Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[C:10]1[C:11](=[O:21])[N:12]([CH3:20])[C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][N:15]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:28](Br)[C:29]#[CH:30].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH2:30][C:29]#[CH:28])=[CH:4][C:3]=1[C:10]1[C:11](=[O:21])[N:12]([CH3:20])[C:13]([C:16]([F:18])([F:17])[F:19])=[CH:14][N:15]=1
Reactant: Cn1c(C(F)(F)F)cnc(-c2cc(O)c(Cl)cc2Cl)c1=O
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCOc1cc(-c2ncc(C(F)(F)F)n(C)c2=O)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.9 %

Procedure:
First, 150 mg of 3-(2,4-dichloro-5-hydroxyphenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-357) was dissolved in 0.90 ml of N,N-dimethylformamide, to which 92 mg of potassium carbonate and 58 mg of propargyl bromide were added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, which afforded 160 mg (yield, 96%) of 3-[2,4-dichloro-5-(propargyloxy)phenyl]-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-370; m.p., 123.7° C.).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]2[CH:13]=[CH:14][CH:15]=[C:16]([SH:17])[C:9]2=[N:8][CH:7]=1)=[O:5])[CH3:2].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]2[CH:13]=[CH:14][CH:15]=[C:16]([S:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]2=[N:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(S)cccn2c1=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2c(SCc3ccccc3)cccn2c1=O
Yield: 95.3 %

Procedure:
To a suspension of 0.3 g of 3-ethoxycarbonyl-9-mercapto-4H-pyrido[1,2-a]pyrimidin-4-one II-1 in 4 ml of anhydrous DMF are added 0.3 g of benzyl bromide VI-1 and 0.5 g of K2CO3, and the resultant mixture is stirred at room temperature for 5 hours. The reaction mixture is diluted with water. The crystal precipitated is filtered and dissolved in CHCl3. The chloroform solution is dried over Na2SO4 and evaporated to give 0.389 g of the titled compound Ic-21.
Reaction SMILES: [CH:1](=O)[C:2]1[C:3]([O:8][CH3:9])=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH3:11][NH:12][CH2:13][CH2:14][NH:15][CH3:16].[O-]S([O-])(=O)=O.[Mg+2]>C(O)C>[CH3:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH:1]1[N:15]([CH3:16])[CH2:14][CH2:13][N:12]1[CH3:11]
Reactant: COc1ccccc1C=O
Reactant: CNCCNC
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCO
Product: COc1ccccc1C1N(C)CCN1C
Reaction time: 0.33 h
Yield: 88 %

Procedure:
A solution of o-anisaldehyde (9.0 g, 66 mmol) and N,N′-dimethylethylenediamine (7.9 mL, 73 mmol) in ethanol (180 mL) was stirred at r.t. for overnight. MgSO4 (30 g) was added and the mixture was stirred for 20 min. The reaction mixture was filtered and washed with ether. The solvent was removed in vacuo to afford 2-(2-methoxyphenyl)-1,3-dimethylimidazolidine as a light yellow solid, 12 g, yield 88%. 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 2.21 (s, 6H) 2.57-2.72 (m, 2H) 3.34 (d, J=2.75 Hz, 2H) 3.82 (s, 3H) 4.13 (s, 1H) 6.88 (d, J=8.24 Hz, 1H) 7.00 (t, J=7.48 Hz, 1H) 7.25-7.30 (m, 1H) 7.67 (d, J=7.63 Hz, 1H).
Reaction SMILES: [CH3:1]C1C(C)=C(N)C=CC=1OC.CC1C=C(N)C=C(C)C=1OC.[NH2:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([O:34][CH3:35])=[CH:26][CH:25]=1>CS(C)=O>[NH2:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([O:34][CH3:35])=[CH:26][C:25]=1[CH3:1]
Reactant: COc1ccc(N)c2ccccc12
Reactant: COc1ccc(N)c(C)c1C
Agent: COc1c(C)cc(N)cc1C
Solvent: CS(C)=O
Product: COc1cc(C)c(N)c2ccccc12
Yield: 67.4 %

Procedure:
In recent years, attempts were made to produce 4-alkoxyanilines in one step from the nitrobenzenes of the above general formula (I) in the presence of noble catalysts in a substantially anhydrous mixed solvent composed of an alcohol and sulfuric acid. For example, Journal of the Chemical Society of Japan [1979 (11), page 1532] reported that 2,4-dimethoxyaniline was obtained in a maximum yield of 27.8% from o-nitroanisole as a material by adding dimethyl sulfoxide (DMSO for short) as a catalyst poison to the reaction system. Journal of the Chemical Society of Japan [1980 (2), page 245] states that 2.2% of p-anisidine was obtained from nitrobenzene, and particularly, when o-methylnitrobenzene was used as a starting material, 2-methyl-4-methoxyaniline was obtained in a maximum yield of 70.2% by adding DMSO (in the absence of DMSO, the yield was 48.3%). Journal of the Chemical Society of Japan [1982 (7), page 1237], subsequently published, reported that 2,3-dimethyl-p-anisidine, 2,6-dimethyl-p-anisidine, 1 -amino-4-methoxy-naphthalene, and 1-amino-2-methyl-4-methoxy-naphthalene were obtained from the corresponding nitro compounds in the presence of DMSO in a maximum yield of 67.4% (63.7% in the absence of DMSO), 72.1% (45.2% in the absence of DMSO), 68%, and 55%, respectively. Furthermore, it was reported long ago that p-anisidine was obtained in a yield of about 40% from phenylhydroxylamine in a mixed solvent of methanol and sulfuric acid [Ber., 31, 1500 (1898)].
Reaction SMILES: [CH2:1]([C:10]1[CH:11]=[CH:12][C:13]2[CH2:14][C:15]3[C:28]([C:29](=O)[C:30]=2[CH:31]=1)=[CH:27][C:26]1[CH2:25][C:24]2[C:19](=[CH:20][C:21]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:22][CH:23]=2)[C:18](=O)[C:17]=1[CH:16]=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]>COCCOCCOC>[CH2:33]([C:21]1[CH:22]=[CH:23][C:24]2[C:19](=[CH:18][C:17]3[C:26]([CH:25]=2)=[CH:27][C:28]2[C:15](=[CH:14][C:13]4[C:30]([CH:29]=2)=[CH:31][C:10]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[CH:11][CH:12]=4)[CH:16]=3)[CH:20]=1)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: CCCCCCCCCc1ccc2c(c1)C(=O)c1cc3c(cc1C2)C(=O)c1cc(CCCCCCCCC)ccc1C3
Solvent: COCCOCCOC
Product: CCCCCCCCCc1ccc2cc3cc4cc5cc(CCCCCCCCC)ccc5cc4cc3cc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 20 grams of 7,14-dihydro-3,10-dinonylpentacene-5,12-dione and 400 mL of 2-methoxyethyl ether was stirred and flushed with nitrogen for 15 minutes. To this was added 11.4 grams of sodium borohydride and stirring was continued at 60° C. for 18 hours. The resulting mixture was cooled to room temperature, 3.0 grams of sodium borohydride was added, and stirring was continued for 16 hours at room temperature. To the resulting mixture was added 170 mL of acetic acid, and the mixture was heated at 60° C. for one hour. To this mixture was added 120 mL of concentrated hydrochloric acid and heating was continued at 60° C. for one hour. The resulting mixture was cooled to room temperature and the solid was collected by filtration and dried to give 2,9-dinonylpentacene.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[CH:5]2.CS(O)(=O)=O.[C:18](O)(=[O:20])C.C(O)(=O)C.I(C1C=CC=CC=1)=O>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[C:5]2[O:20][CH3:18]
Reactant: CC(=O)O
Reactant: O=c1[nH]ccc2cc(Br)ccc12
Agent: CS(=O)(=O)O
Agent: O=Ic1ccccc1
Solvent: CO
Product: COc1c[nH]c(=O)c2ccc(Br)cc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A round bottom flask was charged with 6-bromo-2h-isoquinolin-1-one (1.0 g, 4.46 mmol), methanol (8 mL), and methanesulfonic acid (0.290 ml, 4.46 mmol) and the flask was cooled to 0° C. In a separate flask, iodosobenzene diacetate (1.581 g, 4.91 mmol) was dissolved in methanol (8 mL) and added to the reaction. The reaction was warmed to room temperature and stirred for one hour, then heated to 50° C. and stirred overnight. The reaction was concentrated and triturated with isopropanol. The solution was stirred for 10 minutes, then filtered. The solids were washed with isopropanol and vacuum dried to afford 6-bromo-4-methoxyisoquinolin-1(2H)-one as a tan solid. (ESI) 254.1 (M+H
Reaction SMILES: C(OCC1[C:15]2[C:10](=[CH:11][CH:12]=[C:13](C3C=CC=CC=3OC)[CH:14]=2)[NH:9]C(C)(C)C=1)C=C.Br[CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[O:44][CH3:45])[CH:36]=2)[NH:31][C:30]([CH3:47])([CH3:46])[CH:29]=1.C(O)C=C.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH3:45][O:44][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=1[C:35]1[CH:36]=[C:37]2[C:32](=[CH:33][CH:34]=1)[NH:31][C:30]([CH3:47])([CH3:46])[CH:29]=[C:28]2[CH2:27][NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COc1ccccc1-c1ccc2c(c1)C(CBr)=CC(C)(C)N2
Reactant: C=CCOCC1=CC(C)(C)Nc2ccc(-c3ccccc3OC)cc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C=CCO
Solvent: C1CCOC1
Product: COc1ccccc1-c1ccc2c(c1)C(CNc1ccccc1)=CC(C)(C)N2

Procedure:
4-Allyloxymethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline 40 mg of 4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline, 44 μL of allyl alcohol, and 4 mL of 1 M solution of sodium bis(trimethylsilyl)amide in THF reacted to give 4.5 mg of the title compound as a foam.
Reaction SMILES: [CH2:1]1[CH2:10][O:9][CH:8]2[CH:3]([C@:4]3([CH2:22][C:21](=O)[C@@:20]4([CH3:24])[C@@H:11]([CH2:12][CH2:13][C:14]5[CH:15]=[C:16]([O:25][CH3:26])[CH:17]=[CH:18][C:19]=54)[C@@H:6]3[CH2:7]2)[CH3:5])[O:2]1.Cl.Cl.NN.O.NN.[OH-].[K+].NN>C(O)COCCOCCO.O>[CH2:1]1[CH2:10][O:9][CH:8]2[CH:3]([C@:4]3([CH2:22][CH2:21][C@@:20]4([CH3:24])[C@@H:11]([CH2:12][CH2:13][C:14]5[CH:15]=[C:16]([O:25][CH3:26])[CH:17]=[CH:18][C:19]=54)[C@@H:6]3[CH2:7]2)[CH3:5])[O:2]1
Reactant: COc1ccc2c(c1)CC[C@H]1[C@@H]3CC4OCCOC4[C@@]3(C)CC(=O)[C@]21C
Agent: Cl
Agent: NN
Agent: [K+]
Solvent: O
Solvent: OCCOCCOCCO
Product: COc1ccc2c(c1)CC[C@H]1[C@@H]3CC4OCCOC4[C@@]3(C)CC[C@]21C

Procedure:
A mixture of 534 mg of 17-ethylenedioxy-3-methoxy-9α-methylestra-1,3,5-(10)-trien-11-one, 1 g of hydrazine dihydrochloride and 5 g of hydrazine hydrate in 35 g of triethyleneglycol is heated to a temperature of 130° and maintained there for 21/2 hours. After this time, 1.8 g of potassium hydroxide pellets is added and the temperature raised to 210°. This temperature is also maintained for 21/2 hours whilst a mixture of hydrazine and water is slowly allowed to distill out. The reaction mixture is cooled and diluted with water affording a precipitate which is collected by filtration. The solid is dissolved in methylene chloride and the organic solution is dried over sodium sulfate. Removal of the solvent leaves a residue which is crystallized from hexane-ether to yield 17-ethylenedioxy-3-methoxy-9α-methylestra-1,3,5(10)-triene, m.p. 115° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=1[F:11].Cl[C:13]1[C:14]([N:19]2[CH2:24][CH2:23][N:22]([CH2:25][C:26]3[C:27]([CH3:32])=[N:28][N:29]([CH3:31])[CH:30]=3)[CH2:21][CH2:20]2)=[N:15][CH:16]=[CH:17][N:18]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C(=O)C.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>[CH3:31][N:29]1[CH:30]=[C:26]([CH2:25][N:22]2[CH2:21][CH2:20][N:19]([C:14]3[C:13]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([F:11])[CH:4]=4)=[N:18][CH:17]=[CH:16][N:15]=3)[CH2:24][CH2:23]2)[C:27]([CH3:32])=[N:28]1
Reactant: OB(O)c1ccc(Cl)c(F)c1
Reactant: Cc1nn(C)cc1CN1CCN(c2nccnc2Cl)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: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1nn(C)cc1CN1CCN(c2nccnc2-c2ccc(Cl)c(F)c2)CC1
Temperature: 25 °C
Yield: 13.8 %

Procedure:
Add 4-chloro-3-fluorobenzeneboronic acid (125 mg, 0.72 mmol) to a nitrogen purged solution of 3′-chloro-4-(1,3-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (200 mg, 0.65 mmol) in dry N,N-dimethylacetamide (4 mL) and deoxygenated water (2 mL). Add potassium carbonate (215 mg, 1.72 mmol) then tetrakis(triphenylphosphine)palladium(0) (0.004 g, 0.0035 mmol) and stir at 110° C. for 6 hr. Cool to room temperature, add water (10 mL) and extract with DCM (3×20 mL). Concentrate the combined DCM extracts and purify by reverse phase HPLC to give the title compound (0.036 g, 14%). MS (ES): m/z=401 [M+H]+
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH2:18][CH:19]([NH2:21])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:24](O)(=O)C>C(O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]1[CH2:24][NH:21][CH:19]([CH3:20])[CH2:18][C:12]2=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: CC(N)Cc1c[nH]c2ccc(OCc3ccccc3)cc12
Agent: C=O
Solvent: CCO
Product: CC1Cc2c([nH]c3ccc(OCc4ccccc4)cc23)CN1
Temperature: 80 °C
Yield: 65.1 %

Procedure:
A mixture of 2-(5-benzyloxy-1H-indol-3-yl)-1-methyl-ethylamine (58 mg, 0.21 mmol), 37% formaldehyde (17 uL, 0.23 mmol) and ethanol (2 ml) was heated in a sealed tube at 80° C. for 2 h. The mixture was cooled to rt and acetic acid (60.6 uL, 1.05 mmol) was added. The mixture was heated again in a sealed tube at 80° C. for 5 h. Evaporation of volatiles yielded 6-benzyloxy-3-methyl-2,3,4,9-tetrahydro-1H-β-carboline (40 mg).
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:33])([CH3:32])[O:6][CH2:7][C@@H:8]([CH3:31])[C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([C:17]([CH3:30])([CH3:29])[C@@H:18]([OH:28])[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)([CH3:4])[CH3:3].C(=O)([O-])O.[Na+].[CH:39]([O:41][CH2:42][CH3:43])=[CH2:40]>ClCCl>[CH3:4][C:2]([Si:5]([CH3:32])([CH3:33])[O:6][CH2:7][C@@H:8]([CH3:31])[C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([C:17]([CH3:30])([CH3:29])[C@@H:18]([O:28][CH:39]([O:41][CH2:42][CH3:43])[CH3:40])[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)([CH3:3])[CH3:1]
Reactant: C=COCC
Reactant: C[C@H](CO[Si](C)(C)C(C)(C)C)[C@H]1CC[C@H]2[C@@H]3CC=C4C(C)(C)[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(C)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CO[Si](C)(C)C(C)(C)C)[C@@]4(C)CC[C@@H]32)C1(C)C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
—Pyridinium p-toluenesulfonate (0.31 g) was added to a solution of (3β,20S)-21-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4,4,20-trimethylpregn-5-en-3-ol (WO9852965; 7.28 g) in dichloromethane (50 ml) and ethyl vinyl ether (20 ml). After stirring of the reaction mixture for 6 h at room temperature it was poured into a saturated aqueous solution of sodium hydrogencarbonate. The product was extracted into dichloromethane; the combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to give (3β,20S)-21-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-3-[(1-ethoxyethyl)oxy]-4,4,20-trimethylpregn-5-ene (8.19 g), which was used in the following step without further purification.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1.CN1CCN(C)C1=O.[OH-].[Na+]>C(O)(C)C>[C:18]1([CH3:21])[CH:19]=[CH:20][C:15]([O:13][C:10]2[CH:9]=[CH:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:12][CH:11]=2)=[CH:16][CH:17]=1
Reactant: Cc1ccc(Cl)cc1
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCN(C)C1=O
Solvent: CC(C)O
Product: Cc1ccc(Oc2ccc(-c3ccccc3)cc2)cc1
Yield: 94 %

Procedure:
A mixture of 340 g of p-phenylphenol, 630 g of p-chlorotoluene, 68 g of 1,3-dimethyl-2-imidazolidinone and 81.0 g of sodium hydroxide was stirred at 160° to 168° C., and the water was separated azeotropically was removed by means of a trap. After adding 5.0 g of 8-hydroxyquinoline-copper complex, the mixture was further stirred at 155° to 165° C. for 15 hours. GLC analysis showed that the conversion of p-phenylphenol to the desired product was 98%. The same after treatment as in Example 1 gave 490 g of a crude product in 94% yield. It was dissolved in isopropyl alcohol, decolorized with active carbon and clay, and recrystallized to give 4-biphenylyl p-tolyl ether as white crystals melting at 97° to 98° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][C@@H:31]3[CH3:36])[C:23]3[CH2:29][CH2:28][NH:27][CH2:26][C:24]=3[N:25]=2)=[CH:16][CH:15]=1)=[O:12])[CH3:9].CCN(C(C)C)C(C)C.[CH:46]1([C:49](Cl)=[O:50])[CH2:48][CH2:47]1>C(Cl)Cl>[CH:46]1([C:49]([N:27]2[CH2:28][CH2:29][C:23]3[C:22]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][C@@H:31]4[CH3:36])=[N:21][C:20]([C:17]4[CH:16]=[CH:15][C:14]([NH:13][C:11]([NH:10][CH2:8][CH3:9])=[O:12])=[CH:19][CH:18]=4)=[N:25][C:24]=3[CH2:26]2)=[O:50])[CH2:48][CH2:47]1
Reactant: O=C(Cl)C1CC1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C(=O)C2CC2)C3)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 15 %

Procedure:
To a stirred solution of (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea 2,2,2-trifluoroacetate (100 mg, 0.20 mmol) in DCM was added iPr2NEt (70 uL, 0.40 mmol) and cyclopropanecarbonyl chloride (20 uL, 0.22 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated and purified by prep. HPLC to give a white solid (14 mg, 0.03 mmol, 15% yield).
Reaction SMILES: [CH3:1][C:2]1[N:7]2[C:8](=[O:15])[C:9]([C:12]([OH:14])=O)=[CH:10][N:11]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC)=O.[CH2:29]([NH2:34])[CH2:30][CH2:31][CH2:32][CH3:33]>C(Cl)(Cl)Cl>[CH2:29]([NH:34][C:12]([C:9]1[C:8](=[O:15])[N:7]2[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]2=[N:11][CH:10]=1)=[O:14])[CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: Cc1cccc2ncc(C(=O)O)c(=O)n12
Reactant: CCCCCN
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCNC(=O)c1cnc2cccc(C)n2c1=O
Reaction time: 0.08 h
Yield: 55.8 %

Procedure:
A mixture containing 8.16 g (0.04 mol) of 6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 6.2 ml (0.044 mol) of triethylamine in 240 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 4 ml (0.042 mol) of ethyl chloroformate in 20 ml of chloroform is dropped to the above mixture at -15° C. during 20 minutes. After stirring for 5 minutes, 3.835 g (0.044 mol) of n-pentylamine dissolved in 40 ml of chloroform are dropped to the above solution at -15° C. during 20 minutes. The reaction mixture is stirred below -10° C. for 1 hour and then let to stand overnight under cooling by ice. For working up, the reaction mixture is washed 3 times with 100 ml of 5% sodium hydrogen carbonate solution each and then 3 times with 100 ml of water each. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated to give 6.1 g (55.8%) of the named product as orange yellow crystals after recrystallization from ethanol, m.p.: 112°-116° C.
Reaction SMILES: CON(C)[C:4](=[O:20])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=2)=[CH:7][CH:6]=1.[C:22]([Mg]Br)([CH3:25])([CH3:24])[CH3:23]>C1COCC1>[CH3:23][C:22]([CH3:25])([CH3:24])[C:4]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:15]=[C:14]([C:16]([F:17])([F:18])[F:19])[O:13][N:12]=2)=[CH:9][CH:10]=1)=[O:20]
Reactant: CON(C)C(=O)c1ccc(-c2cc(C(F)(F)F)on2)cc1
Reactant: CC(C)(C)[Mg]Br
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)c1ccc(-c2cc(C(F)(F)F)on2)cc1
Yield: 7 %

Procedure:
Prepared from N-Methoxy-N-methyl-4-(5-trifluoromethyl-isoxazol-3-yl)- benzamide and a 1.7 N THF solution of tert-butylmagnesium bromide as described in Example 5. Chromatographed on silica gel with EtOAc/hexanes (5 then 10%) as eluant to afford product as a colorless solid (21 mg, 7%). 1H NMR (CDCl3) 1.37 (s, 9 H), 7.05 (s, 1 H), 7.79 (d, J=8.4, 2 H), 7.87 (d, J=7.9, 2 H). 19F NMR −64.6. LC/MS 7.28 min, [M+1]+ 298.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:13])[O:10][CH2:11][CH3:12].[H-].[Na+].Cl[C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][C:20]([N+:26]([O-:28])=[O:27])=[CH:19][C:18]=1[C:29]([F:32])([F:31])[F:30].Cl>COCCOCCOC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([C:17]1[C:18]([C:29]([F:31])([F:32])[F:30])=[CH:19][C:20]([N+:26]([O-:28])=[O:27])=[CH:21][C:22]=1[N+:23]([O-:25])=[O:24])[C:9](=[O:13])[O:10][CH2:11][CH3:12]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c(C(F)(F)F)c1
Reactant: CCOC(=O)Nc1ccccc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOCCOC
Product: CCOC(=O)N(c1ccccc1Cl)c1c([N+](=O)[O-])cc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
Ethyl 2-chlorophenylcarbamate (62.6 mg) was dissolved in diglyme (1 ml), and to the solution were added sodium hydride (12.6 mg) and 2-chloro-3,5-dinitrobenzotrifluoride (77.1 mg). The reaction mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, saturated aqueous sodium bicarbonate solution, and then saturated brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resultant residue was purified by preparative TLC (2 mm, 20×20 cm, hexane:ethyl acetate=3:1) to give the title compound (114.8 mg, 93%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C@H:18]([NH:21][C:22]2[CH:23]=[C:24]([CH:29]=[O:30])[C:25]([CH3:28])=NC=2)[CH2:19][CH3:20])=[CH:14][C:13]=1[CH3:31].C[CH2:33][N:34](CC)CC>C(Cl)Cl>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C@H:18]([NH:21][C:22]2[CH:23]=[C:24]([CH:29]=[O:30])[C:25]([CH3:28])=[CH:33][N:34]=2)[CH2:19][CH3:20])=[CH:14][C:13]=1[CH3:31]
Reactant: CC[C@@H](Nc1cnc(C)c(C=O)c1)c1ccc(Cl)c(C)c1
Reactant: CCN(CC)CC
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC[C@@H](Nc1cc(C=O)c(C)cn1)c1ccc(Cl)c(C)c1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
Oxalyl chloride (0.232 mL, 2.70 mmol) was dissolved in CH2Cl2 (15 mL) and the solution was cooled to −78° C. A solution of DMSO (0.383 mL, 5.40 mmol) in CH2Cl2 (3 mL) was added dropwise and the mixture was stirred for 10 minutes at this temperature. Then, a solution of INT 55 (329 mg, 1.079 mmol) in CH2Cl2 (3 mL) was added dropwise and the mixture was stirred for 1 hour at this temperature. NEt3 (0.932 mL, 6.69 mmol) was added and the mixture was stirred further at −78° C. for 1 hour and the mixture was quenched with water. The mixture was poured onto 10% aqueous KHSO4 and extracted with EtOAc. The organic layer was washed with saturated aqueous sodium bicarbonate solution and brine, dried over sodium sulfate, filtered and concentrated. The product was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[CH2:10]([O:14][CH2:15][CH2:16][CH:17]([CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])[CH3:18])[CH2:11][CH2:12][CH3:13].Cl(O)(=O)(=O)=O.C(Cl)Cl>O>[CH2:10]([O:14][CH2:15][CH2:16][CH:17]([CH3:18])[CH2:19][CH2:20][CH2:21][C:22]([C:6]1[CH:5]=[C:4]([CH3:8])[C:3]([OH:9])=[C:2]([CH3:1])[CH:7]=1)([CH3:24])[CH3:23])[CH2:11][CH2:12][CH3:13]
Reactant: CCCCOCCC(C)CCC=C(C)C
Reactant: Cc1cccc(C)c1O
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: ClCCl
Solvent: O
Product: CCCCOCCC(C)CCCC(C)(C)c1cc(C)c(O)c(C)c1

Procedure:
12.2 Parts of 2,6-dimethylphenol, 5.3 parts of citronellyl n-butyl ether, and 1.0 parts of 70% perchloric acid in 30 parts of methylene chloride were stored at room temperature for 3 days. The reaction mixture after pouring into water was extracted with ether, and the ether solution washed with sodium bicarbonate solution, then water and evaporated. Distillation of the residual oil gave 1-n-butyloxy-7-(4-hydroxy-3,5-dimethyl-phenyl)-3,7-dimethyl-octane as a fraction with b0.8, 168°-76° C.