Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]([O:16][C:17]1[CH:59]=[CH:58][CH:57]=[CH:56][C:18]=1[C:19]([NH:21][C:22]1[CH:53]=[CH:52][C:25]([C:26]([N:28]([CH3:51])[C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][C:30]=2[O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42]([N:44]2[CH2:49][CH2:48][N:47]([CH3:50])[CH2:46][CH2:45]2)=[O:43])=[O:27])=[CH:24][C:23]=1[O:54][CH3:55])=[O:20])[CH2:3][CH2:4][N:5]1C(=O)C2=CC=CC=C2C1=O.CN>CO>[NH2:5][CH2:4][CH2:3][C@@H:2]([O:16][C:17]1[CH:59]=[CH:58][CH:57]=[CH:56][C:18]=1[C:19]([NH:21][C:22]1[CH:53]=[CH:52][C:25]([C:26]([N:28]([CH3:51])[C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][C:30]=2[O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42]([N:44]2[CH2:49][CH2:48][N:47]([CH3:50])[CH2:46][CH2:45]2)=[O:43])=[O:27])=[CH:24][C:23]=1[O:54][CH3:55])=[O:20])[CH3:1]
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1ccccc1O[C@@H](C)CCN1C(=O)c2ccccc2C1=O
Agent: CN
Solvent: CO
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1ccccc1O[C@@H](C)CCN

Procedure:
A solution of (S)-4-[2-[1-methyl-3-(phthalimido)prop-1-yl]oxybenzoyl]amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (1.1 g) in methanol (30 ml) was stirred and treated with 40% methylamine in methanol (10 ml). The reaction mixture was refluxed for 30 minutes. Then the solvent was concentrated and purified by silica gel column chromatography (SiO2 40 g, chloroform/methanol/ammonia=90/10/0.5) to give (S)-4-[2-[(3-amino-1-methylprop-1-yl)oxy]benzoyl]amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4](Cl)[N:3]=1.[CH3:10][Mg]Br>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([CH3:10])[N:3]=1
Reactant: C[Mg]Br
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: C1CCOC1
Product: Cc1nc(Cl)nc(Cl)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
To a solution of 2,4,6-trichloro-1,3,5-triazine (20 g, 108 mmol, 1.0 equiv) in THF (8 mL) at −10° C., methylmagnesium bromide (45 ml, 135 mmol, 1.25 equiv) was added dropwise. The reaction mixture was allowed to warm to room temperature and was stirred for 2 h. The mixture was poured onto ice-water and stirred for an additional hour. The product was extracted with ethyl acetate, washed with brine, dried with sodium sulfate, filtered, and concentrated under reduced pressure to afford 14 g of the title compound. The crude product was carried forward in the next step. MS (ES+): m/e 186.1 [M+Na]+.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:31][C:32]1[N:33]=[C:34]([CH3:37])[S:35][CH:36]=1>CN(C=O)C>[ClH:1].[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:31][C:32]4[N:33]=[C:34]([CH3:37])[S:35][CH:36]=4)=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: Cc1nc(CCl)cs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCc1csc(C)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73.4 %

Procedure:
A mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (448 mg, 1.4 mmol), (prepared as described for the starting material in Example 24), and potassium carbonate (676 mg, 4.9 mmol) in DMF (10 ml) was stirred at ambient temperature for 10 minutes. 4-Chloromethyl-2-methylthiazole hydrochloride (310 mg, 168 mmol) was added and the mixture was heated at 70° C. for 3.5 hours. The reaction mixture was allowed to cool and was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine, dried (MgSO4) and the solvent removed by evaporation. The solid residue was purified by column chromatography eluting with a mixture of methylene chloride/acetonitrile/methanol (50/45/5 followed by 50/40/10). The resulting purified solid was dissolved in methylene chloride/methanol and a solution of 5M hydrogen chloride in isopropanol (1 ml) was added. Partial evaporation led to the precipitation of a white solid. This solid was collected by filtration and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-((2-methylthiazol-4-yl)methoxy)quinazoline hydrochloride (240 mg, 35%). m.p. 220-225° C. 1H NMR Spectrum: (DMSOd6) 2.68(s, 3H); 4.0(s, 3H); 5.36(s, 2H); 7.46(dd, 1H); 7.54(s, 1H); 7.61(t, 1H); 7.7(d, 1H); 7.71(s, 1H); 8.26(s, 1H); 8.83(s, 1H) MS-ESI: 431 [MH]+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH2:6][NH2:7].[CH2:13]1[CH2:19][S:16](=[O:18])(=[O:17])[O:15][CH2:14]1>CC(=O)CC>[CH3:12][O:11][C:9]1[CH:8]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[CH:10]=1)[CH2:6][NH:7][CH2:14][CH2:13][CH2:19][S:16]([OH:18])(=[O:17])=[O:15]
Reactant: O=S1(=O)CCCO1
Reactant: COc1cc(CN)cc(OC)c1
Solvent: CCC(C)=O
Product: COc1cc(CNCCCS(=O)(=O)O)cc(OC)c1
Temperature: 25 °C

Procedure:
To a solution of 3,5-dimethoxybenzylamine (2.5 g, 15.0 mmol) in 2-butanone (22 mL) was added 1,3-propane sultone (1.95 g, 15.8 mmol). The mixture was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature. The solid was collected by filtration, washed with acetone (2×25 mL), and dried in vacuo. This allowed the isolation of compound BA, 2.89 g (67%).
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])=[C:4]([NH:14]S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.[Cl:24][C:25]1[CH:34]=[CH:33][C:28]([C:29](=[O:32])[CH2:30]Br)=[CH:27][CH:26]=1>>[CH3:11][O:10][C:8](=[O:9])[CH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([CH3:1])=[CH:13][CH:12]=2)[NH:14][C:30]=1[C:29](=[O:32])[C:28]1[CH:33]=[CH:34][C:25]([Cl:24])=[CH:26][CH:27]=1
Reactant: COC(=O)/C=C/c1ccc(C)cc1NS(=O)(=O)c1ccccc1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Product: COC(=O)Cc1c(C(=O)c2ccc(Cl)cc2)[nH]c2cc(C)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-4-methyl-2-(phenylsulfonylamino)cinnamate (step 2 of Example 149) and 4-chlorophenacyl bromide.
Reaction SMILES: [CH3:1][C:2]([C@@H:18]1[C:21](=[O:22])[NH:20][C@@H:19]1[CH2:23]C(O)=O)([O:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)=[O:6])[CH3:3].[C:27]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=1)(=[O:32])[CH2:28][C:29]([O-])=[O:30]>O1CCCC1>[CH3:1][C:2]([C@@H:18]1[C:21](=[O:22])[NH:20][C@@H:19]1[CH2:23][C:29](=[O:30])[CH2:28][C:27]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=1)=[O:32])([O:4][C:5]([O:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=1)=[O:6])[CH3:3]
Reactant: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@@H]1C(=O)N[C@@H]1CC(=O)O
Reactant: O=C([O-])CC(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Product: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@@H]1C(=O)N[C@@H]1CC(=O)CC(=O)OCc1ccc([N+](=O)[O-])cc1
Yield: 83.3 %

Procedure:
N,N'-Carbonyldiimidazole (540 mg) was added to a solution of [(2R,3R)-3-{1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-4-oxoazetidin-2-yl]acetic acid (1.06 g) in tetrahydrofuran (50 ml) at ambient temperature. After stirring for 7 hours at the same temperature, magnesium salt of mono-p-nitrobenzyl malonate (1.45 g) was added thereto, and the resultant mixture was stirred overnight at ambient temperature, The solvent was distilled off in vacuo. The residue was dissolved in ethyl acetate (100 ml) and filtered. The filtrate was washed in turn with 0.1N hydrochloric acid, water, saturated aqueous sodium chloride, aqueous sodium bicarbonate, water, saturated aqueous sodium chloride, 5% aqueous citric acid, water and saturated aqueous sodium chloride. After drying over magnesium sulfate, the solution was evaporated. The residue was chromatographed on silica gel (30 g) eluting with a mixture of methylene chloride and ethyl acetate (50:1 to 2:1) to give formy substance, which was crystallized from a mixture of chloroform and diisopropyl ether, washed with diisopropyl ether and then dried in vacuo to give 4-nitrobenzyl 4-[(2R,3R)-3-{1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl}-4-oxoazetidin-2-yl]-3-oxobutanoate (1.31 g), mp 123°-125° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([OH:17])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22].Cl[C:39]1[CH:44]=[CH:43][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:41][N:40]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([O:17][C:39]3[CH:44]=[CH:43][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:41][N:40]=3)[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22]
Reactant: COc1cc2c(cc1O)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NC1CCc3ccccc31)CC2
Reactant: FC(F)(F)c1ccc(Cl)nc1
Product: COc1ccc(CC2c3cc(Oc4ccc(C(F)(F)F)cn4)c(OC)cc3CCN2CC(=O)NC2CCc3ccccc32)cc1OC

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide with 2-chloro-5-trifluoromethyl-pyridine
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([CH2:10][OH:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[CH3:19][S:20]([O:11][CH2:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([F:1])[CH:9]=1)(=[O:22])=[O:21]
Reactant: N#Cc1ccc(CO)cc1F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1ccc(C#N)c(F)c1
Reaction time: 1.5 h

Procedure:
2-Fluoro-4-hydroxymethylbenzonitrile (1.3 g, 8.6 mmol; see step (ii) above) was dissolved in 50 mL of CH2Cl2 and cooled on an ice bath. Triethylamine (0.87 g, 8.6 mmol) and methanesulfonyl chloride (0.99 g, 8.7 mmol) were added. After stirring for 1.5 h the reaction mixture washed with 1M HCl. The organic phase was dried (Na2SO4) and evaporated. The product could be used without purification. Yield of a colourless oil: 1.8 g (92%).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.CCN(CC)CC.Cl[C:17]1[S:21][N:20]=[C:19]([CH3:22])[N:18]=1>CCO>[CH3:22][C:19]1[N:18]=[C:17]([N:2]2[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]2)[S:21][N:20]=1
Reactant: Cc1nsc(Cl)n1
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1nsc(N2CCC(=O)CC2)n1
Yield: 8.6 %

Procedure:
To a mixture of piperidin-4-one HCl salt (4.08 g, 30 mmol) and Et3N (20 mL, 78.6 mmol) in EtOH (50 mL) was added 5-chloro-3-methyl-1,2,4-thiadiazole (4.05 g, 30 mmol). The mixture was heated to reflux for 1.5 hours and then concentrated to dryness. The residue was dissolved in EtOAc. The solution was washed with water (30 mL×3) and brine (30 mL), dried over Na2SO4, and concentrated to dryness. The residue was recrystalled from ether to give 1-(3-methyl-1,2,4-thiadiazol-5-yl)piperidin-4-one (510 mg, 8.6%). 1H-NMR (300 MHz, CDCl3) δ 3.86 (t, J=6.3 Hz, 4H), 2.62 (t, J=6.3, Hz, 4H), 2.44 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]([NH2:17])=[O:16])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[N:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH:25]1[CH2:28][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26]1>CN(C)C=O>[NH2:1][C:2]1[C:3]([C:15]([NH2:17])=[O:16])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH:25]3[CH2:26][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:28]3)[C:6]=2[N:14]=1
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Reactant: NC(=O)c1cc2c(nc1N)[nH]c1ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(n2c3ccccc3c3cc(C(N)=O)c(N)nc32)C1
Temperature: 150 °C
Yield: 69 %

Procedure:
To a stirred solution of 2-amino-9H-pyrido[2,3-b]indole-3-carboxamide (5, 44 mg, 0.19 mmol) in N,N-dimethylformamide (4.4 mL) was added powdered cesium carbonate (130 mg, 0.39 mmol), and tert-butyl 3-iodoazetidine-1-carboxylate (Harris, L. J., et al. European Patent Application 1176142, 2002; 0.11 g, 0.39 mmol). The mixture was heated in a microwave at 150° C. for 30 min, concentrated and purified by silica gel chromatography (12 g silica, methylene chloride to 90/10 methylene chloride/methanol gradient) to yield tert-butyl 3-[2-amino-3-(aminocarbonyl)-9H-pyrido[2,3-b]indol-9-yl]azetidine-1-carboxylate (xvi-f, 50 mg, 70%). NH4OAc QC conditions. M+H=382. 1H NMR (300 MHz, CDCl3): δ 8.24 (s, 1H), 7.83 (d, J=7.9 Hz, 1H), 7.60 (d, J=7.9 Hz, 1H), 7.42-7.34 (m, 1H), 7.30-7.22 (m, 1H), 4.75-4.60 (m, 1H), 4.48-4.39 (m, 2H), 4.17-4.07 (m, 2H), 1.51 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH2:14][CH2:13]2)[N:3]=1.[C:27](Cl)(=[O:29])[CH3:28]>>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([NH:23][C:27](=[O:29])[CH3:28])[CH:24]=[CH:25][CH:26]=3)[CH2:16][CH2:17]2)[N:3]=1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Reactant: CC(=O)Cl
Product: CC(=O)Nc1cccc(CCN2CCN(c3cccc4nc(C)ccc34)CC2)c1
Yield: 52 %

Procedure:
The title compound was prepared in 52% yield according to the general procedure for the preparation of the amides (Method B) starting from 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and acetyl chloride.
Reaction SMILES: [CH3:1][C:2]1[O:10][C@@H:9]2[C@@H:4]([C@@H:5]([O:20][C:21]([CH3:23])=[O:22])[C@H:6]([O:16][C:17]([CH3:19])=[O:18])[C@@H:7]([CH2:11][O:12][C:13]([CH3:15])=[O:14])[O:8]2)[N:3]=1.[CH2:24]([O:31][C:32](=[O:35])[CH2:33][OH:34])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(Cl)(Cl)Cl.[Fe](Cl)(Cl)Cl>[CH2:24]([O:31][C:32](=[O:35])[CH2:33][O:34][C@@H:9]1[O:8][C@H:7]([CH2:11][O:12][C:13](=[O:14])[CH3:15])[C@@H:6]([O:16][C:17](=[O:18])[CH3:19])[C@H:5]([O:20][C:21](=[O:22])[CH3:23])[C@H:4]1[NH:3][C:2](=[O:10])[CH3:1])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(CO)OCc1ccccc1
Reactant: CC(=O)OC[C@H]1O[C@@H]2OC(C)=N[C@@H]2[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl[Fe](Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(=O)N[C@H]1[C@H](OCC(=O)OCc2ccccc2)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 21 h

Procedure:
A solution of 600 mg (1.82 mmol) of 2-methyl-(3,4,6-tri-O-acetyl-1,2-dideoxy-α-D-glucopyrano)-[2,1-d]-2-oxazoline of the formula ##STR13## [prepared according to V. K. Srivastava, Carbohydrate Research 103, 286 (1982)]and 605 mg (3.64 mmol) of glycolic acid benzyl ester in 6 ml of methylene chloride is added to a solution of 300 mg (1.85 mmol) of iron(III) chloride (anhydrous) in 6 ml of absolute methylene chloride and the whole is stirred for 21 hours at 22°. 8 ml of cold, saturated sodium bicarbonate solution are added and the mixture is diluted with 100 ml of chloroform and filtered until clear. The organic phase of the filtrate yields, after drying over magnesium sulphate and concentration by evaporation, a yellow oil which is purified by digesting an ethyl acetate solution with hexane and by chromatography on silica gel. 2-(2-acetylamino-3,4,6-tri-O-acetyl-2-deoxy-β-D-glucopyranosyloxy)-acetic acid benzyl ester is obtained in the form of a colourless powder.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][N:12]=1.C(O[CH:21]=[C:22]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:23]([O:25][CH2:26][CH3:27])=[O:24])C>C(OCC)C>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1][CH:2]1[NH:10][C:11]1[N:12]=[CH:13][C:14]([NH:17][CH:21]=[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:15][CH:16]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ccc(NC2Cc3ccccc3C2)nc1
Solvent: CCOCC
Product: CCOC(=O)C(=CNc1ccc(NC2Cc3ccccc3C2)nc1)C(=O)OCC
Temperature: 25 °C
Yield: 68.4 %

Procedure:
A crude mixture of N2-(2,3-dihydro-1H-inden-2-yl)pyridine-2,5-diamine (5 g) and diethyl ethoxymethylenemalonate (5.5 g) was heated under reflux in dry diethyl ether (50 ml) for 1 h. The reaction mixture was then cooled to room temperature, and solvent removed under reduced pressure and the remaining residue finally recrystallised from acetonitrile to give the diethyl 2-((6-(2,3-dihydro-1H-inden-2-ylamino)pyridin-3-ylamino)methylene)malonate (6 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:32][CH2:33][CH3:34])=[C:17]([NH:20][C:21](=[O:31])[CH2:22]P(OCC)(OCC)=O)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1(C)C=CC=CC=1.[CH3:52][N:53]1[CH2:57][CH2:56][CH2:55][C@@H:54]1[CH:58]=O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:32][CH2:33][CH3:34])=[C:17]([NH:20][C:21](=[O:31])/[CH:22]=[CH:58]/[C@H:54]4[CH2:55][CH2:56][CH2:57][N:53]4[CH3:52])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCOc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)CP(=O)(OCC)OCC
Reactant: CN1CCC[C@@H]1C=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)/C=C/[C@H]1CCCN1C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 46.9 %

Procedure:
N-[4-[(3-Chloro-4-fluoro-phenyl)amino]-7-ethoxy-quinazolin-6-yl]-2-diethoxyphosphoryl-acetamide 7b (300 mg, 0.59 mmol) was dissolved in 10 mL of tetrahydrofuran. The mixture was cooled to −78° C. in a dry ice bath. Under argon, a solution of lithium bis(trimethylsilyl)amide (1 M) in toluene (1.2 mL, 1.18 mmol) was added dropwise. After the mixture was stirred for 30 minutes, (2R)-1-methylpyrrolidine-2-carbaldehyde 5c (133 mg, 1.18 mmol) was added, and the mixture was stirred for another 1 hour, then warm up to room temperature and stirred for 12 hours. The reaction mixture was concentrated, added with 10 mL of water, extracted with dichloromethane (25 mL×3). The combined organic extracts were washed with saturated brine (30 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography with elution system A to obtain the title compound (E)-N-[4-[(3-chloro-4-fluoro-phenyl)amino]-7-ethoxy-quinazolin-6-yl]-3-[(2R)-1-methylpyrrolidin-2-yl]prop-2-enamide 9 (130 mg, yield 47.3%) as a yellow solid.
Reaction SMILES: [CH:1]([C:3]1[CH:21]=[CH:20][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[O:8])=[CH:5][CH:4]=1)=[O:2].[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[C@:30]([OH:45])([C@H:37]([S:39][CH:40]([CH2:43]O)[CH2:41][OH:42])[CH3:38])[CH2:31][N:32]1[CH:36]=[N:35][CH:34]=[N:33]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[C@@:30]([OH:45])([CH2:31][N:32]1[CH:36]=[N:35][CH:34]=[N:33]1)[C@H:37]([S:39][C@@H:40]1[CH2:41][O:42][C@@H:1]([C:3]2[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:18])([F:17])[F:19])=[CH:12][CH:11]=3)=[O:8])=[CH:20][CH:21]=2)[O:2][CH2:43]1)[CH3:38]
Reactant: C[C@@H](SC(CO)CO)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: O=Cc1ccc(C(=O)Nc2ccc(C(F)(F)F)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: C[C@@H](S[C@H]1CO[C@H](c2ccc(C(=O)Nc3ccc(C(F)(F)F)cc3)cc2)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
In the same manner as that described in Example 3(3), a reaction was carried out using 4-formyl-4′-(trifluoromethyl)benzanilide (300 mg, 1.0 mmol), (2R,3R)-2-(2,4-difluorophenyl)-3-[[1-(hydroxymethyl)-2-hydroxyethyl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol (334 mg, 0.93 mmol) and p-toluenesulfonic acid monohydrate (318 mg, 1.7 mmol) and the reaction mixture was treated according to a similar procedure to that described in Example 3(3) to give the trans isomer of the title compound (275 mg, yield 47%) as a white solid and the cis isomer (58 mg, yield 10%) as a colorless oil. The trans isomer was recrystallized from ethyl acetate-hexane to give white powdery crystals.
Reaction SMILES: [C:1]1([C:11]([N:13]2[CH2:17][CH:16]([C:18]([OH:20])=[O:19])[CH:15]([CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)[CH2:14]2)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:36]>CO.C1COCC1>[C:1]1([C:11]([N:13]2[CH2:17][CH:16]([C:18]([O:20][CH3:36])=[O:19])[CH:15]([CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)[CH2:14]2)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C1CN(C(=O)c2cccc3ccccc23)CC1CN1CCC(c2ccc(F)cc2)CC1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)C1CN(C(=O)c2cccc3ccccc23)CC1CN1CCC(c2ccc(F)cc2)CC1
Reaction time: 6 h

Procedure:
To a solution of 0.037 g (0.08 mmol) of 1-(1-naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-carboxypyrrolidine in 0.6 mL of MeOH and 1.2 mL of THF at rt was added 0.2 mL (0.4 mmol) of TMSCHN2 (2M in hexanes) and the reaction mixture was stirred for 6 h. The reaction mixture was concentrated and the residue was purified by chromatography (silica, acetone:hexanes, 1:3) to give the title compound. 1H NMR (CDCl3) δ (key peaks) 7.87-7.91 (m, 3H), 7.47-7.56 (m, 4H), 7.15-7.18 and 7.08-7.11 (m, 2H), 6.98 and 6.95 (t, 2H, J=8.5 Hz),3.79 and 3.62 (s, 3H1); Mass Spectrum (ESI) m/e=475 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.[CH3:10][O:11][C:12](=[O:25])[CH2:13][C@@H:14]([C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)[C:15]#[C:16][CH3:17].C([O-])([O-])=O.[Cs+].[Cs+]>CC(C)=O>[CH3:10][O:11][C:12](=[O:25])[CH2:13][C@@H:14]([C:18]1[CH:19]=[CH:20][C:21]([O:24][CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[CH3:1])=[CH:22][CH:23]=1)[C:15]#[C:16][CH3:17]
Reactant: Cc1ccccc1CBr
Reactant: CC#C[C@@H](CC(=O)OC)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CC#C[C@@H](CC(=O)OC)c1ccc(OCc2ccccc2C)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-Methylbenzyl bromide (0.98 g, 5.3 mmol) and phenol 1 (0.97 g, 4.4 mmol) were dissolved in acetone (9 mL) and treated with Cs2CO3 (1.45 g, 4.4 mmol). The reaction was stirred at room temperature for 16 h then filtered and concentrated to an oil which was purified by radial chromatography (2 mm silica gel plate, 10% ethyl acetate in hexanes). Eluant containing compound 13.1 was concentrated to a colorless oil (1.37 g, 96%). This material was analyzed by chiral HPLC (Daicel ChiralPAK AD-H column, eluant: 0.1% TFA in 95:5 hexanes:2-propanol) and was found to have 94% ee. 1H NMR(500 MHz)(MeOH-d4) δ 7.39 (d, 1H, J=7 Hz); 7.28 (d, 2H, J=8.5 Hz); 7.25-7.15 (m, 3H); 5.05 (s, 2H); 4.02 (m, 1H); 3.64 (s, 3H); 2.68 (m, 2H); 2.36 (s, 3H); 1.80 (d, 3H, J=2.5 Hz). MS ESI (pos.) m/e: 323.0 (M+H); 245.1 (M+Na).
Reaction SMILES: O1C2C(=CC=CC=2)/C(=[N:11]/[OH:12])/CC1.[CH2:13]([CH:15]1[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]1=O)[CH3:14]>>[CH2:13]([CH:15]1[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]1=[N:11][OH:12])[CH3:14]
Reactant: O/N=C1\CCOc2ccccc21
Reactant: CCC1Cc2ccccc2C1=O
Product: CCC1Cc2ccccc2C1=NO

Procedure:
Following the procedure for the preparation of (4E)-2,3-dihydro-4H-chromen-4-one oxime but substituting (+/−)-2-ethyl-2,3-dihydro-1H-inden-1-one and making non-critical variations provided the title compound as a colorless syrup. MS-(ESI+) for m/z 176.1 (M+H)+.