Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH3:12][C:13]1[C:19]([OH:20])=[CH:18][CH:17]=[CH:16][C:14]=1[OH:15]>Cl.[Cl-].[Cl-].[Zn+2]>[CH3:12][C:13]1[C:14]2[O:15][C:19]3[C:13]([CH3:12])=[C:14]([OH:15])[CH:16]=[CH:17][C:18]=3[C:4]3([O:6][C:1](=[O:11])[C:2]4[C:3]3=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:16]=2[CH:17]=[CH:18][C:19]=1[OH:20]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Cc1c(O)cccc1O
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Product: Cc1c(O)ccc2c1Oc1c(ccc(O)c1C)C21OC(=O)c2ccccc21
Temperature: 230 °C

Procedure:
In a round bottom flask, phthalic anhydride (16.7 g, 113 mmol) and 2-methylresorcinol (24.9 g, 201 mmol) were combined and melted into a brown liquid at 150° C. Fused ZnCl2 (15 g, 110 mmol) was added over 40 min, and the temperature was slowly increased to 230° C. until all material solidified. The brick red solid was pulverized and boiled in 6M HCl for 30 min. The red solid was collected on a glass frit, washed with water, and dried in air over night (yield: 32.62 g, 91% of the theoretical yield).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([OH:14])=[O:13])=[CH:7]2.S(Cl)(Cl)=O.[CH3:19]O>>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([O:14][CH3:19])=[O:13])=[CH:7]2
Reactant: O=C(O)c1ccc2c(Br)cccc2c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc2c(Br)cccc2c1
Yield: 69 %

Procedure:
5-Bromo-2-naphthoic acid (17.33 g, 69 mmol) and 250 mL of MeOH were combined in a flask under N2 atmosphere. Thionyl chloride (5.84 mL, 80 mmol) was added dropwise over 15 minutes at a temperature of 25-30° C. resulting in a pale yellow mixture. The mixture was heated at reflux for 3¼ hours. The resulting yellow solution was concentrated in vacuo to 137.4 g of solution then placed in the freezer overnight. The resulting thick mixture was filtered and the solid was washed with 100 mL of cold MeOH. The solid was dried in vacuo at 50° C. to give 11.39 g of intermediate title compound as white crystals. A second crop was filtered and washed with 100 mL of cold MeOH. The solid was dried to 1.31 g of white crystals. Yield: 69%, 2 crops.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]([Cl:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:5]=1[SH:13].Br[CH:15]([CH:19]([CH3:21])[CH3:20])[C:16]([OH:18])=[O:17]>CN(C)C=O.O>[Cl:3][C:4]1[C:9]([Cl:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:5]=1[S:13][CH:15]([CH:19]([CH3:21])[CH3:20])[C:16]([OH:18])=[O:17]
Reactant: CC(C)C(Br)C(=O)O
Reactant: COc1ccc(S)c(Cl)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(SC(C(=O)O)C(C)C)c(Cl)c1Cl
Reaction time: 0.2 h
Yield: 80.5 %

Procedure:
To 3.13 g of 99% sodium hydride under nitrogen at room temperature is added a solution of 12.26 g of 2,3-dichloro-4-methoxythiophenol in 100 ml of sieve-dried dimethylformamide over 2 minutes. The reaction is stirred for 12 minutes. A solution of 9.56 g of α-bromoisovaleric acid in 85 ml of dimethylformamide is added over 4 minutes. The reaction is stirred at room temperature for 3 hours, cooled in ice, diluted with 500 ml of water and filtered. The solution is cooled and acidified with 3N hydrochloric acid to give the product. The precipitate is filtered, washed with a small amount of water, dried and recrystallized from acetone-pentane to give 13.14 g of α-(2,3-dichloro-4-methoxyphenylthio)isovaleric acid as a white crystalline powder mp 176.5°-178.5°.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH2:29][CH2:30][N:31]([CH2:33][CH2:34][CH2:35]Cl)[CH3:32])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]>CN(C)C=O>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH2:29][CH2:30][N:31]([CH2:33][CH2:34][CH2:35][O:1][C:2]2[CH:6]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:4][N:3]=2)[CH3:32])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: Oc1cc(-c2ccccc2)on1
Reactant: COc1ccc(CCN(C)CCCCl)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(CCN(C)CCCOc2cc(-c3ccccc3)on2)cc1OC
Temperature: 100 °C
Reaction time: 4 h
Yield: 56.1 %

Procedure:
3.5 g of 3-hydroxy-5-phenyl-isoxazole were dissolved in 100 ml of dimethylformamide. The solution was reacted with 3 g of finely powdered potassium carbonate and the reaction mixture was heated for 15 minutes at 100° C. in a nitrogen atmosphere. Then 5.8 g of 3-[N-(2-(3,4-dimethoxyphenyl)-ethyl)-N-methylamino]-propyl chloride were added batchwise. The reaction mixture was stirred for 4 hours at 100° C., after which the salts that formed were filtered off, the filtrate was concentrated to dryness, and the residue dissolved in methyl-tert-butyl ether. The solution was then washed with aqueous sodium carbonate solution, dried with magnesium sulfate, and concentrated to dryness. The remaining crude oily title compound that was left as a residue was purified by flash chromatography using ethyl acetate as the eluent. 4.75 g of the title compound were obtained.
Reaction SMILES: C[O:2][C:3](=[O:18])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]([O:16]C)=[O:15])=[CH:8][CH:7]=1.Cl>[OH-].[Na+]>[C:14]([CH2:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:18])=[O:2])=[CH:7][CH:8]=1)([OH:16])=[O:15]
Reactant: COC(=O)COc1ccc(OCC(=O)OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)COc1ccc(OCC(=O)O)cc1
Temperature: 70 °C
Yield: 67.3 %

Procedure:
(4-Methoxycarbonylmethoxy-phenoxy)-acetic acid methyl ester 82 (100 grams, 394 mmol) was added to 3.25 M-sodium hydroxide solution (600 mL) and heated to 70° C. for 20 hours and poured onto ice cold water (1 lit) and the pH adjusted to 1 with concentrated hydrochloric acid. Crude 83 was filtered, dried, and recrystallized from DMF by precipitating with water to give pure 83 (60 grams, 67.4%) as a white powder. M.p: 254-256.5° C. IH NMR (CDCl3+DMSO, d6) 4.44(s,2H,OCH2), 6.72(s,2H,Ar).
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[C@@H:9]([CH:16]([CH3:18])[CH3:17])[N:10]=[C:11]([O:14][CH3:15])[CH2:12][N:13]=1.Cl[CH2:20][C:21]1[C:22]([CH3:27])=[N:23][O:24][C:25]=1[CH3:26]>CCCCCC.C1COCC1>[CH3:6][O:7][C:8]1[C@@H:9]([CH:16]([CH3:18])[CH3:17])[N:10]=[C:11]([O:14][CH3:15])[C@H:12]([CH2:20][C:21]2[C:22]([CH3:27])=[N:23][O:24][C:25]=2[CH3:26])[N:13]=1
Reactant: COC1=N[C@H](C(C)C)C(OC)=NC1
Reactant: Cc1noc(C)c1CCl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1Cc1c(C)noc1C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A 1.55M solution of butyllithium (10 ml, 15.5 mmol) in hexane was added by syringe to a stirred solution of (2R)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine (2.85 g, 15.5 mmol) in THF (50 ml) at -78° C. and the solution stirred for 1 hour at -78° C. A solution of 4- chloromethyl-3,5-dimethylisoxazole (2.34 g, 16 mmol) in THF (10 ml) was added gradually and the stirring continued overnight. The solvent was removed under reduced pressure, the residue dissolved in ethyl acetate (50 ml) and extracted with phosphate buffer (pH 7). The water phase was extracted twice with ethyl acetate (2×20 ml). The organic layer was dried (MgSO4), solvent evaporated under reduced pressure and the residue purified by flash chromatography (diethyl ether/hexane 4/1, silica gel).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:13])=[N:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:14]([O:18][C:19]([NH:21][CH2:22][CH2:23]O)=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19]([NH:21][CH2:22][CH2:23][O:13][C:3]1[C:2]([Cl:1])=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][N:4]=1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: Oc1noc(-c2ccccc2)c1Cl
Reactant: CC(C)(C)OC(=O)NCCO
Product: CC(C)(C)OC(=O)NCCOc1noc(-c2ccccc2)c1Cl
Yield: 72.7 %

Procedure:
4-Chloro-3-hydroxy-5-phenylisoxazole (0.58 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.48 g) were subjected to reaction and post-treatment in a similar manner to that described in Example 1 (a) to obtain the title compound (0.73 g, 72%) as colorless crystals.
Reaction SMILES: [CH3:1][O:2]C1C=CC(O)=CC=1.[C:10]([CH:13]([CH2:23][CH2:24][CH2:25][CH:26]([OH:39])[CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32](C(C)(C)C)=[CH:31][CH:30]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])(=[O:12])[CH3:11]>>[C:10]([CH:13]([CH2:23][CH2:24][CH2:25][CH:26]([OH:39])[CH2:27][O:28][C:29]1[CH:30]=[CH:31][C:32]([O:2][CH3:1])=[CH:33][CH:34]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])(=[O:12])[CH3:11]
Reactant: CC(=O)C(CCCCCCC(=O)O)CCCC(O)COc1ccc(C(C)(C)C)cc1
Reactant: COc1ccc(O)cc1
Product: COc1ccc(OCC(O)CCCC(CCCCCCC(=O)O)C(C)=O)cc1

Procedure:
The synthesis of this compound is carried out by the procedure of Example 10 except that an equivalent amount of 4-methoxyphenol is substituted for the 4-tert-butylphenol of Example 10. The title compound is obtained as a viscous oil after purification by silica gel column chromatography.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].[CH3:11][O:12][C:13](=[O:23])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20](O)=[O:21].ON1C2C=CC=CC=2N=N1>C1COCC1.C(OCC)(=O)C>[CH3:11][O:12][C:13](=[O:23])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20](=[O:21])[NH:1][CH2:2][CH:3]([OH:4])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: COC(=O)CCCCCCC(=O)O
Reactant: NCC(O)c1ccccc1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)CCCCCCC(=O)NCC(O)c1ccccc1
Reaction time: 12 h
Yield: 92.1 %

Procedure:
Add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide(EDC) (8.5 g, 44.3 mL) to a solution of 2-amino-1-phenylethanol (5.0 g, 36.4 mmol), suberic acid monomethyl ester (6.85 g, 36.4 mmol) and 1-hydroxybenzotriazole (HOBt, 5.0 g, 37.0 mmol) in THF (200 mL) at room temperature under nitrogen. Stir the mixture for 12 hours. Dilute the mixture with ethyl acetate (600 mL), wash with 1N HCl (2×150 mL), brine (2×150 mL), NaHCO3 (2×150 mL) and brine (150 mL) solutions and dry over sodium sulfate. Remove the solvent under reduced pressure to provide 7-(2-hydroxy-2-phenylethylcarbamoyl)heptanoic acid methyl ester (10.3 g, 91%), which is used in the following step without purification.
Reaction SMILES: [CH2:1]([N:4]([CH2:18][CH2:19][CH3:20])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([S:15]([CH3:17])=[O:16])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].ClC1C=CC=C(C(OO)=[O:29])C=1.[NH4+].[OH-]>FC(F)(F)C(O)=O>[CH2:18]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([S:15]([CH3:17])(=[O:29])=[O:16])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:19][CH3:20]
Reactant: CCCN(CCC)C1CCc2cccc(S(C)=O)c2C1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [NH4+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: CCCN(CCC)C1CCc2cccc(S(C)(=O)=O)c2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 29.9 %

Procedure:
To a solution of 2-dipropylamino-8-methylsulfinyl-1,2,3,4-tetrahydronaphthalene (350 mg, 1.19 mMol) in trifluoroacetic acid (20 ml) was added a solution of metachloroperbenzoic acid (80%, 518 mg, 2.38 mMol) in trifluoroacetic acid (5 mL). The solution was stirred at room temperature for 18 hours and poured over ice. The resulting mixture was made basic (NH4OH) and extracted well with dichloromethane. The organic extracts were combined, dried (Na2SO4) and concentrated in vacuo to give the crude title compound as a brown oil. Purification by flash chromatography (3% methanol in dichloromethane+tr. NH4OH) gave the desired product as a light orange oil (110 mg, 30%). The maleate salt was formed. Recrystallization (ethanol/diethyl ether) gave a colorless solid (70 mg, m.p.=113°-114° C.).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([NH:12][CH:13]([CH3:15])[CH3:14])[N:3]=1.[CH:16]([NH2:20])([CH2:18][CH3:19])[CH3:17]>C(N(CC)CC)C>[CH3:1][C:2]1[N:3]=[C:4]([NH:12][CH:13]([CH3:15])[CH3:14])[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH:20][CH:16]([CH2:18][CH3:19])[CH3:17])[N:7]=1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(NC(C)C)n1
Reactant: CCC(C)N
Solvent: CCN(CC)CC
Product: CCC(C)Nc1nc(C)nc(NC(C)C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.2 %

Procedure:
10 ml of triethylamine are added to 8.05 g (0.035 mol) of 2-methyl-4-chloro-5-nitro-6-isopropylamino-pyrimidine. While cooling with ice, 7.3 g (0.1 mol) of sec- butylamine are slowly added dropwise and the mixture is stirred for 16 hours at room temperature. The reaction solution is evaporated, the residue suspended in 500 ml of water and extracted 3 times with ether, to yield 9.0 g of 2-methyl-4-isopropylamino-6-sec.butylamino-5-nitro-pyrimidine (36.5 %) as an oil.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][C@H:11]3[CH2:20][N:14]4[CH2:15][C:16](=[O:19])[NH:17][CH2:18][C@@H:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.O1CCCC1.[H-].[Na+].Br[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=1>CN(C)C=O>[CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][C@H:11]3[CH2:20][N:14]4[CH2:15][C:16](=[O:19])[N:17]([CH2:29][C:30]5[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:37])([F:38])[F:39])[CH:31]=5)[CH2:18][C@@H:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: O=C1CN2C[C@H](Oc3cnc(C4CC4)cn3)C[C@H]2CN1
Reactant: FC(F)(F)c1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C1CN2C[C@H](Oc3cnc(C4CC4)cn3)C[C@H]2CN1Cc1cccc(C(F)(F)F)c1
Reaction time: 0.5 h

Procedure:
To a solution of the product from Example 201C (64 mg, 0.233 mmol) in 4:1 tetrahydrofuran:N,N-dimethylformamide (2 mL) was added sodium hydride (11.2 mg, 0.280 mmol). The resulting mixture was stirred at ambient temperate for 30 minutes, and 1-(bromomethyl)-3-(trifluoromethyl)benzene (42.8 μL, 0.280 mmol) was added. The mixture was stirred at ambient temperature for 1 hour and was then partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by chromatography on a 12 g silica gel column eluting with 5% ethyl acetate/hexanes for 3 minutes then a gradient to 100% ethyl acetate over 20 minutes. The title compound was obtained as a thick oil (13 mg, 13%). 1H NMR (300 MHz, methanol-d4) δ ppm 7.99 (dt, J=11.3, 5.7 Hz, 2H), 7.65-7.49 (m, 4H), 5.42 (dd, J=12.6, 5.1 Hz, 1H), 4.70 (d, J=3.7 Hz, 2H), 3.81-3.61 (m, 2H), 3.50-3.35 (m, 1H), 3.16 (dd, J=13.4, 8.3 Hz, 2H), 2.87 (qd, J=10.1, 4.9 Hz, 1H), 2.39 (dd, J=10.4, 5.0 Hz, 1H), 2.20-1.85 (m, 3H), 1.02-0.82 (m, 4H); MS (ESI) m/z 275 (M+H)+.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].C(N(CC)CC)C.[CH3:14][C:15]([C:18]1[CH:23]=[C:22]([SH:24])[CH:21]=[C:20]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]=1[OH:29])([CH3:17])[CH3:16]>C(#N)C>[CH3:28][C:25]([C:20]1[CH:21]=[C:22]([S:24][CH2:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])[CH:23]=[C:18]([C:15]([CH3:17])([CH3:16])[CH3:14])[C:19]=1[OH:29])([CH3:26])[CH3:27]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: C=CC(=O)OC
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)CCSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reaction time: 1.5 h

Procedure:
Methyl acrylate (1.1 g, 12.6 mmol) and triethylamine (0.5 mL, 0.4 mmol) are sequentially added to a room temperature solution of 2,6-bis(1,1-dimethylethyl)-4-mercaptophenol (3.0 g, 12.6 mmol) in acetonitrile (6 mL). The reaction is stirred for 1.5 hours and then evaporated under high vacuum to give 3.7 g (90%) of the crude product. A small portion is chromatographed on a silica column with ethyl acetate/hexane (1/9) to afford an analytically pure sample of methyl 3-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]propanoate, mp 64.0°-66.0° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:16][CH2:17][S:18][CH3:19])[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH:27](O)[CH3:28])[CH2:22][CH2:21]1.C(Cl)CCl>CN(C1C=CN=CC=1)C.ClCCl>[CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:16][CH2:17][S:18][CH3:19])[C:13]([O:15][CH:27]([CH2:26][N:23]1[CH2:24][CH2:25][O:20][CH2:21][CH2:22]1)[CH3:28])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(O)CN1CCOCC1
Reactant: CSCCC(NC(=O)OCc1ccccc1)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CSCCC(NC(=O)OCc1ccccc1)C(=O)OC(C)CN1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
A mixture of 2-(benzyloxycarbonylamino)-4-methylsulfanylbutyric acid (1.13 g; 2.76 mmol), 1-(morpholino)propan-2-ol (0.57 ml; 4 mmol), EDC (0.768 g; 4 mmol), DMAP (0.488 g; 4 mmol) in dichloromethane (5 ml) was stirred overnight at ambient temperature. After evaporation of the solvent, the residue was purified by flash chromatography eluting with dichloromethane/ethanol (97/3) to give 1-(morpholinoprop-2-yl 2-(benzyloxycarbonylamino)-4-methylsulfanylbutyrate as a foam. Yield=55%.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[OH:8][CH2:9][CH:10]1[CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[OH:8][CH2:9][CH:10]1[CH2:13][NH:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CC(CO)C1
Solvent: O=C(O)C(F)(F)F
Product: OCC1CNC1
Reaction time: 0.5 h

Procedure:
Trifluoroacetic acid (0.413 ml) was added to tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate (125 mg) with cooling in an ice bath, followed by stirring at the same temperature for 30 minutes. Then the reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated to give a crude product of the title compound (209.8 mg) as a yellow oil.
Reaction SMILES: [H-].[Na+].[S:3]1[CH:7]=[CH:6][C:5]2[C:8]([N:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]4[CH:32]=[C:31]5[C:26]([CH:27]=[CH:28][C:29](=[O:33])[NH:30]5)=[CH:25][CH:24]=4)[CH2:14][CH2:13]3)=[CH:9][CH:10]=[CH:11][C:4]1=2.[C:34](=[O:45])([O:38][CH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1)[O:35][CH2:36][Cl:37].Cl>O1CCCC1>[ClH:37].[CH:39]1([O:38][C:34](=[O:45])[O:35][CH2:36][N:30]2[C:31]3[C:26](=[CH:25][CH:24]=[C:23]([O:22][CH2:21][CH2:20][CH2:19][CH2:18][N:15]4[CH2:14][CH2:13][N:12]([C:8]5[C:5]6[CH:6]=[CH:7][S:3][C:4]=6[CH:11]=[CH:10][CH:9]=5)[CH2:17][CH2:16]4)[CH:32]=3)[CH:27]=[CH:28][C:29]2=[O:33])[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: O=c1ccc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc2[nH]1
Reactant: O=C(OCCl)OC1CCCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(OCn1c(=O)ccc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc21)OC1CCCCC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
Sodium hydride (55% oil) (0.962 g, 22.04 mmol) was suspended in tetrahydrofuran (THF) (200 ml), 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one (8.31 g, 19.17 mmol) was added and the mixture was stirred at 50° C. for 1 hr. The mixture was cooled to 0° C., chloromethyl cyclohexyl carbonate (4.80 g, 24.92 mmol) was added dropwise and the mixture was stirred at room temperature overnight. After cooling to 0° C., excess 2N hydrochloric acid was added to quench the reaction. The precipitated solid was collected by filtration and dried. In addition, the filtrate was extracted with ethyl acetate. The organic layer was concentrated and purified by moderate-pressure silica gel column chromatography (methylene chloride:methanol=100:0 to 20:1). Likewise, the solid was purified by moderate-pressure silica gel column chromatography. Concentration under reduced pressure gave the title compound (yield, 5.04 g, 42%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[N:5]=[CH:4][N:3]=1.[Br:21][C:22]1[CH:23]=[C:24]([N:28]=[C:29]=[O:30])[CH:25]=[CH:26][CH:27]=1>ClCCl>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:10]2[CH:9]=[CH:8][CH:7]=[C:6]3[C:11]=2[C:2]([NH:1][C:29]([NH:28][C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([Br:21])[CH:23]=2)=[O:30])=[N:3][CH:4]=[N:5]3)=[CH:14][CH:15]=1
Reactant: O=C=Nc1cccc(Br)c1
Reactant: COc1ccc(Oc2cccc3ncnc(N)c23)cc1
Solvent: ClCCl
Product: COc1ccc(Oc2cccc3ncnc(NC(=O)Nc4cccc(Br)c4)c23)cc1
Yield: 82.7 %

Procedure:
4-Amino-5-(4-methoxyphenoxy)quinazoline (0.35 g, 1.3 mmol) and 3-bromophenyl isocyanate (0.31 g, 1.6 mmol) were reacted in 20 ml of dichloromethane according to procedure E to give 1-[5-(4-methoxyphenoxy)quinazolin-4-yl]-3-(3-bromophenyl)urea (0.5 g, 83.3%, m.p. 249-251° C.).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[N:11][CH:12]=1.CN([CH:18]=[O:19])C>C1COCC1>[CH3:14][O:13][C:10]1[N:11]=[CH:12][C:7]([CH:18]=[O:19])=[CH:8][CH:9]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(Br)cn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C=O)cn1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A solution of n-butyllithium (3.46 mL of a 1.6 M solution in hexanes) in THF (18 mL) was cooled to −78° C. and treated with a solution of 5-bromo-2-methoxypyridine (Johnson, C. R.; Sirisoma, N. S. Tetrahedron Lett. 1998, 39, 2059) 18-1 (1.04 g, 5.53 mmol) in THF (2 mL). The heterogeneous mixture was stirred for 40 min and neat DMF (1.5 mL) was added. The solution was stirred for 90 min at −78° C. and quenched with satd aq NH4Cl solution (2 mL). The cold bath was removed and the mixture warmed to room temperature. The mixture was extracted with EtOAc (2×30 mL) and the combined organic solutions washed with brine, dried over MgSO4, filtered, and concentrated to the desired aldehyde 18-2.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.FC(F)(F)S(O[CH2:43][CH:44]([F:46])[F:45])(=O)=O>C1COCC1>[CH2:1]([O:8][C:9]([N:11]([CH2:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[CH:23]([CH2:43][CH:44]([F:46])[F:45])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:12])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])cc1CN(C)C(=O)OCc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CC(F)F)c1ccc([N+](=O)[O-])cc1CN(C)C(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 17.4 %

Procedure:
To a solution of 10B (345 mg, 0.893 mmol) in THF (5 mL) at −78° C., was added LDA (2 M, heptane, THF and ethylbenzene) (0.536 mL, 1.071 mmol). The red/black mixture was stirred at −78° C. for 20 min, then a solution of 2,2-difluoroethyl trifluoromethanesulfonate (210 mg, 0.982 mmol) in THF (0.5 mL) was added dropwise. The reaction was removed from the cooling bath and was stirred at rt for 4 h. The reaction mixture was quenched with sat. NH4Cl, diluted with EtOAc. The organic phase was washed with H2O and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (loaded in chloroform onto a 12 g column and eluted with a gradient from 0 to 50% ethyl acetate/hexanes) to give 10C (70 mg, 0.155 mmol, 17.41% yield) pale yellow oil. MS (ESI) m/z: 450.9 (M+H)+. 1H NMR (400 MHz, chloroform-d) δ ppm 8.15 (d, J=7.91 Hz, 1H) 7.97-8.11 (m, 1H) 7.50 (d, J=7.47 Hz, 1H) 7.24-7.43 (m, 5H) 5.10-5.29 (m, 2H) 4.57-4.87 (m, 2H) 4.00-4.39 (m, 3H) 2.91 (br. s., 3H) 2.57-2.87 (m, 1H) 2.19 (s, 1H) 1.05-1.33 (m, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([P:19]([CH3:22])([CH3:21])=[O:20])=[CH:15][CH:14]=2)[N:3]=1.C(N(CC)CC)C.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>C(O)C>[CH3:21][P:19]([C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:4]2[N:3]=[C:2]([N:34]3[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]3)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[CH:14][CH:15]=1)([CH3:22])=[O:20]
Reactant: CP(C)(=O)c1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Reactant: CN1CCNCC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN1CCN(c2nc(Nc3ccc(P(C)(C)=O)cc3)ncc2C(F)(F)F)CC1
Yield: 79 %

Procedure:
To a solution of 4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimidin-2-amine (25 mg, 0.072 mmol) in 1.5 mL of ethanol was added 10 L of triethylamine and 1-Methyl piperazine (7.2 mg, 0.072 mmol). The mixture was microwave at 120 degrees for 20 minutes. The reaction mixture was filtered through a syringe filter and purified by prep-HPLC (Waters Sunfire C18 column with ACN/water mobile phases) to yield a white solid as product (24 mg, 79% yield.) MS/ES+: m/z=414.