Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19]N)[CH2:12][CH2:11]3)=[CH:8][S:7][C:6]=2[CH:21]=1.C([N:24](CC)CC)C.[C:29](Cl)(=[O:31])[CH3:30]>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:30][C:29]([NH2:24])=[O:31])[CH2:12][CH2:11]3)=[CH:8][S:7][C:6]=2[CH:21]=1
Reactant: CCN(CC)CC
Reactant: NCCCCN1CCN(c2csc3cc(F)ccc23)CC1
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: NC(=O)CCCCCN1CCN(c2csc3cc(F)ccc23)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 51.9 %

Procedure:
To a 0° C. solution of 4-(6-fluorobenzo[b]thien-3-yl)-1-piperazine-butanamine (3.13 g, 10.2 mmol), triethylamine (1.45 g, 14.3 mmol), and dichloromethane (60 mL) under a nitrogen atmosphere was added acetyl chloride (0.883 g, 11.3 mmol) rapidly. The reaction was stirred at 0° C. for 2 hours and then at room temperature for an additional 1 hour. The reaction was diluted with dichloromethane (140 mL), washed with 5% aqueous NaOH (100 mL), and dried (K2CO3). The solvent was removed in vacuo to give a brown solid. The crude product was chromatographed on silica gel with 10% methanol/dichloromethane as eluent to afford a tan solid. Recrystallization from ethyl acetate gave 1.85 g (52%) of the title compound as beige crystals: m.p.=141 °-142° C.
Reaction SMILES: C([Li])CCC.CCCCCC.[CH3:12][Si:13]([C:16]1([Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17]1)([CH3:15])[CH3:14].Cl[P:26]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CCOCC>[CH3:22][Si:21]([C:16]1([Si:13]([CH3:12])([CH3:14])[CH3:15])[C:20]([P:26]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:19][CH:18]=[CH:17]1)([CH3:24])[CH3:23]
Reactant: ClP(c1ccccc1)c1ccccc1
Reactant: C[Si](C)(C)C1([Si](C)(C)C)C=CC=C1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: C[Si](C)(C)C1([Si](C)(C)C)C=CC=C1P(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
76.6 ml of a 2.5 molar solution of butyllithium in hexane (0.19 moles) were added over 10 min at 0° C. to a solution of compound 1 (40.2 g, 0.19 moles) in 500 ml of ether. When the addition was complete. the bath was removed and the solution was stirred for 1 h at room temperature. After cooling to 0° C., 42.2 g (0.19 moles) of chlorodiphenylphosphine were added over 10 min, after which the bath was removed and the suspension was heated to room temperature. After stirring for 1 hour at room temperature, the ether was removed under vacuum and the product was dissolved in hexane again. After the salts had been filtered off, the hexane was removed under vacuum to leave 69.1 g (yield: 91%) of compound 16 in the form of an oil. 1H NMR (400 MHz, CDCl3): δ=7.45 (m, 4H); 7.35 (m, 6H); 6.8 (m, 1H); 6.65 (m, 1H); 6.6 (m, 1H); 0 (s, 18H); 31P NMR (161.9 MHz, CDCl3): δ=−19.5 ppm.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[N:14]=[C:13]([NH2:15])[C:12]([O:16][CH3:17])=[CH:11][CH:10]=2)[CH2:3]1.N1C=CC=CC=1.[Br:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>C(Cl)Cl>[Br:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH:15][C:13]2[C:12]([O:16][CH3:17])=[CH:11][CH:10]=[C:9]([N:4]3[CH2:3][C@H:2]([CH3:1])[NH:7][C@H:6]([CH3:8])[CH2:5]3)[N:14]=2)(=[O:33])=[O:32])=[CH:27][CH:26]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)nc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)nc1NS(=O)(=O)c1ccc(Br)cc1
Temperature: 25 °C
Yield: 47.8 %

Procedure:
6-[(3R,5S)-3,5-Dimethyl-1-piperazinyl]-3-(methyloxy)-2-pyridinamine (D7, Method E)(1.5 g, 6.35 mmol) was dissolved in DCM (15 mL) and pyridine (15 mL) and then cooled to 0° C. 4-Bromobenzenesulfonyl chloride (3.04 g, 11.9 mmol), dissolved in DCM (8 mL) was then added dropwise and the reaction then allowed to warm to room temperature overnight. The reaction was then evaporated to a minimum and redissolved in DCM (100 mL) and washed with water (50 mL). Aqueous layer was extracted with DCM (100 mL) and combined organic extracts washed with saturated sodium hydrogen carbonate (2×100 mL) and brine (100 mL). The organic layer was dried (MgSO4) and evaporated to give a brown solid which was triturated with ethyl acetate (3×10 mL) to give the title compound as a pale yellow powder (D17) (1.382 g). MS (ES+) m/e 455/457 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[CH3:16][N:17]1[CH2:22][CH2:21][CH2:20][CH:19]([CH2:23][N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH2:18]1>>[ClH:1].[ClH:1].[ClH:1].[CH3:16][N:17]1[CH2:22][CH2:21][CH2:20][CH:19]([CH2:23][N:24]2[CH2:29][CH2:28][N:27]([C:2]3[N:3]=[N:4][C:5]([C:8]4[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=4)=[CH:6][CH:7]=3)[CH2:26][CH2:25]2)[CH2:18]1
Reactant: CN1CCCC(CN2CCNCC2)C1
Reactant: N#Cc1ccc(-c2ccc(Cl)nn2)cc1
Product: CN1CCCC(CN2CCN(c3ccc(-c4ccc(C#N)cc4)nn3)CC2)C1
Product: Cl

Procedure:
The title compound was prepared by a similar procedure to that described in Example 1, starting from 3-chloro-6-(4-cyanophenyl)pyridazine and (1-methylpiperidin-3-ylmethyl)piperazine.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][C@H:30]2[CH3:35])[C:12]2[CH2:18][N:17]([C:19]3[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[CH:22]=[CH:21][C:20]=3[CH3:28])[CH2:16][CH2:15][C:13]=2[N:14]=1.Br[CH2:37][C:38]([NH2:40])=[O:39].CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([N:29]2[CH2:34][CH2:33][N:32]([CH2:37][C:38]([NH2:40])=[O:39])[CH2:31][C@H:30]2[CH3:35])[C:12]2[CH2:18][N:17]([C:19]3[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[CH:22]=[CH:21][C:20]=3[CH3:28])[CH2:16][CH2:15][C:13]=2[N:14]=1
Reactant: NC(=O)CBr
Reactant: Cc1ccc(C)c(-c2nc3c(c(N4CCNC[C@H]4C)n2)CN(c2cc(C(C)C)ccc2C)CC3)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C)c(-c2nc3c(c(N4CCN(CC(N)=O)C[C@H]4C)n2)CN(c2cc(C(C)C)ccc2C)CC3)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of (R)-2-(2,5-dimethylphenyl)-6-(5-isopropyl-2-methylphenyl)-4-(2-methylpiperazin-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (43 mg, 0.053 mmol), 2-bromoacetamide (14.6 mg, 0.106 mmol) and DIEA (0.074 mL, 0.424 mmol) in DCM (2 mL) was stirred at rt for 16 h. The reaction was then diluted with EtOAc, and washed successively with sat aq NaHCO3, and brine. The organic layer was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by HPLC(C18, 15-85% acetonitrile in H2O with 0.1% NH4OH) to provide (R)-2-(4-(2-(2,5-dimethylphenyl)-6-(5-isopropyl-2-methylphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)acetamide. 1H NMR (400 MHz, DMSO-d6, at 120° C.) δ ppm 7.58 (s, 1 H) 7.08-7.18 (m, 5 H) 6.99 (d, J=1.64 Hz, 1 H) 6.87 (dd, J=7.71, 1.64 Hz, 1 H) 4.01-4.09 (m, 1 H) 3.89-4.01 (m, 2 H) 3.48-3.58 (m, 1 H) 3.37-3.47 (m, 1 H) 2.97 (t, J=5.87 Hz, 2 H) 2.81-2.90 (m, 3 H) 2.78 (d, J=10.36 Hz, 1 H) 2.61 (dd, J=11.62, 1.77 Hz, 1 H) 2.47 (s, 3 H) 2.40 (dd, J=11.31, 3.35 Hz, 1 H) 2.23-2.34 (m, 4 H) 2.20 (s, 3 H) 1.28 (d, J=6.44 Hz, 3 H) 1.19 (dd, J=6.95, 1.52 Hz, 6 H); MS (ESI+) m/z 527.4 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[Cl:13].[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][NH2:19].O>CS(C)=O>[Cl:13][C:5]1[CH:6]=[C:7]([N+:10]([O-:12])=[O:11])[CH:8]=[CH:9][C:4]=1[CH2:3][CH2:2][NH:19][CH2:18][C:17]1[CH:20]=[CH:21][CH:22]=[C:15]([Cl:14])[CH:16]=1
Reactant: NCc1cccc(Cl)c1
Reactant: O=[N+]([O-])c1ccc(CCBr)c(Cl)c1
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(CCNCc2cccc(Cl)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.9 %

Procedure:
To a solution of 1-(2-bromoethyl)-2-chloro-4-nitrobenzene (0.6 g, 1.84 mmol) in DMSO (20 mL), 3-chlorobenzylamine (1.21 g, 4.61 mmol) was added at room temperature. The reaction mixture was stirred for 3 hours at room temperature. After the completion of reaction, water (80 mL) was added and reaction mass was extracted with EtOAc (2×50 mL). The combined organic extracts were washed with water (50 mL), brine (50 mL) and the solvents removed under reduced pressure. The product was purified by column chromatography on neutral silica gel using 5-15% EtOAc in hexane to give the title compound (0.43 g, 55%) as a solid.
Reaction SMILES: [Na].[C:2](OCC)(=O)[CH2:3][C:4](C)=O.[Cl:11][C:12]1[C:22]([Cl:23])=[C:21]([C:24](=O)[CH:25]=[CH:26][CH3:27])[CH:20]=[CH:19][C:13]=1[O:14][CH2:15][C:16]([OH:18])=[O:17].C([OH:31])C>>[Cl:11][C:12]1[C:22]([Cl:23])=[C:21]([C:24]2[CH2:2][CH:3]([CH3:4])[CH2:27][C:26](=[O:31])[CH:25]=2)[CH:20]=[CH:19][C:13]=1[O:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: CCO
Reactant: CC=CC(=O)c1ccc(OCC(=O)O)c(Cl)c1Cl
Reactant: CCOC(=O)CC(C)=O
Agent: [Na]
Product: CC1CC(=O)C=C(c2ccc(OCC(=O)O)c(Cl)c2Cl)C1

Procedure:
To a stirred solution of sodium (0.836 g, 0.0363 mole) in ethanol (70 ml) and ethyl acetoacetate (4.73 g, 0.0363 mole) was added [2,3-dichloro-4-(1-oxo-2-butenyl)phenoxy]acetic acid (4.67 g, 0.0162 mole). The reaction mixture was heated at reflux for 3 hours then the solvent was distilled at reduced pressure. The residue was dissolved in water, acidified with hydrochloric acid, extracted with ether, washed with water, dried over magnesium sulfate and evaporated at reduced pressure to give 3.7 g of [2,3-dichloro-4-(5-methyl-3-oxo-1-cyclohexen-1-yl)phenoxy]acetic acid which melted at 187°-190° C. after recrystallization from acetonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:35])[C@:10]3([C@H:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25](O)=[O:26])[C@@H:11]3[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])[C:5]2=[CH:4][CH:3]=1.N1C(F)=NC(F)=NC=1[F:38].N1C=CC=CC=1>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:35])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25]([F:38])=[O:26])[CH:11]3[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])[C:5]2=[CH:4][CH:3]=1
Reactant: Fc1nc(F)nc(F)n1
Reactant: Cc1ccccc1[C@H]1N(CC(=O)O)C(=O)C[C@@H](c2cccc(Cl)c2)[C@]12C(=O)Nc1cc(Cl)ccc12
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccccc1C1N(CC(=O)F)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To the solution of (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-[(hydroxycarbonyl)-methyl]-2′-(2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.12 g, 0.24 mmol) prepared in example 31 in dichloromethane (40 mL) at 0° C. was added cyanuric fluoride (48 mg, 0.35 mmol) (Alfa) and pyridine (37 mg, 0.48 mmol). After the mixture was stirred at 0° C. for 2 h, the mixture was partitioned between H2O and dichloromethane. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The organic layers were combined, dried over MgSO4, concentrated to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-[(fluorocarbonyl)-methyl]-2′-(2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a yellow gum and used for the next step without further purification (Yield: 0.12 g, 98%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:8]=[C:7]([C:9](Cl)=[O:10])[CH:6]=[CH:5][CH:4]=1.Cl[C:15]1[CH:34]=[CH:33][C:18]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]3[O:32]CC[O:29]3)[CH:23]=2)=O)=[CH:17][CH:16]=1.CC1CC(C(OC)=O)CC[NH:37]1.C(OC(C1CCN(CC2C=CC=C(NC(=O)C3C=CC(Cl)=CC=3)C=2)CC1)=O)C>>[CH3:27][CH:26]1[CH2:25][CH:24]([C:28]([OH:32])=[O:29])[CH2:23][CH2:22][N:21]1[CH2:19][C:18]1[CH:33]=[CH:34][CH:15]=[C:16]([NH:37][C:9]([C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:13])([F:12])[F:1])[N:8]=2)=[O:10])[CH:17]=1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)n1
Reactant: COC(=O)C1CCNC(C)C1
Reactant: O=C(Nc1cccc(C2OCCO2)c1)c1ccc(Cl)cc1
Agent: CCOC(=O)C1CCN(Cc2cccc(NC(=O)c3ccc(Cl)cc3)c2)CC1
Product: CC1CC(C(=O)O)CCN1Cc1cccc(NC(=O)c2cccc(C(F)(F)F)n2)c1

Procedure:
The title compound is prepared according to the reaction sequence 2.001a-2.001d described above using 6-(trifluoromethyl)picolinoyl chloride instead of 4-chlorobenzoyl chloride as in 2.001a and rac-(2S*,4S*)-methyl 2-methylpiperidine-4-carboxylate instead of ethyl isonipecotate as in 2.001c: LC-MS A: tR=0.49 min; [M+H]+=368.07.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:18][C:17]3[CH:19]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:21]=[C:22]([Cl:23])[C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[CH3:28][NH2:29]>C(#N)C>[Cl:23][C:22]1[C:16]2[O:15][CH2:14][C@H:13]([CH2:12][NH:29][CH3:28])[O:18][C:17]=2[CH:19]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3c(Cl)cc(S(C)(=O)=O)cc3O2)cc1
Reactant: CN
Solvent: CC#N
Product: CNC[C@H]1COc2c(Cl)cc(S(C)(=O)=O)cc2O1
Temperature: 120 °C
Yield: 56.1 %

Procedure:
A mixture of [(2R)-5-chloro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.48 g, 1.1 mmol), methanamine (1.5 ml, 33% in EtOH, 4 mmol) and ACN (3 ml) was heated under microwave radiation at 120° C. for 20 min. Purification on SCX-3 column (TEA/MeOH) and by flash column chromatography (MeOH/EtOAc) gave the title compound (0.18 g). The amine was converted to the hydrochloric acid salt and crystallized from MeOH/Et2O. M.p. 262° C. MS m/z (rel. intensity, 70 eV) 291 (M+, 43), 113 (57), 85 (80), 70 (bp), 63 (84), 50 (60) [α]=−61° (MeOH).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[C:9]#[N:10].[OH:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][OH:23])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[OH:23][CH2:22][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:2][CH2:3][O:4][CH2:5][C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=2)[C:9]#[N:10])=[CH:16][CH:17]=1
Reactant: OCCc1ccc(O)cc1
Reactant: N#Cc1cccc(COCCBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cccc(COCCOc2ccc(CCO)cc2)c1
Temperature: 60 °C
Yield: 81.6 %

Procedure:
A mixture of 3-[(2-bromoethoxy)methyl]benzonitrile (5.00 g), 2-(4-hydroxyphenyl)ethanol (3.45 g), and potassium carbonate (5.76 g) in N,N-dimethylformamide (30 ml) was heated at 60° C. for 66 h. The mixture was allowed to cool and partitioned between ethyl acetate and 2N HCl. The aqueous phase was extracted with ethyl acetate and the combined organic phase washed with 2N NaOH, brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography (SPE, eluted with gradient between cyclohexane and 80% EtOAc in cyclohexane) to give the title compound (5.05 g). LCMS RT=2.96 min.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[F:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1>>[CH2:17]1[CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6]3[C:5]([F:19])=[CH:4][N:3]=[C:2]([NH:25][C:24]4[CH:26]=[CH:27][C:21]([F:20])=[CH:22][CH:23]=4)[N:7]=3)=[CH:10][C:11]=2[O:18]1
Reactant: Nc1ccc(F)cc1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Product: Fc1ccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)cc1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 4-fluoroaniline were reacted to yield N4-(3,4-ethylenedioxyphenyl)-N2-(4-fluorophenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.92 (bs, 1H), 7.80 (bs, 1H), 7.60 (bd, 2H), 6.90 (m, 2H), 6.80 (bs, 1H), 6.65 (bs, 1H), 4.25 (s, 4H); LCMS: ret. time: 22.87 min.; purity: 97%; MS (m/e): 357 (MH+).
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([CH2:15][CH3:16])([CH3:14])[CH3:13])[C:7]=1[OH:17])([CH2:4][CH3:5])([CH3:3])[CH3:2].[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.N1CCCCC1>CCCCCCC>[C:1]([C:6]1[C:7](=[O:17])[C:8]([C:12]([CH2:15][CH3:16])([CH3:14])[CH3:13])=[CH:9][C:10](=[CH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:11]=1)([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: CCC(C)(C)c1cccc(C(C)(C)CC)c1O
Reactant: O=Cc1ccccc1
Solvent: CCCCCCC
Solvent: C1CCNCC1
Product: CCC(C)(C)C1=CC(=Cc2ccccc2)C=C(C(C)(C)CC)C1=O
Yield: 41.7 %

Procedure:
6.0 g (0.026 Mol) of 2,6-di-tert-amylphenol, 2.75 g (0.026 mol) of benzaldehyde and 4.37 g (0.05 1 mol) of piperidine are refluxed under nitrogen in 50 ml of heptane on a Dean-Stark trap for 24 hours. The solution is then evaporated in vacuo and the residue chromatographed twice on silica gel with hexane and then with hexane:ethyl acetate (9:1 ) to give 3.5 g of the title compound as a thick yellow oil.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[Br:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH2:22][CH2:23][NH:24]2.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[Br:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH2:22][CH2:23][N:24]2[C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Brc1cccc2c1CCN2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1CCc2c(Br)cccc21
Yield: 72.3 %

Procedure:
The product is prepared according to the procedure described in example 5, using 261 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 402 mg of 4-bromoindoline and 254 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 0.16 ml of pyridine and 4 ml of dimethylformamide. 303 mg of 2-[2-(4-bromo-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one are obtained in the form of a white powder, the characteristics of which are the following:
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([OH:3])=[O:2].[C:12]1([S:18]([NH2:21])(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[N:21][S:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:20])=[O:19])=[CH:6][CH:5]=1)([OH:3])=[O:2]
Reactant: NS(=O)(=O)c1ccccc1
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C(O)c1ccc(C=NS(=O)(=O)c2ccccc2)cc1

Procedure:
In a manner similar to Example 2, 1.00 g (6.6 mmol) of 4-carboxybenzaldehyde, 1.05 g (6.6 mmol) of benzenesulfonamide and 20 mg of TsOH in 120 mL of toluene were heated for 2.5 hours to afford 1.82 g (90%) of SULF-2 as a white powder; IR (Nujol) 3400-2400 (br), 1680, 1605, 1283, 1160, 1083 cm-1 ; 1H NMR (DMSO-d6, TMS ext std) δ9.17 (s, 1), 8.1-7.3 (m, 9).
Reaction SMILES: [H-].[Na+].[N:3]1([C:8]2[N:13]=[CH:12][C:11]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:10][N:9]=2)[CH:7]=[N:6][N:5]=[N:4]1.[CH3:19]I>CN(C=O)C.C(OCC)(=O)C>[N:3]1([C:8]2[N:9]=[CH:10][C:11]([CH:14]([CH3:19])[C:15]([O:17][CH3:18])=[O:16])=[CH:12][N:13]=2)[CH:7]=[N:6][N:5]=[N:4]1
Reactant: COC(=O)Cc1cnc(-n2cnnn2)nc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C(C)c1cnc(-n2cnnn2)nc1
Reaction time: 0.17 h

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil) (19.1 mg, 0.477 mmol) in anhydrous DMF (3.2 mL) was added solution of methyl 2-(2-(1H-tetrazol-1-yl)pyrimidin-5-yl)acetate (100 mg, 0.454 mmol) in anhydrous DMF (1.4 mL) at room temperature. Stirred for 10 min, then added methyl iodide (42.6 μl, 0.681 mmol) dropwise. Stirred at room temperature for 1 h. Reaction mixture was diluted with ethyl acetate and washed with water (3 times). Organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by MPLC, eluting with 20-100% ethyl acetate/hexanes, 26 column volumes. LC/MS: [(M+1)]+=235.2;
Reaction SMILES: [C:1]([Si:5]([O:8][C:9]1[CH:14]=[C:13](Br)[CH:12]=[C:11]([Br:16])[CH:10]=1)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.CN([CH:25]=[O:26])C.[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C.CO>[Br:16][C:11]1[CH:12]=[C:13]([CH:14]=[C:9]([O:8][Si:5]([C:1]([CH3:2])([CH3:3])[CH3:4])([CH3:6])[CH3:7])[CH:10]=1)[CH:25]=[O:26]
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(Br)cc(Br)c1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1cc(Br)cc(C=O)c1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
tert-Butyl-(3,5-dibromo-phenoxy)-dimethyl-silane (22 g; 60.08 mmol) was dissolved in THF (200 mL) in a dried reaction flask under an atmosphere of nitrogen. The mixture was cooled to −78° C. and n-BuLi (1.6 N in hexane; 41.25 mL; 66.09 mmol) was added while the temperature was kept between −60 and −78° C. The mixture was stirred for 15 min. and DMF (4.83 g; 66.08 mmol) was added. The reaction mixture was stirred for 1 h and methanol (5 mL) followed by saturated ammonium chloride was added. Etyl acetate (200 mL) was added and the organic phase was separated from the aqueous phase. The organic phase was washed with water, dried, and evaporated to dryness. The crude product was purified by flash chromatography (heptane: dichloromethane (1:1). Yield 7 g. HPLC-MS: m/z: 317.0 (M+1); Rt: 2.7 min.
Reaction SMILES: COCCO[C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1OCCOC)[N:12]=[CH:11][N:10]=[C:9]2Cl.OC1ON=C(C2C=CC=CC=2)C=1.C(N(CC)CC)C>C(O)(C)C>[N:12]1[C:13]2[C:8](=[CH:7][CH:6]=[CH:15][CH:14]=2)[CH:9]=[N:10][CH:11]=1
Reactant: COCCOc1cc2ncnc(Cl)c2cc1OCCOC
Agent: Oc1cc(-c2ccccc2)no1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: c1ccc2ncncc2c1

Procedure:
0.3 g (1 mmol) of (6,7-bis(2-methoxyethoxy))-4-chloro-quinazoline was dissolved in 5 mL dry isopropanol. Under stirring, a solution of 0.175 g (1 mmol) of 5-hydroxy3-phenyl-isoxazole in 5 mL of isopropanol was slowly added dropwise to the reaction system, followed by the addition 0.101 g (1 mmol) of freshly distilled triethylamine. After the system was stirred at room temperature for 30 min, the reaction was hold at 60. After the completion of the reaction monitored by TLC, the reaction solution was concentrated under vacuum. The residue was directly separated by column chromatography (Vpetroleum ether:Vethyl acetate=5:1-2:1) to give the target compound of (6,7-bis(2-methoxyethoxy))-4-((3-(4-methylphenyl)-isoxazol-5-yl))-methoxy-)-quinazoline (i.e. Q-15 in the following Table). The other compounds were synthesized according to the synthetic process of (6,7-bis(2-methoxyethoxy))-4-((3-(4-methylphenyl)-isoxazol-5-yl))-methoxy-)-quinazoline. The structures were characterized by analytic methods such as IR, 1H NMR, ESI-MS, etc. The physical constants and spectral data of preferred compounds were indicated in the form of table.