Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].[CH3:29][C:30]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([CH3:33])[CH2:31]O.C(P(CCCC)CCCC)CCC.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1.O>[CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[N:9]([CH2:29][C:30]([CH3:33])([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH3:31])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Reactant: CC(C)(CO)c1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: O
Solvent: C1CCOC1
Product: CCc1cc2c(=O)n(CC(C)(C)c3ccccc3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.9 %

Procedure:
To a solution of 4′-[(6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]biphenyl-2-carbonitrile (1.5 g), 2-methyl-2-phenylpropan-1-ol (0.64 g), tributylphosphine (0.86 g) in THF (50 ml) was added ADDP (1.2 g) under ice-cooling, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 4′-{[6-ethyl-3-(2-methyl-2-phenylpropyl)-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (0.2 g). This was dissolved in dimethyl sulfoxide (2 mL), and the mixture was added to a mixture of hydroxylammonium chloride (0.27 g), sodium hydrogencarbonate (0.32 g) and dimethyl sulfoxide (20 mL), which had been stirred at 40° C. for 30 min in advance. The reaction mixture was stirred at 90° C. for 16 hr, diluted with chloroform, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography, dissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.075 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.070 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.073 g, 33%).
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].C(=O)(O)[O-].[Na+].Cl.[CH2:16]([O:18][C:19](=[O:22])[CH2:20][NH2:21])[CH3:17]>CC(C)=O>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([NH:21][CH2:20][C:19]([O:18][CH2:16][CH3:17])=[O:22])[N:7]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CCOC(=O)CN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOC(=O)CNc1nc(Cl)nc(Cl)n1
Temperature: 0 °C
Yield: 51.9 %

Procedure:
To 10 g of ice water was added 1.84 g of cyanuric chloride dissolved in 50 ml of acetone. To this solution kept at an internal temperature of 0° to 5° C. under stirring were added 1.68 g of sodium bicarbonate and 1.40 g of glycine ethylester hydrochloride and the mixture was stirred at said temperature for 30 minutes. The reaction product was extracted with ethyl acetate and dried with sodium sulfate. Then, ethyl acetate was distilled out and separated crystal was recrystallized from cyclohexane to obtain 1.3 g of 4,6-dichloro-2-ethoxycarbonylmethylamino-S-triazine which had a melting point of 89° to 90.5° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][CH2:8][CH2:9][NH2:10])=[CH:3][CH:2]=1.[N+:11]([C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[CH:16]=[CH:17][CH2:18]Cl)([O-:13])=[O:12]>C(O)C>[N+:11]([C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1/[CH:16]=[CH:17]/[CH2:18][NH:10][CH2:9][CH2:8][NH:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1ccccc1C=CCCl
Reactant: NCCNc1ccncc1
Solvent: CCO
Product: O=[N+]([O-])c1ccccc1/C=C/CNCCNc1ccncc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.1 %

Procedure:
A solution of 11 g of N-(4-pyridyl)ethylenediamine and 5.3 g of 2-nitrocinnamyl chloride (trans-form) dissolved in 60 ml of ethanol was stirred at room temperature for 30 minutes and then stirred at 50° C. for 90 minutes. The solvent was distilled off under reduced pressure, and 10% aqueous sodium hydroxide was added to the residue and the mixture was extracted with chloroform. After drying of the extract, chloroform was distilled off and the residue was purified by silica gel column chromatography (solvent: chloroform-methanol-triethylamine=20:1:0.1) to give 2.33 g of (E)-N-(2-nitrocinnamyl)-N'-(4-pyridyl)ethyenediamine as a yellow oily substance.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].C1COCC1.[CH3:17][C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH3:25])[C:19]=1[Mg]Br>CCCCCC>[CH2:2]([C:19]1[C:20]([CH3:25])=[CH:21][C:22]([CH3:24])=[CH:23][C:18]=1[CH3:17])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: Cc1cc(C)c([Mg]Br)c(C)c1
Reactant: CCCCCCCCCCI
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCc1c(C)cc(C)cc1C

Procedure:
1-Iododecane (133.9 mg, 0.5 mmol) and a THF solution (0.66 mL, 1.14 M, 0.75 mmol) of 2,4,6-trimethylphenylmagnesium bromide were used as starting materials, and reacted as in Entry 1. Conditions: The THF solution of 2,4,6-trimethylphenylmagnesium bromide was added dropwise at 40° C. over 3 hours. After thin-layer chromatography (hexane), the title compound was obtained as a colorless liquid (0.121 g, yield 93%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[C:13]([C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1)#[N:14]>ClCCl.C(N(CC)CC)C>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][N:10]([C:19](=[O:20])[C:18]3[CH:22]=[CH:23][C:15]([C:13]#[N:14])=[CH:16][CH:17]=3)[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: c1cc(N2CCNCC2)ccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc(C(=O)N2CCN(c3ccncc3)CC2)cc1
Reaction time: 2 h
Yield: 28.5 %

Procedure:
A solution of 1-(4-pyridyl)piperazine (0.49 g) in dry dichloromethane (20 ml) and triethylamine (0.7 ml) was treated slowly with a solution of 4-cyanobenzoyl chloride (0.50 g) in dry dichloromethane (30ml). The reaction mixture was then stirred under argon for 2 hours. The dichloromethane solvent was removed by evaporation and the residue dissolved in ethyl acetate. The organic extracts were then washed with aqueous sodium hydrogen carbonate solution, water, brine, dried (Na2SO4) and evaporated to give a colourless oil which was crystallised from ethyl acetate/isohexane to afford 1-(4-pyridyl)4-(4-cyanobenzoyl)piperazine (0.25 g) as a solid, m.p. 164-165° C.; microanalysis, found: C, 69.7; H, 5.6; N, 18.5%; C17H16N4O requires: C, 69.8; H, 5.52; N, 19.2%; NMR: (CDCl3) 3.38(bs,4H), 3.75(bs,4H), 6.67(dd,2H), 7.56(dd,2H), 7.76(dd,2H), 8.32(dd,2H): MS: m/z 293 (MH)+.
Reaction SMILES: [CH2:1]1[O:24][C:23]2[CH:22]=[CH:21][C:5]([CH2:6][CH2:7][C:8]3[S:9][CH:10]=[CH:11][C:12]=3[S:13](N3C=CC=C3)(=[O:15])=[O:14])=[CH:4][C:3]=2[O:2]1.S(Cl)([Cl:28])(=O)=O>>[Cl:28][S:13]([C:12]1[CH:11]=[CH:10][S:9][C:8]=1[CH2:7][CH2:6][C:5]1[CH:21]=[CH:22][C:23]2[O:24][CH2:1][O:2][C:3]=2[CH:4]=1)(=[O:15])=[O:14]
Reactant: O=S(=O)(c1ccsc1CCc1ccc2c(c1)OCO2)n1cccc1
Reactant: O=S(=O)(Cl)Cl
Product: O=S(=O)(Cl)c1ccsc1CCc1ccc2c(c1)OCO2
Yield: 42 %

Procedure:
3-Chlorosulfonyl-2-[3,4-(methylenedioxy)phenethyl]thiophene was prepared in the same manner as described in the Example 15E using N-{2-[3,4-(methylenedioxy)phenethyl]thiophene-3-sulfonyl}pyrrole by conducting basic hydrolysis (iso-propanol and potassium hydroxide) of the sulfonamide to the potassium sulfonate (93%) followed by conversion of the salt to the corresponding sulfonyl chloride in a 42% yield.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](=[O:9])[N:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:4]=1[S-:16])#[N:2].[Na+].Cl[CH2:19][C:20]#[N:21].O>CC#N>[NH2:2][C:1]1[C:3]2[CH:8]=[CH:7][C:6](=[O:9])[N:5]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:4]=2[S:16][C:19]=1[C:20]#[N:21]
Reactant: N#CCCl
Reactant: N#Cc1ccc(=O)n(-c2ccccc2)c1[S-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: N#Cc1sc2c(ccc(=O)n2-c2ccccc2)c1N

Procedure:
A mixture of Example 1 (100 g at 100%) and chloracetonitrile (30.4 mL) in MeCN (500 mL) was heated at reflux for 2 h. The mixture was cooled, initially to 40° C. when water (300 mL) was added, and then to +10° C. The reaction was maintained at +10° C. for at least 1 h when the product was recovered by filtration. The filter cake was washed with cold (+10° C.) H2O (500 mL) followed by a cold (+10° C.) mixture of MeCN and H2O (1:1, 300 mL). The product was dried under vacuum at 50° C. to constant weight to give the title compound as an off-white solid (100.9 g). δH (DMSO-d6) 7.90 (1H, d, J 9.6 Hz), 7.46-7.33 (3H, m), 7.25 (2H, m), 6.95 (2H, br s), 6.35 (1H, d, J 9.6 Hz). LCMS (ES+) RT 2.69 minutes, 268 (M+H)+.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[N:15])[N:9]=1)(=[O:3])[CH3:2].[C:16](OC)(=[O:24])[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[SH:19].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]([O:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[S:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[C:16](=[O:24])[N:15]=2)[N:9]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccccc1S
Reactant: CC(=O)OCCCc1cccc(C#N)n1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(=O)OCCCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 56.3 %

Procedure:
3-(6-Cyano-2-pyridyl)propyl acetate (1.5 g, 7.3 mmol) and methyl thiosalicylate (1.9 g, 11.0 mmol) were dissolved in toluene (5 ml), and triethylamine (2.1 ml, 15.1 mmol) was added thereto. The reaction mixture was refluxed for 16 hrs and kept at room temperature to precipitate crystals. The crystals were washed with toluene and recrystallized from ethanol to give the titled compound (1.4 g, 56%) as white crystals.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH:4]([NH2:8])[CH2:5][CH2:6][CH3:7].C(N(CC)CC)C.[O:16]1[C:20]2[CH:21]=[CH:22][C:23]([C:25](Cl)=[O:26])=[CH:24][C:19]=2[O:18][CH2:17]1>ClCCl>[CH3:1][CH2:2][CH2:3][CH:4]([NH:8][C:25]([C:23]1[CH:22]=[CH:21][C:20]2[O:16][CH2:17][O:18][C:19]=2[CH:24]=1)=[O:26])[CH2:5][CH2:6][CH3:7]
Reactant: CCCC(N)CCC
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(CCC)NC(=O)c1ccc2c(c1)OCO2
Reaction time: 1 h
Yield: 48.5 %

Procedure:
To a solution of heptan-4-amine (8.06 mL, 54 mmol) in triethylamine (15.3 mL, 108 mmol) and dichloromethane (135 mL), was added, dropwise at 0° C., a solution of benzo[1,3]dioxole-5-carbonyl chloride (10 g, 54 mmol) dissolved in dichloromethane (135 mL). The reaction mixture was stirred for 1 h. Solvent was removed under reduced pressure and the residue was dissolved in EtOAc. The organic layer was washed successively with 1 N aq. HCl, 1 N aq. NaOH, water, brine, dried (MgSO4) and concentrated. The residue was recrystallized in EtOAc and Hexanes to afford 6.9 g of N-(heptan-4-yl)benzo[d][1,3]dioxole-5-carboxamide (48.3%) as a white solid. 1H NMR (500 MHz, CDCl3): δ 0.92 (t, 6H), 1.38 (m, 6H), 1.53 (m, 2H), 4.11 (m, 1H), 5.63 (m, 1H), 6.01 (s, 2H), 7.98 (d, 1H), 7.27 (s, d, 2H). MS (M+H, 264).
Reaction SMILES: [OH:1]S(O)(=O)=O.[CH2:6]1[O:14][CH:7]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)C>[C:8]1([CH:7]([OH:1])[CH2:6][OH:14])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=S(=O)(O)O
Reactant: c1ccc(C2CO2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Solvent: CCOCC
Product: OCC(O)c1ccccc1
Reaction time: 2 h
Yield: 91 %

Procedure:
A 2 l stirrer fitted with reflux condenser, thermometer and dropping funnel was charged with 600 g of 0.1% strength H2SO4 and 2 g of tetrabutylammonium hydrogensulfate, and then, at 20° C. to 25° C., 200 g (1.67 mol) of styrene oxide (2) were added over the course of 1 h. When the dropwise addition was complete, the mixture was then stirred for 2 h and then worked up. 200 ml of diethyl ether were added to the reaction mixture, and the organic phase was washed until neutral with sodium carbonate solution and water, and dried over Na2SO4, and the solvent was distilled off under reduced pressure, leaving 223 g of crude product (91% pure according to GC).
Reaction SMILES: [C:1]([O:9]CC)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:13][NH2:14]>C(O)C>[C:1]([NH:13][NH2:14])(=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccccc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 100 ml 3-neck flask were added 40 ml of ethanol and 6 g of ethyl benzoate, to which 12.5 g of 85% hydrazine hydrate was added slowly and dropwise with stirring. After the addition was completed, the mixture was heated under reflux for 8 hours and then cooled to room temperature. The solvent was distilled under reduced pressure and water was added. The solid was precipitated. The mixture was allowed to stand for 30 min until the solid was fully precipitated, which was filtrated and washed with water. Recrystallization with anhydrous ethanol gave benzoyl hydrazine.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([O:7][C:8]1([CH2:13][CH3:14])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:6].[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.N1C(C)=CC=CC=1C.[I-].[Na+]>O>[C:16]1([NH:15][CH2:2][CH2:3][CH2:4][C:5]([O:7][C:8]2([CH2:13][CH3:14])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:6])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1ccccc1
Reactant: CCC1(OC(=O)CCCCl)CCCC1
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: Cc1cccc(C)n1
Product: CCC1(OC(=O)CCCNc2ccccc2)CCCC1
Temperature: 80 °C
Reaction time: 36 h
Yield: 74.1 %

Procedure:
In a nitrogen atmosphere, a mixture of 15 g of 1-ethylcyclopentyl 4-chlorobutyrate, 19 g of aniline, 7.3 g of 2,6-lutidine, and 1.5 g of sodium iodide was heated at 80° C. and stirred for 36 hours at the temperature. The reaction mixture was cooled, after which 15 g of water was added dropwise to quench the reaction. This was followed by ordinary aqueous work-up and vacuum distillation (135° C./13 Pa), recovering 14 g (yield 76%) of 1-ethylcyclopentyl 4-(phenylamino)butyrate.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[NH2:32][CH2:33][CH:34]([OH:37])[CH2:35][OH:36].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:37][CH:34]([CH2:35][OH:36])[CH2:33][NH:32][C:3](=[O:5])[CH:2]([OH:1])[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:18]=3[C:28]([F:30])([F:29])[F:31])[O:14][N:13]=2)=[CH:8][CH:7]=1
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: NCC(O)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(NCC(O)CO)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 31.4 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 30 mg, 0.070 mmol), (R/S)-3-aminopropane-1,2-diol (9.51 mg, 0.104 mmol), 4-methylmorpholine (28.1 mg, 0.278 mmol), and HATU (34.4 mg, 0.090 mmol) were dissolved in DMF (1 mL). The mixture was stirred for 1 h and then purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×250 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 30 min, 25 mL/min, 220 nM, product retention=28.9 min) to provide (R/S)-N-(2,3-dihydroxypropyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (15 mg, 0.022 mmol, 32.1% yield): LCMS=505.1 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.17 (2 H, d, J=8.35 Hz), 7.50-7.81 (7 H, m), 5.15 (1 H, s), 3.65-3.79 (1 H, m), 3.41-3.52 (2 H, m), 3.23-3.39 (2 H, m); HPLC peak RT=7.9 min (Method A).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[F:18])[N:14]=[C:13](Cl)[C:12]([Cl:20])=[N:11]2>CCO>[Cl:20][C:12]1[C:13]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[N:14][C:15]2[C:10](=[CH:9][C:8]([F:7])=[C:17]([F:18])[CH:16]=2)[N:11]=1
Reactant: C1CNCCN1
Reactant: Fc1cc2nc(Cl)c(Cl)nc2cc1F
Solvent: CCO
Product: Fc1cc2nc(Cl)c(N3CCNCC3)nc2cc1F
Temperature: 75 °C

Procedure:
Piperazine (0.86 g, 10 mmol) was added to a stirred suspension of 6,7-difluoro-2,3-dichloroquinoxaline*(1.18 g, 5 mmol) in EtOH (50 mL) at room temperature. The mixture was heated at 75° C. for 17 h, allowed to cool and filtered to give the product as a pale yellow solid: yield 0.40 g (28%); mp 294-297° C. (dec). MS m/z 285/287 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:16][CH3:17])=[C:6]([CH:15]=1)[O:7][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].C([Li])CCC.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([O:33][CH3:34])[CH:32]=1)[CH:28]=[O:29]>>[C:11]([Si:8]([CH3:10])([CH3:9])[O:7][C:6]1[CH:15]=[C:2]([CH:28]([C:27]2[CH:30]=[C:31]([O:33][CH3:34])[CH:32]=[C:25]([O:24][CH3:23])[CH:26]=2)[OH:29])[CH:3]=[CH:4][C:5]=1[O:16][CH3:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: COc1cc(C=O)cc(OC)c1
Reactant: COc1ccc(Br)cc1O[Si](C)(C)C(C)(C)C
Agent: [Li]CCCC
Product: COc1cc(OC)cc(C(O)c2ccc(OC)c(O[Si](C)(C)C(C)(C)C)c2)c1
Yield: 69.5 %

Procedure:
(5-Bromo-2-methoxyphenoxy)-tert-butyldimethylsilane (0.98 g, 3.09 mmol), n-butyl lithium (1.24 ml, 3.09 mmol), and 3,5-dimethoxybenzaldehyde (0.47 g, 2.81 mmol) were treated in the same manner as described above for the synthesis of (2,3-drihydrobenzo[1,4]dioxin-6-yl)-(3,5-dimethoxyphenyl)methanol. The crude material was purified via flash column chromatography (5% EtOAc in hexane gradient to 30% EtOAc in hexane in about 40 min.) to give [3-(tert-butyl-dimethyl-silanyloxy)-4-methoxy-phenyl]-(3,5-dimethoxy-phenyl)-methanol as an oil (0.79 g, 69%), HPLC purity was 98.3% at 2.55 min. (90/10 ACN/0.1% H3PO4): 1HNMR (CDCl3) δ 6.92-6.78 (m, 3H, Ar), 6.53 (d, J=2 Hz, 2H, Ar), 6.35 (t, J=2 Hz, 1H, Ar), 5.66 (d, J=3 Hz, 1H, CH), 3.78 (s, 3H, single OCH3), 3.76 (s, 6H, 2OCH3), 2.15 (d, J=3 Hz, 1H, OH), 0.97 (s, 9H, 3OCH3), 0.13 (s, 6H, 2OCH3). The product was carried over to the next step.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][OH:16])[N:10]=[CH:9]2)C=CC=CC=1.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34](O)=[CH:33][CH:32]=1>>[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([O:16][CH2:15][CH2:14][CH2:13][C:11]2[N:10]=[CH:9][NH:8][CH:12]=2)=[CH:33][CH:32]=1
Reactant: OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: COc1ccc(O)cc1
Product: COc1ccc(OCCCc2c[nH]cn2)cc1

Procedure:
5 mmol of 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanol and 6 mmol of 4-methoxyphenol are treated as described in Example 76.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[Br:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[C:17]=1O)[C:11]([O:13][CH3:14])=[O:12]>CN(C=O)C.CCOC(C)=O>[Br:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[C:17]=1[Cl:4])[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1cc(Br)c(O)c([N+](=O)[O-])c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)c(Cl)c([N+](=O)[O-])c1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 93.8 %

Procedure:
(I4B): Anhydrous DMF (242 ml) was cooled to −20° C. in a dry ice/acetone bath and the internal temperature was monitored carefully and maintained at or below this temperature. Neat oxalyl chloride (9.51 ml, 109 mmol) was then slowly added dropwise via addition funnel and the vessel was properly vented to allow the escape of gases generated. Following the addition, the cloudy-white suspension was stirred at −20° C. for 30 min. A solution containing methyl 3-bromo-4-hydroxy-5-nitrobenzoate (10 g, 36.2 mmol) in DMF (121 ml) was then added slowly, not allowing the internal temp to exceed −10° C. Following the addition, the suspension was warmed to rt and then heated to 100° C. for 2 h. The reaction was cooled to rt and stirred over weekend. The dark brown solution was poured into ice water and diluted with EtOAc. The aqueous phase was extracted twice with EtOAc. The combined organics were washed with water and brine, then dried over anhydrous sodium sulfate. Filtration and concentration afforded methyl 3-bromo-4-chloro-5-nitrobenzoate (10 g) as a yellow solid that was dried in vacuo overnight.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[F:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([CH:7]=1)[NH:17][C:16]1[CH:18]=[CH:19][C:13]([F:12])=[CH:14][CH:15]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: Nc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(F)cc1Nc1ccc(F)cc1
Temperature: 25 °C

Procedure:
A mixture of 2,4-difluoronitrobenzene (5.5 ml), 4-fluoro aniline (14.2 ml) and sodium carbonate (5.3 g) was heated at 180° for 3 h. The reaction mixture was cooled to room temperature, then diluted with DCM, washed with water (50 ml), brine (2×50 ml) dried and evaporated under vacuum to give the crude compound (22.6 g), which was purified by flash chromatography with CH-EA 4/1 to give the title compound as an orange solid (12.35 g) M.p. 115°-6° T.l.c. (CH-EA (10:1), Rf 0.52.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])O[C:4](=[O:9])[CH:3]=1.[NH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1>O>[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[C:4](=[O:9])[CH:3]=1
Reactant: NCc1ccccn1
Reactant: Cc1cc(O)cc(=O)o1
Solvent: O
Product: Cc1cc(O)cc(=O)n1Cc1ccccn1
Yield: 91.8 %

Procedure:
To a suspension of 12.6 g (0.1 mol) of 4-hydroxy-6-methyl-2-pyrone in 50 ml water was added 2-(aminomethyl)pyridine (10.3 ml, 0.1 mol) and the mixture heated to reflux for 2.5 hours. The resulting light yellow compound was filtered from the cooled mixture. Concentration of the filtrate and trituration of the resulting gum with dichloromethane afforded a second crop of the title compound (19.85 g, 92%). 1H NMR (DMSO-d6, ppm): 10.5 (s, 1H), 8.5 (d, 1H), 7.7-7.8 (t, 1H), 7.2 (t, 1H), 7.1 (d, 1H), 5.8 (s, 1H), 5.5 (s, 1H), 5.2 (s, 2H), 2.2 (s, 3H). FIA: m/z−215.1 ES−/217.1 ES+
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=2)=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH:3]=1.[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[OH:34]>>[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[O:34][C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=2)=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH:3]=1
Reactant: Oc1ccc(F)cc1F
Reactant: COc1ccc(-c2cc(Cl)nnc2-c2ccc(OC)c(OC)c2)cc1
Product: COc1ccc(-c2cc(Oc3ccc(F)cc3F)nnc2-c2ccc(OC)c(OC)c2)cc1

Procedure:
In a similar manner as in Example 2, 6-chloro-3-(3,4-dimethoxyphenyl)-4-(4-methoxyphenyl)pyridazine (203 mg, 0.589 mmol) and 2,4-difluorophenol were reacted as starting materials at 150° C. for 20 hours and post-treatment was then conducted, whereby the title compound was obtained as a pale yellow amorphous solid (260 mg, quantitative).