Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.OS(O)(=O)=O.O.[Br:18]N1C(=O)CCC1=O>[OH-].[Na+]>[Br:18][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[CH:11][C:2]([Cl:1])=[N:3]2
Reactant: Clc1ccc2ccccc2n1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Clc1ccc2c(Br)cccc2n1
Temperature: 35 °C
Reaction time: 38 h
Yield: 5.3 %

Procedure:
To a solution of 2-Chloroquinoline (8) (1.0 g, 6.11 mmol) in 1:1 H2SO4 : H2O (30 ml) was added N-Bromosuccinimide (1.7 g, 9.55 mmol). The mixture was stirred at 35° C. for 38 h and then cooled. The solution was diluted with enough 50% NaOH (aq) to maintain pH<1 and the mixture was extracted with CH2Cl2. The combined organic layers were washed with sat. NaHCO3 (aq) and dried (MgSO4). Concentration of the solvent afforded a dark brown oil (0.078 g, 79%) which was sequentially purified by flash chromatography (85:15 Hexane:CH2Cl2) and MPLC (85:15 Hexane:CH2Cl2) to afford 9 (0.22 g, 15%) as a white amorphous solid (m.p. 71° -72° C.). 1H NMR d (ppm): 7.39 d (CH arom), 7.51 dd (CH arom), 7.74 d (CH arom), 7.91 d (CH atom), 8.37 d (CH arom).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:21]([Cl:25])=[CH:22][C:23]=1[F:24])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[F:26][C:27]([F:38])([F:37])[C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31](O)=[O:32].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[Cl:25][C:21]1[C:4]([O:5][C:6]2[CH:7]=[CH:8][C:9]3[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]4[CH2:19][CH2:20]4)=[O:17])[N:14]=3)[N:11]=2)=[CH:3][C:2]([NH:1][C:31](=[O:32])[C:30]2[CH:34]=[CH:35][CH:36]=[C:28]([C:27]([F:26])([F:37])[F:38])[CH:29]=2)=[C:23]([F:24])[CH:22]=1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c(Cl)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c(Cl)cc1F)c1cccc(C(F)(F)F)c1
Yield: 20.2 %

Procedure:
Using N-[6-(3-amino-6-chloro-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (181 mg, 0.50 mmol), 3-(trifluoromethyl)benzoic acid (114 mg, 0.60 mmol), 1-hydroxybenzotriazole (81 mg, 0.60 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (115 mg, 0.60 mmol) and N,N-dimethylformamide (5.0 mL) as starting materials and in the same manner as in Example 106, the title compound (54 mg, 20%) was obtained as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[C:10]([C:11]([O:13]C)=[O:12])=[N:9][CH:8]=[CH:7][N:6]=1.[OH-].[K+]>CO.O>[F:1][C:2]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[C:10]([C:11]([OH:13])=[O:12])=[N:9][CH:8]=[CH:7][N:6]=1
Reactant: COC(=O)c1nccnc1Oc1ccc(F)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1nccnc1Oc1ccc(F)cc1F

Procedure:
A solution of 5.3 g (20 mmol) of methyl 2-(2,4-difluorophenoxy)-3-pyrazinecarboxylate in 50 ml of methanol is treated with 5.6 g (0.1 mol) of potassium hydroxide at room temperature for 2 hours. The reaction mixture is freed from the solvent under reduced pressure and the residue is taken up in distilled water. On acidification to pH 2-3, the 2-(2,4-difluorophenoxy)-3-pyrazinecarboxylic acid is precipitated from the solution.
Reaction SMILES: [CH3:1][C:2]1([CH2:15][N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:6][C:5]2[C:7]([CH3:14])=[C:8]([NH2:13])[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1.[CH3:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=1>>[CH3:1][C:2]1([CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:27](=[O:28])[C:26]3[CH:30]=[CH:31][C:23]([CH3:22])=[CH:24][CH:25]=3)[CH2:18][CH2:17]2)[CH2:6][C:5]2[C:7]([CH3:14])=[C:8]([NH2:13])[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1
Reactant: Cc1ccc(C(=O)O)cc1
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCNCC1)O2
Product: Cc1ccc(C(=O)N2CCN(CC3(C)Cc4c(C)c(N)c(C)c(C)c4O3)CC2)cc1
Yield: 53 %

Procedure:
Using 2,3-dihydro-2,4,6,7-tetramethyl-2-[(1-piperazinyl)methyl]-5-benzofuranamine and 4-methylbenzoic acid, the procedure of Example 10, presented hereinafter, was otherwise followed to provide the title compound. Yield 53%.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[CH:9][C:8]=2[CH:12]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OP([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])(OCC)=O)C.[H-].[Na+].Cl>CN(C)C=O>[C:1]1([C:7]2[O:11][N:10]=[CH:9][C:8]=2/[CH:12]=[CH:22]/[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1cnoc1-c1ccccc1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cnoc1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
To a mixture of 5-phenylisoxazole-4-carbaldehyde (7.18 g), ethyl diethylphosphonoacetate (9.35 g) and N,N-dimethylformamide (150 ml) was added sodium hydride (60%, oil, 1.65 g) at 0° C., and the mixture was stirred at room temperature for 3 hr. The reaction mixture was poured into dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl (E)-3-(5-phenyl-4-isoxazolyl)propenoate (8.88 g, yield 88%) was obtained as a yellow oil from a fraction eluted with ethyl acetate-hexane (1:4, volume ratio). NMR (CDCl3) δ: 1.33 (3H, t, J=7.2 Hz), 4.27 (2H, q, J=7.2 Hz), 6.34 (1H, d, J=15.4 Hz), 7.48–7.82 (6H, m), 8.52 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](=[O:16])[CH2:10][CH2:11][CH2:12][C:13](O)=[O:14].S(=O)(=O)(O)O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:9](=[O:16])[CH2:10][CH2:11][CH2:12][C:13]1=[O:14]
Reactant: O=C(O)CCCC(=O)Cc1ccccc1Cl
Agent: O=S(=O)(O)O
Product: O=C1CCCC(=O)C1c1ccccc1Cl
Temperature: 120 °C
Yield: 63.2 %

Procedure:
A 500 ml round bottom flask was charged with 10.0 g (0.0416 mol) of 6-(2'-chlorophenyl)-5-ketohexanoic acid and 100 ml of 72% sulfuric acid. The reaction mixture was stirred and heated to 120° C. for 51/2 hours (oil bath), then poured into 600 ml of an ice water mixture. A tacky, white solid formed, and this was extracted into 300 ml of methylene chloride. The CH2Cl2 was washed six times with water, dried over anhydrous MgSO4 and stripped to leave 8.87 g of a tacky, white solid. This material was recrystallized from ethyl acetate to give 5.85 g (63%) of 2-(2'-chlorophenyl)-1, 3-cyclohexanedione as a white, crystalline solid, m.p. 148.5°-149° C.
Reaction SMILES: [Cl:1][C:2]1[C:3](=O)[NH:4][C:5](=[O:9])[NH:6][C:7]=1[CH3:8].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:12]>O1CCOCC1>[Cl:1][C:2]1[C:3](=[S:12])[NH:4][C:5](=[O:9])[NH:6][C:7]=1[CH3:8]
Reactant: Cc1[nH]c(=O)[nH]c(=O)c1Cl
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: C1COCCO1
Product: Cc1[nH]c(=O)[nH]c(=S)c1Cl
Yield: 75 %

Procedure:
5-Chloro-6-methyluracil (prepared as described in Johnson, B. T. J. Amer. Chem. Soc. 65 (1943) (1220) (0.018 mol) and phosphorus pentasulphide (0.019 mol) were heated together in refluxing dioxan (200 ml) for 45 min. The hot reaction mixture was then filtered and the cold filtrate concentrated and diluted with ether. The participate collected after a few hours in the cold, was recrystallised from water; yield 75% m.p. 297°-300° C. (decomp.); (Found: C, 32.69; H, 3.96. Calc. for C5H5ClN2OS.1/2H2O: C, 32.35; H, 3.25).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[CH:5]=[C:6]([F:9])[C:7]=1F.[F:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1>CN(C=O)C>[F:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:7]2[C:6]([F:9])=[CH:5][C:4]([N+:10]([O-:12])=[O:11])=[CH:3][C:2]=2[F:1])=[CH:16][CH:15]=1
Reactant: Oc1ccc(F)cc1
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(F)c(Oc2ccc(F)cc2)c(F)c1
Temperature: 25 °C
Yield: 105 %

Procedure:
A mixture of 3,4,5-trifluoronitrobenzene (20.0 g, 113 mmol, commercially available from AsymChem of Durham, N.C.), dry DMF (100 ml), 4-fluorophenol (13.9 g, 124 mmol), and CS2CO3 (56 g, 172 mmol) was stirred under N2 at 60-70° C. for 1-2 hrs. After cooling to room temperature, the reaction mixture was partitioned between H2O and EtOAc. The phases were separated and the aqueous phase was further extracted with EtOAc (2×). The EtOAc extractions were washed with sat'd NaCl (1×), dried over Na2SO4, and concentrated in vacuo to give 4-(4-fluorophenoxy)-3,5-difluoronitrobenzene (32.0 g, 105%) which was used in the next step without further purification. 1H NMR (DMSO-d6): δ 7.15 (m, 2H), 7.22 (m, 2H), 8.31 (d, 2H, J=7.6 Hz).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]1[C:8](=[O:14])[NH:9][C:10](=[S:13])[NH:11][CH:12]=1.[CH3:15]I.[OH-].[Na+].O>C(O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]1[C:8](=[O:14])[NH:9][C:10]([S:13][CH3:15])=[N:11][CH:12]=1
Reactant: CI
Reactant: O=c1[nH]c(=S)[nH]cc1Cc1cccs1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CSc1ncc(Cc2cccs2)c(=O)[nH]1
Yield: 89 %

Procedure:
5-(2-Thienylmethyl)-2-thiouracil (4.5 g) was warmed at 65° with a mixture of methyl iodide (2.8 g), sodium hydroxide (0.8 g), water (75 ml) and ethanol (150 ml) to give 5-(2-thienylmethyl)-2-methylthio-4-pyrimidone (89%) m.p. 170.5°-171.5° (ethanol).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:15])=[C:6]([CH:14]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]>CO.C(N(CC)C(C)C)(C)C.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>[Cl:15][C:5]1[CH:4]=[CH:3][C:2]([C:7]([O:9][CH3:10])=[O:8])=[CH:14][C:6]=1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: CC(C)(C)OC(=O)c1cc(Br)ccc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COC(=O)c1ccc(Cl)c(C(=O)OC(C)(C)C)c1
Reaction time: 12 h
Yield: 76 %

Procedure:
tert-Butyl 5-bromo-2-chlorobenzoate (1.9 g) (WO2003095430) was dissolved in methanol (18 ml) with N,N-diisopropylethylamine (2 mL) and dichlorobis(triphenylphosphine)-palladium(II) (0.134 g). The mixture was carbonylated at 85° C. for 12 h. The cooled solution was evaporated and purified by flash chromatography, eluting with 5:95 ethyl acetate/isohexane, to yield the subtitle compound as a colourless oil (0.67 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[O:6][CH2:7][C:8](O)=O.[CH:14]1([NH2:17])[CH2:16][CH2:15]1>>[CH:14]1([NH:17][CH2:8][CH2:7][O:6][C:5]2[CH:11]=[CH:12][CH:13]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:16][CH2:15]1
Reactant: NC1CC1
Reactant: COc1cccc(OCC(=O)O)c1
Product: COc1cccc(OCCNC2CC2)c1

Procedure:
Synthesized according to typical procedures C and D from (3-methoxyphenoxy)-acetic acid and cyclopropylamine.
Reaction SMILES: [CH:1]1[C:6]([CH:7]=O)=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.[CH:12]1([NH2:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.[Ni]>[CH:12]1([NH:20][CH2:7][C:6]2[CH:1]=[CH:2][C:3]3[O:11][CH2:10][O:9][C:4]=3[CH:5]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: NC1CCCCCCC1
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: [Ni]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: c1cc2c(cc1CNC1CCCCCCC1)OCO2

Procedure:
16.5 g of piperonal, 12,7a g of cyclooctylamine and a catalytical amount of p-toluene-sulfonic acid were hydrogenated for 6 hours in 500 ml of methanol over Raney nickel at 100° C/100 atmospheres gauge pressure. After removal of the catalyst, evaporation of the solution and treatment of the residue with methanolic HCl, there were obtained 23 g of N-cyclooctyl-3,4-methylenedioxy-benzylamine. Melting point 164°-165° C (from ethanol/ether).
Reaction SMILES: Cl.[NH2:2][OH:3].[Cl:4][C:5]1[CH:6]=[C:7]([C@@H:15]([CH2:26][CH:27]2[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]2)[C:16]([NH:18][C:19]2[CH:24]=[N:23][C:22]([Cl:25])=[CH:21][N:20]=2)=[O:17])[CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12]>CO.N1C(C)=CC=CC=1C>[Cl:4][C:5]1[CH:6]=[C:7]([C@@H:15]([CH2:26][CH:27]2[CH2:32][CH2:31][C:30](=[N:2][OH:3])[CH2:29][CH2:28]2)[C:16]([NH:18][C:19]2[CH:24]=[N:23][C:22]([Cl:25])=[CH:21][N:20]=2)=[O:17])[CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCC(=O)CC2)C(=O)Nc2cnc(Cl)cn2)cc1Cl
Reactant: NO
Agent: Cl
Solvent: Cc1cccc(C)n1
Solvent: CO
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCC(=NO)CC2)C(=O)Nc2cnc(Cl)cn2)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.6 %

Procedure:
A solution of hydroxylamine hydrochloride (7.0 mg, 0.099 mmol) in methanol (0.2 mL) and 2,6-lutidine (0.2 mL) was treated with 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-N-(5-chloro-pyrazin-2-yl)-3-(4-oxo-cyclohexyl)-propionamide (prepared as in Example 61, 31 mg, 0.066 mmol). The reaction mixture was stirred at 25° C. for 30 min and was then concentrated in vacuo to remove methanol. The resulting residue was suspended in ethyl acetate (10 mL), washed with water 1×5 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 12S, Silica, 13/7 hexanes/ethyl acetate to 2/3 hexanes/ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-N-(5-chloro-pyrazin-2-yl)-3-(4-hydroxyimino-cyclohexyl)-propionamide (30 mg, 93.7%) was a white foam: [α]23589=−23.24° (c=0.37, chloroform); EI-HRMS m/e calcd for C20H22Cl2N4O4S (M+H)+ 485.0812. found 485.0822.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]O)=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.S(Cl)([Cl:24])=O.C(=O)(O)[O-].[Na+].O>ClCCl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][Cl:24])=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cnc2cc(Br)ccc2c1NCCCCCO
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1cnc2cc(Br)ccc2c1NCCCCCCl
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A suspension of 5-(7-bromo-3-nitroquinolin-4-ylamino)pentan-1-ol (0.92 g, 2.6 mmol) in dichloromethane (13 mL) was cooled to 0° C.; thionyl chloride was added dropwise. The reaction was stirred for five minutes at 0° C. then allowed to warm to ambient temperature and stirred overnight. Saturated aqueous sodium bicarbonate (25 mL) was slowly added followed by water (25 mL). The aqueous layer was separated and extracted with dichloromethane (3×50 mL), and the combined organic fractions were dried over magnesium sulfate and concentrated under reduced pressure to provide 0.91 g of (7-bromo-3-nitroquinolin-4-yl)-(5-chloropentyl)amine as a yellow semisolid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3([CH3:20])[CH2:18][C:17](=N)[NH:16][NH:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl.C([OH:24])C>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3([CH3:20])[CH2:18][C:17](=[O:24])[NH:16][NH:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC1(c2ccc(-c3ccc(F)cc3)cc2)CC(=N)NN1
Reactant: CCO
Agent: Cl
Product: CC1(c2ccc(-c3ccc(F)cc3)cc2)CC(=O)NN1

Procedure:
26.9 g of 3-(4'-fluoro-4-biphenylyl)-3-methyl-5-imino-pyrazolidine [obtainable from 3-(4'-fluoro-4-biphenylyl)-2-butenoic acid nitrile and hydrazine] are boiled for 10 minutes with 150 ml of 20% strength aqueous hydrochloric acid and 150 ml of ethanol, and the solution is concentrated, neutralized and worked up in the usual manner to give 3-(4'-fluoro-4-biphenylyl)-3-methyl-pyrazolidin-5-one, m.p. 194°-196°.
Reaction SMILES: [Cl:1]C(Cl)C.S(Cl)(Cl)=O.[CH3:9][C:10]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:11]=1[O:12][CH2:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](O)=[O:17]>CN(C)C=O>[CH3:9][C:10]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:11]=1[O:12][CH2:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([Cl:1])=[O:17]
Reactant: CC(Cl)Cl
Reactant: Cc1ccc(C)c(OCc2ccccc2C(=O)O)c1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: Cc1ccc(C)c(OCc2ccccc2C(=O)Cl)c1

Procedure:
Dichloroethane (20 ml), thionyl chloride (1.31 g, 0.011 mol) and N,N-dimethylformamide (0.1 ml) were added to 2-(2,5-dimethylphenoxymethyl)benzoic acid (2.56 g, 0.01 mol), and the mixture was stirred under reflux for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give crude 2-(2,5-dimethylphenoxymethyl)benzoyl chloride. 1.6M n-butyllithium/n-hexane solution (6.25 ml, 0.01 mol) was added to a mixture of 1-methylpyrazole (0.99 g, 0.012 mol) and THF (10 ml) at −70 to −60° C. over 15 minutes, and then the mixture was stirred at −70° C. to room temperature for 1 hour. The reaction mixture was cooled to −70° C., and a solution of the crude 2-(2,5-dimethylphenoxymethyl)benzoyl chloride in THF (10 ml) was added, and the mixture was stirred at −70° C. for 1 hour. After completion of the reaction, iN hydrochloric acid (100 ml) was added, and the mixture was extracted with ether. The ether layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-(2,5-dimethylphenoxymethyl)phenyl 1-methylpyrazol-5-yl ketone (0.50 g, 15.6%) as colorless crystals.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[C:11]([C:26]#[N:27])[C:12](=[O:25])[NH:13][C:14]=2[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[CH:6]=[CH:5][N:4]=1.[C:28](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C>[CH3:28][N:13]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)=[C:9]([C:7]2[CH:6]=[CH:5][N:4]=[C:3]([S:2][CH3:1])[N:8]=2)[CH:10]=[C:11]([C:26]#[N:27])[C:12]1=[O:25]
Reactant: O=C([O-])[O-]
Reactant: CSc1nccc(-c2cc(C#N)c(=O)[nH]c2-c2cccc(C(F)(F)F)c2)n1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: CSc1nccc(-c2cc(C#N)c(=O)n(C)c2-c2cccc(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.1 %

Procedure:
To a solution of 5-(2-methylsulfanylpyrimidin-4-yl)-2-oxo-6-(3-trifluoromethylphenyl)-1,2-dihydropyridine-3-carbonitrile (150 mg, 0.00040 mol) in 3 mL DMF was added cesium carbonate (200 mg, 0.00060 mol) and methyl iodide (1 mL, 0.0154 mol) and the solution stirred at room temperature for 1 h. The mixture was the partitioned between H2O and EtOAc and the organic phase dried over anhydrous sodium sulfate and concentrated. Chromatography on silica with 3% MeOH in CH2Cl2 yields 100 mg (65%) 1-methyl-5-(2-methylsulfanyl-pyrimidin-4-yl)-2-oxo-6-(3-trifluoromethyl-phenyl)-1,2-dihydropyridine-3-carbonitrile as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-:14])=[O:13])=[C:5]2Cl.[CH3:16][O:17][C:18]1[N:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=1.O>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-:14])=[O:13])=[C:5]2[NH:24][C:21]1[CH:22]=[N:23][C:18]([O:17][CH3:16])=[CH:19][CH:20]=1
Reactant: O=[N+]([O-])c1cnc2ccc(Br)cc2c1Cl
Reactant: COc1ccc(N)cn1
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(Nc2c([N+](=O)[O-])cnc3ccc(Br)cc23)cn1
Reaction time: 8 h

Procedure:
6-Bromo-4-chloro-3-nitroquinoline (compound of step 1, 5.2 mmol) and 6-methoxypyridin-3-amine (commercially available, 5.2 mmol) was dissolved in acetic acid (5 mL) and the mixture was stirred overnight. Water was added and the yellow precipitate was filtered off. The precipitate was washed with water and dried. The solid obtained was partitioned and extracted with EtOAc and THF, washed with saturated aqueous NaHCO3. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the title compound. 1H NMR (DMSO-d6, 300 MHz): 10.03 (s, 1H), 9.01 (s, 1H), 8.72 (d, J=1.5 Hz, 1H), 8.04-7.90 (m, 3H), 7.50 (dd, J=2.4, 8.7 Hz, 1H), 6.82 (d, J=9.0 Hz, 1H), 3.85 (s, 3H); MS (m/z): 377.0 (M+1)+.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:10](OC(OCC)OCC)C>B(F)(F)F.CCOCC>[O:1]1[CH:10]=[N:9][C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N:2]1
Reactant: CCOC(=O)C(=N)NO
Reactant: CCOC(OCC)OCC
Agent: FB(F)F
Solvent: CCOCC
Product: CCOC(=O)c1ncon1
Yield: 83.7 %

Procedure:
To a suspension of ethyl 2-(hydroxyamino)-2-iminoacetate (3 g, 22.71 mmol) in triethylorthoformate (14 mL, 84.08 mmol) was added boron trifluoride diethyl etherate (0.144 mL, 1.14 mmol). It was heated for 90 minutes. The reaction mixture was concentrated under reduced pressure and the residue dissolved in chloroform. The resulting organic layer was washed with aqueous hydrochloric acid 2N (2×80 mL), aqueous sodium bicarbonate 4% (1×80 mL) and water (2×80 mL), it was dried over anhydrous sodium sulphate and the solvent removed under reduced pressure to yield the title compound (2.70 g, 79%) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:17](=[O:18])[NH:16][C:15]2[C:10]1=[N:11][C:12]([NH:24][CH2:25][C@H:26]1[CH2:30][CH2:29][CH2:28][NH:27]1)=[N:13][C:14]=2[C:19]([O:21]CC)=O.C(OC([N:38]1CCC[C@@H]1CNC1N=C2C(NC(=O)N2C2C=CC=CC=2OC)=C(C(OCC)=O)N=1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:17](=[O:18])[NH:16][C:15]2[C:10]1=[N:11][C:12]([NH:24][CH2:25][C@H:26]1[CH2:30][CH2:29][CH2:28][NH:27]1)=[N:13][C:14]=2[C:19]([NH2:38])=[O:21]
Reactant: CCOC(=O)c1nc(NC[C@H]2CCCN2C(=O)OC(C)(C)C)nc2c1[nH]c(=O)n2-c1ccccc1OC
Reactant: CCOC(=O)c1nc(NC[C@H]2CCCN2)nc2c1[nH]c(=O)n2-c1ccccc1OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1-n1c(=O)[nH]c2c(C(N)=O)nc(NC[C@H]3CCCN3)nc21
Yield: 100 %

Procedure:
(R)-Ethyl 9-(2-methoxyphenyl)-8-oxo-2-(pyrrolidin-2-ylmethylamino)-8,9-dihydro-7H-purine-6-carboxylate. (R)-Ethyl 2-((1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methylamino)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxylate (0.381 g, 0.744 mmol) was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (1 mL) was added. The solution was stirred for two h and condensed under reduced pressure to afford the crude title compound (0.420 g, >100%). MS (ESI) m/z 413.1 [M+1]+.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([C:16]2[S:20][C:19](=[S:21])[NH:18][N:17]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].[H-].[Na+].IC.[CH3:26]COCC>O1CCCC1>[CH3:15][C:12]([C:9]1[CH:8]=[C:7]([C:16]2[S:20][C:19]([S:21][CH3:26])=[N:18][N:17]=2)[CH:6]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:10]=1[OH:11])([CH3:13])[CH3:14]
Reactant: CCOCC
Reactant: CC(C)(C)c1cc(-c2n[nH]c(=S)s2)cc(C(C)(C)C)c1O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CSc1nnc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
5-[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazole-2(3H)-thione (3.0 g, 0.0093 mole) in tetrahydrofuran (15 ml) is added dropwise to a stirred 0° C. suspension of sodium hydride (0.37 g of a 60% dispersion in mineral oil, 0.0093 mole) in tetrahydrofuran (15 ml) under nitrogen. After 30 minutes, a solution of iodomethane (1.5 g, 0.0102 mole) in tetrahydrofuran (5 ml) is added dropwise. After stirring one hour at 0° C., ether (20 ml) is added and the resulting mixture is washed with aqueous 2M HCl (10 ml), saturated aqueous NaCl, and dried over MgSO4. Filtration and concentration in vacuo, followed by recrystallization from ether/hexane gives 2.6 g of 2,6-bis(1,1-dimethylethyl)-4-[5-(methylthio)-1,3,4-thiadiazol-2-yl]phenol (3.1 g, theor., 83%), mp 122°-122.5° C.