Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH2:5]Cl)=O.[Cl:7][C:8]1[N:13]=[N:12][C:11]([NH2:14])=[CH:10][CH:9]=1>C(#N)C>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH:5]=[C:3]([CH2:2][Cl:1])[N:14]=2)[N:13]=1
Reactant: O=C(CCl)CCl
Reactant: Nc1ccc(Cl)nn1
Solvent: CC#N
Product: ClCc1cn2nc(Cl)ccc2n1
Yield: 38.5 %

Procedure:
1,3-Dichloroacetone (21.4 g, 168.0 mmol) was added to a solution of 6-chloropyridazin-3-amine (10 g, 77.2 mmol) in acetonitrile (200 ml). The mixture was heated at reflux for 14 h (the reaction was monitored by TLC). The volatiles were removed under reduced pressure and the reaction mixture was diluted with water. The pH was adjusted to ˜7.5 with sodium bicarbonate solution and then extracted with EtOAc. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 14% ethyl acetate in n-hexane and silica gel (230-400 mesh) to afford 6-chloro-2-(chloromethyl) imidazo[1,2-b]pyridazine (6.0 g, 64.1%) as white solid. 1H NMR: 200 MHz, CDCl3: δ 8.0 (s, 1H), 7.9 (d, 1H), 7.1 (d, 1H), 4.75 (s, 2H). MS: [M+H]+: m/z=202.8.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH:5]([C:7]1[C:12]([O:13][CH2:14][O:15][CH3:16])=[CH:11][CH:10]=[CH:9][N:8]=1)[OH:6]>[O-2].[O-2].[Mn+4].C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[C:5]([C:7]1[C:12]([O:13][CH2:14][O:15][CH3:16])=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:6]
Reactant: COCOc1cccnc1C(O)c1cccc(Br)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOC(C)=O
Product: COCOc1cccnc1C(=O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.9 %

Procedure:
A mixture of 2-(3-bromo-α-hydroxybenzyl)-3-methoxymethoxypyridine (6.43 g), activated manganese dioxide (18.4 g) and ethyl acetate (50 mL) was stirred overnight at room temperature, which was then subjected to filtration. The filtrate was subjected to concentration under reduced pressure. The concentrate was purified by means of a silica gel column (ethyl acetate--hexane) to afford 2-(3-bromobenzoyl)-3-methoxymethoxypyridine (5.55 g) (compound B-1). Physical properties and spectrum data of the product are shown in Table 3 and Table 4. In substantially the same manner as above, compounds B-2 to B-4, B-7 and B-8 shown in Table 3 were produced.
Reaction SMILES: [C:1]1([N:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:24]1[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:30][C:27]1[CH:28]=[CH:29][C:24]([C:11]2[CH:12]=[CH:13][C:8]([N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:9][CH:10]=2)=[CH:25][CH:26]=1
Reactant: OB(O)c1ccc(N(c2ccccc2)c2ccccc2)cc1
Reactant: Brc1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Brc1ccc(-c2ccc(N(c3ccccc3)c3ccccc3)cc2)cc1
Yield: 87 %

Procedure:
A mixture of (4-(diphenylamino)phenyl)boronic acid (1.5 g, 5.19 mmol), 4-iodo-1-bromobenzene (1.33 g, 4.71 mmol), Na2CO3 (1.78 g, 16.8 mmol) and Pd(PPh3)4 (0.163 g, 0.141 mmol) in THF/H2O (28 mL/17 mL) was degassed and the resulting mixture was heated at reflux overnight under an argon atmosphere. After cooling, the mixture was poured into dichloromethane (150 mL), then washed with water (2×150 mL) and brine (100 mL). The organic phase was dried over Na2SO4, purified with flash column chromatography (silica gel, hexanes/ethyl acetate 50:1) then recrystallized in dichloromethane/methanol to afford a white solid (Compound 35)(1.64 g, in 87% yield).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[OH:7][C:8]1[C:9]([CH3:17])=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11](O)=[O:12].C[N:19](C)C=O>ClCCl>[OH:7][C:8]1[C:9]([CH3:17])=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([NH2:19])=[O:12]
Reactant: Cc1c(O)cccc1C(=O)O
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: Cc1c(O)cccc1C(N)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 45 %

Procedure:
Oxalyl chloride (4.19 ml, 48 mmol) was added to an ice-cold solution of 3-hydroxy-2-methylbenzoic acid (3.62 g, 24 mmol) in dichloromethane (30 mL). N,N-dimethylformamide (2 mL) was then added and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the residue was concentrated in vacuo three times from toluene. The residue was then suspended in tetrahydrofuran (10 mL), added to ice-cold 0.88 ammonia solution (10 mL) and stirred for 2.5 hours, allowing the temperature to rise to ambient. The reaction mixture was then extracted with ethyl acetate, dried over magnesium sulfate and concentrated in vacuo and the residue was concentrated in vacuo from acetone and triturated with diethyl ether to afford the title compound as a solid in 45% yield. LRMS APCI m/z 152 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]([N:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][O:30][CH:31]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:24][CH2:23]2)=[O:21])[CH:6]=[C:7]([O:16][CH3:17])[C:8]=1[O:9]COCCOC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]([N:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][O:30][CH:31]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:24][CH2:23]2)=[O:21])[CH:6]=[C:7]([O:16][CH3:17])[C:8]=1[OH:9]
Reactant: COCCOCOc1c(OC)cc(C=CC(=O)N2CCN(CCOC(c3ccccc3)c3ccccc3)CC2)cc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc(C=CC(=O)N2CCN(CCOC(c3ccccc3)c3ccccc3)CC2)cc(OC)c1O
Yield: 75 %

Procedure:
To a solution of 588 mg (0.995 mmol) of the amide compound in methanol (10 ml) was added 190 mg (0.999 mmol) of p-toluenesulfonic acid monohydrate, and the mixture was refluxed for 1 hour. The reaction mixture was diluted with water and adjusted to a pH value of 10 by the addition of aqueous solution of sodium carbonate and then extracted with ethyl acetate. The organic layer was washed with water and concentrated by evaporation under reduced pressure, The residue was subjected to Sephadex column chromatography, eluted with methanol, to give 375 mg (0.746 mmol) of N-[3-(3,5-dimethoxy-4-hydroxyphenyl) -2-propenoyl]-N'-(2-benzhydroxyethyl) piperazine. Spectrophotometric data of the product support the structure shown below. ##STR92##
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:24]1[S:25][CH:26]=[CH:27][N:28]=1)CCC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:24]1[S:25][CH:26]=[CH:27][N:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(cc(Br)n2Cc2ccccc2)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Clc1ccc2c(cc(-c3nccs3)n2Cc2ccccc2)n1
Temperature: 110 °C

Procedure:
A mixture of 1-benzyl-2-bromo-5-chloro-1H-pyrrolo[3,2-b]pyridine (0.10 g, 0.31 mmol, from Example 62, Step 2) and 2-(tributylstannyl)-1,3-thiazole (0.12 g, 0.31 mmol, Aldrich) in toluene (6.0 mL) was degassed by a stream of nitrogen through the solution. Tetrakis(triphenylphosphine)palladium(0) (36 mg, 0.031 mmol) was added and the mixture was heated to 110° C. for 4 hours. Toluene was removed in vacuo and the residue was dissolved in MeCN, filtered, and purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN and H2O containing 0.15% NH4OH). Yield: (33 mg, 32%).
Reaction SMILES: Cl.[CH2:2]([C:6]1[C:10]2[CH:11]=[C:12]([NH:15]N)[CH:13]=[CH:14][C:9]=2[S:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].[CH3:17][N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1>C(O)CO>[CH2:2]([C:6]1[C:10]2=[C:11]3[C:12](=[CH:13][CH:14]=[C:9]2[S:8][CH:7]=1)[NH:15][C:21]1[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][C:20]3=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCc1csc2ccc(NN)cc12
Reactant: CN1CCC(=O)CC1
Agent: Cl
Solvent: OCCO
Product: CCCCc1csc2ccc3[nH]c4c(c3c12)CN(C)CC4
Temperature: 100 °C

Procedure:
The compound is formed analogously to that described in Example 5, from 25.6 g of 3-butyl-5-hydrazinobenzothiophene hydrochloride and 13.5 g of 1-methyl-4-piperidone in ethylene glycol, the mixture being heated to 100° C. for 30 minutes and then to 180° C. Melting point: 192°-193° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH:11]([N:12]2[C:16]([C:17]([OH:19])=[O:18])=[CH:15][N:14]=[CH:13]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:20])[O:3]1.CN(C)C=O.C(Cl)(=O)C(Cl)=O.[CH:33](O)([CH3:35])[CH3:34]>ClCCl>[CH:33]([O:18][C:17]([C:16]1[N:12]([CH:11]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4](=[O:20])[O:3][C:2]2([CH3:21])[CH3:1])[CH:13]=[N:14][CH:15]=1)=[O:19])([CH3:35])[CH3:34]
Reactant: CC1(C)OC(=O)c2ccccc2C1n1cncc1C(=O)O
Reactant: CC(C)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)OC(=O)c1cncn1C1c2ccccc2C(=O)OC1(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3-(3,3-Dimethyl-1-oxo-isochroman-4-yl)-3H-imidazole-4-carboxylic acid (0.075 g, 0.262 mmol) (Example 23) is dissolved in dichloromethane (2 mL). Catalytic amount of dimethylformamide (0.002 mL, 0.0262 mmol) is added to the reaction mixture and cooled to 0° C. Oxalyl chloride (0.016 mL, 0.655 mmol) is added and the cooling bath is removed. The mixture is stirred at room temperature for 2 h and concentrated in vacuo. The residue obtained is redissolved in dichloromethane, and isopropanol (10 mL) is added. The reaction mixture is stirred at room temperature for 1 h, whereupon the volatiles are removed in vacuo. Saturated aqueous sodium bicarbonate is added and extracted with dichloromethane. The combined organic phase is dried over Na2SO4 and concentrated in vacuo. The residue is purified by silica gel chromatography (hexane-ethyl acetate, 1:1) to give 3-(3,3-dimethyl-1-oxo-isochroman-4-yl)-3H-imidazole-4-carboxylic acid isopropyl ester; MS (ESI) m/z 329.0 (M+H); 1H NMR (400 MHz, MeOD) of the HCl salt δ ppm 1.34 (s, 3 H), 1.48 (d, J=5.9 Hz, 3 H), 1.49 (d, J=5.9 Hz, 3 H), 1.62 (s, 3 H), 5.42 (sept, J=5.9 Hz, 1 H), 7.02 (s, 1 H), 7.67 (d, J=7.6 Hz, 1 H), 7.75-7.81 (m, 1 H), 7.82-7.90 (m, 1 H), 8.33 (dd, J=7.8, 1.5 Hz, 1 H), 8.38 (d, J=1.3 Hz, 1 H), 8.76 (d, J=1.0 Hz, 1 H)
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([C:20]([OH:22])=[O:21])[CH:14]=[CH:13]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C1(N=C=NC2CCCCC2)CCCCC1.[F:38][C:39]1[C:44](O)=[C:43]([F:46])[C:42]([F:47])=[C:41]([F:48])[C:40]=1[F:49]>C(OCC)(=O)C>[CH2:1]([O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([C:20]([O:22][C:44]1[C:43]([F:46])=[C:42]([F:47])[C:41]([F:48])=[C:40]([F:49])[C:39]=1[F:38])=[O:21])[CH:14]=[CH:13]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: CCCCCCCCOc1ccc2cc(C(=O)O)ccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: CCCCCCCCOc1ccc2cc(C(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 110.3 %

Procedure:
To a suspension of 6-octyloxy-2-naphthoic acid (3.15 g, 10.5 mmol) and dicyclohexylcarbodiimide in ethyl acetate (25 ml) at 0° C. was added pentafluorophenol (2.12 g, 11.5 mmol). The mixture was stirred at 25° C. for a period of 18 h. The precipitate was removed by s filtration. The filtrate was washed with water (2×150 ml) and brine and dried with magnesium sulfate. Removal of the ethyl acetate in vacuo gave 5.4 g of pentafluorphenyl 6-octyloxy-2-naphthoate as a solid: 1H NMR (400 MHz, CH3OD) δ 0.88 (t, 3, J=6.9 Hz), 4.10 (t, 2, J=6.6 Hz), 7.16 (d, 1), 7.21 (d, 1), 7.80 (d, 1), 7.87 (d,1), 8.08 (dd, 1), 8.69 (d, 1).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH2:13][CH2:14][C:15](=[O:18])[NH:16][N:17]=2)=[CH:4][CH:3]=1.O[C:20]1C=CC=C[C:21]=1[C:22](CCC(O)=O)=[O:23].N1CCCCC1.[OH-].[Na+]>ClCCl>[O:23]1[CH2:22][CH:21]1[CH2:20][O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH2:13][CH2:14][C:15](=[O:18])[NH:16][N:17]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)CCC(=O)c1ccccc1O
Reactant: O=C1CCC(c2ccc(O)c3ccccc23)=NN1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCNCC1
Solvent: ClCCl
Product: O=C1CCC(c2ccc(OCC3CO3)c3ccccc23)=NN1
Yield: 71.7 %

Procedure:
A mixture of 6-(4-hydroxy-1-naphthyl)-4,5-dihydro-3(2H)-pyridazinone (0.5 g, 0.002 mole), epichlorohydrin (2g, 0.02 mole), and piperidine (0.02 g) was heated on a steam bath for 1.5 hours. Evaporation under reduced pressure gave an oil which was dissolved in dichloromethane and shaken with dilute sodium hydroxide (5 ml). The organic phase was washed with water, dried and evaporated to an oil which with ethanol-ether gave crystalline 6[4-(2,3-epoxy-propoxy)-1-naphthyl]-4,5-dihydro-3(2H)-pyridazinone (0.425 g, 69%, m.p. 151°-155° C). Crystallisation from ethanol gave the pure epoxide, m.p. 153.5°-155.5° C.
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:3]=1[O:4][CH2:5][CH:6]([OH:9])[CH2:7][OH:8].[Br:15][CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[Cl:26])=O.CC1C=CC(S(O)(=O)=O)=CC=1.C(O)CCC>CC1C=CC=CC=1>[Br:15][CH2:16][C:17]1([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])[O:9][CH:6]([CH2:5][O:4][C:3]2[C:10]([CH3:14])=[CH:11][CH:12]=[CH:13][C:2]=2[CH3:1])[CH2:7][O:8]1
Reactant: O=C(CBr)c1ccc(Cl)cc1Cl
Reactant: Cc1cccc(C)c1OCC(O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCO
Solvent: Cc1ccccc1
Product: Cc1cccc(C)c1OCC1COC(CBr)(c2ccc(Cl)cc2Cl)O1

Procedure:
A mixture of 11.8 parts of 3-(2,6-dimethylphenoxy)-1,2-propanediol, 13.6 parts of 2-bromo-1-(2,4-dichlorophenyl)-1-ethanone, 3 parts of 4-methylbenzenesulfonic acid, 80 parts of butanol and 180 parts of methylbenzene is stirred and refluxed for 3 days. The reaction mixture is evaporated and the residue is dissolved in 2,2'-oxybispropane. The solution is stirred for 30 minutes with silica gel. The latter is filtered off and the filtrate is evaporated, yielding A + B 2-(bromomethyl)-2-(2,4-dichlorophenyl)-4-(2,6-dimethylphenoxymethyl)-1,3-dioxolane as a residue.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]1[C@@H:11]([CH3:12])[C@H:10]([C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=2I)[O:9][C:8]1=[O:24].[CH:34]([C:37]1[CH:38]=[CH:39][C:40]([O:46][CH3:47])=[C:41](B(O)O)[CH:42]=1)([CH3:36])[CH3:35]>>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]1[C@@H:11]([CH3:12])[C@H:10]([C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=2[C:41]2[CH:42]=[C:37]([CH:34]([CH3:36])[CH3:35])[CH:38]=[CH:39][C:40]=2[O:46][CH3:47])[O:9][C:8]1=[O:24]
Reactant: COc1ccc(C(C)C)cc1B(O)O
Reactant: C[C@H]1[C@H](c2cc(C(F)(F)F)ccc2I)OC(=O)N1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1[C@@H]1OC(=O)N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]1C

Procedure:
Following the procedure described in EXAMPLE 81, 40 mg of (4S,5S)-3-[3,5-bis(trifluoromethyl)benzyl]-5-[2-iodo-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one and 17 mg of (5-isopropyl-2-methoxyphenyl)boronic acid gave the title compound. Mass spectrum (ESI) 620.4 (M+1). 1H NMR signals are doubled because of atropoisomerism. 1H NMR (500 MHz, CDCl3): δ 7.53-7.80 (m, 5H), 7.33 (d, J=8 Hz, 1H), 7.21-7.29 (m, 1H), 7.00, 6.76 (d, J=2.5 Hz, 1H), 6.91, 6.86 (d, J=8.5 Hz, 0.4H), 5.15, 5.10 (d, J=4.5 Hz, 1H), 4.80, 4.74 (d, J=16 Hz, 1H), 4.25, 4.21 (d, 16 Hz, 1H), 3.76 (s, 2H), 3.49 (s, 1H), 3.43 (m, 0.4H), 3.18 (m, 0.5H), 2.77-2.98 (m, 1H), 1.24 (m, 3H), 1.16 (m, 3H), 0.78, 0.61 (d, J=6.5 Hz, 3 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[S:10][C:9](=[O:11])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(O[CH:16]1[O:38][C@H:37]([CH2:39][O:40][C:41](=[O:48])[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C@@H:27]([O:28][C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@H:17]1[O:18][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=O)C.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C>C[Si](N[Si](C)(C)C)(C)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]([C@@H:16]2[O:38][C@H:37]([CH2:39][O:40][C:41](=[O:48])[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C@@H:27]([O:28][C:29](=[O:36])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C@H:17]2[O:18][C:19](=[O:26])[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:4]2=[N:8][C:9](=[O:11])[S:10][C:3]=12
Reactant: CC(=O)OC1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Reactant: Nc1ncnc2[nH]c(=O)sc12
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Product: Nc1ncn([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)c2nc(=O)sc1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
Compound 30 (460 mg, 2.7 mmol) was glycosylated in the same manner as that used to prepare 6, requiring HMDS (30 mL), benzoyl-blocked sugar (5: 1.5 g, 3.0 mmol), and TMS-triflate (0.76 mL, 3.9 mmol). The reaction mixture was allowed to stir overnight at room temperature and was then worked up as described for 6 to yield 1.6 g (95%) of 31 isolated as a foam: UV λmax (MeOH) 230 nm (ε), 310 (): 1H NMR (DMSO-d6) δ 6.45 (d, J=2.73 Hz, 1H, C1,H), 7.4-8.0 (m, 15H, benzoyl aromatics), 8.59 (s, 1H, C5H), and other sugar protons C31H24N4O8S: C, 60.78: H, 3.95: N, 9.15: S, 5.23. Found:
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH2:11][CH2:12][CH:13]([CH3:41])[CH:14]([OH:40])[CH:15]([CH3:39])[C:16](=[O:38])[CH:17]([CH2:36][CH3:37])[CH:18]2[CH:22]([CH3:23])[CH2:21][C:20]([CH2:34][CH3:35])([CH:24]3[CH2:29][CH2:28][C:27]([CH2:31][CH3:32])([OH:30])[CH:26]([CH3:33])[O:25]3)[O:19]2)=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:42])=[C:4]([CH3:43])[CH:3]=1.[C:44](OC(=O)C)(=[O:46])[CH3:45].C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C>[C:44]([NH:1][C:2]1[C:10]([CH2:11][CH2:12][CH:13]([CH3:41])[CH:14]([OH:40])[CH:15]([CH3:39])[C:16](=[O:38])[CH:17]([CH2:36][CH3:37])[CH:18]2[CH:22]([CH3:23])[CH2:21][C:20]([CH2:34][CH3:35])([CH:24]3[CH2:29][CH2:28][C:27]([CH2:31][CH3:32])([OH:30])[CH:26]([CH3:33])[O:25]3)[O:19]2)=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:42])=[C:4]([CH3:43])[CH:3]=1)(=[O:46])[CH3:45]
Reactant: CCC(C(=O)C(C)C(O)C(C)CCc1c(N)cc(C)c(O)c1C(=O)O)C1OC(CC)(C2CCC(O)(CC)C(C)O2)CC1C
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCC(C(=O)C(C)C(O)C(C)CCc1c(NC(C)=O)cc(C)c(O)c1C(=O)O)C1OC(CC)(C2CCC(O)(CC)C(C)O2)CC1C

Procedure:
To a suspension of 1.21 g. (2 mmole) of 5-amino-3-methyl-6-{7-ethyl-4-hydroxy-3,5-dimethyl-6-oxo-7-[5-ethyl-3-methyl-5-(5-ethyl-5-hydroxy-6-methyl-2-tetrahydropyranyl)-2-tetrahydrofuryl]-heptyl}salicylic acid in 50 ml. glacial acetic acid was added 1 ml. acetic anhydride (~10 mmoles). On warming the mixture to 70° on a steam bath, the amine dissolved and after a further half an hour at room temperature, the solution was poured on to crushed ice. The mixture was carefully made alkaline with sodium carbonate solution and extracted twice with 400 ml. ether. After drying (NaSO4) the ethereal solution was evaporated to approximately 100 ml. The resulting microcrystalline product had m.p. 189°-190°, [α]D -17.45° (1%, MeOH).
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([S:19][C:20]2[N:24]4[CH:25]=[C:26]([C:29](=O)[CH3:30])[CH:27]=[CH:28][C:23]4=[N:22][N:21]=2)=[CH:14][CH:13]=3)[CH2:4][CH2:3]1.[NH2:32][O:33][CH2:34][CH2:35][OH:36]>CO.Cl>[OH:36][CH2:35][CH2:34][O:33]/[N:32]=[C:29](/[C:26]1[CH:27]=[CH:28][C:23]2[N:24]([C:20]([S:19][C:15]3[CH:16]=[C:17]4[C:12](=[CH:13][CH:14]=3)[N:11]=[CH:10][C:9]([CH2:8][N:5]3[CH2:6][CH2:7][O:2][CH2:3][CH2:4]3)=[CH:18]4)=[N:21][N:22]=2)[CH:25]=1)\[CH3:30]
Reactant: NOCCO
Reactant: CC(=O)c1ccc2nnc(Sc3ccc4ncc(CN5CCOCC5)cc4c3)n2c1
Agent: Cl
Solvent: CO
Product: C/C(=N\OCCO)c1ccc2nnc(Sc3ccc4ncc(CN5CCOCC5)cc4c3)n2c1
Temperature: 85 °C
Reaction time: 3 h
Yield: 54.2 %

Procedure:
To a solution of 1-(3-(3-(morpholinomethyl)quinolin-6-ylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethanone hydrochloride (79.3) (23 mg, 0.047 mmol) and 2-(aminooxy)ethanol (10.80 mg, 0.140 mmol) in MeOH (5 ml) was added 2 drops of HCl (2 N) by a 1-ml syringe to reach pH about 3 and the mixture was stirred in a sealed tube at 85° C. for 3 h. The mixture was evaporated to dryness and the residue was dissolved in water. The solution was neutralized by adding solid NaHCO3 until pH reached 9, then extracted by DCM (3×). The combined organic layers were washed by water again, dried over Na2SO4, filtered and evaporated. The residue was purified by preparative base HPLC (gradient eluent NB from 20/80 to 95/5. mobile phase A: NH4OH/CH3CN 0.04%; mobile phase B: NH4OH/H2O 0.04%). The desired fractions were collected, evaporated by BUCHI under 30 mbar at 35° C. to remove CH3CN. The remained solution was lyophilized to afford the title compound (12.2 mg, yield 54.2%).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[S:3]([C:6]1[O:10][C:9]2[CH:11]=[CH:12][CH:13]=[C:14]([O:15]C)[C:8]=2[CH:7]=1)(=[O:5])=[O:4].B(Br)(Br)Br>>[CH3:1][N:2]([CH3:17])[S:3]([C:6]1[O:10][C:9]2[CH:11]=[CH:12][CH:13]=[C:14]([OH:15])[C:8]=2[CH:7]=1)(=[O:5])=[O:4]
Reactant: COc1cccc2oc(S(=O)(=O)N(C)C)cc12
Agent: BrB(Br)Br
Product: CN(C)S(=O)(=O)c1cc2c(O)cccc2o1
Yield: 97.7 %

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 5 using 2-(N,N-dimethylsulfamoyl)-4-methoxybenzo(b)furan (1.30 g) and boron tribromide (2.6 ml), the title compound (1.20 g) was obtained as colorless crystals, melting point 150-153° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([O:7][C:8]2[N:9]=[N:10][CH:11]=[C:12]([O:14]C3N(C)N=C(C(F)(F)F)C=3)[CH:13]=2)=[CH:5][C:4]([C:25]([F:28])([F:27])[F:26])=[N:3]1.[OH-].[Na+].O.Cl>CS(C)=O>[CH3:1][N:2]1[C:6]([O:7][C:8]2[N:9]=[N:10][CH:11]=[C:12]([OH:14])[CH:13]=2)=[CH:5][C:4]([C:25]([F:28])([F:26])[F:27])=[N:3]1
Reactant: Cn1nc(C(F)(F)F)cc1Oc1cnnc(Oc2cc(C(F)(F)F)nn2C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Cn1nc(C(F)(F)F)cc1Oc1cc(O)cnn1
Temperature: 80 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
3,5-Bis[[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]oxy]pyridazine (Compound No. 11, 3.0 g, 0.0073 mole) and 2.5N NaOH (14.7 mL, 0.0367 mole) were stirred in dimethylsulfoxide (45 mL) at room temperature under N2 for 15 minutes. The mixture was then heated to 80° C. for 5 minutes. The mixture was cooled to room temperature and allowed to stir for 1 h. The mixture was then poured into water and made acidic with 12N HCl. The mixture was extracted 3×200 mL with ethyl acetate and the organic layer was dried (MgSO4), filtered and evaporated in vacuo. The residue was triturated with a minimum amount of ethyl acetate and filtered to collect the product. The mother liquor was condensed and this process was repeated two more times. 6-[[1-Methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]oxy]-4-pyridazinol (1.35 g, 71% yield) was obtained as a white solid.