Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12](O)=[N:11][CH:10]=[CH:9]2.P(Cl)(Cl)[Cl:18]>>[Cl:18][C:12]1[C:13]2[C:8](=[CH:7][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:15][CH:14]=2)[CH:9]=[CH:10][N:11]=1
Reactant: ClP(Cl)Cl
Reactant: COCCOc1ccc2c(O)nccc2c1
Product: COCCOc1ccc2c(Cl)nccc2c1
Yield: 80 %

Procedure:
To 6-(2-methoxyethoxy)isoquinolin-1-ol (3.15 g, 14.4 mmol) was added phosphorus trichloride (70 mL) under nitrogen atmosphere. The mixture was heated at reflux giving a nearly opaque brown solution. After 2 h at reflux, the solution was concentrated in vacuo until 20 mL remained and poured onto ice water (100 mL). The pH of the resulting mixture was adjusted to 6.5 with the addition of solid potassium carbonate and extracted with dichloromethane (3×100 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL) and concentrated in vacuo. The resulting tan solid was taken up in dichloromethane, adsorbed on silica gel and purified by flash chromatography (gradient:hexane/ethyl acetate, 60:40→40:60) to give, after drying in vacuo, 2.73 g (80% yield) of the title compound as a pale yellow solid. MS(AP+), 238 (100, M++1), 202 (33), 179 (33).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1)=[O:4].C([O-])=[O:14].[Na+]>CO>[OH:14][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1)=[O:4]
Reactant: O=C[O-]
Reactant: O=C(CBr)c1ccc(Cl)c(Cl)c1
Agent: [Na+]
Solvent: CO
Product: O=C(CO)c1ccc(Cl)c(Cl)c1
Yield: 41.9 %

Procedure:
A mixture of 2-bromo-3′,4′-dichloroacetophenone (78.0 g), sodium formate (68.0 g) and methanol (300 ml) was stirred with heating under reflux for 16 hours. The reaction mixture was concentrated and poured into water (1 L). The solid precipitates were filtered, washed with water and then isopropyl ether, and air-dried. The residue was dried under reduced pressure to give crystals of 2-hydroxy-3′,4′-dichloroacetophenone (25.0 g, 42%). Recrystallization from ethyl acetate-hexane gave pale yellow prisms. Melting point 115-118° C.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][Cl:19])=[CH:11][CH:10]=1)=O)C.O.[NH2:22][NH2:23]>C(O)(C)C>[Cl:19][CH2:18][CH2:17][CH2:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]2[CH2:6][CH2:5][C:4](=[O:3])[NH:22][N:23]=2)=[CH:10][CH:11]=1
Reactant: CCOC(=O)CCC(=O)c1ccc(OCCCCl)cc1
Reactant: NN
Solvent: O
Solvent: CC(C)O
Product: O=C1CCC(c2ccc(OCCCCl)cc2)=NN1

Procedure:
In a 500 mL round bottom flask, 4-[4-(3-chloro-propoxy)-phenyl]-4-oxo-butyric acid ethyl ester (7.85 g, 26.3 mmol), and hydrazine monohydrate (2.55 mL, 52.7 mmol), in isopropanol (200 mL) was heated to reflux 14 h. The reaction was cooled and the solvent concentrated under vacuum. Purification with silica gel chromatography eluting with methylene chloride/methanol (95:5) produced 5.2 g (74%). MS m/z 267 (M+H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]([NH:14][C@H:15]([C:24](O)=[O:25])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]>>[C:7]([NH:14][C@H:15]([C:24]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:25])[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=1)([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(Cl)cc1)C(=O)O
Reactant: C1COCCN1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(Cl)cc1)C(=O)N1CCOCC1

Procedure:
In substantially the same manner as in Example 5, morpholine (257 μl) was condensed with Boc-p-chloro-L-phenylalanine (800 mg, manufactured by Bachem Fein Chemikalien AG, Switzerland) to give N-(Boc-p-chloro-L-phenylalanyl)morpholine (913 mg) as a colorless oily product (yield 93%). After Boc group elimination with 4N HCl/ethyl acetate, the product was condensed with (2S,3S)-ethyl hydrogen trans-epoxysuccinate (238 mg) as obtained in Reference Example 8 to yield the title compound (compound 67; mg) as a white powder (yield 58%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH2:34][C:33](=[O:35])[NH:32][N:31]=2)[CH:25]=1.[H-].[Na+]>CN(C=O)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[N:5]=[CH:4][N:3]=[C:2]2[O:35][C:33]1[CH:34]=[C:30]([C:26]2[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=2)[NH:31][N:32]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Reactant: O=C1CC(c2cccnc2)=NN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc(-c4cccnc4)[nH]n3)ncnc2cc1OCCCN1CCOCC1
Yield: 59.5 %

Procedure:
Using an analogous procedure to that described for Example 9, 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (134 mg, 0.4 mmol), (prepared as described for the starting material in Example 2), was reacted with 3-(3-pyridyl)-4,5-dihydro-1H-pyrazol-5-one (161 mg, 1 mmol) in the presence of sodium hydride (40 mg, 1 mmol, prewashed with THF) in DMF (3 ml) to give 6-methoxy-7-(3-morpholinopropoxy)-4-(5-(3-pyridyl)pyrazol-3-yloxy)quinazoline (110 mg, 59%).
Reaction SMILES: C([O:3][C:4](=[O:15])[CH2:5][S:6][C:7]1[N:12]=[C:11]([Cl:13])[CH:10]=[C:9](Cl)[N:8]=1)C.[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:20][NH2:21].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[Cl:13][C:11]1[CH:10]=[C:9]([NH:21][CH2:20][C:19]2[CH:22]=[CH:23][C:24]([Cl:25])=[C:17]([Cl:16])[CH:18]=2)[N:8]=[C:7]([S:6][CH2:5][C:4]([OH:3])=[O:15])[N:12]=1
Reactant: CCOC(=O)CSc1nc(Cl)cc(Cl)n1
Reactant: NCc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C(O)CSc1nc(Cl)cc(NCc2ccc(Cl)c(Cl)c2)n1

Procedure:
A stirred mixture of 8.0 g of (4,6-dichloro-2-pyrimidinylthio)acetic acid ethyl ester, 5.3 g of 3,4-dichlorobenzylamine and 3.2 g of sodium carbonate in 200 ml. of ethanol was heated under reflux for 6 hr. The reaction mixture was filtered and water was added to the filtrate to the cloudy point. The mixture was cooled in ice and the resulting precipitate which formed was removed by filtration and recrystallized from 70% aqueous ethanol. The product amounted to 4.8 g, mp. 64°-69°C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.[CH3:28][O:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[C:34]([O:38][CH3:39])[C:35]=1[O:36][CH3:37].C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>CC#N.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:32]4[CH:33]=[C:34]([O:38][CH3:39])[C:35]([O:36][CH3:37])=[C:30]([O:29][CH3:28])[CH:31]=4)[CH:3]=3)[NH:8][CH:9]=2)=[CH:16][CH:15]=1
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccc(F)cc3)c3cc(Br)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1cc(-c2cnc3[nH]cc(-c4ccc(F)cc4)c3c2)cc(OC)c1OC
Yield: 28.7 %

Procedure:
5-Bromo-3-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (37 mg, 0.083 mmol), 3,4,5-trimethoxyphenylboronic acid (21 mg, 0.1 mmol) and dichlorobis(triphenylphosphine)palladium (II) (3 mg, 0.004 mmol) were combined in CH3CN (1.5 ml) and 1 M Na2CO3 (2 ml) and reacted in a microwave reactor for 20 min at 150° C. EtOAc was added and the mixture was washed with water, dried, evaporated and purified by silica gel chromatography using 0-2% MeOH:DCM to yield 9 mg (29%) of the title compound. MS ESI (m/z): 379.2 (M+1)+, calc. 378.
Reaction SMILES: [CH2:1]([C:3]1([CH2:16][CH3:17])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[CH2:6][CH2:5][C:4]1=O)[CH3:2].Cl.[NH2:19][OH:20]>N1C=CC=CC=1>[CH2:1]([C:3]1([CH2:16][CH3:17])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[CH2:6][CH2:5][C:4]1=[N:19][OH:20])[CH3:2]
Reactant: NO
Reactant: CCC1(CC)C(=O)CCc2ccc(OC)cc21
Agent: Cl
Solvent: c1ccncc1
Product: CCC1(CC)C(=NO)CCc2ccc(OC)cc21
Temperature: 25 °C

Procedure:
1,1-diethyl-7-methoxy-3,4-dihydro-1H-naphthalen-2-one (4.40 g, 18.96 mmol) in dry pyridine (20 mL) with the hydroxylamine hydrochloride salt (10.54 g, 151.7 mmol) was heated to 80 ° C. for one day. The mixture was cooled down to r.t., then the pyridine was removed under vaccum. The green gum was dissolved with AcOEt, washed with H2O, HCl 10%, H2O, brine, dried over MgSO4 and filtered through a small silica pad. The crude compound was used without any other purification (4.69 g, 100%). 1H NMR (CDCl3): 7.94 (1H, s, OH), 7.06 (1H, d, J=8 Hz, H5), 6.84 (1H, d, J=2.5 Hz, H8), 6.73 (1H, dd, J=2.5 and 8 Hz, H6), 3.83 (3H, s, OCH3), 2.80-2.75 (4H, m, PhCH2CH2), 2.08 (2H, m, CH2), 1.85 (2H, m, CH2), 0.68 (6H, t, J=7.5 Hz, CH3).
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[CH:10][S:11][C:5]=2[N:4]=[C:3]1[CH2:12][CH3:13].[C:14]12([CH2:24][C:25](Cl)=[O:26])[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2>>[C:14]12([CH2:24][C:25]([NH:1][N:2]3[C:7](=[O:8])[C:6]4[CH:9]=[CH:10][S:11][C:5]=4[N:4]=[C:3]3[CH2:12][CH3:13])=[O:26])[CH2:21][CH:20]3[CH2:19][CH:18]([CH2:17][CH:16]([CH2:22]3)[CH2:15]1)[CH2:23]2
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Reactant: CCc1nc2sccc2c(=O)n1N
Product: CCc1nc2sccc2c(=O)n1NC(=O)CC12CC3CC(CC(C3)C1)C2

Procedure:
3-Amino-2-ethylthieno[2,3-d]pyrimidin-4(3H)-one and 1-adamantaneacetyl chloride were reacted as described in Example 5 to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.20 (t, J=7.3 Hz, 3H), 1.59-1.74 (m, 12H), 1.93-1.98 (m, 3H), 2.08-2.18 (m, 2H), 2.56-2.80 (m, 2H), 7.39 (d, J=6.0 Hz, 1H), 7.59 (d, J=6.0 Hz, 1H), 10.83 (s, 1H) ppm; MS (DCI/NH3) m/z 372 (M+H)+; Elemental Analysis: Calculated for C20H25N3O2S: C, 63.74; H, 6.85; N, 11.15. Found: C, 63.77; H, 6.89; N, 11.13.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:8]=[N:9][C:10]2[C:15]([C:16]=1Cl)=[CH:14][CH:13]=[CH:12][CH:11]=2)=O.Cl.[CH2:19]([O:26][NH2:27])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)(C)C>[CH2:19]([O:26][N:27]1[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:6]=[C:4]1[CH2:3][CH2:2][Cl:1])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(CCCl)Nc1cnc2ccccc2c1Cl
Reactant: NOCc1ccccc1
Agent: Cl
Solvent: CC(C)O
Product: ClCCc1nc2cnc3ccccc3c2n1OCc1ccccc1
Temperature: 40 °C
Yield: 29.9 %

Procedure:
A mixture of 3-chloro-N-(4-chloroquinolin-3-yl)propanamide (1.682 g, 6.243 mmol) and O-benzylhydroxylamine hydrochloride (1.10 g, 6.87 mmol) in 60 mL of isopropanol was heated to 40° C. under an atmosphere of N2. After 25 hours the mixture was cooled, solids were filtered off and rinsed with hexane. Chromatography (SiO2, 8-100% EtOAc/dichloromethane) gave 0.6308 g of 1-(benzyloxy)-2-(2-chloroethyl)-1H-imidazo[4,5-c]quinoline as a tan solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH2:9][CH:10]([NH:34][C:35]([O:37][CH3:38])=[O:36])[CH2:11][O:12][C:13](=[O:33])[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])(=[O:7])=[O:6].C(SCC(OC)CNS(CCC[I:66])(=O)=O)CCCCCCCCCCCCCCC>>[I:66][CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH2:9][CH:10]([NH:34][C:35]([O:37][CH3:38])=[O:36])[CH2:11][O:12][C:13](=[O:33])[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])(=[O:7])=[O:6]
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCI)OC
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCCl)NC(=O)OC
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCI)NC(=O)OC

Procedure:
3-(3-Chloropropylsulfonylamino)-2-methoxycarbonylamino-1-octadecylcarbamoyloxypropane IIIe1 is allowed to react and worked up by the same procedure as described in (5). m.p. 97° C. The summary of the experimental condition and the physical data of the product are listed in Table 8.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[NH2:11])([CH3:3])[CH3:2].[Br:12]Br>C(O)(=O)C>[Br:12][C:8]1[CH:7]=[C:6]([CH3:10])[C:5]([NH2:11])=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:9]=1
Reactant: BrBr
Reactant: Cc1cccc(C(C)C)c1N
Solvent: CC(=O)O
Product: Cc1cc(Br)cc(C(C)C)c1N
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2-isopropyl-6-methyl-phenylamine (1 ml, 6.4 mmol) in 6.5 mL acetic acid, was added bromine (0.33 ml, 6.4 mmol) dropwise over 10 minutes at room temperature. The mixture was stirred at room temperature under argon for 20 minutes. A precipitate was formed and collected by filtration and washed with ether to give pure 4-bromo-2-isopropyl-6-methyl-phenyl amine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](C(F)(F)F)[CH:5]=[CH:4][C:3]=1[NH:12][CH2:13]CCO.Cl.[O-:18]C#N.[K+]>O>[N:12]1[C:13](=[O:18])[N:1]=[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=12
Reactant: N#C[O-]
Reactant: Nc1cc(C(F)(F)F)ccc1NCCCO
Agent: Cl
Agent: [K+]
Solvent: O
Product: O=C1N=c2ccccc2=N1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred mixture of 21 parts of 3-{[2-amino-4-(trifluoromethyl)phenyl]amino}-1-propanol and 100 parts of water are added 14.4 parts of hydrochloric acid solution. The whole is stirred for 10 minutes at room temperature. After cooling to 0°-10° C, there is added dropwise a solution of 18 parts of potassium cyanate in 50 parts of water. Upon completion, stirring is continued for 2 hours. The precipitated product is filtered off and dried. Then it is melted and the melt is stirred for 10 minutes. After cooling, it is dissolved in trichloromethane while heating. The solution is filtered and the product is allowed to crystallize from the filtrate. It is filtered off and dried, yielding 8 parts (34%) of 1,3-dihydro-1-(3-hydroxypropyl)-5-trifluoromethyl)-2H-benzimidazol-2-one.
Reaction SMILES: [CH3:1][C:2]1([N:7]2[CH2:12][CH2:11][CH:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:9][CH2:8]2)[CH2:6][CH2:5][NH:4][CH2:3]1.C(OC([NH:26][CH2:27][C:28](O)=[O:29])=O)(C)(C)C>>[NH2:26][CH2:27][C:28]([N:4]1[CH2:5][CH2:6][C:2]([CH3:1])([N:7]2[CH2:12][CH2:11][CH:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:9][CH2:8]2)[CH2:3]1)=[O:29]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CC1(N2CCC(c3ccccc3)CC2)CCNC1
Product: CC1(N2CCC(c3ccccc3)CC2)CCN(C(=O)CN)C1

Procedure:
The title compound was prepared from 1-(3-methylpyrrolidin-3-yl)-4-phenylpiperidine and 2-(tert-butoxycarbonylamino)acetic acid using general procedures G, F.
Reaction SMILES: [C:1](Cl)(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:16][C:17]1[C:21]2[C:22]([OH:30])=[C:23]([CH2:27][CH2:28][CH3:29])[CH:24]=[C:25]([Cl:26])[C:20]=2[O:19][CH:18]=1>C(Cl)CCl>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:1]([C:18]2[O:19][C:20]3[C:25]([Cl:26])=[CH:24][C:23]([CH2:27][CH2:28][CH3:29])=[C:22]([O:30][C:1](=[O:10])[C:2]4[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=4)[C:21]=3[C:17]=2[CH3:16])=[O:10])=[CH:3][CH:4]=1
Reactant: CCCc1cc(Cl)c2occ(C)c2c1O
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCCc1cc(Cl)c2oc(C(=O)c3ccc(OC)cc3)c(C)c2c1OC(=O)c1ccc(OC)cc1
Reaction time: 0.17 h
Yield: 77.9 %

Procedure:
A solution of p-anisoyl chloride (3.5 gm; 20.5 mmoles) in ethylene dichloride (10 mL) was added slowly to a cooled suspension of aluminium chloride (4.0 gm; 30 mmoles) in ethylene dichloride (100 mL). After stirring for a period of 10 minutes, 3-methyl-4-hydroxy-5-propyl-7-chlorobenzofuran (1.14 gm; 5 mmoles) in dichloroethylene (5 mL) was added over a period of 2 minutes. The reaction mixture was stirred at room temperature for 1 hour. It was cooled with an ice bath and ice was added slowly. When the vigorous reaction subsided, the organic layer was separated and the aqueous phase was extracted with methylene chloride. The organic phases were combined, dried (Na2SO4), and concentrated in vacuo. The residue was chromatographed on silica gel and eluted with 10% ethylacetate in hexane to yield 1.92 gm (78%) of 2-(p-methoxybenzoyl)-3-methyl-4-(p-methoxybenzoyloxy)-5-propyl-7-chlorobenzofuran, mp.103°-105° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=2[CH2:15]O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].S(Cl)([Cl:23])=O>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=2[CH2:15][Cl:23])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: O=S(Cl)Cl
Reactant: COc1cc(-c2ccccc2CO)cc(OC)c1OC
Solvent: ClC(Cl)Cl
Product: COc1cc(-c2ccccc2CCl)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-(3,4,5-Trimethoxyphenyl)benzyl alcohol (630 mg) was dissolved in chloroform (10 mL), and to the solution thionyl chloride (0.153 mL) was added at 0° C. After 30 minutes, the mixture was warmed to room temperature and stirred for 4 hours. The reaction mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was then recrystallized from chloroform-hexane to obtain the title compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[N:12]([C@@H:15]3[O:20][C@H:19]([CH2:21][O:22]C(C4C=CC=CC=4)(C4C=CC(OC)=CC=4)C4C=CC(OC)=CC=4)[C@@H:17]([OH:18])[CH2:16]3)[CH:13]=[N:14][C:7]=12.[C:46](OC(=O)C)(=[O:48])[CH3:47].O>N1C=CC=CC=1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[N:12]([C@@H:15]3[O:20][C@H:19]([CH2:21][OH:22])[C@@H:17]([O:18][C:46](=[O:48])[CH3:47])[CH2:16]3)[CH:13]=[N:14][C:7]=12
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(-c5cccs5)ccnc43)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1C[C@H](n2cnc3c(-c4cccs4)ccnc32)O[C@@H]1CO
Temperature: 25 °C
Reaction time: 48 h
Yield: 90.4 %

Procedure:
Compound 7 (124 mg, 0.20 mmol) was azeotroped three times with anhydrous pyridine. This was dissolved in anhydrous pyridine (2.0 ml), and 38 μl (0.40 mmol) of acetic anhydride was further added thereto. The resulting mixture was stirred at room temperature for 2 days. The mixture was poured into water (50 ml) and extracted with methylene chloride (50 ml×3). After drying over Na2SO4, the solvent was distilled off under reduced pressure. The residue was dissolved in 20 ml anhydrous methylene chloride, and 200 μl dichloroacetic acid was added thereto at 0° C. After stirring at 2° C. for 15 minutes, the mixture was poured into 8 ml saturated aqueous sodium bicarbonate, diluted with 42 ml water, and then extracted with methylene chloride (50 ml×3). After drying over Na2SO4, the solvent was distilled off under reduced pressure. The residue was purified by flash silica gel chromatography using methylene chloride:ethyl acetate (9:1 to 3:2) as an elution solvent to give 65 mg of Compound 9 in a yield of 88%.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH2:4][CH:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.CN(C)C1C=CC=CC=1.Cl[C:23]([N:25]=[C:26]=[O:27])=[O:24]>ClCCl>[C:7]1([CH:5]2[N:6]3[C:23](=[O:24])[NH:25][C:26](=[O:27])[CH:1]=[C:2]3[O:3][CH2:4]2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C=NC(=O)Cl
Reactant: CC1=NC(c2ccccc2)CO1
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Product: O=c1cc2n(c(=O)[nH]1)C(c1ccccc1)CO2
Temperature: 25 °C
Reaction time: 14 h
Yield: 99 %

Procedure:
To 2-methyl-4-phenyl-4,5-dihydrooxazole (5.70 g, 35.4 mmol) and N,N-dimethylaniline (4.68 g, 6.83 mmol) in dichloromethane (25 mL) at 0° C. was added dropwise chlorocarbonyl isocyanate (3.80 g, 35.4 mmol). The mixture was allowed to warm to room temperature and was stirred for 14 h, during which time a thick white precipitate formed. The suspension was filtered, and the solid was triturated with diethyl ether (3×10 mL) to give a white powder (8.07 g, 99%). 1H NMR (TMS/CDCl3, 300 MHz): 7.44-7.24 (m, 5H); 5.57 (dd, J=3.3, 8.1 Hz, 1H), 5.12 (s, 1H); 5.00 (dd, J=8.1, 8.7 Hz, 1H); 4.54 (dd, J=3.3, 8.7 Hz, 1H); 3.04 (s, 1H). MS=231.0 ((M+H)+).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)N)=[CH:5][CH:4]=1.O=[C:21]([CH2:29][CH3:30])[CH2:22][CH2:23][CH2:24][C:25]([O:27]C)=[O:26]>C(O)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:12]3[C:17](=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:29]([CH3:30])=[C:21]2[CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:5][CH:4]=1
Reactant: CCC(=O)CCCC(=O)OC
Reactant: COc1ccc(N(N)Cc2ccc(Cl)cc2)cc1
Agent: Cl
Solvent: CCO
Product: COc1ccc2c(c1)c(C)c(CCCC(=O)O)n2Cc1ccc(Cl)cc1

Procedure:
Following the procedure of Example 2, but using 1-[(4-chlorophenyl)methyl]-1-(4-methoxyphenyl)hydrazine hydrochloride and methyl 5-oxoheptanoate as the starting materials and ethanol as the solvent, the title compound was prepared.