Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5](C(OC(C)(C)C)=O)[CH2:6][CH2:7][CH2:8][N:9](C(OC(C)(C)C)=O)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18](C(OC(C)(C)C)=O)[CH2:19][CH2:20][CH2:21][N:22]([CH2:30][CH2:31][CH2:32][CH3:33])C(OC(C)(C)C)=O)[CH2:2][CH2:3][CH3:4].Cl>CCO.CCOCC>[CH2:30]([NH:22][CH2:21][CH2:20][CH2:19][NH:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][NH:9][CH2:8][CH2:7][CH2:6][NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH2:31][CH2:32][CH3:33]
Reactant: CCCCN(CCCN(CCCCCCCCN(CCCN(CCCC)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: CCCCNCCCNCCCCCCCCNCCCNCCCC
Reaction time: 8 h
Yield: 98.4 %

Procedure:
Dissolve 1.32 gm (0.0017 mol) of the product of Step A of this example in 1.7 ml of EtOH, treat with 17 ml of 2N HCl in Et2O and stir the mixture overnight. Filter and wash the precipitate with Et2 O, recrystallize the washed material from isopropanol/water. Filter and dry the crystals (P2O5 at 79° C. at 0.1 mm) to yield 0.62 gm of the title compound, mp >300° C. Rf is 0.47 (silica gel plates eluted with 20% conc. NH3 /CH3OH).
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([C:13]([N:15]2[CH:19]([CH:20]([CH3:22])[CH3:21])[CH2:18][O:17][C:16]2=[O:23])=[O:14])[CH2:9][C:10]([OH:12])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1.CN1CCOCC1>CN(C=O)C>[CH:1]1([CH2:7][CH:8]([CH2:9][C:10]([N:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)=[O:12])[C:13]([N:15]2[CH:19]([CH:20]([CH3:22])[CH3:21])[CH2:18][O:17][C:16]2=[O:23])=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)C1COC(=O)N1C(=O)C(CC(=O)O)CC1CCCCC1
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)C1COC(=O)N1C(=O)C(CC(=O)N1CCOCC1)CC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
A mixture of 3-cyclohexylmethyl-4-(4-isopropyl-2-oxooxazolidin-3-yl)-4-oxobutyric acid (2.00 g, 6.14 mmol) and HBTU (2.56 g, 6.76 mmol) in DMF (20 mL) were treated with morpholine (0.591 mL, 6.76 mmol) and N-methylmorpholine (0.811 mL, 7.37 mmol). The mixture was stirred overnight at ambient temperature and then partitioned between 4:1:2:3 ethyl acetate/THF/water/brine (100 mL total). The organic phase was washed with 1M hydrochloric acid, saturated aqueous sodium bicarbonate and brine (50 mL each), dried (MgSO4) filtered and concentrated to dryness. The residue dissolved in ethyl acetate/hexane and product was crystallized out to provide 2-cyclohexylmethyl-1-(4-isopropyl-2-oxooxazolidin-3-yl)-4-morpholin-4-ylbutane-1,4-dione (1.63 g). MS (M+1): 395.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.Br[CH2:24][CH2:25][CH3:26]>>[CH3:18][CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:24][CH2:25][CH3:26])=[CH:7][N:6]=2)=[CH:10][CH:11]=1
Reactant: CC(=O)NC(C)CCc1ccc(Oc2ccc(O)cn2)cc1
Reactant: CCCBr
Product: CCCOc1ccc(Oc2ccc(CCC(C)NC(C)=O)cc2)nc1

Procedure:
N-{3-[4-(5-Hydroxypyridin-2-yloxy)phenyl]-1-methylpropyl}acetamide was reacted with 1-bromopropane in analogy to example 10b. Yield: 38 mg (66%), M+H+: 343.13.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:24](=[CH:25][CH:26]=1)[O:23][C:22]([CH3:28])([CH3:27])[C:18]1([CH2:21][O:20][CH2:19]1)[C@@:5]12[CH2:9][O:8][C:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[N:6]1.[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([C:36](O)=[O:37])=[N:34][CH:35]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]([NH:1][C:2]2[CH:3]=[C:4]3[C:24](=[CH:25][CH:26]=2)[O:23][C:22]([CH3:28])([CH3:27])[C:18]2([CH2:21][O:20][CH2:19]2)[C@@:5]23[CH2:9][O:8][C:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:14])[CH3:15])=[N:6]2)=[O:37])=[N:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(CO1)c1cc(N)ccc1OC(C)(C)C21COC1
Reactant: O=C(O)c1ccc(Cl)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1=N[C@@]2(CO1)c1cc(NC(=O)c3ccc(Cl)cn3)ccc1OC(C)(C)C21COC1
Reaction time: 8 h
Yield: 75 %

Procedure:
To a mixture of tert-butyl [(4S)-6′-amino-2′,2′-dimethyldispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-2-yl]carbamate (1.00 g, 2.57 mmol) and CH2Cl2 (10 mL) were added 5-chloro-2-pyridinecarboxylic acid (526 mg, 3.34 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (640 mg, 3.34 mmol), 1-hydroxybenzotriazole (451 mg, 3.34 mmol) and N,N-diisopropylethylamine (0.571 mL, 3.34 mmol) at ambient temperature. After stirring overnight at the same temperature, the reaction mixture was purified with column chromatography on silica gel (hexane-EtOAc, a linear gradient of EtOAc from 0 to 90%) and then on NH-silica gel (hexane-EtOAc, a linear gradient of EtOAc from 0 to 90%) to give tert-butyl [(4S)-6′-{[(5-chloropyridin-2-yl)carbonyl]amino}-2′,2′-dimethyldispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-2-yl]carbamate (1.02 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:11][CH2:10][NH:9][C:8]2=[O:12])=[CH:3][CH:2]=1.Br[CH2:14][C:15]#[CH:16]>>[CH2:16]([N:9]1[CH2:10][CH2:11][N:7]([C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)[C:8]1=[O:12])[C:15]#[CH:14]
Reactant: O=C1NCCN1c1ccncc1
Reactant: C#CCBr
Product: C#CCN1CCN(c2ccncc2)C1=O

Procedure:
The starting raw material, 1-(2-propynyl)-3-(4-pyridyl)-2-imidazolidinone was synthesized similarly to Referential example 1, using 1-(4-pyridyl)-2-imidazolidinone as material and using 3-bromopropyne in place of 4-fluoronitrobenzene.
Reaction SMILES: Br[CH2:2]/[C:3](/[C:11]([O:13][CH3:14])=[O:12])=[CH:4]\[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[S:15]([O-:18])([O-:17])=[O:16].[Na+:19].[Na+].[Br-].[Na+].[K+].[Br-]>O.CO>[Na+:19].[C:11](/[C:3](=[CH:4]/[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)/[CH2:2][S:15]([O-:18])(=[O:17])=[O:16])([O:13][CH3:14])=[O:12]
Reactant: O=S([O-])[O-]
Reactant: COC(=O)/C(=C/c1ccccc1)CBr
Agent: [Br-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)/C(=C/c1ccccc1)CS(=O)(=O)[O-]
Temperature: 50 °C
Reaction time: 0.75 h

Procedure:
To a 12 L, 3-neck round bottom flask fitted with a mechanical stirrer, thermometer and an addition funnel was added the resultant product from Example 1B (400 g, 1.57 mol) and methanol (4 L) . The mixture was warmed to 50° C. and a solution of sodium sulfite (199 g, 1.57 mol) dissolved in water (4 L) was added over 75 min while the internal temperature of the flask was maintained at 50° C. After the addition was complete, the clear solution was allowed to stir at 50° C. for an additional 45 minutes. The reaction mixture in solution was taken to the next step without additional purification. The compound may be isolated by concentration to an amorphous powder, which is contaminated with one equivalent of sodium bromide: IR (KBr) 1711, 1628, 1215 cm-1 ; 1H NMR (DMSO-d6, 300 MHz) δ 3.70 (s, 3H), 3.77 (s, 2H), 7.33-7.41 (m, 3H), 7.48 (s, 1H), 7.87-7.89 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ 49.88, 51.93, 127.36, 128.33, 128.91, 129.82, 134.75, 139.06, 168.60.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH3:23])=[N:8][N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=3[CH3:21])=[C:12]([CH3:22])[O:11][C:10]=12)=[O:5])C.O.[OH-].[Li+]>CCO.O>[CH3:21][C:15]1[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:14]=1[C:13]1[N:9]2[N:8]=[C:7]([CH3:23])[C:6]([C:4]([OH:5])=[O:3])=[C:10]2[O:11][C:12]=1[CH3:22]
Reactant: CCOC(=O)c1c(C)nn2c(-c3ccc(C)cc3C)c(C)oc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(-c2c(C)oc3c(C(=O)O)c(C)nn23)c(C)c1
Temperature: 45 °C

Procedure:
A stirred mixture of 3-(2,4-dimethyl-phenyl)-2,6-dimethyl-pyrazolo[5,1-b]oxazole-7-carboxylic acid ethyl ester (224 mg, 0.72 mmol, 1 eq.) and lithium hydroxide monohydrate (150 mg, 3.59 mmol, 5 eq.) in EtOH (4 ml) and water (2 ml) is heated at 45° C. for 14 h. The reaction mixture is cooled to RT then concentrated under reduced pressure. The residue is dissolved in water and the resulting aqueous solution is neutralized using 2M HCl in water (1.8 ml). The resulting precipitate is filtered, washed with water and dried under vacuum to yield the title compound as a white solid. The crude compound is used without further purification. HPLC: AtRet=2.12; MS: m/z 285.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 2.20 (s, 3H), 2.33 (s, 3H), 2.36 (s, 3H), 2.39 (s, 3H), 7.16 (m, 1H), 7.24 (br. s., 1H), 7.31 (m, 1H), 12.30 (br. s., 1H).
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.[Si](C=[N+]=[N-])(C)(C)C.[Cl:16][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1.O>C1COCC1>[C:25]([C:24]1[CH:27]=[CH:28][C:21]([O:20][CH2:19][CH2:18][CH2:17][Cl:16])=[CH:22][CH:23]=1)#[CH:2]
Reactant: CC(C)[N-]C(C)C
Reactant: O=Cc1ccc(OCCCCl)cc1
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1ccc(OCCCCl)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To LDA (2M in THF, 15 mL) in THF (100 mL) at −78° C., TMSCHN2 (2M in hexanes, 15 mL) was added dropwisely. Ten minutes later, 4-(3-chloropropoxy)benzaldehyde (0.025 mol, 4.97 g) in THF (60 mL) was added. After 1 h stirring at −78° C., the mixture was warmed up and refluxed for 3 h. Water (250 mL) was added and extracted by EtOAc (2×200 mL). After being dried over Na2SO4 and concentration, the title compound (4.8 g) was obtained.
Reaction SMILES: [N+]([O-])([O-])=O.[NH4+].[Ce+4].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=[O:20].[CH2:23]([O:25][C:26]([C:28]1[O:29][C:30]([C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=2)=[C:31]2[C:36]=1[CH:35]=[CH:34][CH:33]=[CH:32]2)=[O:27])[CH3:24]>O>[CH2:23]([O:25][C:26](=[O:27])[C:28]([C:36]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:30](=[O:29])[C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1)=[O:20])[CH3:24]
Reactant: O=[N+]([O-])[O-]
Reactant: CCOC(=O)c1oc(-c2ccc(Cl)cc2)c2ccccc12
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Product: CCOC(=O)C(=O)c1ccccc1C(=O)c1ccc(Cl)cc1
Temperature: 0 °C

Procedure:
11.5 G. of cerium (IV) ammonium nitrate are dissolved in 20 ml. of water and 20 ml. of glacial acid. Thereafter, there are added 3.0 g. of 3-(p-chlorophenyl)-isobenzofuran-1-carboxylic acid ethyl ester and the mixture is boiled for 2-3 minutes until the color of the solution obtained changes from orange to light-yellow. After cooling, there are added 150 ml. of ice-water and the mixture is stirred for 1 hour in an ice-bath. The product which first separates as an oil solidifies. The solid is separated by decantation of the aqueous solution and is dissolved in ether. The ethereal solution is washed with 2-N sodium carbonate and water, dried over sodium sulfate and evaporated. After crystallization of the residue from ethanol, there is obtained [o-(p-chlorobenzoyl)-phenyl]glyoxylic acid ethyl ester in the form of colorless crystals having a melting point of 79°-81° C.
Reaction SMILES: CC1(C)[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]#[C:15][C:16]([O:18][CH2:19]C)=[O:17])[CH:5]=[CH:4][C:3]1=2.CC1(C)C2C(=CC=C(C#C)C=2)[O:26]CC1.COC(Cl)=O.C([Li])CCC>>[CH3:12][C:9]1([CH3:13])[C:8]2[C:3](=[CH:4][CH:5]=[C:6]([C:14]#[C:15][C:16]([O:18][CH3:19])=[O:17])[CH:7]=2)[O:26][CH2:11][CH2:10]1
Reactant: C#Cc1ccc2c(c1)C(C)(C)CCO2
Reactant: CCOC(=O)C#Cc1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: COC(=O)Cl
Agent: [Li]CCCC
Product: COC(=O)C#Cc1ccc2c(c1)C(C)(C)CCO2

Procedure:
Employing the same general procedure as used for the preparation of ethyl 3-[5,5,8,8,-tetramethyl-5,6,7,8-tetrahydro-naphth-2-yl]propiolate (Compound A) but instead using 1.86 g (10 mmols) of [4,4-dimethylchroman-6-yl]ethyne, 2 g (21.3 mmols) of methylchloroformate and 11 mmols of n-butyllithium the title compound was obtained as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[N+:9]([O-])=O.[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1I>>[NH2:9][C:3]1[CH:4]=[C:5]([Br:8])[CH:6]=[CH:7][C:2]=1[C:16]1[CH:15]=[CH:14][C:13]([F:12])=[CH:18][C:17]=1[F:19]
Reactant: Fc1ccc(I)c(F)c1
Reactant: O=[N+]([O-])c1cc(Br)ccc1Br
Product: Nc1cc(Br)ccc1-c1ccc(F)cc1F

Procedure:
2,5-Dibromo-1-nitrobenzene and 2,4-difluoro-1-iodobenzene were reacted under Ullmann conditions to give 4-bromo-2',4'-difluoro-2-nitrobiphenyl, b.p. 126°-136°C./0.2mm (m.p. 52°-53°C. after recrystallisation from methanol). This was reduced to give 2-amino-4-bromo-2',4'-difluorobiphenyl, b.p. 120°-124°C./0.5mm, which was subjected to a Schiemann reaction, using hydrofluoroboric acid to give the product, m.p. 67°-69°C., after distillation.
Reaction SMILES: [O:1]=[CH:2][CH2:3][C@@H:4]([C@@H:6]([CH2:8][OH:9])[OH:7])[OH:5].[H][H]>O.[Ni]>[CH2:2]([OH:1])[CH2:3][C@@H:4]([C@@H:6]([CH2:8][OH:9])[OH:7])[OH:5]
Reactant: [H][H]
Reactant: O=CC[C@H](O)[C@H](O)CO
Agent: [Ni]
Solvent: O
Product: OCC[C@H](O)[C@H](O)CO
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
An 80 g (0.60 mole) portion of 2-deoxy-D-ribose was dissolved in 240 ml of water to form an aqueous solution into which 15 g of Raney nickel were added. The thus prepared reaction mixture in an autoclave was heated under a hydrogen pressure of 40 kg/cm2G up to a temperature of 70° C. taking 30 minutes and kept for additional 1 hour at the same temperature and under the same hydrogen pressure. After cooling, the reaction mixture taken out of the autoclave was filtered to remove the solid catalyst and the filtrate, as combined with the washings of the solid catalyst with water, was subjected to removal of the water to give about 80 g of 2-deoxy-D-erythropentitol. The yield of the product was almost quantitative.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.O=S(Cl)Cl.[CH3:15][CH2:16]OCC>CCO>[CH2:15]([O:9][C:8]([CH:5]1[CH2:6][CH2:7][CH:2]([NH2:1])[CH2:3][CH2:4]1)=[O:10])[CH3:16]
Reactant: CCOCC
Reactant: NC1CCC(C(=O)O)CC1
Solvent: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C1CCC(N)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of 4-amino-cyclohexanecarboxylic acid (G) (5 g, 35 mmol) in EtOH (175 mL) at 0° C. was added SOCl2 (12.6 mL, 174 mmol) dropwise via a syringe. The reaction mixture was warmed to room temperature and stirred for 16 h. After concentration of the reaction mixture, ether was added and the suspension was filtered to give 4-amino-cyclohexanecarboxylic acid ethyl ester (H) (mixture of cis/trans) as a white solid (4.8 g): 1H NMR (300 MHz, CDCl3) δ8.35 (br s, 3 H), 4.18 (m, 2 H), 3.36-3.15 (m, 1 H), 2.54 (m, 1 H), 2.30-1.45 (series of m, 8 H), 1.13 (t, 3 H); mass spectrum m/z 172 [(M+H)+; calcd for C9H18NO2: 172].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24].C(=O)([O-])[O-].[K+].[K+].[Br:35][CH2:36][CH2:37]Br>CN(C)C=O>[Br:35][CH2:36][CH2:37][O:21][C:15]1[CH:14]=[C:13]2[C:18]([C:9]([O:8][C:6]3[CH:5]=[CH:4][C:3]([NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24])=[C:2]([Cl:1])[CH:7]=3)=[N:10][CH:11]=[N:12]2)=[CH:17][C:16]=1[O:19][CH3:20]
Reactant: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(O)c(OC)cc23)cc1Cl
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(OCCBr)c(OC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 45 %

Procedure:
N-{2-Chloro-4-[(7-hydroxy-6-methoxy-4-quinazolinyl)oxy]phenyl}-N′-propylurea (72 mg), potassium carbonate (30 mg), and 1,2-dibromoethane (62 μl) were dissolved in N,N-dimethylformamide (4 ml), and the solution was stirred at room temperature for 3 hr. The solvent was removed by distillation under the reduced pressure. Water was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was washed with ether to give 40 mg (yield 45%) of N-(4-{[7-(2-bromoethoxy)-6-methoxy-4-quinazolinyl]-oxy}-2-chlorophenyl)-N′-propylurea as an intermediate. The intermediate (45 mg), potassium carbonate (30 mg), and morpholine (80 μl) were dissolved in N,N-dimethylformamide (2 ml), and the solution was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure. A saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by chromatography on silica gel by development with chloroform/methanol to give 42 mg (yield 56%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12]CC=C)[CH:7]=[O:8])[CH3:2].[OH-].[Na+].[C:18]1(C)[CH:23]=C(C)C=C(C)[CH:19]=1>>[CH2:23]([C:10]1[CH:9]=[C:6]([CH:5]=[C:4]([O:3][CH2:1][CH3:2])[C:11]=1[OH:12])[CH:7]=[O:8])[CH:18]=[CH2:19]
Reactant: C=CCOc1ccc(C=O)cc1OCC
Reactant: Cc1cc(C)cc(C)c1
Agent: [Na+]
Agent: [OH-]
Product: C=CCc1cc(C=O)cc(OCC)c1O

Procedure:
3-Ethoxy-4-(2-propenyloxy)benzaldehyde (20.0 g, 0.087 mol) was heated under reflux in 75 ml mesitylene (1,3,5-trimethylbenzene) for 20 hours. After cooling, 250 ml 2N sodium hydroxide were added to the reaction mixture. The aqueous phase was washed two times with diethyl ether. The aqueous phase was subsequently acidified with concentrated hydrochloric acid under ice cooling and then extracted with ethyl acetate. After drying and concentrating the organic phase, there remained a light orange-colored oil that crystallized on cooling.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)=O.[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][CH:14]=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]2[O:18][CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=3)[N:19]=2)=[CH:15][CH:14]=1
Reactant: Cc1ccc(C(=O)CBr)cc1
Reactant: NC(=O)c1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2coc(-c3ccc(Br)cc3)n2)cc1
Temperature: 160 °C

Procedure:
A mixture of 2-bromo-4′-methylacetophenone (152 mg, 0.7 mmol) and 4-bromobenzamide (200 mg, 1.0 mmol) was heated to 160° C. for 3 hours, cooled to room temperature, dissolved in ethyl acetate (20 mL), and treated with 5% sodium bicarbonate (20 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×10 mL). The combined extracts were dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 50% ethyl acetate/hexanes to provide the desired product. MS (DCI) m/e 314, 316 (M−H)−, (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ8.70 (s, 1H), 8.00-7.97 (m, 2H), 7.79-7.76 (m, 2H), 7.77-7.74 (m, 2H), 7.29-7.27 (m, 2H), 2.34 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]([OH:14])=O.[F:15][C:16]([F:29])([F:28])[C:17]1[CH:18]=[C:19]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[NH2:20]>>[OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]([NH:20][C:19]1[CH:21]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:23]=[C:17]([C:16]([F:15])([F:28])[F:29])[CH:18]=1)=[O:14]
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(O)c1c(O)ccc2ccccc12
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1c(O)ccc2ccccc12
Yield: 30.2 %

Procedure:
Using 2-hydroxynaphthalene-1-carboxylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 1(1) gave the title compound.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[OH:12].Cl[CH2:14][C:15](=[O:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[CH2:14]([O:12][C:3]1[C:2]([F:1])=[C:7]([F:8])[CH:6]=[CH:5][C:4]=1[N+:9]([O-:11])=[O:10])[C:15]([CH3:16])=[O:17]
Reactant: CC(=O)CCl
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)COc1c([N+](=O)[O-])ccc(F)c1F
Yield: 65.3 %

Procedure:
5.8 g of 2,3-difluoro-6-nitrophenol, 5.0 g of monochloroacetone, 8.0 g of potassium carbonate and 0.8 g of potassium iodide were added to 100 ml of acetone and the mixture was refluxed for 4 hours. After the removal of insoluble material by filtration, the solvent was evaporated and the residue was distributed between chloroform and water. The chloroform layer was washed with water and was dried, then the solvent was evaporated. The residue was treated with n-hexane to provide 5.0 g of 2-acetonyloxy-3,4-difluoronitrobenzene as light yellow crystals with m.p. 61° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.[Cl:11][CH2:12][C:13]([CH2:15]Cl)=O>C(OCC)(=O)C.CCCCCCC>[Cl:11][CH2:12][C:13]1[N:8]=[C:6]([C:5]2[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)[O:7][CH:15]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=O)c1ccc(F)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: Fc1ccc(-c2nc(CCl)co2)cc1
Temperature: 25 °C

Procedure:
At 120° C., 31 g (123 mmol) of p-fluorobenzamide and 33 g (123 mmol) of 1,3-dichloroacetone were stirred in the absence of a solvent for 2 hours. After cooling to room temperature, the product was dissolved in 250 ml of ethyl acetate. This solution was diluted with 400 ml of n-heptane and washed 3 times with saturated NaCl solution. The organic phase was filtered through 250 ml of silica gel, and the filter pad was then washed with 200 ml of n-heptane/ethyl acetate (4:1). The solvent was distilled off, giving 4-chloromethyl-2-(4-fluorophenyl)oxazole 1 as crude product. This was dissolved in 650 ml of acetone, and 90 g of NaI were then added. The mixture was then heated at reflux for 16 hours, most of the solvent was then removed and the solid residue was suspended in 200 ml of n-heptane/ethyl acetate (1:1) and filtered through 200 ml of silica gel. The precipitate was washed with 500 ml of n-heptane/ethyl acetate (1:1), and the organic phase was concentrated. On concentration, the iodide 2 began to crystallize as white crystals. TLC n-heptane/ethyl acetate (6:1) Rf 0.4 for 2 and Rf=0.35 for 1. C10H7FINO (303.08) MS(ESI): 304 (M+H+).
Reaction SMILES: [NH2:1][C@@H:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH2:10][C@@H:9]([NH:14][C:15](=[O:29])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C@@H:24]3[CH2:28][CH2:27][CH2:26][O:25]3)=[CH:18][CH:17]=1)[CH2:8][CH2:7]2)[CH3:3].Br[CH2:31][CH2:32][CH:33]([CH3:37])[CH2:34][CH2:35]Br.C(N(C(C)C)C(C)C)C>C(#N)C>[CH3:37][CH:33]1[CH2:34][CH2:35][N:1]([C@@H:2]([C:4]2[CH:5]=[C:6]3[C:11](=[CH:12][CH:13]=2)[CH2:10][C@@H:9]([NH:14][C:15](=[O:29])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C@@H:24]4[CH2:28][CH2:27][CH2:26][O:25]4)=[CH:18][CH:17]=2)[CH2:8][CH2:7]3)[CH3:3])[CH2:31][CH2:32]1
Reactant: C[C@@H](N)c1ccc2c(c1)CC[C@H](NC(=O)c1ccc(OC[C@@H]3CCCO3)cc1)C2
Reactant: CC(CCBr)CCBr
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCN([C@H](C)c2ccc3c(c2)CC[C@H](NC(=O)c2ccc(OC[C@@H]4CCCO4)cc2)C3)CC1
Temperature: 40 °C

Procedure:
A mixture of N-[(S)-6-((R)-1-aminoethyl)-1,2,3,4-tetrahydronaphthalen-2-yl]-4-[(S)-1-(tetrahydrofuran-2-yl)methoxy]benzamide (50 mg), 1,5-dibromo-3-methylpentane (31 mg), ethyldiisopropylamine (0.10 ml) and acetonitrile (1 ml) was heated to 40° C. for 8 hours. The cooled reaction mixture was concentrated and the residue was purified by preparative HPLC. The product was thus obtained with the molecular weight of 476.66 (C30H40N2O3); MS (ESI): 477 (M+H+).