Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH2:3][CH2:4][CH2:5][C:6]([OH:8])=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[S:42]1[CH:46]=[CH:45][N:44]=[C:43]1[C:47]1[N:51]=[C:50]([CH:52]2[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]2)[O:49][N:48]=1>CN(C=O)C>[F:9][C:2]([F:1])([F:10])[CH2:3][CH2:4][CH2:5][C:6]([N:55]1[CH2:54][CH2:53][CH:52]([C:50]2[O:49][N:48]=[C:47]([C:43]3[S:42][CH:46]=[CH:45][N:44]=3)[N:51]=2)[CH2:57][CH2:56]1)=[O:8]
Reactant: O=C(O)CCCC(F)(F)F
Reactant: c1csc(-c2noc(C3CCNCC3)n2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(CCCC(F)(F)F)N1CCC(c2nc(-c3nccs3)no2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
5,5,5-Trifluoropentanoic acid (1.3 equiv), EDCI (1.3 equiv), HOBt (0.3 equiv) and DIEA (4 equiv) were mixed in DMF (40 mL) for 5 minutes. 4-(3-thiazol-2-yl-[1,2,4]oxadiazol-5-yl)-piperidine hydrochloride (5c) (8.18 g, 30 mmol, 1 equiv) was added with 20 mL of DMF and the reaction mixture was stirred overnight at room temperature and then evaporated under reduced pressure. The residue was dissolved in AcOEt and then washed twice with saturated aqueous NaHCO3, twice with HCl 1N and once with brine, then dried over MgSO4 and evaporated under reduced pressure. The residue was purified by chromatography on silica gel (DCM/MeOH 100-0 to 98.5-1.5) and then recrystallized in a mixture of isopropanol and diisopropyl ether. Yield 62%; 1H NMR (CD2Cl2) δ 8.06 (d, J=3.0 Hz, 1H), 7.65 (d, J=3.0 Hz, 1H), 4.51-4.55 (m, 1H), 3.90-3.95 (m, 1H), 3.22-3.39 (m, 2H), 2.91-2.98 (m, 1H), 2.44 (t, J=7.2 Hz, 2H), 2.15-2.27 (m, 4H), 1.83-2.01 (m, 4H); 13C NMR (CDCl3) δ 182.06, 169.56, 163.97, 154.00, 144.95, 127.37 (q, J=275 Hz), 122.66, 44.33, 40.60, 34.43, 32.97 (q, J=29 Hz), 31.34, 29.44, 28.90, 17.52. mp 75.6-76.3° C.; tR LCMS 6.1 min. Purity >99%; MS [M+H]+ m/z 375.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]=[S:13].[CH3:14][NH:15][NH2:16]>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:11][C:12](=[S:13])[N:15]([CH3:14])[NH2:16]
Reactant: CNN
Reactant: O=[N+]([O-])c1ccc(N=C=S)c(Cl)c1
Solvent: CCO
Product: CN(N)C(=S)Nc1ccc([N+](=O)[O-])cc1Cl
Temperature: 65 °C
Reaction time: 18 h
Yield: 80.8 %

Procedure:
To a stirred solution of 60.0 g (0.280 mole) of 2-chloro-4-nitrophenyl isothiocyanate in 500 ml of ethanol was added 12.9 g (0.280 mole) of methylhydrazine. This mixture was heated and was stirred at 65° C. for approximately 18 hours. The mixture was then heated to reflux and was cooled. A solid had formed and was collected by filtration. The filter cake was rinsed with aqueous ethanol and was dried under reduced pressure to yield 59.0 g of 4-(2-chloro-4-nitrophenyl)-2-methyl-3-thiosemicarbazide, mp 164°-167° C. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]2[C:12]([CH3:15])=[N:13][NH:14][C:8]=2[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[F:16][C:17]1[CH:32]=[CH:31][C:20]([C:21]([C:23]2[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=2)=[O:22])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([N:5]1[C:10](=[O:11])[C:9]2=[C:12]([CH3:15])[N:13]([CH2:27][C:26]3[CH:25]=[CH:24][C:23]([C:21](=[O:22])[C:20]4[CH:31]=[CH:32][C:17]([F:16])=[CH:18][CH:19]=4)=[CH:30][CH:29]=3)[N:14]=[C:8]2[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(c1ccc(F)cc1)c1ccc(CBr)cc1
Reactant: Cc1n[nH]c2cnn(C(C)(C)C)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c2c(=O)n(C(C)(C)C)ncc2nn1Cc1ccc(C(=O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
In DMF (10 ml) was dissolved 5-t-butyl-3-methyl-1H-pyrazolo [3,4-d]pyridazin-4(5H)-one (516 mg) followed by addition of 4-(4-fluorobenzoyl)benzyl bromide (1.1 g) and potassium carbonate (525 mg), and the mixture was stirred at room temperature for 15 hours. This reaction mixture was extracted with diethyl ether and the organic layer was serially washed with water and saturated aqueous NaCl solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (n-hexaneethyl acetate=1:1), washed with the following solvent, and dried. As the washing solvent, n-hexanediethyl ether was used for 5-t-butyl-1-[4-(4-fluorobenzoyl) benzyl]-3-methyl-1H-pyrazolo[3,4-d]-pyridazin-4(5H)-one and diethyl ether-ethyl acetate for 5-t-butyl-2-[4-(4-fluorobenzoyl)benzyl]-3-methyl-2H-pyrazolo [3,4-d]pyridazin-4(5H)-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:20]=[CH:19][C:18](I)=[C:17]([O:22][CH3:23])[CH:16]=2)[N:10]=1.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]#[CH:32])[C:26]=1[F:33].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>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.CS(C)=O>[Cl:24][C:25]1[C:26]([F:33])=[C:27]([C:31]#[C:32][C:18]2[CH:19]=[CH:20][C:15]([N:11]3[C:12](=[O:14])[NH:13][C:9]([C:3]4[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])=[N:10]3)=[CH:16][C:17]=2[O:22][CH3:23])[CH:28]=[CH:29][CH:30]=1
Reactant: C#Cc1cccc(Cl)c1F
Reactant: COc1cc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)ccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Product: COc1cc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)ccc1C#Cc1cccc(Cl)c1F
Yield: 28.9 %

Procedure:
The title compound was prepared according to the procedure described in Example-3 using 3-(2-chloro-6-fluorophenyl)-1-(4-iodo-3-methoxyphenyl)-1H-1,2,4-triazol-5(4H)-one (Intermediate-32, 0.050 g, 0.11 mmol), 1-chloro-3-ethynyl-2-fluorobenzene (Intermediate-24, 0.033 g, 0.22 mmol), TBAF (0.080 g, 0.30 mmol), bis(triphenylphosphine)palladium(II) chloride (0.020 g, 0.022 mmol) and DMSO (3.0 ml) at 80° C. to afford 0.015 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 3.89 (s, 3H), 7.28 (t, J=7.8 Hz, 1H), 7.48 (t, J=9.0 Hz, 1H), 7.56-7.70 (m, 7H), 12.79 (m, 1H); MS (m/z): 470.00 (M−H)−.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>N1C=CC=CC=1>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:19](=[O:21])[CH3:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)OC(C)=O
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Solvent: c1ccncc1
Product: CC(=O)NCCCOc1cccc(CN2CCCCC2)c1
Reaction time: 4 h

Procedure:
One gram of 3-[3-(1-piperidinylmethyl)phenoxy]propylamine was dissolved in 1 ml of pyridine, and 0.5 ml of acetic anhydride was added. The mixture was allowed to stand at room temperature for 4 hours. The solvent was distilled off under reduced pressure, and small amounts of water and potassium carbonate were added. The mixture was extracted with chloroform, washed with water, and dried. Then, the solvent was distilled off. The residue was purified by TLC (developing solvent: chloroform/methanol=9/l) to afford 753 mg of N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl] acetamide as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:17][C:18]1[CH:22]=[C:21]([C:23](Cl)=[O:24])[O:20][N:19]=1>CC(C)=O>[C:6]([C:5]1[CH:9]=[CH:10][C:2]([NH:1][C:23]([C:21]2[O:20][N:19]=[C:18]([CH3:17])[CH:22]=2)=[O:24])=[CH:3][CH:4]=1)([OH:8])=[O:7]
Reactant: Cc1cc(C(=O)Cl)on1
Reactant: Nc1ccc(C(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc(C(=O)Nc2ccc(C(=O)O)cc2)on1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.7 %

Procedure:
To a stirred suspension of 6.9g of p-aminobenzoic acid and 3.5 g of potassium carbonate in 60 ml of acetone was added 7.3 g of 3-methylisoxazole-5-carbonyl chloride. The mixture was stirred at room temperature for 1 hr. and then refluxed for 1 hr. The precipitate was filtered off and dissolved in water. The solution was acidified with concentrated hydrochloride acid. The precipitate was filtered off and washed with ethanol. There was obtained 9.1 g of N-(p-carboxyphenyl)-3-methylisoxazole-5-carboxamide. Melting point: above 300° C. Yield: 73.4%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:4][C:3]=1[C:21]([F:24])([F:23])[F:22].Cl.[CH2:26]([O:28][C:29](=[O:32])[CH2:30][NH2:31])[CH3:27].O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>>[CH2:26]([O:28][C:29](=[O:32])[CH2:30][NH:31][C:16](=[O:17])[C:15]1[CH:14]=[CH:13][C:12]([S:9](=[O:11])(=[O:10])[NH:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:21]([F:22])([F:23])[F:24])[CH:4]=2)=[CH:20][CH:19]=1)[CH3:27]
Reactant: O=C(O)c1ccc(S(=O)(=O)Nc2ccc(F)c(C(F)(F)F)c2)cc1
Reactant: CCOC(=O)CN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)CNC(=O)c1ccc(S(=O)(=O)Nc2ccc(F)c(C(F)(F)F)c2)cc1

Procedure:
Under the conditions of Example 2(a), 3.633 g (10 mmol) of 4-[N-(4-fluoro-3-trifluoromethylphenyl)sulfamoyl]benzoic acid, 1.396 g (10 mmol) of glycine ethyl ester hydrochloride, 1.531 g (10 mmol) of hydroxybenzotriazole, hydrate, as well as 1.012 g (10 mmol) of triethylamine and 2.063 g (10 mmol) of dicyclohexylcarbodiimide are reacted and worked up analogously. The crude product is chromatographed on silica gel. The title compound is eluted with ethyl acetate.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH2:17][N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[C:33]1([CH2:39][C:40](Cl)=[O:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(#N)C>[O:32]=[C:26]1[CH:25]([N:18]2[CH2:17][C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:40](=[O:41])[CH2:39][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C(Cc1ccccc1)NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.5 h
Yield: 55.1 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.7 g, 4.3 mmol) was added to a stirred suspension of 3-[4-(aminomethyl)-1-oxo-1,3-dihydro-isoindol-2-yl]piperidine-2,6-dione hydrochloride (0.6 g, 1.9 mmol) in acetonitrile (50 mL). After stirring for 30 minutes, phenylacetyl chloride (0.4 g, 2.3 mmol) was added. The mixture was stirred at room temperature for 17 hours. Solvent was removed and the residue was stirred with water (40 mL) to give N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-2-phenyl-acetamide (0.41 g, 54%) as a white solid: mp 236-238° C.; 1H NMR (DMSO-d6) δ 1.94-1.98 (m, 1H, CH2), 2.15-2.19 (m, 1H, CH2), 2.49-2.63 (m, 1H, CH2), 2.85-2.99 (m, 1H, CH2), 3.47 (s, 2H, CH2), 4.23-4.43 (m, 4H, 2CH2), 5.07-5.14 (dd, J=5.1 and 13.2 Hz, 1H, CH), 7.18-7.33 (m, 5H, Ar), 7.46-7.64 (m, 3H, Ar), 8.61 (t, J=5.6 Hz, 1H, NH), 11.03 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.51, 31.14, 42.23, 46.08, 51.47, 121.70, 126.34, 128.22, 128.95, 130.73, 131.69, 134.49, 136.16, 140.09, 167.99, 170.18, 170.87, 172.81; Anal. calcd. for C22H21N3O4+0.07H2O: C, 67.29; H, 5.43; N, 10.70. Found: C, 66.94; H, 5.22; N, 10.63.
Reaction SMILES: [C:1]1(=[O:8])[CH:6]=[CH:5][C:4](=[O:7])[CH:3]=[CH:2]1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([OH:18])=[O:17])=[CH:12][CH:11]=1>CCO.O>[F:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([C:6]2[CH:5]=[C:4]([OH:7])[CH:3]=[CH:2][C:1]=2[OH:8])(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: O=C1C=CC(=O)C=C1
Reactant: O=S(O)c1ccc(F)cc1
Solvent: O
Solvent: CCO
Product: O=S(=O)(c1ccc(F)cc1)c1cc(O)ccc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.1 %

Procedure:
A solution of benzoquinone (23.5 g, 217 mmol) in 500 ml EtOH was added at RT over 30 min to a solution of 4-fluoro-benzenesulfinic acid (34.8 g, 217 mmol) in EtOH (300 mL) and water (500 mL). The resulting solution was stirred 2 h at RT, then diluted to 4l with warm water. The solution was cooled to 4° C. for 62 h and crystals formed. The crystalline solid was collected by suction filtration and washed with water (3×500 mIL and hexanes (2×500 mL) and dried to give the title compound of Step B (40.8 g). MS (APCl−) Calc.: 268.0, Found: 267.1 (M−1).
Reaction SMILES: [Br:1]Br.[O:3]=[C:4]1[C:9]([C:10]#[N:11])=[CH:8][CH:7]=[CH:6][NH:5]1>C(O)(=O)C>[Br:1][C:7]1[CH:8]=[C:9]([C:10]#[N:11])[C:4](=[O:3])[NH:5][CH:6]=1
Reactant: N#Cc1ccc[nH]c1=O
Reactant: BrBr
Solvent: CC(=O)O
Product: N#Cc1cc(Br)c[nH]c1=O

Procedure:
Bromine (29 ml, 560 mmol) was added to a stirred solution of 2-oxo-1,2-dihydro-pyridine-3-carbonitrile (34 g, 280 mmol) in acetic acid (180 ml) at room temperature. After 14 hours the reaction mixture was concentrated in vacuo and the resulting oil was trituated with ethanol to afford the title compound as a solid.
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1[OH:20]>C1(C)C=CC=CC=1>[CH:1]1([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=2[OH:20])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: O=C=NC1CCCCC1
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc([N+](=O)[O-])cc1O)NC1CCCCC1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
To a solution of cyclohexyl isocyanate (400 mg, 3.19 mmol) in toluene, 2-amino-5-nitrophenol (492 mg, 3.19 mmol) was added. The reaction mixture was stirred at 80° C. for 24 hours, then cooled to room temperature. The product was purified by precipitation from toluene and filtering (752 mg, 93%). m.p: 1850-186.0° C.; EI-MS m/z 280 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[C:9]([N+:15]([O-:17])=[O:16])=[N:10][C:11]([Br:14])=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:21]I>CN(C=O)C>[C:1]([O:5][C:6](=[O:18])[N:7]([C:8]1[C:9]([N+:15]([O-:17])=[O:16])=[N:10][C:11]([Br:14])=[CH:12][CH:13]=1)[CH3:21])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Br)nc1[N+](=O)[O-]
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1ccc(Br)nc1[N+](=O)[O-]
Reaction time: 0.25 h
Yield: 88.7 %

Procedure:
To a stirred solution of (6-bromo-2-nitro-pyridin-3-yl)-carbamic acid tert-butyl ester (6) (290 mg, 0.91 mmol) in DMF (10 mL), NaH (57 mg, 1.36 mmol, 57% dispersion in oil) was added at 0° C. After stirring for 15 minutes, methyl iodide (79 μL, 1.27 mmol) was added and the reaction mixture was stirred for 1 hour. The reaction mixture was then quenched with saturated ammonium chloride solution (15 mL) and extracted with ethyl acetate (2×40 mL). The combined organic extracts were washed with water, brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography using 20% ethyl acetate in hexane to give compound (7) (268 mg) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:18]([CH3:19])=[CH:17][C:5]([O:6][C:7]2[CH:12]=[C:11]([CH3:13])[C:10]([O:14]C)=[C:9]([CH3:16])[CH:8]=2)=[CH:4][C:3]=1[CH3:20].Br>C(O)(=O)C>[Cl:1][C:2]1[C:18]([CH3:19])=[CH:17][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH3:16])[C:10]([OH:14])=[C:11]([CH3:13])[CH:12]=2)=[CH:4][C:3]=1[CH3:20]
Reactant: COc1c(C)cc(Oc2cc(C)c(Cl)c(C)c2)cc1C
Agent: Br
Solvent: CC(=O)O
Product: Cc1cc(Oc2cc(C)c(Cl)c(C)c2)cc(C)c1O
Yield: 102.4 %

Procedure:
40 g of 4(4-chloro-3,5-dimethyl-phenoxy)-2,6-dimethylanisole were added to a solution of 125 ml of 48% hydrobromic acid and 300 ml of glacial acetic acid. The mixture was then refluxed for 2 hours at the reflux condenser. After concentration under reduced pressure, water was added to the residue and the mixture was extracted with methylene chloride. After the organic extract had been shaken several times with water, it was concentrated and the residue was distilled under greatly reduced pressure. 39 g of 4(4-chloro-3,5-dimethyl-phenoxy-2,6-dimethyl-phenol were obtained, boiling point: 186°-190° C. under a pressure of 2-3 mm mercury.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[N:6][CH:7]=1.[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br>>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:11][CH2:10][CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1
Reactant: BrCCCCCCBr
Reactant: OCCCc1ccc(Br)cn1
Product: BrCCCCCCOCCCc1ccc(Br)cn1
Yield: 68.4 %

Procedure:
From 3-(5-bromo-2-pyridinyl)propanol (2 g) and 1,6-dibromohexane (6.77 g) with a reaction time of 3 h. FCC eluting with hexane→hexane:ether (100:0→90:10) gave the title compound as a yellow oil (2.4 g), t.l.c. (hexane:ether 9:1) Rf 0.08.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[OH-].[Na+].[CH3:17]O>CCOC(C)=O.O>[CH3:17][O:8][C:7]([C:5]1[S:6][C:2]([Br:1])=[CH:3][CH:4]=1)=[O:9]
Reactant: CO
Reactant: O=C(O)c1ccc(Br)s1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Br)s1

Procedure:
To a solution of 5-bromo-thiophene-2-carboxylic acid (1.04 g, 5.0 mmol) in 15 mL of methanol, add concentrated sulfuric acid (0.5 ml, 10 mmol). After heating to reflux for an hour, cool the reaction to room temp, and dilute with EtOAc/H2O=50/50. Then, neutralize with 1.0 N NaOH to pH=7, extract the aqueous solution with ethyl acetate (30 ml×3), and dry the combined organic layers over sodium sulfate. Purify the crude material via flash chromatograpgy on sila gel to give the title compound 0.62 g. GC/MS (m/z) 222 (M+1), 191 (M—OMe+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[CH3:13][Si](C=[N+]=[N-])(C)C>C1(C)C=CC=CC=1.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)CCc1ccc(F)cc1
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)CCc1ccc(F)cc1
Reaction time: 1 h

Procedure:
To a solution of 3-(4-fluorophenyl)propionic acid (4.75 g, 28.2 mmol) in toluene (130 mL) and methanol (20 mL) was added trimethylsilyldiazomethane (2M solution in hexane, 16.24 mL, 32.5 mmol). The mixture was allowed to stir for 1 hour and gas evolution was observed initially. After 1 hour, the mixture became homogeneous and was quenched via addition of 3.5 mL of acetic acid. The mixture was concentrated in vacuo, and purified via column chromatography on a Biotage 65i column eluting with 0% ethyl acetate in hexanes (1 CV) followed by a gradient to 50% ethyl acetate in hexanes (over 7 CV) to furnish the desired product. 1H NMR (CDCl3, 500 MHz) δ 7.16 (dd, J=8.0 Hz, 5.6 Hz, 2H), 6.97 (t, J=8.5 Hz, 2H), 3.66 (s, 3H), 2.92 (t, J=7.5 Hz, 2H), 2.61 (t, J=7.7 Hz, 2H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH2:7])[CH2:3][CH2:2]1.[Cl:8][C:9]1[CH:10]=[C:11]([C:16]2[N:21]=[C:20]([CH3:22])[N:19]=[C:18]([N:23]([CH2:33][C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)[CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[N:17]=2)[C:12](F)=[N:13][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1>[Cl:8][C:9]1[CH:10]=[C:11]([C:16]2[N:21]=[C:20]([CH3:22])[N:19]=[C:18]([N:23]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)[CH2:33][C:34]3[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=3)[N:17]=2)[C:12]([NH:7][CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[N:13][CH:14]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3F)n2)cc1
Reactant: NC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3NC3CCOCC3)n2)cc1
Temperature: 120 °C
Yield: 74.4 %

Procedure:
A mixture of tetrahydro-2H-pyran-4-amine (130 mg, 1.285 mmol), 4-(5-chloro-2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (345 mg, 0.719 mmol), and cesium carbonate (165 mg, 0.506 mmol) in THF (2.5 mL) was heated under microwave irradiation (100° C., 15 min; 120° C., 2×15 min). The mixture was partitioned between EtOAc (10 mL) and water (5 mL). The organic layer was washed with water, saturated NH4Cl, dried over Na2SO4 and concentrated. The resulting solid was triturated with hot MeOH (10 mL) to give a yellow solid (300 mg). LCMS (ES, pos.): calcd for C30H33ClN6O3: 560.2. found: 561.2 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 9.48 (d, J=7.24 Hz, 1H); 8.67 (d, J=2.54 Hz, 1H); 8.13 (d, J=2.54 Hz, 1H); 7.18 (t, J=9.10 Hz, 4H); 6.87 (d, J=8.61 Hz, 4H); 4.82 (s, 2H); 4.77 (s, 2H); 4.17-4.29 (m, 1H); 3.91 (dt, J=11.74, 3.62 Hz, 2H); 3.81 (s, 3H); 3.80 (s, 3H); 3.55 (td, J=11.25, 1.96 Hz, 2H); 2.52 (s, 3H); 1.96 (br. s., 2H); 1.33-1.48 (m, 2H).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[CH3:14])[C:8]([OH:10])=O.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[C:37](=[N:40]O)([NH2:39])[CH3:38]>CN(C)C=O>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:8]2[O:10][N:40]=[C:37]([CH3:38])[N:39]=2)[CH:11]=[CH:12][C:13]=1[CH3:14]
Reactant: COCOc1cc(C(=O)O)ccc1C
Reactant: CC(N)=NO
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1cc(-c2nc(C)no2)ccc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3-methoxymethoxy-4-methyl-benzoic acid (1.96 g, 10 mmol) (from Example 50 supra), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.92 g, 10 mmol) (Aldrich) and 1-hydroxybenzotriazole hydrate (1.35 g, 10 mmol) (Aldrich) in N,N-dimethylformamide (25 mL) was stirred at room temperature for 30 minutes. Acetamide oxime (0.74 g, 10 mmol) (GFS Chemicals) was added and mixture heated at 140 C for 2 hours. After cooling, mixture was partitioned between ethyl acetate (2×) and saturated aqueous bicarbonate solution. Ethyl acetate solutions were combined and concentrated and residue purified by flash chromatography to give 5-(3-methoxymethoxy-4-methyl-phenyl)-3-methyl-[1,2,4]oxadiazole. (Yield 1.23 g, 52.5%).
Reaction SMILES: [NH:1]1[C:5](=O)[CH2:4][CH2:3][C:2]1=[O:7].[CH2:8](Br)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:8]([CH:5]1[NH:1][C:2](=[O:7])[CH2:3][CH2:4]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CCC(=O)N1
Product: O=C1CCC(Cc2ccccc2)N1

Procedure:
5-Benzylpyrrolidin-2-one is synthesized from pyrrolidine-2,5-dione and benzyl bromide according to S. Lebrun et al. (Tetrahedron Asymmetry 2003, 14, 2625-2632).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([NH:10][N:11]([CH2:13][C:14]([OH:16])=O)[CH3:12])=[O:9])=[CH:4][CH:3]=1.[NH2:19][C@@H:20]([CH3:44])[C:21]([N:23]([C@@H:35]([CH3:43])[CH:36]([O:40][CH2:41][CH3:42])[O:37][CH2:38][CH3:39])[CH2:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1)=[O:22]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8](=[O:9])[NH:10][N:11]([CH2:13][C:14]([NH:19][C@@H:20]([CH3:44])[C:21]([N:23]([C@@H:35]([CH3:43])[CH:36]([O:40][CH2:41][CH3:42])[O:37][CH2:38][CH3:39])[CH2:24][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=[CH:27][CH:26]=2)=[O:22])=[O:16])[CH3:12])=[CH:17][CH:18]=1
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](C)N
Reactant: CN(CC(=O)O)NC(=O)NCc1ccc(Cl)cc1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](C)NC(=O)CN(C)NC(=O)NCc1ccc(Cl)cc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(2-(4-chlorobenzylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-7) 114 mg (0.42 mmol) was coupled with (S)-2-amino-N—((S)-1,1-diethoxypropan-2-yl)-N-(naphthalen-1-ylmethyl)propanamide (Compound IV-10) 100 mg (0.28 mmol) to obtain the title compound.