Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:10]=2)[CH3:8])[O:4][N:3]=1.[CH2:23](O)[CH2:24][OH:25]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[NH2:1][C:2]1[N:6]=[C:5]([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[O:25][CH2:24][CH2:23][O:22]3)[CH:10]=2)[CH3:8])[O:4][N:3]=1
Reactant: OCCO
Reactant: CC(c1cccc(C(=O)c2ccccc2)c1)c1nc(N)no1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(c1cccc(C2(c3ccccc3)OCCO2)c1)c1nc(N)no1
Temperature: 25 °C
Yield: 76.8 %

Procedure:
To 3-amino-5-(1-(3-benzoylphenyl)ethyl)-1,2,4-oxadiazole (1.20 g, 4.09 mmol) in toluene (10 ml) were added ethylene glycol (0.80 g, 12.9 mmol) and p-toluenesulfonic acid monohydrate (0.025 g, 0.15 mmol). After reflux for 10 h, the mixture was cooled at room temperature and extracted with toluene. The extracts were washed with aqueous sodium hydrogen carbonate and then water, dried with anhydrous sodium sulfate, and evaporated under reduced pressure to a residue, which was chromatographed to afford 3-amino-5-(1-(3-(2-phenyl-1,3-dioxolan-2-yl)phenyl)ethyl)-1,2,4-oxadiazole (1.06 g, 77% yield) as crystalline material: mp 112.0°-113.5° C.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][N:10]=[C:9]([Cl:13])[CH:8]=1)=O.N(O)=O.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([NH:26][C:27]([NH2:29])=[NH:28])[CH:23]=[CH:24][CH:25]=1.[OH-].[Li+]>CC(O)CC>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([NH:26][C:27]2[N:29]=[C:5]([C:7]3[CH:12]=[CH:11][N:10]=[C:9]([Cl:13])[CH:8]=3)[CH:4]=[CH:3][N:28]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: COc1cccc(NC(=N)N)c1
Reactant: CN(C)C=CC(=O)c1ccnc(Cl)c1
Agent: O=NO
Agent: [Li+]
Agent: [OH-]
Solvent: CCC(C)O
Product: COc1cccc(Nc2nccc(-c3ccnc(Cl)c3)n2)c1
Temperature: 25 °C
Yield: 85.6 %

Procedure:
A mixture of 3-dimethylamino-1-(2-chloro-4-pyridyl)-2-propen-1-one (2.22 g, 10.5 mmol), 3-methoxy-phenyl-guanidine nitrite (2.40 g, 10.5 mmol), lithium hydroxide (350 mg, 14.5 mmol) in 2-butanol (25 mL) is heated to reflux for 8 hours. The reaction mixture is cooled to room temperature, concentrated and water (60 mL) is added. The resultant solid is collected by filtration and washed with water, isopropanol and dried to give N-[3-methoxy-phenyl]-4-(2-chloro-4-pyridyl)-2-pyrimidineamine (2.81 g); ESI-MS (m/z): 313 (M++H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[OH:14])/[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.Cl[CH2:16][C:17]([N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:18].C(N(C(C)C)C(C)C)C.[I-].[Na+]>C(#N)C.C(OCC)(=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][CH2:16][C:17]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:18])/[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1
Reactant: CCOC(=O)/C(=N\O)c1csc(N)n1
Reactant: O=C(CCl)N1CCCCC1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)/C(=N\OCC(=O)N1CCCCC1)c1csc(N)n1
Yield: 58.2 %

Procedure:
83.8 g of ethyl 2-(2-amino-4-thiazolyl)-2-(Z)-hydroxyimino-acetate, 94.4 g of N-chloroacetylpiperidine, 202.5 ml of N-ethyldiisopropylamine and 87.6 g of sodium iodide are stirred at room temperature for 12 hours in 1420 ml of acetonitrile. The mixture is diluted with 7 l of ethyl acetate, washed with water, dried over magnesium sulphate and concentrated to a small volume. The substance which crystallizes ot is filtered off and dried. There are obtained 77.2 g of ethyl 2-(2-amino-4-thiazolyl)-2-[(Z)-[(1-piperidinecarbonyl)methoxy]imino]-acetate of melting point 151°-152° C.
Reaction SMILES: [CH2:1]([N:5]1[C:14](=O)[C:13]([C:16]#[N:17])=[C:12]2[C:7]([CH:8](O)[CH2:9][CH2:10][CH2:11]2)=[CH:6]1)[CH2:2][CH2:3][CH3:4].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:28])=CC=1.CO>C1(C)C=CC=CC=1>[CH2:1]([N:5]1[C:14](=[S:28])[C:13]([C:16]#[N:17])=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH2:11]2)=[CH:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCCCn1cc2c(c(C#N)c1=O)CCCC2O
Solvent: CO
Solvent: Cc1ccccc1
Product: CCCCn1cc2c(c(C#N)c1=S)CCCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.1 %

Procedure:
2-Butyl-3-oxo-2,3,5,6,7,8-hexahydroisoquinoline-4-carbonitrile (7-013) (80 mg, 0.35 mmol) was dissolved in toluene (8 mL), and to the reaction mixture was added Lawesson's reagent (169 mg, 0.42 mmol), the reaction mixture was heated under reflux for 12 h. The reaction mixture was cooled to room temperature, and methanol was added to the reaction mixture, and the reaction mixture was stirred at room temperature for 1 h, and evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 2-butyl-3-thioxo-2,3,5,6,7,8-hexahydroisoquinoline-4-carbonitrile (7-014) (63 mg, 73%) as a pale brown powder.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[NH2:8].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:27]=[CH:28][C:29]=1[O:30][CH2:31][O:32][CH3:33])[CH:22]=[CH:23][C:24](O)=O>>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:27]=[CH:28][C:29]=1[O:30][CH2:31][O:32][CH3:33])/[CH:22]=[CH:23]/[C:24]1[NH:1][C:2]2[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=2[N:8]=1
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Reactant: COCOc1ccc(C=CC(=O)O)cc1OC
Product: CCCn1c(=O)c2[nH]c(/C=C/c3ccc(OCOC)c(OC)c3)nc2n(CCC)c1=O
Yield: 66.7 %

Procedure:
Substantially the same procedure as in Reference Example 1 was repeated using 4.0 g (17.7 mmol) of 5,6-diamino-1,3-dipropyluracil and 4.63 g (19.4 mmol) of 3-methoxy-4-methoxymethoxycinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 5.06 g (yield 67%) of Compound 194 as pale yellow flocculent precipitates.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:19]([O-:21])=[O:20])=[C:6]([NH:8][CH:9]([C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=2)[CH3:10])[CH:7]=1.[N:22]1([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:18][C:13]1[CH:12]=[C:11]([CH:9]([NH:8][C:6]2[CH:7]=[C:2]([N:25]3[CH2:24][CH2:23][N:22]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:27][CH2:26]3)[CH:3]=[CH:4][C:5]=2[N+:19]([O-:21])=[O:20])[CH3:10])[CH:16]=[C:15]([CH3:17])[CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1cc(C)cc(C(C)Nc2cc(F)ccc2[N+](=O)[O-])c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1cc(C)cc(C(C)Nc2cc(N3CCN(C(=O)OC(C)(C)C)CC3)ccc2[N+](=O)[O-])c1
Yield: 43 %

Procedure:
5-fluoro-N-(1-(3,5-dimethylphenyl)ethyl)-2-nitrobenzenamine (762 mg, 2.4 mmol), t-butyl piperazine-1-carboxylate (443 mg, 2.4 mmol), N,N-diisopropylethylamine (614 mg, 4.8 mmol) were stirred at 80° C. in dry acetonitrile (50 mL) for 48 h. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated and the crude compound was purified by silica chromatography using 25% ethyl acetate in hexanes to afford the title compound (469 mg, 41% yield). 1H NMR (400 MHz, CDCl3): δ 8.68 (s, 1H), 8.05 (d, 1H), 6.49 (s, 2H), 6.33 (s, 1H), 6.14 (d, 1H), 5.70 (s, 1H), 4.47 (m, 1H), 3.76 (s, 6H), 3.43 (m, 4H), 3.23 (m, 2H), 3.15 (m, 2H), 1.62 (d, 3H), 1.46 (s, 9H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[Mg+2].[Cl-].[Cl-].[CH2:22]=[O:23].Cl>C(#N)C>[C:1]([C:5]1[C:6]([OH:11])=[C:7]([CH:8]=[CH:9][CH:10]=1)[CH:22]=[O:23])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1O
Reactant: C=O
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)c1cccc(C=O)c1O

Procedure:
A mixture of 2-(tert-butyl)phenol (15 g, 0.1 mol), Et3N (37 g, 374 mmol), MgCl2 (14.3 g, 0.15 mol) and paraformaldehyde (20.2 g, 674 mmol) in ACN (200 mL) was heated at reflux for 5 h, cooled, poured into aq. HCl (2N, 200 mL) and extracted with Et2O. The organic layer was concentrated and purified by CC (PE/EA=8/1) to give compound P7a (13 g, 74%) as a colorless oil.
Reaction SMILES: [Br-:1].O=[S:3]1(=O)[CH:8]([CH3:9])[CH2:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4]1.C([O-])(=O)C.[Na+].II>C(O)(=O)C>[Br:1][C:11]1[CH:12]=[CH:13][C:5]2[O:4][S:3][CH:8]([CH3:9])[CH2:7][C:6]=2[CH:10]=1
Reactant: [Br-]
Reactant: CC1Cc2ccccc2OS1(=O)=O
Agent: CC(=O)[O-]
Agent: II
Agent: [Na+]
Solvent: CC(=O)O
Product: CC1Cc2cc(Br)ccc2OS1
Temperature: 40 °C
Reaction time: 24 h

Procedure:
6.7 g of bromide are added dropwise to a mixture of 7.92 g of 3,4-dihydro-2,2-dioxo-3-methyl-1,2-benzoxathiine, 6.5 g of sodium acetate, 0.1 g of iodine and 60 ml of glacial acetic acid, which is then stirred for 24 hours at a temperature of 40° C. The mixture is concentrated and taken up with a mixture of water and ethyl acetate. The organic phase is separated, twice washed with an aqueous solution of sodium hydrogen-carbonate, dried and evaporated. The oily residue is introduced into the following reaction step without further purification operations.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:14])=[CH:4][C:5]2[CH:9]=[C:8]([CH2:10][OH:11])[S:7][C:6]=2[C:12]=1[Cl:13].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+].CC(=O)CC>CN(C)C=O>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][O:14][C:3]1[C:2]([Cl:1])=[C:12]([Cl:13])[C:6]2[S:7][C:8]([CH2:10][OH:11])=[CH:9][C:5]=2[CH:4]=1)[CH3:21]
Reactant: OCc1cc2cc(O)c(Cl)c(Cl)c2s1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc2cc(CO)sc2c(Cl)c1Cl
Yield: 107.9 %

Procedure:
A solution of 1.24 g of 6,7-dichloro-5-hydroxy-2-hydroxymethylbenzo[b]thiophene, 0.9 g of ethyl bromoacetate, 0.6 g of potassium carbonate, 25 ml of 2-butanone and 0.5 ml of dimethylformamide is stirred under reflux for 2 hrs. The aqueous layer is extracted twice with 50 ml portions of dichloromethane. The combined organic extracts, are washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give a clear oil which crystallizes on standing. Recrystallization of the crude product from acetone-hexane gives 1.8 g of ethyl[(6,7-dichloro-2-hydroxymethylbenzo[b]thien-5-yl)oxy]acetate mp 117°-118.5°.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:18]=[CH:17][C:9]([CH:10]=[C:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:8][CH:7]=1.C(N(CC)CC)C.[F:26][C:27]([F:38])([F:37])[C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1>C(OCC)(=O)C.C(Cl)Cl>[O:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]([CH:10]=[C:11]2[CH2:12][CH2:13][N:14]([C:32](=[O:33])[C:31]3[CH:35]=[CH:36][C:28]([C:27]([F:26])([F:37])[F:38])=[CH:29][CH:30]=3)[CH2:15][CH2:16]2)=[CH:17][CH:18]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: C(=C1CCNCC1)c1ccc(C2=NCCO2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(C(F)(F)F)cc1)N1CCC(=Cc2ccc(C3=NCCO3)cc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
120 mg (0.5 mmol) of 4-[4-(2-oxazolin-2-yl)benzylidene]piperidine and 75 mg (0.75 mmol) of triethylamine in 3 ml of ethyl acetate and 2 ml of methylene chloride are cooled to -5° to -10° C. and 104.3 mg (0.5 mmol) of 4-trifluoromethylbenzoyl chloride are added. The mixture is stirred at ambient temperature for 1.5 hours, diluted with ethyl acetate, washed successively with water, 2N sodium hydroxide solution and saturated saline solution, dried and evaporated down. 115 mg (56% of theory) of the title compound of melting point 142° C. are obtained.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[C:6]2[N:12]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:22].C([O-])([O-])=O.[K+].[K+].[CH2:31](Br)[CH:32]=[CH2:33]>CC(C)=O>[CH2:33]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([C:2]([F:23])([F:1])[F:24])=[CH:11][CH:10]=2)[C:6]([N:12]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:22])=[N:7]1)[CH:32]=[CH2:31]
Reactant: C=CCBr
Reactant: O=C1c2ccccc2C(=O)N1c1n[nH]c2ccc(C(F)(F)F)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCn1nc(N2C(=O)c3ccccc3C2=O)c2cc(C(F)(F)F)ccc21

Procedure:
2-(5-Trifluoromethyl-1H-indazol-3-yl)-isoindole-1,3-dione (500 mg, 1.51 mmol), K2CO3 (313 mg, 2.26 mmol) and allyl bromide (365 mg, 3.02 mmol) in acetone (10 mL) were heated to reflux overnight. The reaction was filtered, and the residue was concentrated and purified by silica gel column chromatography using hexanes:ethyl acetate 2:1 to give the title compound as white solid.
Reaction SMILES: Cl[C:2]1[CH:19]=[CH:18][C:5]2[C:6](=[O:17])[C:7]3[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1.[F:20][C:21]1[C:27]([F:28])=[C:26]([F:29])[CH:25]=[CH:24][C:22]=1[NH2:23].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C1(C)C=CC=CC=1>CC([O-])=O.CC([O-])=O.[Pd+2].C(O)(C)(C)C>[CH3:16][O:15][C:13]1[CH:12]=[CH:11][C:8]2[CH2:9][CH2:10][C:4]3[CH:3]=[C:2]([NH:23][C:22]4[CH:24]=[CH:25][C:26]([F:29])=[C:27]([F:28])[C:21]=4[F:20])[CH:19]=[CH:18][C:5]=3[C:6](=[O:17])[C:7]=2[CH:14]=1
Reactant: Nc1ccc(F)c(F)c1F
Reactant: COc1ccc2c(c1)C(=O)c1ccc(Cl)cc1CC2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)C(=O)c1ccc(Nc3ccc(F)c(F)c3F)cc1CC2
Yield: 72 %

Procedure:
In accordance with general method AA, 0.50 g (1.8 mmol) of 2-chloro-7-methoxy-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one (34), 0.27 g (1.8 mmol) of 2,3,4-trifluoroaniline, 0.05 g (0.22 mmol) of Pd(OAc)2, 0.10 g (0.21 mmol) of 2-(dicyclohexylphosphino)-2′-,4′-,6′-triisopropyl-biphenyl, 0.60 g (6.2 mmol) of Na—O-tert-butylate, 5 ml of toluene and 1 ml of tert-BuOH are used. Reaction time: 1 h. Purification is carried out via flash chromatography (SiO2, hexane/ethyl acetate 8+2). Yield: 72%; melting point: 128° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[NH:15][C@@H:14]([C@@H:16]([OH:18])[CH3:17])[CH2:13][O:12][CH2:11]2)[CH:5]=[C:6]([F:9])[C:7]=1[F:8].N1C=CC=CC=1.[C:25](Cl)(=[O:29])[C:26](Cl)=[O:27]>ClCCl.O>[CH3:17][C@H:16]1[C@H:14]2[CH2:13][O:12][CH2:11][C@@H:10]([C:4]3[CH:3]=[C:2]([F:1])[C:7]([F:8])=[C:6]([F:9])[CH:5]=3)[N:15]2[C:26](=[O:27])[C:25](=[O:29])[O:18]1
Reactant: C[C@H](O)[C@H]1COC[C@@H](c2cc(F)c(F)c(F)c2)N1
Reactant: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: C[C@@H]1OC(=O)C(=O)N2[C@@H]1COC[C@H]2c1cc(F)c(F)c(F)c1
Reaction time: 1 h

Procedure:
To a solution consisting of (S)-1-[(3R,5R)-5-(3,4,5-trifluorophenyl)morpholine-3-yl]ethanol (1.18 g) and pyridine (5 mL) in dichloromethane (20 mL) was dropwise added oxalyl chloride (1.18 mL) while cooling with ice. The resultant solution was stirred at the same temperature for 30 minutes, and then at room temperature for 1 hour. The reaction solution was diluted with water, and the organic layer was partitioned. The organic layer was then dried over anhydrous magnesium sulfate. Solvent was removed by distillation under reduced pressure, and the resulting residue was purified by silica gel column chromatography (heptane/ethyl acetate→ethyl acetate), to thereby obtain the titled compound (912 mg). The physical properties of the compound were as follows. ESI-MS; m/z 316 [M++H]. 1H-NMR (CDCl3) δ (ppm): 1.54 (d, J=7.2 Hz, 3H), 3.50 (dd, J=11.6, 11.6 Hz, 1H), 3.68 (dd, J=12.4, 8.0 Hz, 1H), 4.06 (dd, J=11.6, 4.4 Hz, 1H), 4.18 (dd, J=12.4, 4.8 Hz, 1H), 4.49 (ddd, J=12.0, 4.4, 4.0 Hz, 1H), 4.64-4.70 (m, 1H), 4.78 (dd, J=8.4, 5.2 Hz, 1H), 7.01 (dd, J=8.0, 6.4 Hz, 2H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:6]=[CH:5][C:4]=1[NH:13][C:14]1[C:15]2[O:22][CH:21]=[C:20]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[C:16]=2[N:17]=[CH:18][N:19]=1.Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31].O>N1C=CC=CC=1.C(Cl)Cl>[F:2][C:3]1[CH:8]=[C:7]([S:9]([CH3:12])(=[O:10])=[O:11])[CH:6]=[CH:5][C:4]=1[NH:13][C:14]1[C:15]2[O:22][CH:21]=[C:20]([CH:23]3[CH2:28][CH2:27][N:26]([C:30]([O:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[O:31])[CH2:25][CH2:24]3)[C:16]=2[N:17]=[CH:18][N:19]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc3c(C4CCNCC4)coc23)c(F)c1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc(Nc2ncnc3c(C4CCN(C(=O)OCc5ccccc5)CC4)coc23)c(F)c1
Yield: 51 %

Procedure:
N-[2-Fluoro-4-(methylsulfonyl)phenyl]-7-(piperidin-4-yl)furo[3,2-d]pyrimidine-4-amine hydrochloride (9.0 mg, 0.021 mmol) was dissolved in pyridine (0.4 mL), and a 0.25 mol/L solution of benzyl chloroformate in anhydrous methylene chloride (0.1 mL) was added dropwise slowly under ice-cooling, and then the resultant mixture was stirred for 15 minutes under ice-cooling, and water was added, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under a reduced pressure, and the obtained residue was purified by silica gel preparative thin layer chromatography (chloroform:methanol=20:1) to give the titled compound (5.6 mg, 51%) as a yellow oily substance.
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:46]1[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=1)[CH2:10][CH2:11][C@@H:12]1[C@@H:15]([C:16]2[CH:21]=[CH:20][C:19](B3OC(C)(C)C(C)(C)O3)=[CH:18][C:17]=2[O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[N:14]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:13]1=[O:45])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:53]([O:56][C@@H:57]1[C@@H:62]([O:63][C:64](=[O:66])[CH3:65])[C@H:61]([O:67][C:68](=[O:70])[CH3:69])[C@@H:60]([CH2:71][O:72][C:73](=[O:75])[CH3:74])[O:59][C@H:58]1[C:76]1[CH:81]=[CH:80][CH:79]=[C:78](Br)[CH:77]=1)(=[O:55])[CH3:54].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[C:53]([O:56][C@@H:57]1[C@@H:62]([O:63][C:64](=[O:66])[CH3:65])[C@H:61]([O:67][C:68](=[O:70])[CH3:69])[C@@H:60]([CH2:71][O:72][C:73](=[O:75])[CH3:74])[O:59][C@H:58]1[C:76]1[CH:77]=[C:78]([C:19]2[CH:20]=[CH:21][C:16]([C@@H:15]3[C@@H:12]([CH2:11][CH2:10][C@H:9]([O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2])[C:46]4[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=4)[C:13](=[O:45])[N:14]3[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[C:17]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:33])[CH3:34])[CH:18]=2)[CH:79]=[CH:80][CH:81]=1)(=[O:55])[CH3:54]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2cccc(Br)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC1(C)OB(c2ccc([C@@H]3[C@@H](CC[C@H](O[Si](C)(C)C(C)(C)C)c4ccc(F)cc4)C(=O)N3c3ccccc3)c(O[Si](C)(C)C(C)(C)C)c2)OC1(C)C
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: CCO
Solvent: Cc1ccccc1
Product: CC(=O)OC[C@H]1O[C@@H](c2cccc(-c3ccc([C@@H]4[C@@H](CC[C@H](O[Si](C)(C)C(C)(C)C)c5ccc(F)cc5)C(=O)N4c4ccccc4)c(O[Si](C)(C)C(C)(C)C)c3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Yield: 27 %

Procedure:
The resulting brown oil which is (3R,4S)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-[2-{[tert-butyl(dimethyl)silyl]oxy}-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-phenylazetidin-2-one was dissolved with (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-(3-bromophenyl)-D-glucitol in 4.0 mL of toluene and 0.5 mL of ethanol. 0.150 mL of 4 N potassium carbonate was added followed by 7 mg of tetrakis(triphenylphosphine)palladium(0). The entire reaction was degassed three times with argon then heated to reflux for 1.5 h. After this time the reaction was cooled to room temperature and diluted with 25 mL of water and extracted with 1:1 hexane-ethyl acetate (3×75 mL). The organic layers were combine, dried over sodium sulfate, filtered, concentrated and purified by column chromatography (12 g silica gel, 5% to 95% ethyl acetate-hexane) to afford 41.6 mg (27%) of (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-(3′-{[tert butyl(dimethyl)silyl]oxy}-4′-{(2S,3R)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl)-D-glucitol as a clear oil.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12].[OH-].[K+].[Cl:15][CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1>C(O)(C)C>[ClH:15].[CH3:31][C:28]1[CH:27]=[CH:26][C:25]([N:22]2[CH2:21][CH2:20][N:19]([CH2:18][CH2:17][CH2:16][O:1][C:2]3[CH:11]=[CH:10][CH:9]=[C:8]4[C:3]=3[CH2:4][CH2:5][CH2:6][C:7]4=[O:12])[CH2:24][CH2:23]2)=[CH:30][CH:29]=1
Reactant: Cc1ccc(N2CCN(CCCCl)CC2)cc1
Reactant: O=C1CCCc2c(O)cccc21
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: Cc1ccc(N2CCN(CCCOc3cccc4c3CCCC4=O)CC2)cc1
Product: Cl
Yield: 93.5 %

Procedure:
A solution of 8.1 g (0.05 mol) 5-hydroxy-1-oxotetraline and 3.09 g (0.055 mol) potassium hydroxide in 260 ml isopropanol was boiled under reflux for fifteen minutes. Thereafter, a solution of 13.9 g (0.055 mol) 1-(3-chloropropyl)-4-(4-methylphenyl)-piperazine in 50 ml isopropanol was added thereto and the reaction mixture further heated under reflux for six hours. During this time, a weak current of nitrogen was passed through the apparatus. After cooling and filtering off with suction the precipitated potassium chloride, 15 ml of approximately 7N methanolic hydrochloric acid was stirred into the filtrate. Colorless crystals separated out upon cooling with ice. There were obtained 19.40 g (93.5% of theory) 5-{3-[4-(4-methylphenyl)-1-piperazinyl]-propoxy}-3,4-dihydro-2H-naphthalene-1-one hydrochloride after filtering off with suction. This compound melts at 197°-202°C. After recrystallization from one liter of water, there was obtained the analytically pure substance; yield 13.66 g (66.0% of theory); m.p. 204°-206°C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.[C:13](Cl)(=[O:16])[CH2:14][CH3:15].[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1>>[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:23]([NH:24][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:2]([NH:1][C:13](=[O:16])[CH2:14][CH3:15])[CH:3]=2)=[CH:22][CH:21]=1
Reactant: COc1ccc(N)cc1
Reactant: CCC(=O)Cl
Reactant: COc1ccc(C(=O)O)cc1N
Product: CCC(=O)Nc1cc(C(=O)Nc2ccc(OC)cc2)ccc1OC

Procedure:
Compound 2611 is synthesized following a similar method as in Example 1 and using 3-amino-4-methoxybenzoic acid, propionyl chloride and 4-methoxyaniline as materials. Total yield of the two steps: 70%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[N:9]=[CH:8][NH:7][C:6]2=O.S(Cl)([Cl:24])=O.Br[C:27]1[C:33]([OH:34])=[CH:32][C:30]([NH2:31])=[C:29]([F:35])[CH:28]=1>CN(C=O)C.C(O)(C)C.CC(C)=O>[ClH:24].[Cl:24][C:27]1[C:33]([OH:34])=[CH:32][C:30]([NH:31][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][N:16]4[CH2:20][CH2:19][CH2:18][CH2:17]4)=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][N:7]=2)=[C:29]([F:35])[CH:28]=1
Reactant: O=S(Cl)Cl
Reactant: Nc1cc(O)c(Br)cc1F
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCCN1CCCC1
Solvent: CC(C)O
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3cc(O)c(Cl)cc3F)ncnc2cc1OCCN1CCCC1
Product: Cl
Yield: 83 %

Procedure:
A mixture of 6-methoxy-7-(2-(pyrrolidin-1-yl)ethoxy)-3,4-dihydroquinazolin-4-one (260 mg, 0.90 mmol), thionyl chloride (5 ml) and DMF (2 drops) was heated at reflux for 45 minutes and allowed to cool. The excess thionyl chloride was removed by evaporation, and the residue azeotroped with toluene. A solution of 4-chloro-2-fluoro-5-hydroxyaniline (160 mg, 1.0 mmol), (as described in EP 61741 A2), in isopropanol (5 ml) was added to the residue and the mixture was heated at reflux for 1 hour and then allowed to cool. The mixture was diluted with acetone, and the solid product collected by filtration, washed with acetone and dried to give 4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-(2-(pyrrolidin-1-yl)ethoxy)quinazoline hydrochloride(381 mg, 83%).