 0.25 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:8][OH:9])=[N:4][N:5]([CH3:7])[CH:6]=1.[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].N1C=CN=C1.C(Cl)Cl>CN(C)C1C=CN=CC=1>[Br:1][C:2]1[C:3]([CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])=[N:4][N:5]([CH3:7])[CH:6]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cn1cc(Br)c(CO)n1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: Cn1cc(Br)c(CO[Si](C)(C)C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (4-bromo-1-methyl-1H-pyrazol-3-yl)methanol (100.0 mg, 0.5235 mmol), tert-butyldimethylsilyl chloride (236.7 mg, 1.570 mmol), 4-dimethylaminopyridine (12.79 mg, 0.1047 mmol), 1H-Imidazole (106.9 mg, 1.570 mmol) and DCM (40 mL, 700 mmol) was stirred at rt for 1 h. The material was transferred to a separatory funnel and partitioned between DCM and water. The organic layer was dry-loaded onto silica gel for column chromatography, eluting with 2% EtOAc/hexanes. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a clear oil. MS (ES+): m/z=305.06/307.06 (100/100) [MH+]. HPLC: tR=1.82 min (polar—3 min, UPLC-ACQUITY).
Reaction SMILES: C([O:5][C:6](=[O:36])[C:7]([CH3:35])([S:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][C:16](=[O:34])[NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[N:14]=1)[CH3:8])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:35][C:7]([S:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][C:16](=[O:34])[NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[N:14]=1)([CH3:8])[C:6]([OH:36])=[O:5]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CC(=O)Nc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(Sc1nc(CC(=O)Nc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cs1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 60 %

Procedure:
2-Methyl-2-{[4-(2-oxo-2-{[4′-(trifluoromethyl)biphenyl-4-yl]amino}ethyl)-1,3-thiazol-2-yl]thio}propionic acid tert-butyl ester (540 mg) obtained in Example 458-2 was dissolved in dichloromethane (10 mL), trifluoroacetic acid (4 mL) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=1:1 to 0:1) to give the title compound (290 mg) as a white solid.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([CH2:14]O)=[N:10][CH:9]=1>C(Cl)(Cl)Cl>[CH3:5][O:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][Cl:3])=[N:10][CH:9]=1
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1ccc(CO)nc1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(CCl)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
Thionyl chloride (5.0 ml, 2.0 eq) was added dropwise to a solution of alcohol (III, 5.7 g) in anhydrous chloroform (50 mL) cooling with a water bath. The resulting solution was stirred at room temperature for 2 hours. The reaction was quenched with saturated aqueous sodium bicarbonate solution followed by CH2Cl2 extractions. The combined organic layers were dried over MgSO4 and filtered. The filtrate was concentrated in vacuo and then passed through a silica gel pad (eluent 5% MeOH in CH2Cl2) to afford the desired product (7.0 g, 90%) as a off-white solid. MS-ESI m/z 186.09 (M+H)+; 1H NMR (CDCl3) δ 9.18 (d, J=2 Hz, 1H), 8.35 (dd, J=2 and 8.5 Hz, 1H), 7.61 (d, J=8.5 Hz, 1H), 4.74 (s, 2H), 3.98 (s, 3H) ppm.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](N)=[O:8])=[CH:5][CH:4]=1)#[N:2].Cl[O-].[Na+].S(=O)(=O)(O)[OH:16]>O>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:16])=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C(N)=O)cc1
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Product: N#Cc1ccc(C(=O)O)cc1
Temperature: 15 °C
Yield: 99 %

Procedure:
p-Cyanobenzamide (146 g) which had been synthesized separately and water (584 g) were placed in a four-neck flask, and the mixture was cooled to 15° C. with stirring. Subsequently, an aqueous solution (1775 g) of sodium hypochlorite (effective chlorine 12%) was added to the reaction mixture over six hours while a 50% aqueous solution of sulfuric acid was added so as to maintain the pH of the mixture at 5-6. Liquid chromatographic analysis revealed that the reaction mixture contained 145.5 g of crude p-cyanobenzoic acid (yield 99%). To the reaction mixture, concentrated sulfuric acid was added so as to adjust the pH to 3.0 and precipitate p-cyanobenzoic acid from its salt. The precipitate was dissolved by adding methanol (820 g) with heat, and the solution was cooled for crystallization, to thereby obtain 138.9 g of p-cyanobenzoic acid having a purity of 99.5% (yield 94%).
Reaction SMILES: [NH2:1]/[C:2](/[C:10]([F:13])([F:12])[F:11])=[C:3](/[F:9])\[C:4]([O:6]CC)=O.[Cl:14][C:15]1[C:20]([O:21][CH:22]([CH3:24])[CH3:23])=[CH:19][C:18]([N:25]=[C:26]=[O:27])=[C:17]([F:28])[CH:16]=1>>[Cl:14][C:15]1[C:20]([O:21][CH:22]([CH3:23])[CH3:24])=[CH:19][C:18]([N:25]2[C:4](=[O:6])[C:3]([F:9])=[C:2]([C:10]([F:11])([F:12])[F:13])[NH:1][C:26]2=[O:27])=[C:17]([F:28])[CH:16]=1
Reactant: CCOC(=O)/C(F)=C(\N)C(F)(F)F
Reactant: CC(C)Oc1cc(N=C=O)c(F)cc1Cl
Product: CC(C)Oc1cc(-n2c(=O)[nH]c(C(F)(F)F)c(F)c2=O)c(F)cc1Cl

Procedure:
using ethyl 3-amino-2,4,4,4-tetrafluorocrotonate and 4-chloro-2-fluoro-5-isopropoxyphenyl isocyanate there is obtained 3-(4-chloro-2-fluoro-5-isopropoxyphenyl)-5-fluoro-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione, m.p. 133°-135° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:8][C:9](=O)[CH3:10])[S:5][C:6]=1[CH3:7].[H-].[Na+].Cl.[CH3:15][N:16](CCCl)[CH3:17]>CN(C)C=O>[CH3:15][N:16]([CH3:17])[CH2:10][CH2:9][NH:8][C:4]1[S:5][C:6]([CH3:7])=[C:2]([CH3:1])[N:3]=1
Reactant: CC(=O)Nc1nc(C)c(C)s1
Reactant: CN(C)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(NCCN(C)C)sc1C
Temperature: 90 °C
Reaction time: 2 h

Procedure:
Dissolve 30.0 g. (0.176 moles) of N-(4,5-dimethyl-2-thiazolyl) acetamide in 375 ml. of dimethylformamide under nitrogen followed by 7.7 g. of 50% sodium hydride in 2 portions at room temperature. When gas evolution ceases, 27.5 g. (0.191 moles) of dimethylaminoethylchloride hydrochloride is added along with 8.35 g. of 50% sodium hydride. The mixture is stirred at 60°-70° C. for 1/2 hour, 90° C. for 2 hours, cooled to room temperature, and concentrated in vacuo. The residue is taken up in 200 ml. of 6 N hydrochloric acid and refluxed for 24 hours. The mixture is extracted with hexane and made basic with sodium hydroxide with cooling. The aqueous layer is extracted with methylene chloride, the organic layer washed with saturated sodium chloride, dried over sodium sulfate and evaporated. The residue is distilled and the fraction boiling at 110°-113° C./0.7 mm. of Hg, collected (29.2 g.) and identified as N,N-dimethyl-N'-(4,5-dimethyl-2-thiazolyl)-1,2-ethanediamine.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][N:10]1[C:14]([C:15]2[CH:16]=[C:17]([NH:29]C(=O)C)[CH:18]=[CH:19][C:20]=2[O:21][CH2:22][C:23]([CH3:28])([N+:25]([O-:27])=[O:26])[CH3:24])=[CH:13][CH:12]=[N:11]1.[OH-].[Na+].O>CO>[Br:1][C:13]1[CH:12]=[N:11][N:10]([CH3:9])[C:14]=1[C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][C:20]=1[O:21][CH2:22][C:23]([CH3:28])([N+:25]([O-:27])=[O:26])[CH3:24])[NH2:29]
Reactant: CC(=O)Nc1ccc(OCC(C)(C)[N+](=O)[O-])c(-c2ccnn2C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1ncc(Br)c1-c1cc(N)ccc1OCC(C)(C)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 61 %

Procedure:
N-Bromosuccinimide (0.931 g, 5.23 mmol) was added to a suspension of N-(3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-methyl-2-nitropropoxy)phenyl)acetamide (1.58 g, 4.75 mmol) in 10 mL of methanol, and the mixture was stirred at room temperature. A clear solution was obtained within minutes. After 20 min, a solution of sodium hydroxide (1.14 g, 28.5 mmol) in water (1.00 mL, 55.5 mmol) was added, and the solution was heated to 160° C. for 0.5 hr under microwave irradiation in a heavy walled sealed tube. The solvent was evaporated under reduced pressure, and the residue was taken up in saturated sodium bicarbonate and extracted twice with dichloromethane. The extracts were combined, dried with sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by flash chromatography (ethyl acetate—hexanes 1:2, then 1:1) to afford the title compound as an off-white solid (1.07 g, 61%). LCMS m/z (%)=371.0 (M+H 81Br 36%), 369.1 (M+H 79Br 30%). 1H NMR (400 MHz, CDCl3) δ ppm 1.44 (s, 3 H), 1.50 (s, 3 H), 3.63 (s, 3 H), 3.81 (d, J=9.85 Hz, 1 H), 4.34 (d, J=9.85 Hz, 1 H), 6.72 (d, J=1.52 Hz, 1 H), 6.87-6.93 (m, 2 H), 7.51 (s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[N:10]=1)[C:5]([OH:7])=[O:6].N1C=CC=CC=1.[C:18](Cl)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]>CN(C)C=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH3:11][C:9]1[CH:8]=[C:4]([CH:3]=[C:2]([NH:1][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[N:10]=1)[C:5]([OH:7])=[O:6]
Reactant: Cc1cc(C(=O)O)cc(N)n1
Reactant: CC(C)(C)C(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cc1cc(C(=O)O)cc(NC(=O)C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 179.6 %

Procedure:
To a stirred mixture of 2-amino-6-methylisonicotinic acid (150 mg, 0.99 mmol) and pyridine (310 mg, 3.9 mmol) in N,N-dimethylformamide (2.0 mL) is added pivaloyl chloride (240 mg, 2.0 mmol) at room temperature. The mixture is stirred overnight at room temperature, and diluted with saturated aqueous citric acid (10 mL). Whole is extracted with ethyl acetate/toluene (2:1, 10 mL×3). Combined organic layers are washed with water, brine, dried over sodium sulfate. The organic solvent is removed under reduced pressure to give 420 mg (quantitative yield) of the titled compound as a white solid.
Reaction SMILES: CI.[C:3](=O)([O-])[O-].[K+].[K+].[Cl:9][C:10]1[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([N+:33]([O-:35])=[O:34])=[C:17]([N:19]2[C:24](=[O:25])[NH:23][C:22](=[O:26])[N:21]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[C:20]2=[O:32])[CH:18]=1.[Cl-].[NH4+]>CN(C)C=O>[Cl:9][C:10]1[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([N+:33]([O-:35])=[O:34])=[C:17]([N:19]2[C:24](=[O:25])[N:23]([CH3:3])[C:22](=[O:26])[N:21]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[C:20]2=[O:32])[CH:18]=1
Reactant: COC(=O)Cn1c(=O)[nH]c(=O)n(-c2cc(Oc3ccc(Cl)cc3Cl)ccc2[N+](=O)[O-])c1=O
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)Cn1c(=O)n(C)c(=O)n(-c2cc(Oc3ccc(Cl)cc3Cl)ccc2[N+](=O)[O-])c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl iodide (0.15 mL, 2.41 mmol) and potassium carbonate (0.19 g, 1.34 mmol) are added to a solution of methyl 3-[5-(2,4-dichlorophenoxy)-2-nitrophenyl]-tetrahydro-2,4,6-trioxo-s-triazine-1(2H)-acetate (0.40 g, 0.83 mmol) in N,N-dimethylformamide. The reaction mixture is stirred overnight at room temperature and poured into a saturated ammonium chloride solution. The aqueous mixture is extracted with ethyl acetate. The organic extracts are combined, washed sequentially with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a yellow oil. Column chromatography of the oil using silica gel and an ethyl acetate/hexanes (1:3) solution gives the title product as a yellow foam which is identified by NMR spectral analysis.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].C(=O)([O-])[O-].[Na+].[Na+].O.[C:20](Cl)(Cl)=[O:21]>C1(C)C=CC=CC=1>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:20](=[O:21])[O:9][C:7](=[O:8])[C:6]=2[CH:10]=1
Reactant: CNc1ccc(I)cc1C(=O)O
Reactant: O=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cn1c(=O)oc(=O)c2cc(I)ccc21
Reaction time: 2 h

Procedure:
To a stirred solution of 5-iodo-2-(methylamino)benzoic acid (10 g, 36 mmol), sodium carbonate (4 g, 36 mmol) and water (130 ml, 7218 mmol), cooled to 0° C., was slowly added, via addition funnel, a 2M phosgene (18 ml, 36 mmol) solution in toluene. After 2 hrs, the precipitated product was isolated by filtration. The solids were washed with 100 ml of water, 150 ml of a 1:1 mixture ethanol and ether, 100 ml of ether, and dried under vacuum to give the desired product. Yield=7.15 g.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=3)[NH2:17])=[N:9]2)=[CH:4][CH:3]=1.[CH2:21]([C:23]1([CH2:30][CH3:31])[CH2:28][C:27](=[O:29])[O:26][C:24]1=[O:25])[CH3:22]>N1C=CC=CC=1>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:15]=[C:16]([NH:17][C:27](=[O:29])[CH2:28][C:23]([CH2:30][CH3:31])([CH2:21][CH3:22])[C:24]([OH:26])=[O:25])[CH:18]=[CH:19][CH:20]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: Nc1cccc(OCc2ccc3ccc(Br)cc3n2)c1
Reactant: CCC1(CC)CC(=O)OC1=O
Solvent: c1ccncc1
Product: CCC(CC)(CC(=O)Nc1cccc(OCc2ccc3ccc(Br)cc3n2)c1)C(=O)O
Reaction time: 0.5 h

Procedure:
2 g of 3-(7-bromo-2-quinolinylmethoxy)aniline and 1.9 g of 2,2-diethylsuccinic acid anhydride (purified by distillation) are stirred in 28 ml of pyridine for 72 hours at 20° and concentrated by evaporation. The residue is suspended in 25 ml of 2N aqueous hydrochloric acid and the suspension is stirred for 30 min. at 20° and filtered. The precipitate is washed with water and crystallised from ethanol to give the title compound in the form of colourless crystals of m.p. 175°, IR (Nujol): inter alia 3600-2100, 3308, 1710, 1670, 1610, 1600, 1497 cm-1.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[CH2:3]1.Br[CH2:39][C:40]1[C:48]2[N:47]([CH2:49][O:50][CH2:51][CH2:52][Si:53]([CH3:56])([CH3:55])[CH3:54])[C:46](=[O:57])[N:45]([CH2:58][CH3:59])[C:44]=2[CH:43]=[CH:42][CH:41]=1>>[CH2:58]([N:45]1[C:44]2[CH:43]=[CH:42][CH:41]=[C:40]([CH2:39][O:1][CH:2]3[CH:7]([C:8]4[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=5[O:26][CH3:27])=[CH:10][CH:9]=4)[CH2:6][CH2:5][N:4]([C:28]([O:30][CH2:31][C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)=[O:29])[CH2:3]3)[C:48]=2[N:47]([CH2:49][O:50][CH2:51][CH2:52][Si:53]([CH3:54])([CH3:56])[CH3:55])[C:46]1=[O:57])[CH3:59]
Reactant: CCn1c(=O)n(COCC[Si](C)(C)C)c2c(CBr)cccc21
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2O)cc1
Product: CCn1c(=O)n(COCC[Si](C)(C)C)c2c(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCCOCc4ccccc4OC)cc3)cccc21

Procedure:
Analogously to Method D, 0.340 g of benzyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 0.272 g of 4-bromomethyl-1-ethyl-3-(2-trimethylsilanylethoxymethyl)-1,3-dihydrobenzimidazol-2-one are reacted. The title compound is obtained as a dark yellow resin. Rf=0.50 (1:1 EtOAc-heptane); Rt=6.67.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]2[N:12]=[C:11]([NH2:13])[NH:10][N:9]=2)[CH:2]=1.[C:14]1([N:20]=[C:21]=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1.C(Cl)Cl>[C:14]1([NH:20][C:21]([N:10]2[C:11]([NH2:13])=[N:12][C:8]([NH:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[N:9]2)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1nc(Nc2cccnc2)n[nH]1
Reactant: O=C=Nc1ccccc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: Nc1nc(Nc2cccnc2)nn1C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.3 %

Procedure:
To a solution of N3-(3-pyridyl)-1H-[1,2,4]triazole-3,5-diamine (0.43 mmol) in dry THF (3 mL) and dry DCM (3 mL) was added phenylisocyanate (0.43 mmol) dropwise over 1 minute, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and the residue purified by column chromatography [Merck silica, eluted with EtOAc and Hexanes (4:1)] to afford compound the title compound (22.0 mg, 17%). 1H NMR (400 MHz, DMSO-d6) 7.17 (1H, t), 7.28 (1H, m), 7.39 (4H, m), 7.65 (2H, d), 8.09 (1H, m), 8.23 (1H, m), 8.79 (1H, d), 9.44 (1H, s), 9.64 (1H, s); MS (ES+): m/e=296.3 (100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:15])[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH:16]1[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[O:22])[CH2:17]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:15])[CH2:13][CH2:12][CH:11]([N:16]3[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=4)=[O:22])[CH2:17]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: O=C1CCC(O)(c2ccc(F)cc2)CC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(O)(c3ccc(F)cc3)CC2)C1

Procedure:
The title compound was prepared as a white solid by reductive amination of 4-(4-fluoro-phenyl)-4-hydroxy-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedure described in Step C of Example 4.