Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5](=[O:11])[CH2:6][C:7]([O:9][CH3:10])=[O:8].C(N(CC)CC)C.C(NC1C=CC(S([N:33]=[N+:34]=[N-])(=O)=O)=CC=1)(=O)C>C(#N)C>[CH3:10][O:9][C:7](=[O:8])[C:6](=[N+:33]=[N-:34])[C:5](=[O:11])[CH2:4][C:3]([O:2][CH3:1])=[O:12]
Reactant: COC(=O)CC(=O)CC(=O)OC
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)CC(=O)C(=[N+]=[N-])C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 3-ketoglutaric acid dimethyl ester 15.0 g, triethylamine 9.6 g and acetonitrile 300 ml is portionwise added 4-acetylaminobenzensulfonylazide 20.7 g at 0° C. The mixture is stirred at room temperature for 30 minutes. After removal of the precipitate by filtration the filtrate is concentrated in vacuo. The residue is diluted with a mixture of hexane and diethyl ether (1:1). The insoluble materials are removed by filtration and the filtrate is concentrated in vacuo. The residue is purified with column chromatography (silica gel 225 g, solvent; hexane:ethyl acetate=5:13:1) to give 2-diazo-3-ketoglutaric acid dimethyl ester as a pale yellow oil, 16.03 g.
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[CH3:15]I.O=O.[OH-].[Na+]>O.C(O)C>[CH3:15][S:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: CI
Reactant: O=C(O)CCCCCCCCCCS
Agent: O=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CSCCCCCCCCCCC(=O)O
Yield: 58.7 %

Procedure:
Into a 3-neck round-bottom flask fitted with a condenser and an addition funnel were added 20 g of 11-mercaptoundecanoic acid, 13 g of methyl iodide and 200 mL of ethanol. A slow flow of nitrogen through the reactor was started to exclude oxygen because mercaptans can be converted into disulfides in the presence of air and strong alkali. A solution of 7.33 g of sodium hydroxide in 14.66 g of water was added dropwise to the reaction mixture via the addition funnel. Any unreacted methyl iodide, the ethanol and the water were removed using a rotovap. The residue was acidified using a mixture of concentrated hydrochloric acid and ice. After isolation the product was distilled. After a small amount of a low boiling fraction was collected, the crude product was collected at ~1 mm of Hg at 180° C. weighing 22.75 g. The crude product was distilled to yield 12.5 g of desired product representing 58.7% of theoretical based upon the weight of starting 11-mercaptoundecanoic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:25]=1)[C:7](=[O:24])[CH:8]=[C:9]([CH:11]([NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:12])[N:10]=2.[Br:26]Br.O>C(O)(=O)C>[Br:26][C:8]1[C:7](=[O:24])[N:6]2[CH:25]=[C:2]([F:1])[CH:3]=[CH:4][C:5]2=[N:10][C:9]=1[CH:11]([NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:12]
Reactant: CC(NC(=O)OCc1ccccc1)c1cc(=O)n2cc(F)ccc2n1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: CC(NC(=O)OCc1ccccc1)c1nc2ccc(F)cn2c(=O)c1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.7 %

Procedure:
E1 (385 mg, 1.13 mmol) was dissolved in 14 mL of acetic acid. Bromine (58 μL, 1.13 mmol) was added dropwise. The reaction was stirred for 30 min at room temperature. Water (40 mL) was added into the reaction, and the reaction was stirred for another 30 min generating a white precipitate that was filtered, washed with water and dried to yield E2 (312 mg).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1O.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.P([O-])(OC1C=CC=CC=1)OC1C=CC=CC=1>O>[C:13]1([NH:12][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Oc1ccc2ccccc2c1
Reactant: Nc1ccccc1
Agent: [O-]P(Oc1ccccc1)Oc1ccccc1
Solvent: O
Product: c1ccc(Nc2ccc3ccccc3c2)cc1
Reaction time: 5 h
Yield: 95 %

Procedure:
288 parts of β-naphthol, 220 parts of aniline and 6 parts of diphenyl phosphite are mixed and fused at 130° C. At 190° C internal temperature, the reaction commences, with elimination of water. After 5 hours, the internal temperature has reached 235° C and 36 parts of water have distilled off. Thereafter, 416 parts of N-phenyl-β-naphthylamine, of melting point 100° - 102° C, distil, passing over at 230° C/15 mm Hg. This corresponds to a yield of 95% of theory.
Reaction SMILES: [Na].[OH:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.[Cl:11][P:12]1(Cl)[N:17]=[P:16](Cl)(Cl)[N:15]=[P:14](Cl)(Cl)[N:13]=1>C1COCC1>[CH:7]([C:6]1[CH:9]=[CH:10][C:3]([O:2][P:16]2([O:2][C:3]3[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=3)[N:17]=[P:12]([O:2][C:3]3[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=3)([Cl:11])[N:13]=[P:14]([O:2][C:3]3[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=3)([O:2][C:3]3[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=3)[N:15]=2)=[CH:4][CH:5]=1)=[O:8]
Reactant: O=Cc1ccc(O)cc1
Reactant: ClP1(Cl)=NP(Cl)(Cl)=NP(Cl)(Cl)=N1
Agent: [Na]
Solvent: C1CCOC1
Product: O=Cc1ccc(OP2(Cl)=NP(Oc3ccc(C=O)cc3)(Oc3ccc(C=O)cc3)=NP(Oc3ccc(C=O)cc3)(Oc3ccc(C=O)cc3)=N2)cc1
Reaction time: 12 h
Yield: 70 %

Procedure:
2591 mg of 4-hydroxybenzaldehyde sodium salt (18 mmol) are added at 0° C. and under an inert atmosphere to a solution containing 1.2 g of hexachlorocyclotriphosphazene (3.45 mmol) in THF (300 mL). The reaction medium is stirred for 12 hours while the temperature is allowed to gradually return to room temperature. The crude reaction product is evaporated to dryness then purified by “flash” chromatography on a silica column. The product is isolated in the form of a translucent oil with a yield of 70%.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH2:11]([OH:13])[CH3:12].[OH-].[K+]>>[CH2:11]([O:13][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1)[CH3:12]
Reactant: CCO
Reactant: Clc1ncnc2[nH]ccc12
Agent: [K+]
Agent: [OH-]
Product: CCOc1ncnc2[nH]ccc12
Temperature: 120 °C
Yield: 66.9 %

Procedure:
4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (9, 300 mg, 1.95 mmol) is combined with 3.00 mL of ethanol (10, 51.4 mmol), then potassium hydroxide (0.226 g, 4.03 mmol) is added. The reaction is heated at 120° C. for 3 hours in a microwave, then extracted with ethyl acetate and aqueous saturated ammonium chloride. The organic layer is washed with brine, dried with magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is recrystallized from methanol to provide the desired compound (11, 213 mg). MS (ESI) [M+H+]+=164.9.
Reaction SMILES: [CH:1]1[C:14]2[CH:13]([C:15]([O:17][CH3:18])=[O:16])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:19][C:20](C)([O-])C.[K+].BrCC>O1CCCC1>[CH2:19]([C:13]1([C:15]([O:17][CH3:18])=[O:16])[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[O:6][C:7]2[C:12]1=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:20]
Reactant: COC(=O)C1c2ccccc2Oc2ccccc21
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCBr
Solvent: C1CCOC1
Product: CCC1(C(=O)OC)c2ccccc2Oc2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
10.0 g (0.042 mol) of methyl 9-xanthenecarboxylate (obtainable according to step 1.1.a) are dissolved in 100 mL of tetrahydrofuran and combined batchwise with 5.16 g (0.044 mol) of potassium tert-butoxide while cooling. Then at about 18° C. to 22° C., 6.296 mL (0.083 mol) of bromoethane are added dropwise; after it has all been added, the mixture is stirred for about 1.5 hours at ambient temperature. The precipitate formed is suction filtered and the solvent is removed by distillation. The residue remaining is taken up in diethyl ether and extracted with water. The organic phase is dried over magnesium sulfate and the solvent is removed by distillation. The crude product obtained is used in the next step without any further purification. Yield: 7.92 g of yellow oil (70% of theoretical yield).
Reaction SMILES: CN(C)CCN(C)C.[Li]CCCC.[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([SH:21])=[CH:17][CH:16]=1.CN([CH:25]=[O:26])C.Cl>C1CCCCC1>[CH3:14][C:15]1[CH:16]=[CH:17][C:18]([SH:21])=[C:19]([CH:20]=1)[CH:25]=[O:26]
Reactant: CN(C)C=O
Reactant: Cc1ccc(S)cc1
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCCCC1
Product: Cc1ccc(S)c(C=O)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 80.5 %

Procedure:
Tetramethylethylenediamine (TMEDA)(12.6 mL, 83.5 mmol) was added via syringe to n-BuLi (33 mL of 1.6 M in hexanes, 82.5 mmol) and the solution was chilled to 0° C. A solution of p-thiocresol (4.53 g, 36.5 mmol) in cyclohexane (40 mL) was added with stirring over 5 minutes. The resulting tan slurry was stirred overnight at room temperature, chilled to 0° C., and DMF (4.0 mL, 3.77 g, 51.6 mmol) was added via syringe over 2 minutes. The resulting gummy slurry was stirred at room temperature for 1.3 hours. The reaction mixture was added to 3 N HCl (150 mL). This mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo yielding a brown oil. This oil was purified by flash chromatography over silica gel, eluting with 10% ethyl acetate-hexanes to afford 5-methyl-2-mercaptobenzaldehyde (4.47 g, 69%) as an intensely yellow solid suitable for use without further purification.
Reaction SMILES: [CH3:1][N:2]([CH:4]=O)[CH3:3].[CH2:6]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]3[N:29]([CH2:30][C:31]4[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:32]=4[O:39][CH3:40])[CH2:28][CH2:27][C:26]([C:41]([OH:43])=O)=[CH:25][C:24]=3[CH:44]=2)=[CH:16][CH:15]=1)[CH2:7][CH2:8][CH3:9].S(Cl)(Cl)=O>O1CCCC1>[CH2:6]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]3[N:29]([CH2:30][C:31]4[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:32]=4[O:39][CH3:40])[CH2:28][CH2:27][C:26]([C:41]([NH:29][C:23]4[CH:24]=[CH:44][C:20]([CH2:4][N:2]([CH3:1])[CH:3]5[CH2:12][CH2:11][O:10][CH2:6][CH2:7]5)=[CH:21][CH:22]=4)=[O:43])=[CH:25][C:24]=3[CH:44]=2)=[CH:16][CH:15]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CN(C)C=O
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2cc(OC)ccc2OC)cc1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3Cc2cc(OC)ccc2OC)cc1
Reaction time: 1 h

Procedure:
One droplet of DMF was added to a solution of 7-(4-butoxyethoxyphenyl)-1-(2,5-dimethoxybenzyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (200 mg) in tetrahydrofuran (10 ml). Then, thionyl chloride (134 mg) was added at 0° C., the temperature was returned to room temperature, and the mixture was stirred under nitrogen atmosphere for 1 hour. The solvent and excess thionyl chloride were evaporated under reduced pressure, the resulting residue was suspended in tetrahydrofuran (30 ml), and the suspension was added to a solution of 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline (100 mg) and triethylamine (455 mg) in tetrahydrofuran (10 ml) at 0° C. The suspension was stirred under nitrogen atmosphere at room temperature overnight, to the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, the resulting residue was separated and purified with silica gel column chromatography (methanol:ethyl acetate=1:8), which was recrystallized from hexane-ethyl acetate to give 7-(4-butoxyethoxyphenyl)-1-(2,5-dimethoxybenzyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 65) (210 mg) as yellow crystals.
Reaction SMILES: [C:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9](Cl)=[O:10])[CH2:5][CH2:4]1)#[N:2].[CH3:12][Zn]C>CC([O-])=O.CC([O-])=O.[Pd+2].O1CCOCC1>[C:9]([C@H:6]1[CH2:7][CH2:8][C@H:3]([C:1]#[N:2])[CH2:4][CH2:5]1)(=[O:10])[CH3:12]
Reactant: N#C[C@H]1CC[C@H](C(=O)Cl)CC1
Reactant: C[Zn]C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: CC(=O)[C@H]1CC[C@H](C#N)CC1
Temperature: 38 °C

Procedure:
To the product from step 1 (1.44 g, 8.42 mmol) was added dioxane (56 mL) and the solution was degassed via subsurface bubbling with argon for 30 minutes. Pd(OAc)2 (95 mg, 0.42 mmol) was added and argon was bubbled through the solution for 15 minutes. Dimethylzinc (2.0 M in toluene, 4.21 mL, 8.42 mmol) was added and the solution was evacuated and then purged with argon 5 times. The reaction was heated overnight at 38° C. The mixture was then cooled to room temperature, diluted carefully with water and ethyl acetate, filtered through a pad of CELITE and washed with ethyl acetate. The organic layer of the filtrate was then dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel to afford trans-4-acetylcyclohexanecarbonitrile. 1H NMR (500 MHz, CDCl3) δ 2.52-2.32 (m, 2H), 2.23-2.12 (m, 5H), 2.07-1.93 (m, 2H), 1.72-1.53 (m, 2H), 1.48-1.33 (m, 2H).
Reaction SMILES: [N:1]1([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:52][C:53]1[S:54][CH:55]=[C:56]([C:58]2[CH:66]=[CH:65][C:61]([C:62]([OH:64])=[O:63])=[CH:60][CH:59]=2)[N:57]=1>CN(C=O)C>[CH2:12]([O:11][C:9]([N:1]1[CH2:8][CH2:7][CH2:6][CH:2]1[C:3](=[O:5])[NH:52][C:53]1[S:54][CH:55]=[C:56]([C:58]2[CH:59]=[CH:60][C:61]([C:62]([OH:64])=[O:63])=[CH:65][CH:66]=2)[N:57]=1)=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1nc(-c2ccc(C(=O)O)cc2)cs1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(-c2csc(NC(=O)C3CCCN3C(=O)OCc3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Z-ProOH (0.56 g, 2.2 mmol) and HATU (2.2 mmol, 0.83 g) were combined in 35 mL of DMF. To this solution was added DIEA (2.4 mmol, 0.42 mL). This solution was stirred at room temperature for 1 hr. 4-(2-Amino-thiazol-4-yl)-benzoic acid (2.2 mmol, 0.5 g) was then added to the solution. The reaction mixture was stirred at 70° C. overnight. It was brought to room temperature and then evaporated to dryness. The crude was purified using reverse phase HPLC. MS: 452.1 (M+H+)
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24](O)=[O:25])[N:23]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.Cl.[NH:28]1[CH2:32][CH2:31][N:30]=[C:29]1[C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][NH:41][CH3:42])=[CH:35][CH:34]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([N:41]([CH2:40][CH2:39][C:36]3[CH:35]=[CH:34][C:33]([C:29]4[NH:30][CH2:31][CH2:32][N:28]=4)=[CH:38][CH:37]=3)[CH3:42])=[O:25])[N:23]=2)[S:5]([C:8]2[C:9]([CH3:17])=[CH:10][C:11]([O:15][CH3:16])=[CH:12][C:13]=2[CH3:14])(=[O:7])=[O:6])[CH2:3][CH2:2]1
Reactant: CNCCc1ccc(C2=NCCN2)cc1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)O)co2)C2CC2)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)N(C)CCc3ccc(C4=NCCN4)cc3)co2)C2CC2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AH using 2-({cyclopropyl[(4-methoxy-2,6-dimethylphenyl)sulfonyl]amino}methyl)-1,3-oxazole-4-carboxylic acid (100 mg, 0.26 mmol), the bis HCl salt of 2-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]-N-methylethanamine (65 mg, 0.23 mmol), EDCI (60 mg, 0.31 mmol), HOBt (42 mg, 0.31 mmol) and DIPEA (0.2 mL, 1.04 mmol) in DMF (8 mL).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[CH2:25]([N:32]1[CH2:37][CH2:36][CH:35](O)[CH2:34][CH2:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH:35]1[CH2:34][CH2:33][N:32]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:37][CH2:36]1)=[O:5]
Reactant: Cc1ccc(C(=O)O)c(C)c1
Reactant: OC1CCN(Cc2ccccc2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)OC2CCN(Cc3ccccc3)CC2)c(C)c1
Yield: 83 %

Procedure:
0.45 g (0.003 mol) of 2,4-dimethylbenzoic acid were boiled under reflux in 5.2 ml (0.06 mol) of oxalyl chloride for 3 hrs. After removal of the excess oxalyl chloride the mixture was concentrated twice with 5 ml of toluene each time. The residue was dissolved in 20 ml of toluene, treated with 0.74 ml (0.0053 mol) of triethylamine and 0.574 g (0.003 mol) of 1-benzyl-4-hydroxypiperidine and boiled at reflux for 18 hrs. After removal of the solvent the residue was chromatographed on silica gel with ethyl acetate/hexane (1:3). 0.805 g (83%) of 1-benzyl-piperidin-4-yi 2,4-dimethyl-benzoate was obtained as a yellow oil. MS: me/e=324 (C21H26NO2 +).
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:16][CH:15]=3)[C:10]2=[O:26])[CH:6]=[CH:7][CH:8]=1.[N:27]#[C:28][NH2:29]>O1CCOCC1>[ClH:1].[NH:2]([C:3]1[CH:4]=[C:5]([N:9]2[CH2:13][CH2:12][N:11]([C:14]3[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:19]=3)[C:10]2=[O:26])[CH:6]=[CH:7][CH:8]=1)[C:28]([NH2:29])=[NH:27]
Reactant: N#CN
Reactant: COC(=O)CCc1ccc(N2CCN(c3cccc(N)c3)C2=O)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)CCc1ccc(N2CCN(c3cccc(NC(=N)N)c3)C2=O)cc1

Procedure:
Prepared from 1-(3-amino-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-one hydrochloride by refluxing for three hours with cyanamide in dioxane.
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:23]O>>[CH3:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([O:11][CH3:23])=[O:10])=[CH:4][CH:3]=1
Reactant: Cc1ccc(Oc2ccccc2C(=O)O)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccccc1Oc1ccc(C)cc1

Procedure:
A solution of 37.70 g of 2-(4-methylphenoxy)-benzoic acid was 12.0 mL of concentrated sulfuric acid in 500 mL of methanol was refluxed for 14 hours. After cooling, the reaction mixture was concentrated in vacuo and the residue was added to a mixture of methylene chloride and water. The organic phase was separated, washed with saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was kugelrohr distilled (120°-135°/0.025 torr) to furnish 35.08 g of methyl 2-(4-methylphenoxyl)benzoate, m.p. 31°-34°. NMR (200 MHz, CDCl3) δ7.87 (d, of d, 1H); 7.39 (t of d, 1H); 7.11 (m, 3H); 6.88 (m, 3H); 3.81 (s, 3H); 2.30 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12](N(OC)C)=[O:13].[CH3:18][Mg]Br.CCOCC>O1CCCC1>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12](=[O:13])[CH3:18]
Reactant: CON(C)C(=O)c1ccc2ccccc2c1Br
Reactant: C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)c1ccc2ccccc2c1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 1-bromo-N-methoxy-N-methyl-2-naphthamide (0.708 g, 0.00241 mol) in tetrahydrofuran (10 mL) was added 3.00 M of methylmagnesium bromide in ether (8.19 mL, 0.0246 mol). The reaction was stirred at room temperature for 2 h, quenched with water at 0° C., then acidified with 1 N HCl, and extracted with EtOAc. The combined organic layers were washed with saturated sodium bicarbonate and brine, dried over magnesium sulfate, and evaporated to dryness under reduced pressure. The residue was used directly in next step (488 mg, 81%). LCMS calculated for C12H10BrO(M+H)+: m/z=249.0.; found: 249.2.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[Cl-:12].[NH2:13][N+:14]1[CH:18]=[CH:17][N:16]([NH2:19])[C:15]=1[CH2:20][CH3:21]>C(O)(=O)C>[Cl-:12].[CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[N:13][N+:14]2[CH:18]=[CH:17][N:16]([N:19]=[CH:7][C:6]3[CH:9]=[CH:10][C:3]([N:2]([CH3:11])[CH3:1])=[CH:4][CH:5]=3)[C:15]=2[CH2:20][CH3:21])=[CH:5][CH:4]=1
Reactant: CCc1n(N)cc[n+]1N
Reactant: CN(C)c1ccc(C=O)cc1
Agent: [Cl-]
Solvent: CC(=O)O
Product: CCc1n(N=Cc2ccc(N(C)C)cc2)cc[n+]1N=Cc1ccc(N(C)C)cc1
Reaction time: 20 h

Procedure:
705 mg (4.7 mmol) of 4-dimethylaminobenzaldehyde are added to a solution of 348 mg (2.1 mmol) of 1,3-diamino-2-ethyl-imidazolium chloride in 4.4 ml of glacial acetic acid, whereupon the mixture is stirred for 20 hours. The yellow crystals obtained are filtered off and recrystallized from ethanol. There is obtained 1,3-bis[[p-(dimethyl-amino)benzylidene]amino]-2-ethylimidazolium chloride of melting point 248°.
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][CH2:34][O:35][CH3:36])=[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.[CH3:54][N:55]1[CH2:59][CH2:58][CH2:57][C@@H:56]1[CH:60]=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][CH2:34][O:35][CH3:36])=[C:17]([NH:20][C:21](=[O:31])/[CH:22]=[CH:60]/[C@H:56]4[CH2:57][CH2:58][CH2:59][N:55]4[CH3:54])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CN1CCC[C@@H]1C=O
Reactant: CCOP(=O)(CC(=O)Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCCOC)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COCCOc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)/C=C/[C@H]1CCCN1C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 54.1 %

Procedure:
N-[4-[(3-Chloro-4-fluoro-phenyl)amino]-7-(2-methoxyethoxy)quinazolin-6-yl]-2-diethoxyphosphoryl-acetamide 8d (200 mg, 0.37 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 (740 μL, 0.74 mmol) was added dropwise. After stirring for 30 minutes, (2R)-1-methylpyrrolidine-2-carbaldehyde 5c (84 mg, 0.74 mmol) was added to the reaction solution. The reaction mixture was stirred for another 1 hour, then warmed 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-(2-methoxyethoxy)quinazolin-6-yl]-3-[(2R)-1-methylpyrrolidin-2-yl]prop-2-enamide 8 (100 mg, yield 54.2%) as a yellow solid.
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[N:25]=[CH:24][N:23]=[C:22]([CH:26]([CH:33]2[CH2:35][CH2:34]2)[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:21]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[CH:33]1([CH:26]([C:22]2[CH:21]=[C:20]([CH2:19][OH:18])[N:25]=[CH:24][N:23]=2)[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:34][CH2:35]1
Reactant: CCOC(=O)CC(c1cc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)ncn1)C1CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CC(c1cc(CO)ncn1)C1CC1
Reaction time: 0.08 h
Yield: 71.1 %

Procedure:
To a solution of ethyl 3-(6-(((tert-butyldiphenylsilyl)oxy)methyl)pyrimidin-4-yl)-3-cyclopropylpropanoate (6.70 g) in THF (50 mL) was added a 1.0 M solution of tetrabutylammonium fluoride in THF (27.4 mL) at room temperature, and the mixture was directly stirred for 5 min. Water was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.44 g) as a yellow oil.