Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]([NH2:12])=[C:7]([Cl:13])[CH:6]=[CH:5][C:4]=2[N:3]=1.[CH:14]1([CH2:20][C:21](O)=[O:22])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.Cl>CN1CCCC1=O.O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:13])[C:8]=2[NH:12][C:21](=[O:22])[CH2:20][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[N:3]=1
Reactant: O=C(O)CC1CCCCC1
Reactant: Nc1c(Cl)ccc2nc(Cl)ccc12
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(Cl)ccc12
Temperature: 50 °C
Yield: 31 %

Procedure:
To a stirred solution of 2,6-dichloroquinolin-5-amine (prepared as described in (d) below) (1 g) in N-methylpyrrolidinone (12 mL) was added 4-N,N-dimethylaminopyridine (1.2 g), cyclohexaneacetic acid (1 g) and PyBroP (4.4 g). The reaction mixture was heated to 50° C. for 10 hours. The mixture was cooled to room temperature and poured into water (10 mL) which was subsequently acidified to pH1 with aqueous 2M hydrochloric acid. The resulting solution was extracted with dichloromethane (3×20 mL). The combined organic extracts were dried, filtered and partially concentrated to give a white precipitate which was removed by filtration. Purification by chromatography (SiO2, methanol:dichloromethane 1:10 as eluant) gave the sub-title compound (490 mg).
Reaction SMILES: [CH2:1](Cl)[C:2](=[CH2:4])[CH3:3].C(Cl)C=C.[Li]C.[O:12]1[CH:14]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:13]1>C1COCC1>[CH3:3][C:2]([CH2:1][CH2:13][CH:14]([OH:12])[CH2:15][CH2:16][CH2:17][CH3:18])=[CH2:4]
Reactant: C=C(C)CCl
Reactant: CCCCC1CO1
Agent: [Li]C
Solvent: C=CCCl
Solvent: C1CCOC1
Product: C=C(C)CCC(O)CCCC
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 67.3 %

Procedure:
Methallylchloride (3.16 mmol) was weighed into an 8 ml vial, sealed with a septum and placed under argon. THF (2 to 4 ml) was added to the vial and the allyl chloride solution was cooled to -78° C. The allyl chloride was added rapidly via a cannula to a suspension of the zerovalentcopper species prepared according to the procedure of Example 1 (7.96 mmol)at -100° C. and stirred for 10 min. MeLi (6.30 mmol) was added to the newly formed organocopper solution at -90° C. and stirred for 15 min. 1,2-Epoxyhexane (1.01 mmol) was added from a vial to the new organocopper solution at -90° C., warmed to 0° C. over 3 hours, and held at 0° C. for 12 hours. The reaction was quenched with NH4Cl (sat'd), extracted with Et2O (2×50 ml), washed with brine (2×50 ml), and dried over MgSO4. Flash silicagel chromatography, using gradient mixtures of hexane and ethyl acetate, afforded 2-methyl-1-nonen-5-ol (0.68 mmol, Entry 10 in Table III). Rf =0.23 in 9:1 (v/v) hexane and ethyl acetate, respectively (67% yield): IR (neat) 3317, 3070, 3016, 2954, 2931, 2869, 2854, 1647, 1452, 1375, 1126, 1084, 1053, 1036, 1003, 885 cm-1. 1H NMR (360 MHz) 4.72 (bs, 2H), 3.63-3.58 (m, 1H), 2.20-2.05 (m, 2H), 1.74 (s, 3H), 1.68-1.30 (m, 8H), 0.91 (t, J=7.0 Hz, 3H). 13C NMR (50 MHz) 145.9, 110.0, 71.7, 37.2, 35.2, 34.0, 27.8, 22.7, 22.4, 14.0.
Reaction SMILES: [Si]([O:8][C@H:9]([C:11]1[N:15]([C:16]2[N:21]=[C:20]([CH3:22])[N:19]=[C:18]([C@@H:23]3[CH2:25][C@H:24]3[C:26]3[N:30]([CH3:31])[C:29]4[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=4[N:27]=3)[CH:17]=2)[N:14]=[C:13]([CH3:36])[N:12]=1)[CH3:10])(C(C)(C)C)(C)C.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH3:36][C:13]1[N:12]=[C:11]([C@@H:9]([OH:8])[CH3:10])[N:15]([C:16]2[CH:17]=[C:18]([C@@H:23]3[CH2:25][C@H:24]3[C:26]3[N:30]([CH3:31])[C:29]4[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=4[N:27]=3)[N:19]=[C:20]([CH3:22])[N:21]=2)[N:14]=1
Reactant: Cc1nc([C@@H]2C[C@H]2c2nc3ccccc3n2C)cc(-n2nc(C)nc2[C@H](C)O[Si](C)(C)C(C)(C)C)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1nc([C@@H]2C[C@H]2c2nc3ccccc3n2C)cc(-n2nc(C)nc2[C@H](C)O)n1
Reaction time: 16 h

Procedure:
A solution of 13-1 (2.8 g, 5.6 mmol), acetic acid (0.41 ml, 7.2 mmol) and 1 N tetrabutylammonium fluoride (7.8 mL, 7.8 mmol) in THF (15.6 ml) was stirred at 23° C. for 16 h. Additional 1 N tetrabutylammonium fluoride in THF (4 mL, 4 mmol) was added and stirring was continued for 16 h. The white precipitate that formed was collected by filtration, washed with THF (2×50 mL) followed by ether (2×50 mL). The white solid was dissolved in DCM (100 mL) and washed with saturated aqueous sodium bicarbonate solution (2×100 mL), brine (2×100 mL) and water (2×100 mL) successively. The organic layer was dried over sodium sulfate, filtered, and concentrated to afford a clear oil. The oil was triturated from 5:1 ether/EtOAc and the resulting white solid was collected by filtration and air dried to provide Example 13. 1H NMR (500 MHz, CDCl3) δ 7.77 (s, 1H), 7.71-7.69 (m, 1H), 7.32-7.24 (m, 3H), 6.12 (d, 1H, J=5.4 Hz), 5.19-5.17 (m, 1H), 3.83 (s, 3H), 2.89-2.86 (m, 2H), 2.73 (s, 3H), 2.44 (s, 3H), 2.09-2.00 (m, 2H), 1.73 (d, 3H, J=6.6 Hz); MS: m/z=390.3 (M+H).
Reaction SMILES: [CH3:1]C1C=CC(OC2C=CC(N)=CC=2)=CC=1.[CH2:16]([N:20]([CH2:34][CH:35]1[O:37][CH2:36]1)[C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:23][CH:22]=1)[CH:17]1[O:19][CH2:18]1>>[CH2:34]([N:20]([CH2:16][CH:17]1[O:19][CH2:18]1)[C:21]1[CH:22]=[CH:23][C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([CH3:1])=[CH:30][CH:29]=2)=[CH:25][CH:26]=1)[CH:35]1[O:37][CH2:36]1
Reactant: c1ccc(Oc2ccc(N(CC3CO3)CC3CO3)cc2)cc1
Reactant: Cc1ccc(Oc2ccc(N)cc2)cc1
Product: Cc1ccc(Oc2ccc(N(CC3CO3)CC3CO3)cc2)cc1

Procedure:
Except that 4-(4-methyl phenoxy)aniline was used as the amine compound acting as precursor for synthesizing the epoxy resin, the same procedures as for the N,N-diglycidyl-4-phenoxy aniline was carried out under the same reaction conditions for glycidyl formation, producing N,N-diglycidyl-4-(4-methyl phenoxy)aniline
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4](S([O-])=O)=[CH:3][CH:2]=1.[Na+].C[N:13]1[CH:17]=[CH:16][CH:15]=[C:14]1C=O>>[CH2:17]([N:13]1[C:6]2[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=2)[CH:10]=[C:14]1[CH3:15])[CH3:16]
Reactant: Cn1cccc1C=O
Reactant: Cc1ccc(S(=O)[O-])cc1
Agent: [Na+]
Product: CCn1c(C)cc2ccccc21
Yield: 94 %

Procedure:
Following a procedure similar to that described in Example 1A but employing 6.3 g. of 85% sodium p-toluenesulfinate, 2.2 g. of 98% 1-methylpyrrole-2-carboxaldehyde and 3.8 g. of 94% 1-ethyl-2-methyl-1H-indole, there was obtained 8.4 g. of 3-[(1-methyl-2-pyrrolyl)(4-methylphenylsulfonyl)methyl]-1-ethyl-2-methyl-1H-indole, m.p. 180° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:21]([CH2:23]O)[N:22]=3)[CH2:14][C@H:13]2[O:30][CH3:31])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].CCN(S(F)(F)[F:38])CC>ClCCl.[Cl-].[Na+].O>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:21]([CH2:23][F:38])[N:22]=3)[CH2:14][C@H:13]2[O:30][CH3:31])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCN(CC)S(F)(F)F
Reactant: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)nc1CO
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)nc1CF
Reaction time: 0.5 h
Yield: 58.4 %

Procedure:
Ethyl cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-(hydroxymethyl)-1,3-thiazole-5-carboxylate obtained by the method described in Example (27b) (0.14 g, 0.30 mmol) was dissolved in dichloromethane (5 mL). A solution of DAST (0.05 mL, 0.38 mmol) in dichloromethane (2 mL) was added dropwise at −40° C. The mixture was stirred at that temperature for 30 minutes. Brine was added to the reaction solution, followed by extraction with dichloromethane. The organic layer was washed with brine and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=4/1, 3/1, 1/1) to obtain 83 mg of the title compound as a colorless oily substance (59%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:6]=[C:5]([C:15]2[CH:16]=[N:17][CH:18]=[C:19]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH:25]=3)[CH:20]=2)[CH:4]=1.I[CH:33]([CH3:35])[CH3:34]>CN(C=O)C.CCOC(C)=O>[CH:33]([N:29]1[CH2:30][CH2:31][CH:26]([N:24]2[CH:25]=[C:21]([C:19]3[CH:20]=[C:15]([C:5]4[CH:4]=[C:3]([NH:2][CH3:1])[N:8]=[C:7]([C:9]5[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=5)[CH:6]=4)[CH:16]=[N:17][CH:18]=3)[CH:22]=[N:23]2)[CH2:27][CH2:28]1)([CH3:35])[CH3:34]
Reactant: CNc1cc(-c2cncc(-c3cnn(C4CCNCC4)c3)c2)cc(-c2ccccn2)n1
Reactant: CC(C)I
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNc1cc(-c2cncc(-c3cnn(C4CCN(C(C)C)CC4)c3)c2)cc(-c2ccccn2)n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of Methyl-[5″-(1-piperidin-4-yl-1H-pyrazol-4-yl)-[2,2′;4′,3″]terpyridin-6′-yl]-amine (Example 2.183) (1 eq, 0.122 mmol, 50 mg) in DMF (3 ml) cooled at 0° C. is added 2-iodopropane (7 eq, 0.854 mmol, 0.084 ml) and the reaction is stirred at room temperature for 5 hours. The reaction mixture is dissolved in EtOAc and washed with water. The combined organic extracts are washed with brine, dried over MgSO4 and concentrated in vacuo. The residue is purified by reverse phase column chromatography (Isolute™ C18, 0-20% acetonitrile in water—0.1% TFA). The appropriate fractions by HPLC are combined and concentrated in vacuo. The resulting residue is dissolved in MeOH and loaded onto a SCX-2 cartridge eluting with MeOH followed by 2M NH3 in MeOH. The methanolic ammonia fractions are combined, concentrated in vacuo and dried under vacuum to afford the title compound; [M+H]+ 454.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[CH:9][CH:10]=[O:11].[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:29]=[C:28]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[CH2:27][C:22]3([CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:21]=2)=[CH:16][CH:15]=1.[OH-].[Na+]>C(#N)C>[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:29]=[C:28]([C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)[CH2:27][C:22]3([CH2:23][CH2:24][CH2:25][CH2:26]3)[C:21]=2/[CH:8]=[CH:9]/[CH:10]=[O:11])=[CH:16][CH:15]=1
Reactant: CN(C)C=CC=O
Reactant: Fc1ccc(C2=CC3(CCCC3)CC(c3ccc(F)cc3)=C2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: O=C/C=C/C1=C(c2ccc(F)cc2)C=C(c2ccc(F)cc2)CC12CCCC2
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
To a solution of phosphorus oxychloride (1.69 ml, 18.15 mmoles) in 50 ml of acetonitrile cooled in an ice bath was added 3-dimethylaminoacrolein (1.68 ml, 16.75 mmoles) dropwise over 3 minutes. The mixture was stirred for 5 minutes and a solution of 7.9-di-(4-fluorophenyl)-spiro[4.5]-deca-6,8-diene (4.5 g, 13.96 mmoles) in 150 ml of warm acetonitrile was added dropwise over 30 minutes. The mixture was stirred at room temperature for 16 hours and was then heated in an oil bath at 60° C. for 6 hours. The mixture was cooled and poured into 400 ml of cold 1N sodium hydroxide. The mixture was extracted with ether. The ether was washed with water and evaporated in vacuo.
Reaction SMILES: [C:1]([O-:6])(=[O:5])[CH:2]([CH3:4])[CH3:3].C[N+](C)(C)C.C(O)(=O)C(C)C.[C:18](=[O:28])([S:26][CH3:27])[O:19][O:20][CH:21](Cl)[CH:22]([CH3:24])[CH3:23]>CCOC(C)=O>[C:18](=[O:28])([S:26][CH3:27])[O:19][O:20][CH:21]([O:6][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])[CH:22]([CH3:24])[CH3:23]
Reactant: CSC(=O)OOC(Cl)C(C)C
Reactant: CC(C)C(=O)[O-]
Agent: C[N+](C)(C)C
Solvent: CC(C)C(=O)O
Solvent: CCOC(C)=O
Product: CSC(=O)OOC(OC(=O)C(C)C)C(C)C
Temperature: 80 °C
Yield: 67.7 %

Procedure:
To a 3 L three neck round bottom flask equipped with a mechanical stirrer and Teflon-coated thermocouple was added (13) (1672 g, 9 mol), isobutyric acid (264 g, 1.5 mol), and (12) (1050 g, 5.76 mol). The reaction mixture was heated to 80° C. for 12 h, monitoring the reaction progress by 1H NMR. The reaction mixture was cooled to 20° C., diluted with EtOAc (1 L) and washed with water (2×1 L), saturated NaHCO3 (1×2 L) and water (1 L). The organic phase was separated and concentrated under reduced pressure to afford the title compound (11) (905 g, 3.9 mol, 65% yield) as a colorless liquid. 1H NMR (CDCl3, 400 MHz): δ 1.0 (d, 6H), 1.2 (dd, 6H), 2.05 (m, 1H), 2.35 (s, 3H), 2.6 (m, 1H), 6.7 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]#[C:12][C:13]([CH3:19])([CH3:18])[C:14]([O:16][CH3:17])=[O:15].N1C=CC=CC=1.[C:26](Cl)(=[O:30])[CH2:27][CH2:28][CH3:29]>C(Cl)Cl>[C:26]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]#[C:12][C:13]([CH3:19])([CH3:18])[C:14]([O:16][CH3:17])=[O:15])(=[O:30])[CH2:27][CH2:28][CH3:29]
Reactant: CCCC(=O)Cl
Reactant: COC(=O)C(C)(C)C#Cc1cc([N+](=O)[O-])ccc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCC(=O)Nc1ccc([N+](=O)[O-])cc1C#CC(C)(C)C(=O)OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.1 %

Procedure:
To a solution of methyl 4-(2-amino-5-nitrophenyl)-2,2-dimethylbut-3-ynoate (260 mg, 1.0 mmol) and pyridine (160 mg, 2.0 mol) in CH2Cl2 (20 mL) was added butyryl chloride (140 mg, 1.3 mmol) at 0° C. The reaction mixture was warmed to room temperature and stirred for 3 h before the mixture was poured into ice-water. The organic layer was separated and the aqueous phase was extracted with CH2Cl2 (30 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtain methyl 4-(2-butyramido-5-nitrophenyl)-2,2-dimethylbut-3-ynoate (150 mg, 45%), which was used directly in the next step. 1H NMR (400 MHz, CDCl3) δ 8.79 (brs, 1 H), 8.71 (d, J=9.2 Hz, 1 H), 8.24 (d, J =2.8 Hz, 1 H), 8.17 (dd, J=2.8, 9.2 Hz, 1 H), 3.82 (s, 3 H), 2.55 (t, J=7.2 Hz, 2 H), 1.85-1.75 (m, 2 H), 1.63 (s, 6 H), 1.06 (t, J=6.8 Hz, 3 H).
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:19]([CH2:20][CH2:21][C@:4]12[CH3:5])[C@:17]1([CH3:18])[C@H:12]([CH2:13][C:14](=[O:22])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3.[Li][CH3:24]>C1COCC1.C(Cl)Cl>[CH3:24][C@@:14]1([OH:22])[CH2:15][CH2:16][C@@:17]2([CH3:18])[C@@H:12]([CH2:11][CH2:10][C@@H:9]3[C@@H:19]2[CH2:20][CH2:21][C@@:4]2([CH3:5])[C@H:6]3[CH2:7][CH2:8][C@@H:3]2[O:2][CH3:1])[CH2:13]1
Reactant: [Li]C
Reactant: CO[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: C1CCOC1
Solvent: ClCCl
Product: CO[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@](C)(O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 33.1 %

Procedure:
A solution of 17β-methoxy-5α-androstan-3-one (101 mg, 0.33 mmol) in dry THF (20 mL) was treated with MeLi (1 mL, 1.5M in THF, 1.5 mmol) at -75° C. After stirring the mixture at -78° C. for 0.5 hr, the mixture was quenched with NH4Cl solution (5 mL). The solvents were removed and the residue was extracted with EtOAc. The organic layer was washed with water, and brine. After drying over anhyd. MgSO4 the solution was filtered and evaporated to yield the crude product. This crude product was then dissolved in a small amount of CH2Cl2 and poured on a column of silica gel. Elution with toluene:acetone mixture (95:5) gave 3β-methyl-3α-hydroxy-17β-methoxy-5α-androstane (35 mg); mp 151-154° C.; TLC Rf (hexane:acetone 7:3)=0.43; and then 3α-methyl-30-hydroxy-17β-methoxy-5α-androstane (30 mg) as a colorless solid; TLC Rf (hexane:acetone 7:3)=0.27.
Reaction SMILES: C([Li])CCC.[O:6]1CCCC1.Cl[C:12]1[N:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH:15]=[CH:14][N:13]=1>C(OCC)(=O)C.O>[F:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][O:18][C:16]2[CH:15]=[CH:14][NH:13][C:12](=[O:6])[N:17]=2)=[CH:21][CH:22]=1
Reactant: Fc1ccc(COc2ccnc(Cl)n2)cc1
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: O
Solvent: CCOC(C)=O
Product: O=c1nc(OCc2ccc(F)cc2)cc[nH]1
Reaction time: 0.5 h
Yield: 24 %

Procedure:
n-Butyl lithium (2.6 M n-hexane solution, 7.2 mL) was added to tetrahydrofuran solution (10 mL) of 2-popenyl alcohol (1.8 mL) at −78° C., and stirred at the same temperature for 30 minutes. This reaction liquid was gradually added to tetrahydrofuran solution (20 mL) of 2-chloro-4-(4-fluorobenzyloxy)pyrimidine (4.36 g) and stirred at 60° C. for 4 hours, followed by 24 hours' reflux. Cooling the reaction liquid to room temperature, ethyl acetate was added thereto, followed by washing with water and saturated brine and drying over anhydrous magnesium sulfate. Concentrating the solvent under reduced pressure, the residue was dissolved in tetrahydrofiaan (20 mL). To the solution piperidine (2 mL) and tetrakis(triphenylphosphine)palladium (780 mg) were added and stirred at room temperature for 4 hours. The reaction liquid was added to water (100 mL)-ethyl acetate (50 mL) mixture, and the insoluble matter was recovered by filtration to provide the title compound (0.96 g, 24%).
Reaction SMILES: [NH2:1][C:2]1[N:9]=[CH:8][CH:7]=[C:6]([O:10]C)[C:3]=1[C:4]#[N:5].Cl[CH2:13][CH:14]=O.CCOCC>CCO>[OH:10][C:6]1[CH:7]=[CH:8][N:9]2[CH:13]=[CH:14][N:1]=[C:2]2[C:3]=1[C:4]#[N:5]
Reactant: O=CCCl
Reactant: COc1ccnc(N)c1C#N
Solvent: CCO
Solvent: CCOCC
Product: N#Cc1c(O)ccn2ccnc12
Temperature: 150 °C

Procedure:
To a mixture of compound D3 (2 g, 13.404 mmol) in EtOH (5 ml) was added chloroacetaldehyde (1.58 g, 20.11 mmol). The reaction mixture was subjected to microwave heating at 150° C. for 45 min. After cooling to room temperature, the solvent was evaporated in vacuo. The residue thus obtained was then treated with Et2O and a solid precipitated. The solid thus obtained was filtered off, washed with EtOAc and dried in vacuo to yield compound D21 (1.5 g, 70%).
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][C:21]1[CH:22]=[C:23]([N:27]2[C:32]3=[N:33][C:34](S(C)(=O)=O)=[N:35][CH:36]=[C:31]3[CH2:30][N:29]([C:41]3[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][C:42]=3[Cl:48])[C:28]2=[O:49])[CH:24]=[CH:25][CH:26]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:50]([N:52]([CH2:63][CH3:64])[CH2:53][CH2:54][O:55][C:56]1[CH:62]=[CH:61][C:59]([NH2:60])=[CH:58][CH:57]=1)[CH3:51]>>[Si:1]([O:18][CH2:19][CH2:20][C:21]1[CH:22]=[C:23]([N:27]2[C:32]3=[N:33][C:34]([NH:60][C:59]4[CH:58]=[CH:57][C:56]([O:55][CH2:54][CH2:53][N:52]([CH2:63][CH3:64])[CH2:50][CH3:51])=[CH:62][CH:61]=4)=[N:35][CH:36]=[C:31]3[CH2:30][N:29]([C:41]3[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][C:42]=3[Cl:48])[C:28]2=[O:49])[CH:24]=[CH:25][CH:26]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](OCCc1cccc(N2C(=O)N(c3ccc(Cl)cc3Cl)Cc3cnc(S(C)(=O)=O)nc32)c1)(c1ccccc1)c1ccccc1
Reactant: CCN(CC)CCOc1ccc(N)cc1
Product: CCN(CC)CCOc1ccc(Nc2ncc3c(n2)N(c2cccc(CCO[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)c2)C(=O)N(c2ccc(Cl)cc2Cl)C3)cc1
Temperature: 180 °C
Yield: 33.2 %

Procedure:
A mixture of 500 mg (0.7 mmol) of 1-[3-(tert-butyldiphenylsilyloxyethyl)phenyl]-3-(2,4-dichlorophenyl)-3,4-dihydro-7-methanesulfonyl-pyrimido[4,5-d]pyrimidin-2(1H)-one and 1 g (4.8 mmol) of 4-[2-(diethylamino)ethoxy]aniline was heated at 180° C. for 30 minutes. The mixture was cooled and the product purified by column chromatography on silica gel using dichloromethane/methanol/acetic acid/water (240:24:3:2) for the elution. Product-containing fractions were combined, evaporated and the residue evaporated with toluene. The residue was then dissolved in 40 ml of dichloromethane, washed with 40 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to afford 200 mg (33%) of 1-[3-(tert-butyldiphenylsilyloxyethyl)phenyl]-3-(2,4-dichlorophenyl)-7-[4-[2-(diethylamino)ethoxy]anilino]-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one as a yellow gum. [Mass spectrum (ESI) MH+ =859].
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:6]([C:7]2[C:8](OS(C(F)(F)F)(=O)=O)=[CH:9][C:10]([F:17])=[C:11]([CH:16]=2)[C:12]([O:14][CH3:15])=[O:13])=[CH:5][CH2:4][CH2:3]1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.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>[CH3:26][C:2]1([CH3:1])[C:6]([C:7]2[CH:16]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[C:10]([F:17])=[CH:9][C:8]=2[C:29]2[CH:30]=[C:31]([O:34][CH3:35])[CH:32]=[CH:33][C:28]=2[F:27])=[CH:5][CH2:4][CH2:3]1
Reactant: COC(=O)c1cc(C2=CCCC2(C)C)c(OS(=O)(=O)C(F)(F)F)cc1F
Reactant: COc1ccc(F)c(B(O)O)c1
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: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(C2=CCCC2(C)C)c(-c2cc(OC)ccc2F)cc1F
Temperature: 90 °C
Reaction time: 17 h
Yield: 93 %

Procedure:
To a stirred solution of 66.43F (1.05 g, 2.65 mmol) in DMF (5 mL) at 23° C. was added 2-fluoro-5-methoxyphenylboronic acid (0.90 g, 5.32 mmol) (commercially available from Aldrich) and potassium carbonate (1.10 g, 7.96 mmol) followed by tetrakis(triphenylphosphine)palladium (0.31 g, 0.27 mmol). The mixture was heated to 90° C. After 17 hours, the mixture was cooled to room temperature and then diluted with water. After extracting three times with EtOAc, the mixture was concentrated in vacuo and then purified on silica gel (0%-10% EtOAc/hexane) to give 66.43G as a clear oil that was used without further purification (0.92 g, 93% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.79 (1H, d, J=7.4 Hz), 7.13 (1H, d, J=11.3 Hz), 6.99 (1H, t, J=9.0 Hz), 6.84 (1H, dt, J=8.7, 3.7 Hz), 6.78 (1H, dd, J=5.9, 3.1 Hz), 5.55 (1H, s), 3.96 (3H, s), 3.79 (3H, s), 2.27 (2H, td, J=7.1, 2.5 Hz), 1.67 (2H, t, J=7.0 Hz), 0.84 (6H, s).
Reaction SMILES: N[C:2]1[C:11]2[N:10]=[CH:9][C:8](=[O:12])[NH:7][C:6]=2[N:5]=[C:4]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=2[F:22])[N:3]=1.C(Br)(Br)[Br:24].C(ON=O)CC(C)C>CS(C)=O>[Br:24][C:2]1[C:11]2[N:10]=[CH:9][C:8](=[O:12])[NH:7][C:6]=2[N:5]=[C:4]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=2[F:22])[N:3]=1
Reactant: Nc1nc(SCc2cccc(F)c2F)nc2[nH]c(=O)cnc12
Reactant: BrC(Br)Br
Agent: CC(C)CCON=O
Solvent: CS(C)=O
Product: O=c1cnc2c(Br)nc(SCc3cccc(F)c3F)nc2[nH]1
Temperature: 125 °C
Reaction time: 0.08 h

Procedure:
The product of step (a) (0.5 g) was suspended in DMSO (10 ml) and bromoform (10 ml) and the mixture was heated to 125° C. Isoamylnitrite (2 ml) was added and the mixture was stirred at 125° C. for 5 minutes before being cooled in an ice bath. Solvent was removed by evaporation under high vacuum and the residue suspended in dichloromethane (100 ml). This suspension was washed with saturated aqueous ammonium chloride (50 ml) and then filtered through a plug of celite. The filtrate was evaporated and purified by column chromatography, eluting with 10% ethyl acetate in dichloromethane to give the subtitled compound as a white solid (0.22 g).