Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4](=[O:15])[C:5](=[CH:7][C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:6]=1.[F:16][C:17](=[C:21]([F:23])[F:22])[CH2:18][CH2:19][OH:20]>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1>[F:14][C:11]1[CH:10]=[CH:9][C:8]([CH:7]=[C:5]([NH:6][C:2](=[O:3])[CH3:1])[C:4]([O:20][CH2:19][CH2:18][C:17]([F:16])=[C:21]([F:23])[F:22])=[O:15])=[CH:13][CH:12]=1
Reactant: CC1=NC(=Cc2ccc(F)cc2)C(=O)O1
Reactant: OCCC(F)=C(F)F
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: CC(=O)NC(=Cc1ccc(F)cc1)C(=O)OCCC(F)=C(F)F
Yield: 49.1 %

Procedure:
8.2 g (40 mmol) of 2-methyl-4-(4-fluorobenzylidene)-oxazol-5-one of Example (II-1) in 100 ml of toluene are heated overnight under reflux with 6.3 g (50 mmol) of 3,4,4-trifluorobut-3-enol, with the addition of 200 mg of 4-dimethylaminopyridine. After cooling, the solution is washed with water and concentrated under reduced pressure and the brown solid is chromatographed over silica gel using the system chloroform/ethyl acetate (4:1). 6.5 g (Yield 49% of theory) of 3,4,4-trifluorobut-3-enyl 3-(4-fluorophenyl)-2-acetylamino-prop-2-enoate of mp.: 116° are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=O.Cl.[NH2:13]O.[Na+].C([O-])(=O)C>C(O)(=O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[C:5]#[N:13]
Reactant: NO
Reactant: COc1ccc(C=O)cc1O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(C#N)cc1O

Procedure:
First, a mixture of 3-hydroxy-4-methoxy benzaldehyde (25 g, 164.3 mmol), hydroxylamine hydrochloride (13.7 g, 197.2 mmol), and acetic acid sodium salt (27 g, 328.6 mmol) in acetic acid (200 ml) was refluxed overnight. After cooling, the acetic acid was evaporated under reduced pressure. Water was added to the residue and the resulting precipitate was collected by filtration. The crude product was recrystalized to give 3-hydroxy-4-methoxy benzonitrile. (23.54 g, 96%)
Reaction SMILES: O[C:2]1([C:19]2[O:20][C:21]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:23]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:24]1([C:22]2[N:23]=[C:19]([C:2]3[CH:3]([CH2:10][C:11]4[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=4)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=3)[O:20][C:21]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COc1cccc(CC2CCCCCCC2(O)c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1cccc(CC2CCCCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reaction time: 4 h
Yield: 112.9 %

Procedure:
A mixture of 1-(hydroxy)-1-(4,5-diphenyloxazol-2-yl)-2-(3-methoxybenzyl)cyclooctane (3.5 g) and p-toluenesulfonic acid (500 mg) in toluene (50 ml) was stirred for 4 hours under reflux. The solution was washed with water, sat. NaHCO3, and brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by chromatography on silica gel to afford 1-(4,5-diphenyloxazol-2-yl)-8-(3-methoxybenzyl)-1-cyclooctene (3.8 g).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:19][O:20][CH2:21][CH3:22])[N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([OH:23])=[CH:5][C:4]=2[N:3]=1.[CH3:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28]Br.C(=O)([O-])[O-].[Cs+].[Cs+].CN1CCCC1=O>CN(C=O)C>[CH2:21]([O:20][CH2:19][C:13]1[N:14]([CH2:15][CH:16]([CH3:17])[CH3:18])[C:10]2[C:9]3[CH:8]=[CH:7][C:6]([O:23][CH2:24][C:25]4[CH:32]=[CH:31][CH:30]=[C:27]([CH3:28])[CH:26]=4)=[CH:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=1)[CH3:22]
Reactant: CCOCc1nc2c(N)nc3cc(O)ccc3c2n1CC(C)C
Reactant: Cc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CN(C)C=O
Product: CCOCc1nc2c(N)nc3cc(OCc4cccc(C)c4)ccc3c2n1CC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.1 %

Procedure:
The general method described for Examples 22-32 was followed using the following modifications. 4-Amino-2-ethoxymethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-ol (310 mg, 0.97 mmol) was dissolved in DMF (15 mL) with heating but precipitated from the solution as it cooled to room temperature. A solution of 3-methylbenzyl bromide (197 mg, 1.07 mmol) in DMF (0.5 mL) was added followed by solid cesium carbonate (643 mg, 1.97 mmol). N-Methylpyrrolidone (1 mL) was added to the reaction, and the reaction was stirred overnight. The crude product was purified by column chromatography on silica gel (eluting with chloroform:methanol), triturated with acetonitrile, and isolated by filtration to provide 175 mg of 2-ethoxymethyl-7-(3-methylbenzyloxy)-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, mp 207.0-208.0° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:14])[C:6](=[CH:10][C:11]=1[O:12][CH3:13])[C:7]([OH:9])=O.O=S(Cl)Cl.[Cl:19][C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH2:22].C(Cl)(Cl)Cl>C1C=CC=CC=1>[NH2:14][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:11]([O:12][CH3:13])=[CH:10][C:6]=1[C:7]([NH:22][C:21]1[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=1[Cl:19])=[O:9]
Reactant: Nc1ccccc1Cl
Reactant: COc1cc(N)c(C(=O)O)cc1OC
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Product: COc1cc(N)c(C(=O)Nc2ccccc2Cl)cc1OC
Yield: 55.2 %

Procedure:
Prepared according to Procedure A using 4,5-dimethoxyanthranilic acid (5.0 g, 25.4 mmol) and SOCl2 (5.5 mL, 76.1 mmol) in benzene (100 mL), followed by 2-chloroaniline (6.7 mL, 63.5 mmol) and CHCl3 (75 mL). The product was washed with aqueous NaHCO3 (2×25 mL) and HCl (0.5 M, 75 mL) and purified by chromatography in CH2Cl2 to provide 4.3 g of a brown foam (55%). 1H NMR (CDCl3) δ: 8.42 (dd, J=1.5, 8.3 Hz, 1H); 8.32 (br s, 1H); 7.40 (dd, J=1.4, 8.0 Hz, 1H); 7.31 (dt, J=1.4, 7.9 Hz, 1H); 7.05 (dt, J=1.5, 7.7 Hz, 1H); 7.03 (s, 1H); 6.24 (s, 1H); 3.88 (s, 3H); 3.87 (s, 3H). MS (ES): m/z 307.0 (M+).
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]([CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=1)[NH2:25].C(=O)([O-])O.[Na+]>C(O)(C)C>[Cl:21][C:22]1[CH:23]=[C:24]([NH:25][C:2]2[C:3]3[N:10]([CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:26]=[CH:27][C:28]=1[O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=1
Reactant: Nc1ccc(Oc2cccc(Cl)c2)c(Cl)c1
Reactant: CC(C)(C)OC(=O)NCCn1ccc2ncnc(Cl)c21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)NCCn1ccc2ncnc(Nc3ccc(Oc4cccc(Cl)c4)c(Cl)c3)c21
Temperature: 80 °C
Reaction time: 15 h
Yield: 81.9 %

Procedure:
A mixture of tert-butyl 2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethylcarbamate (1.19 g), 3-chloro-4-(3-chlorophenoxy)aniline (1.22 g) and isopropyl alcohol (12.0 mL) was stirred at 80° C. for 15 hrs. Under ice-cooling, aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer washed with brine, and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (eluent:hexane/ethyl acetate=50/50→100/0), and washed with diisopropyl ether-hexane to give the title compound (1.69 g) as crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[CH:6][CH:7]=1.[CH2:9]([N:11](CC)CC)C.C[Si](C#N)(C)C>C(#N)C>[C:9]([C:3]1[C:2]([Br:1])=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:11]
Reactant: [O-][n+]1cccc(Br)c1
Reactant: CCN(CC)CC
Agent: C[Si](C)(C)C#N
Solvent: CC#N
Product: N#Cc1ncccc1Br
Yield: 25.6 %

Procedure:
Under nitrogen, a solution of 156 g (0.90 mol) of 3-bromopyridine N-oxide from step 1 was dissolved in 1000 mL of acetonitrile and treated with 256 mL (1.84 mol) of triethylamine and 275 g (2.8 mol) of trimethylsilyl cyanide. The reaction was stirred at reflux overnight and concentrated in vacuo; the residue was dissolved in 2.5M aqueous sodium hydroxide and extracted with methylene chloride. The organic phase was dried (MgSO4) and concentrated in vacuo; this residue was decolorized with carbon and recrystallized from methanol to give 42.2 g (26%) of 2-cyano-3-bromopyridine as a cream colored solid: mp 97°-98° C.; NMR (CDCl3) δ7.42 (dd, J=8 and 5 Hz, 1H), 8.05 (dd, J=8 and 2 Hz, 1H), 8.67 (dd, J=5 and 2 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1>>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:1]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(=O)c1ccc(O)cc1
Product: CC(=O)c1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1

Procedure:
Entry 60: 4-Hydroxyacetophenone was reacted with 4-fluoronitrobenzene according to Method A13, Step 1 to give 4-(4-acetylphenoxy)nitrobenzene. The nitrobenzene was reduced according to Method 13, Step 4 to afford 4-(4-acetylphenoxy)aniline, which was converted to the 4-(4-(1-(N-methoxy)iminoethyl)phenoxyaniline HCl salt according to Method A16. According to Method C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(4-acetylphenoxy)aniline to afford the urea.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][CH2:9]2)=[CH:5][CH:4]=1.[N:12](OCCC(C)C)=[O:13].Cl.C[OH:22]>>[OH:13]/[N:12]=[C:8]1/[C:9](=[O:22])[C:10]2[C:6]([CH2:7]/1)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:11]=2
Reactant: COc1ccc2c(c1)CCC2
Reactant: CC(C)CCON=O
Reactant: CO
Agent: Cl
Product: COc1ccc2c(c1)C(=O)/C(=N/O)C2
Temperature: 40 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
6-methoxy-2,3-dihydro-1H-inden-(17.2 g, 106 mmol) was dissolved in methanol (700 mL). The mixture was heated to 40° C., then isoamyl nitrite (30 mL, 220 mmol) and concentrated hydrochloric acid (17 mL) were added. The reaction mixture was stirred at 40° C. for 2 hours. After cooled to room temperature, the precipitate was collected by filtration and dried under high vacuum to obtain product (10.0 g, yield 50%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:12]([CH3:14])[CH3:13])[C:9]([NH2:11])=[O:10])=[CH:4][CH:3]=1.[O:15]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25]Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.ClCCl>CCOCC.F[B-](F)(F)F.[Ag+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH:12]([CH3:14])[CH3:13])[C:9](=[NH:11])[O:10][CH2:25][C:24]2[CH:27]=[CH:28][CH:29]=[C:22]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:23]=2)=[CH:6][CH:7]=1
Reactant: CC(C)C(C(N)=O)c1ccc(Cl)cc1
Reactant: BrCc1cccc(Oc2ccccc2)c1
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)C(C(=N)OCc1cccc(Oc2ccccc2)c1)c1ccc(Cl)cc1

Procedure:
To a refluxing solution of 2.72 g (12.9 mmol) of 2-(4-chlorophenyl)-3-methylbutyramide and 2.27 g (8.6 mmol) of 3-phenoxybenzyl bromide in a solution of 15 ml dichloromethane and 3 ml ethyl ether is added a solution of 1.83 g (9.5 mmol) of silver tetrafluoroborate in ether. The mixture is refluxed for 2 hours and then separated by pouring into ice cold aqueous ethyl acetate/sodium bicarbonate. The organic phase is washed with water, dried and stripped of solvent. The residue is triturated with ether and filtered. The filtrate is concentrated and chromatographed on silica gel, eluting with 25% ethyl acetate/hexane, and then on plates using 35% ethyl acetate/hexane, to yield 3-phenoxybenzyl 2-(4-chlorophenyl)-3-methylbutanimidate, MS m/e 393 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:35][N:36]1[CH2:41][CH2:40][N:39]([CH2:42][CH2:43][CH:44]([OH:48])[CH2:45][CH2:46][CH3:47])[CH2:38][CH2:37]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:24](=[O:26])[O:48][CH:44]([CH2:43][CH2:42][N:39]2[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]2)[CH2:45][CH2:46][CH3:47])=[CH:18][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: CCCC(O)CCN1CCN(C)CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(CCN1CCN(C)CC1)OC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1
Yield: 42 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-(4-methylpiperazino)-3-hexanol (52 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, and the extract was washed with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (37 mg, yield 35%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([O:16][C:17]2[S:18][CH:19]=[CH:20][N:21]=2)[CH:13]=[C:12]([C:22](O)=[O:23])[CH:11]=1)#[N:2].[CH3:25][C:26]1[N:31]=[CH:30][C:29]([C@H:32]([NH2:34])[CH3:33])=[CH:28][N:27]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([O:16][C:17]2[S:18][CH:19]=[CH:20][N:21]=2)[CH:13]=[C:12]([C:22]([NH:34][C@@H:32]([C:29]2[CH:28]=[N:27][C:26]([CH3:25])=[N:31][CH:30]=2)[CH3:33])=[O:23])[CH:11]=1)#[N:2]
Reactant: Cc1ncc([C@@H](C)N)cn1
Reactant: Cc1ccc(-c2cc(Oc3nccs3)cc(C(=O)O)c2)c(C#N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(Oc3nccs3)cc(C(=O)N[C@H](C)c3cnc(C)nc3)c2)c(C#N)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2′-cyano-4′-methyl-5-(thiazol-2-yloxy)biphenyl-3-carboxylic acid (30 mg, 0.089 mmol) in N,N-dimethylformamide (1 mL) were added (R)-1-(2-methylpyrimidin-5-yl)ethanamine (30 mg, 0.22 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (100 mg, 0.26 mmol), and N,N-diisopropylethylamine (100 μL, 0.57 mmol). The reaction mixture was stirred for 16 hours at 25° C., and then purified by preparative HPLC to afford a brown solid.
Reaction SMILES: BrC1C=CC=C[C:3]=1[C:8]1([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[O:12][CH:11]([CH3:13])[CH2:10][O:9]1.[OH:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C(=O)C>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[C:8]1([CH2:3][O:22][C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[O:12][CH:11]([CH3:13])[CH2:10][O:9]1
Reactant: Oc1cccnc1
Reactant: CC1COC(c2ccc(Cl)cc2Cl)(c2ccccc2Br)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC1COC(COc2cccnc2)(c2ccc(Cl)cc2Cl)O1
Reaction time: 18 h

Procedure:
A mixture of 2-(bromophenyl)-2-(2,4-dichlorophenyl)-4-methyl-1,3-dioxolane (10 g.), 3-hydroxypyridine (3.8 g.) and potassium carbonate (5.5 g.) in N,N-dimethylacetamide (90 ml.) was refluxed with stirring for 18 hours. After the mixture was allowed to cool, it was poured into water and extracted with toluene. The toluene fraction, thereby obtained, was washed with 5% aqueous sodium hydroxide and evaporated to yield 3-[[2-(2,4-dichlorophenyl)-4-methyl-1,3-dioxolan-2-yl]methoxy]pyridine as an oil.
Reaction SMILES: N1C2C(=CC=CC=2)C=C[C:2]1=O.[CH3:12][O:13][C:14]1C(=O)NC2C(C=1OC)=CC=CC=2.[CH3:27][O:28][C:29]1[CH:30]=[CH:31][CH:32]=[C:33]2[C:38]=1[N:37]([CH3:39])[C:36](=[O:40])[C:35]([O:41][CH3:42])=[C:34]2[OH:43]>>[CH3:12][O:13][CH3:14].[CH3:27][O:28][C:29]1[CH:30]=[CH:31][CH:32]=[C:33]2[C:38]=1[N:37]([CH3:39])[C:36](=[O:40])[C:35]([O:41][CH3:42])=[C:34]2[O:43][CH3:2]
Reactant: O=c1ccc2ccccc2[nH]1
Reactant: COc1c(O)c2cccc(OC)c2n(C)c1=O
Reactant: COc1c(OC)c2ccccc2[nH]c1=O
Product: COC
Product: COc1c(OC)c2cccc(OC)c2n(C)c1=O

Procedure:
As compounds having substituent groups on the aromatic ring of a quinolinone, Indian J. Chem., Sect. B, 15B(5), pp. 440-444, 1977, discloses 3,4-dimethoxy-2(1H)-quinolinone, 8-methoxy-3-methoxy-4-hydroxy-1-methyl-2(1H)-quinolinone, and a methyl ether thereof, 8-methoxy-3,4-dimethoxy-1-methyl-2(1H)-quinolinone as compounds obtained from the bark of Chloroxylon swietenia DC.
Reaction SMILES: [N:1]([O:3]CCC(C)C)=O.[CH3:9][C:10]([CH3:18])=[CH:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15].[ClH:19]>>[Cl:19][C:10]([CH3:18])([CH3:9])[CH:11]([N:1]=[O:3])[CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)CCC=C(C)C
Reactant: Cl
Reactant: CC(C)CCON=O
Product: COC(=O)CCC(N=O)C(C)(C)Cl
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
A mixture of isoamyl nitrite (12 mL) and methyl 5-methyl-4-hexenoate (4.90 g, 35.00 mmol) was cooled to -15° C. To this stirred solution, concentrated HCl (12.5 mL) was added dropwise from an addition flask maintaining the temperature of the reaction mixture below -5° C. After the addition, the reaction mixture was stirred at 0° C. for 30 minutes, filtered and the precipitate washed with ethanol (-10° C.). The light blue colored solid thus obtained was dispersed in petroleum ether (50 mL), cooled to ~-50° C. and filtered to provide the title product as a colorless solid. Yield: 3.0 g (41.3%); m.p. 90°-91° C. 1H NMR (CDCl3) δ 1.68 & 1.71 [2s, 6H, C(CH3)2 ], 2.35 [m, 4H, (CH2)2 ], 3.73 (s, 3H, COOCH3) and 5.11 (t, 1H, CH). MS m/e 208 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH:6]([CH3:8])[CH2:5][N:4]([CH2:9][C:10]([OH:28])([CH2:15][C:16]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[O:26][CH3:27])([CH3:18])[CH3:17])[C:11]([F:14])([F:13])[F:12])[CH2:3]1.[CH:29](OC=O)=[O:30].C(N=C=NC(C)C)(C)C.C(O)=O>C(Cl)Cl.N1C=CC=CC=1>[F:25][C:23]1[CH:22]=[CH:21][C:20]([O:26][CH3:27])=[C:19]([C:16]([CH3:18])([CH3:17])[CH2:15][C:10]([OH:28])([C:11]([F:12])([F:13])[F:14])[CH2:9][N:4]2[CH2:3][CH:2]([CH3:1])[N:7]([CH:29]=[O:30])[CH:6]([CH3:8])[CH2:5]2)[CH:24]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CN1CC(C)NC(C)C1)C(F)(F)F
Reactant: O=COC=O
Agent: CC(C)N=C=NC(C)C
Solvent: ClCCl
Solvent: O=CO
Solvent: c1ccncc1
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CN1CC(C)N(C=O)C(C)C1)C(F)(F)F
Reaction time: 1 h

Procedure:
To a solution of 2-(3,5-dimethylpiperazin-1-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol (20 mg) in methylene chloride (1 mL) at 0° C. was added pyridine (60.7 μL) followed by formic anhydride (2M in methylene chloride, 0.5 mL). (Formic anhydride was freshly prepared by slow addition of one equivalent of 1,3-diisopropylcarbodiimide to 2 equivalents of formic acid in methylene chloride. The resulting suspension was stirred for 1 hour, and filtered). The resulting mixture was stirred overnight for 20 hours, filtered through a cotton plug, poured into half-saturated aqueous sodium bicarbonate solution, and extracted twice with methylene chloride. The combined organic phases were dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel (eluted with 5% methanol-methylene chloride) to give the title compound as a clear oil (19.3 mg).
Reaction SMILES: [CH2:1]([N:4]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:5]([C:7]1[CH:18]=[CH:17][C:10]2[N:11]([CH3:16])[C:12]([CH2:14]Cl)=[N:13][C:9]=2[CH:8]=1)=[O:6])[CH2:2][CH3:3].[C:26]([C:28]1[CH:33]=[CH:32][C:31]([SH:34])=[CH:30][CH:29]=1)#[N:27].C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH2:1]([N:4]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:5]([C:7]1[CH:18]=[CH:17][C:10]2[N:11]([CH3:16])[C:12]([CH2:14][S:34][C:31]3[CH:32]=[CH:33][C:28]([C:26]#[N:27])=[CH:29][CH:30]=3)=[N:13][C:9]=2[CH:8]=1)=[O:6])[CH2:2][CH3:3]
Reactant: CCCN(CCC(=O)OCC)C(=O)c1ccc2c(c1)nc(CCl)n2C
Reactant: N#Cc1ccc(S)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCN(CCC(=O)OCC)C(=O)c1ccc2c(c1)nc(CSc1ccc(C#N)cc1)n2C

Procedure:
A mixture of 1.5 g (4.1 mMol) of 2-chloromethyl-1-methyl-benzimidazol-5-yl-carboxylic acid-N-(n-propyl)-N-(2-ethoxycarbonylethyl)-amide and 0.65 g (4.8 mMol) of p-cyanothiophenol was heated in 10 ml of dimethylformamide and 10 ml of diisopropylethylamine for 1 hour to 100° C. The solvent was distilled off in vacuo, the crude product was dissolved in 30 ml ethyl acetate, washed with 30 ml water, and after concentration purified by flash chromatography (silica gel; methylene chloride/ethanol (49:1 to 19:1). Yield: 1.5 g (79% of theory) of brown oil, Rf value: 0.65 (silica gel; ethyl acetate/ethanol/ammonia =90:10:1)
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]([OH:14])=[O:13].[Br:15]Br>C(O)(=O)C>[Br:15][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([OH:1])=[C:3]([C:12]([OH:14])=[O:13])[CH:4]=1
Reactant: O=C(O)c1ccc2ccccc2c1O
Reactant: BrBr
Solvent: CC(=O)O
Product: O=C(O)c1cc(Br)c2ccccc2c1O
Reaction time: 72 h

Procedure:
To a solution of 1-hydroxy-2-naphthoic acid (10.2 g, 53.9 mmol) in 100 mL of acetic acid was added bromine (6.60 mL, 53.9 mmol) dropwise. After 72 hours, the reaction was filtered and the filter cake was washed with acetic acid (40 mL) and hexanes (150 mL) to provide 4-bromo-1-hydroxy-2-naphthoic acid that gave a proton NMR spectra consistent with theory.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]([N:20]1[CH2:25][CH:24]=[CH:23][CH2:22][CH2:21]1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[O:9]1[CH:23]2[CH:24]1[CH2:25][N:20]([C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:21][CH2:22]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(c1ccccc1)N1CC=CCC1
Solvent: ClCCl
Product: O=C(c1ccccc1)N1CCC2OC2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of metachloroperbenzoic acid (12 mmole) in methylene chloride is added dropwise to a solution of 39 at 4 C. The reaction mixture is allowed to stir overnight at room temperature. It is made basic and then extracted with methylene chloride. Following work-up and flash chromatography affords 40.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[C:5]([OH:7])=[O:6].[CH3:13]N(C=O)C.C(Cl)(=O)C.CO>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[C:5]([O:7][CH3:13])=[O:6]
Reactant: CN(C)C=O
Reactant: COc1cc(Br)cc(C(=O)O)c1
Solvent: CO
Solvent: CC(=O)Cl
Solvent: ClCCl
Product: COC(=O)c1cc(Br)cc(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred mixture of crude 3-bromo-5-methoxybenzoic acid (40% purity, 0.8 g, 1.4 mmol) in CH2Cl2 (50 mL) at 0° C. were added DMF (0.1 mL) and acetyl chloride (0.2 mL, 3 mmol). The mixture was slowly warmed to rt and stirred overnight. Then the mixture was cooled to 0° C. and methanol (2 mL) was slowly added. The mixture was stirred at rt for 3 h and then washed with aq. Na2CO3 solution, brine, dried (Na2SO4), and concentrated. The residue was purified via flash chromatography to afford the desired product as a white solid. 1H NMR (CDCl3, 400 MHz): 7.76 (t, J=1.6 Hz, 1H), 7.49 (t, J=1.3 Hz, 1H), 7.24 (t, J=2.2 Hz, 1H), 3.92 (s, 3H), 3.84 (s, 3H).