Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[NH:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(=O)(O)[O-].[Na+].Br[CH2:26][C:27](=[O:32])[C:28]([F:31])([F:30])[F:29]>C(O)(C)C>[OH:32][C:27]1([C:28]([F:31])([F:30])[F:29])[CH2:26][N:11]([C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=2)[C:12]([C:14]2[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=2)=[N:13]1
Reactant: O=C(CBr)C(F)(F)F
Reactant: CS(=O)(=O)c1ccc(NC(=N)c2ccncc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CS(=O)(=O)c1ccc(N2CC(O)(C(F)(F)F)N=C2c2ccncc2)cc1
Yield: 25.1 %

Procedure:
To a mixture of the amidine of step 1 (4.75 g, 16 mmol) and sodium bicarbonate (2.86 g, 34.4 mmol) in isopropanol (400 ml), 3-bromo-1,1,1-trifluoroacetone (2.7 ml, 26 mmol) was added. After heating at 75°-80° C. for 24 hours, the reaction mixture was cooled and filtered. The residue was washed with methylene chloride and the combined organic fractions were dried over sodium sulfate, filtered and concentrated. The crude product (16.2 g) was chromatographed (silica gel, ethyl acetate/isopropanol (95/5)) to give 4-[4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazol-2-yl]pyridine (1.55 g, 23%) as a white solid: mp 219° C., Anal. Calc'd. for C16H14N3SO3F3C, 49.87, H, 3.66, N, 10.90, S, 8.32. Found C, 49.93, H, 3.51, N, 10.79, S, 8.66.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([O:23][C:24]5([C:27](O)=[O:28])[CH2:26][CH2:25]5)[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][C:6]([CH3:30])=[N:5]1)([CH3:3])[CH3:2].[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.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>CN(C=O)C>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([O:23][C:24]5([C:27]([N:35]6[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]6)=[O:28])[CH2:25][CH2:26]5)[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][C:6]([CH3:30])=[N:5]1)([CH3:3])[CH3:2]
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(OC4(C(=O)O)CC4)cc2OCC3)n(C(C)C)n1
Reactant: CN1CCNCC1
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: Cc1nc(-c2cn3c(n2)-c2ccc(OC4(C(=O)N5CCN(C)CC5)CC4)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]cyclopropanecarboxylic acid (90 mg, 0.22 mmol), 1-methylpiperazine (29 uL, 0.26 mmol), HATU (108 mg, 0.29 mmol) and DIPEA (52 uL, 0.31 mmol) in DMF (3 mL) was stirred at RT for 2 h. Volatiles were removed under reduced pressure and the resulting residue was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with water, followed by brine, then dried (MgSO4) and concentrated in vacuo affording {1-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]cyclopropyl}-(4-methylpiperazin-1-yl)methanone (quantitative). LCMS: RT 2.08 min [M+H]+ 492.2
Reaction SMILES: [NH2:1][C:2]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.C(O)(C(F)(F)F)=O.[C:16]1(=O)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.S([O-])([O-])(=O)=O.[Na+].[Na+]>C(Cl)Cl>[CH2:6]1[C:2]2([NH:1][C:16]3([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[O:8][CH2:7]2)[CH2:3][CH2:4][CH2:5]1
Reactant: O=C1CCCCC1
Reactant: NC1(CO)CCCC1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C1CCC2(CC1)NC1(CCCC1)CO2
Temperature: 20 °C
Reaction time: 72 h
Yield: 97.2 %

Procedure:
To a solution of 1-amino-1-(hydroxymethyl)cyclopentane (Method B1c; 1.44 g, 12.54 mmol) in CH2Cl2 (10 mL) at 4° C. was added TFA (0.097 mL, 1.25 mmol), cyclohexanone (1.30 mL, 12.54 mmol) and sodium sulfate (2 g) and the reaction was warmed to 20° C. The reaction was stirred for 72 h and was sequentially washed with water (10 mL) and a saturated NaHCO3 solution (20 mL), dried (MgSO4), and concentrated under reduced pressure to give 14-aza-7-oxadispiro[4.2.5.1]tetradecane (2.38 g, 97%): GC-MS m/z 195 (M+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@H:13]([O:16][C:17]2[C:22]([CH2:23]C=C)=[CH:21][CH:20]=[CH:19][C:18]=2[C:26]2[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:33])[CH:14]=[CH2:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H][H]>ClCCl.C(OCC)(=O)C.C(O)C.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1C=CC(C=[Ru](Cl)Cl)=CC=1.[Pt](=O)=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@H:13]2[CH2:14][CH2:15][CH2:23][C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([C:26]4[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=4[Cl:33])[C:17]=3[O:16]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: C=CCc1cccc(-c2c(Cl)cccc2Cl)c1O[C@H](C=C)COS(=O)(=O)c1ccc(C)cc1
Reactant: [H][H]
Agent: Cl[Ru](Cl)=Cc1ccccc1
Agent: O=[Pt]=O
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CCCc3cccc(-c4c(Cl)cccc4Cl)c3O2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.4 %

Procedure:
To a solution of (2R)-2-[(3-allyl-2′,6′-dichlorobiphenyl-2-yl)oxy]but-3-en-1-yl 4-methylbenzenesulfonate (702 mg, 1.394 mmol) in anhydrous dichloromethane (35 mL) at room temperature under nitrogen was added benzylidene-bis(tricyclohexylphosphine)dichlororuthenium (114 mg, 0.1394 mmol) and the reaction mixture stirred at room temperature for 5 hours. The reaction mixture was then concentrated under reduced pressure to afford a brown syrup. The crude product was dissolved in ethyl acetate (7 mL) and the solution added to a suspension of platinum (IV) oxide (32 mg, 0.139 mmol) in absolute ethanol (21 mL). The mixture was then hydrogenated at 12 psi of hydrogen for 1 hour. The reaction mixture was filtered through celite and the filtrate concentrated under reduced pressure to afford a brown syrup. Purification by flash chromatography using a solvent gradient of 3 to 10% ethyl acetate in hexane afforded 0.615 g (92%) of [(2R)-9-(2,6-dichlorophenyl)-2,3,4,5-tetrahydro-1-benzoxepin-2-yl]methyl 4-methylbenzenesulfonate as a yellow solid. MS (ESI) m/z 477 ([M+H]+).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][C:5](C(OC)=O)([C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH:3]1C(OC)=O.[Cl-].[Na+].O>CN(C=O)C>[O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH2:3]1
Reactant: COC(=O)C1CC(C(=O)OC)(C(=O)OC)CCC1=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1CCC(=O)CC1

Procedure:
A 55 g (0.2 mole) portion of trimethyl 4-oxocyclohexane-1,1,3-tricarboxylate is dissolved in 240 ml DMF and to this is added 26 g (0.445 mole) of sodium chloride and 16 ml (0.89 mole) of water, under nitrogen. This mixture is heated to reflux and maintained for 48 hours, under nitrogen. The reaction is then stripped to dryness under reduced pressure, the residue added to water and the crude product extracted into dichloromethane (3×100 ml). The combined extracts are dried over MgSO4 and stopped to dryness, giving a yellow oil. This crude product is vacuum-distilled to obtain methyl 4-oxocyclohexane-1-carboxylate (b.p. 82°-108° C. at 1.0 mm Hg) which is used directly in the next step.
Reaction SMILES: [CH:1]1([C:4]2[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.Br[C:13]1C=CC(C2CCCC2)=C[CH:14]=1.BrC1C=CC(C2CCCC=2)=CC=1.[Li]CCCC.CCCCCC.CN(C=O)C>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([CH:8]=[O:9])=[CH:10][CH:11]=2)[CH2:3][CH2:2][CH2:14][CH2:13]1
Reactant: Brc1ccc(C2CCCC2)cc1
Reactant: O=Cc1ccc(C2CC2)cc1
Agent: Brc1ccc(C2=CCCC2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: O=Cc1ccc(C2CCCC2)cc1

Procedure:
The title compound was synthesized in analogy to 4-cyclopropyl benzaldehyde (described in example S53) using 720 mg of a mixture of 1-bromo-4-cyclopentyl-benzene and 1-bromo-4-cyclopent-1-enyl-benzene (˜3.2 mmol), 2.2 ml of a 1.6 molar solution of n-BuLi in hexane (3.52 mmol) and 492 μl of DMF (6.40 mmol). 4-Cyclopentyl-benzaldehyde was isolated by flash column chromatography (5:95 EtOAc/c-hexane) as a yellow liquid (165 mg, 30%). 1H NMR (CDCl3, 300 MHz): δ 1.53-1.91 (m, 6H), 2.11 (m, 2H), 3.07 (quint, J=8.5 Hz, 1H), 7.40 (d, J=8 Hz, 2H), 7.80 (d, J=8 Hz, 2H), 9.97 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:9]1[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.O.C(Cl)CCl.Cl.[CH3:33][NH:34][CH3:35]>C1COCC1>[CH3:33][N:34]([CH3:35])[C:10]([C@@H:9]1[CH2:13][C@@H:14]([OH:16])[CH2:15][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[O:11]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reactant: CNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCCl
Product: CN(C)C(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reaction time: 0.25 h

Procedure:
To a solution of 25.1 g of (4R)-1-(tert-butoxy carbonyl)-4-hydroxy-L-proline in THF (250 ml) was added 24.9 g of HOBt/H2O and 24.9 g of EDC/HCl under ice cooling, and the reaction mixture was stirred for 15 minutes. To the reaction mixture was added dropwise 10.7 g of an aqueous solution of 50% dimethylamine over 10 minutes, then, the reaction mixture was stirred at room temperature for 15 hours. The solvent was evaporated under reduced pressure, then, an aqueous solution of saturated NaHCO3 was added to the solution, and the resulting mixture was extracted with CHCl3. After drying with Na2SO4, the drying agent was separated by filtration, and the solution was concentrated under reduced pressure. The residue was purified by column chromatography (silicagel 60N; mobile phase: CHCl3/MeOH=20/1 to 9/1; v/v) to obtain 26.2 g of the title compound (colorless solid).
Reaction SMILES: N[CH:2]1[C:25](=[O:26])[N:4]2[C:5]([C:22]([OH:24])=[O:23])=[C:6](CSC3N(CCCCCC)N=NN=3)[CH2:7][S:8][C@H:3]12.C[Si](CC(N)=O)(C)C.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl.O>[S:8]1[C@@H:3]2[CH2:2][C:25](=[O:26])[N:4]2[C:5]([C:22]([OH:24])=[O:23])=[CH:6][CH2:7]1
Reactant: CCCCCCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: C[Si](C)(C)CC(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)C1=CCS[C@@H]2CC(=O)N12
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
On the other hand, a mixture of 7-amino-3-[(1-hexyl-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (5.89 g) and trimethylsilyl acetamide (16 g) in methylene chloride (150 ml) was warmed to make a clear solution. The solution was cooled to -15° C. and added all at once to the activated acid solution prepared above. The reaction mixture was stirred for 30 minutes at -15° to 0° C. and for additional 30 minutes at ambient temperature. The solvent was removed by distillation from the reaction mixture under reduced pressure to give a residue, to which ethyl acetate (150 ml) and water (100 ml) were added, and then the mixed solution was adjusted to pH 3 with an aqueous solution of sodium bicarbonate. The organic layer was separated out, washed two times with an aqueous solution of sodium chloride and dried over magnesium sulfate, and then evaporated to dryness to give a brownish oil. This oil was washed three times with diethyl ether (70 ml) and triturated with diisopropyl ether to give a powder of 7-[2-(6-formamidopyridin-2-yl)-2-hydroxyiminoacetamido]-3-(1-hexyl-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (syn isomer), mp 74°-84° C. (dec.).
Reaction SMILES: [CH3:1][NH2:2].CO.CO.Cl[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1>C(N(CC)CC)C>[CH3:1][NH:2][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: CN
Reactant: ClCc1cccc2ccccc12
Solvent: CO
Solvent: CCN(CC)CC
Product: CNCc1cccc2ccccc12
Temperature: 0 °C
Yield: 91.9 %

Procedure:
1.14 g (11.3 mmol), of triethylamine was mixed with a 40% methylamine-methanol solution and 5 ml of the methanol containing 2.00 g (11.3 mmol), of 1-chloromethylnaphthalene was dropped while stirring in an ice bath. After dropping, the reaction mixture was taken out of the ice bath and stirred at room temperature for 60 hours. The solvent was distilled off under reduced pressure and extracted with ether-2N hydrochloric acid. The organic extract was washed with saturated saline and dried with sodium sulfate. Then, the solvent was distilled off under reduced pressure to obtain 1.78 g (yield: 91.9%), of the target compound as a pale yellow oil.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10]1)(=[O:8])[C:2]1C=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:20]1C=CC=C1CC(Cl)=O>>[S:20]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:2][C:1]([N:9]1[CH2:14][CH2:13][CH2:12][C@H:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10]1)=[O:8]
Reactant: CCOC(=O)C1CCCN(C(=O)c2ccccc2)C1
Reactant: O=C(Cl)Cc1cccs1
Product: CCOC(=O)[C@H]1CCCN(C(=O)Cc2cccs2)C1

Procedure:
The reaction was run in the same manner as ethyl 1-benzoyl-3-piperidinecarboxylate, starting with commercially available S-ethyl nipecotate (1.0 g; 6.37 mmol; Chemi SpA; Italy) and 2-thiopheneacetyl chloride (785 μl; 6.37 mmol). The crude product was distilled as 225° C./0.1 torr, giving (S)-ethyl 1-(2-thiopheneacetyl)-3-piperidinecarboxylate (1.23 g) as a light yellow oil. MS m/z (positive ion), 585 (dimer+Na+; 10), 304 (M+Na+; 50), 282 (MH+; 100), 158 (50). OR (MeOH; 589) +62.96°. Product was shown to be >98% ee by chiral capillary electrophoresis using a 20% solution of ·-HSCD (highly sulfated cyclodextrin) at a voltage of 20 kV.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15](Cl)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2].CS(C)=O.[C:21]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1)#[N:22]>O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:28][CH2:27][C:26]4[CH:29]=[CH:30][C:23]([C:21]#[N:22])=[CH:24][CH:25]=4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2]
Reactant: CCn1ncc2c(Cl)c3ccccc3nc21
Reactant: N#Cc1ccc(CN)cc1
Solvent: CS(C)=O
Solvent: O
Product: CCn1ncc2c(NCc3ccc(C#N)cc3)c3ccccc3nc21
Reaction time: 8 h
Yield: 19.9 %

Procedure:
A mixture of 1-ethyl-4-chloro-1H-pyrazolo[3,4-b]quinoline (1.0 g, 4.3 mmol), DMSO (3 ml) and 4-cyanobenzylamine (1.2 g, 9 mmol) is heated on a steam bath for 3 hours, then is allowed to sit at room temperature overnight. The reaction mixture is poured into water and an oil separated. The oil is extracted with hot 10% ethanol/ethyl acetate, washed with water, and the organic layer is dried and evaporated. The residue is crystallized from ether/ethyl acetate and then is purified by recrystallization from ethyl acetate/hexane, followed by column chromatography on silca gel eluting with ethyl acetate and finally crystallization of the residue thus obtained from ethyl acetate/hexane to afford 280 mg of 1-ethyl-N-(4-cyanophenylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine, as yellow crystals, m.p. 233°-234° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.[Al+3].[Cl-].[Cl-].[Cl-].[Br:22][CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([C:7]([C:29]2[CH:30]=[CH:31][C:26]([CH2:25][CH2:24][CH2:23][Br:22])=[CH:27][CH:28]=2)=[O:9])[CH:10]=1
Reactant: BrCCCc1ccccc1
Reactant: O=C(O)c1cc(Br)ccc1Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(c1ccc(CCCBr)cc1)c1cc(Br)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of 5-bromo-2-chlorobenzoic acid (2.31 g, 9.80 mmol) and oxalyl chloride (1.41 g, 11.11 mmol) in CH2Cl2 (30 mL) was added 0.05 mL of DMF. Once the vigorous evolution of gas ceased, the reaction was stirred overnight and then the volatiles were removed under reduced pressure. The resulting crude 5-bromo-2-chlorobenzoyl chloride was dissolved in dichloromethane (30 mL), and the solution was cooled to 0˜5° C. Then AlCl3 (1.31 g, 9.8 mmol) was added in portions, the mixture was stirred for 30 min, and (3-bromopropyl)benzene (1.50 g, 6.53 mmol) in dichloromethane (4 mL) was added. The reaction solution was warmed to room temperature and stirred for 4 h. The reaction was quenched by pouring into ice water. The suspension was diluted with water and extracted 3× with CH2Cl2. The combined organic extracts were washed 2× with 1N HCl, 1× with water, 2× with 1M NaOH, and 2× with brine, and then dried over Na2SO4. After removal of the volatiles, the crude product was purified by column chromatography (eluent EA:PE=1:20) to obtain intermediate DD (2.4 g) as a light yellow oil. 1H-NMR (CDCl3, 400 MHz): δ 7.68˜7.66 (d, 2H), 7.50˜7.47 (dd, 1H), 7.42 (d, 1H), 7.28˜7.19 (m, 3H), 3.33 (t, J=6.8 Hz, 2H), 2.80 (t, J=7.6 Hz, 2H), 2.17˜2.10 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].C([O-])([O-])=O.[K+].[K+].C1(C)C=CC=CC=1.[CH2:31]([O:37][C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1)[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>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.O>[CH2:31]([O:37][C:38]1[CH:39]=[CH:40][C:41]([C:2]2[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:10]=[CH:9][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:42][CH:43]=1)[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCOC(=O)c1ccc(C(=O)OCC)c(Br)c1
Reactant: CCCCCCOc1ccc(B(O)O)cc1
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: O
Solvent: Cc1ccccc1
Product: CCCCCCOc1ccc(-c2cc(C(=O)OCC)ccc2C(=O)OCC)cc1
Temperature: 85 °C
Reaction time: 7 h

Procedure:
Diethyl bromoterephthalate (30.1 g, 100 mmol), K2CO3 (27.6 g, 200 mmol) and 140 ml of toluene and 140 ml of H2O were placed in a reaction vessel and argon was passed in for 30 minutes. 4-hexyloxyphenylboronic acid (26.7 g, 120 mmol) (cf. B1) and Pd(PPh3)4 (1.16 g, 1 mmol) were subsequently added under protective gas. The yellow-green, turbid mixture was stirred vigorously under a blanket of protective gas at an internal temperature of 85° C. After 7 hours, the reaction wag complete. After phase separation, the organic phase was shaken with dilute HCl/H2O (until neutral). The aqueous phase was shaken with toluene and the organic phases were combined. After filtering off any palladium residues, the solution was evaporated. The product was obtained as a yellowish brown oil in sufficient purity (about 86%): 44.7 g (1112%).
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)[CH2:4][C:5]([O:7][CH3:8])=[O:6].C(N(CC)CC)C.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31](Cl)=[O:32].O>O1CCCC1>[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31]([NH:2][CH:3]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)[CH2:4][C:5]([O:7][CH3:8])=[O:6])=[O:32]
Reactant: COC(=O)CC(N)c1ccc(OC)c(OC)c1
Reactant: COc1cccc(C(=O)Cl)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)CC(NC(=O)c1cccc(OC)c1)c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To an ice bath stirred suspension of methyl 3-amino-3-(3',4'-dimethoxyphenyl)propionate hydrochloride (0.689 grams, 2.50 mmol) and 0.7 milliliters of triethylamine in 20 milliliters of anhydrous tetrahydrofuran was added 3-methoxybenzoyl chloride (2.5 mmol) via syringe. After 30 minutes, the reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was then treated with 20 milliliters of water. The tetrahydrofuran was removed in vacuo and the resulting mixture extracted with methylene chloride (2 times with 25 milliliters). The combined extracts were dried over sodium sulfate and contracted to afford a thick oil. The crude product was purified by flash chromatography (silica gel, 1.4/8.6 ethyl acetate/hexanes) to afford 0.5 grams (56%) as a pale green solid (wax): mp 123.5°-125° C.; 1H NMR (CDCl3 /TMS) δ 8.96 (d, J=7.9, 1 H), 8.19 (m, 1 H), 7.45 (m, 1 H), 7.12-6.68 (m, 5 H), 5.59 (m, 1 H), 4.00 (s, 3 H, OCH3), 3.87 (s, 3 H, OCH3), 3.85 (s, 3 H, OCH3), 3.63 (s, 3 H, OCH3), 2.96 (m, 2 H, CH2); 13C NMR (CDCl3 /TMS) δ 171.6, 164.4, 157.6, 148.9, 148.2, 133.8, 132.8, 132.3, 121.3, 121.2, 118.1, 111.3, 111.2, 109.9. 55.8, 55.8, 51.6, 49.7, 40.4; TLC (2/8 ehtyl acetate/hexanes, UV) Rf =0.26. Anal. Calcd for C20 H23NO6. Theory C, 64.33; H, 6.21; N, 3.75. Found C, 64.31; H, 6.25; N, 3.63.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][NH:3][C:2]1=[O:6].[C:7](Cl)(=[O:11])[CH2:8][CH2:9][CH3:10].[Cl-].[Al+3].[Cl-].[Cl-].O>ClCCl>[O:11]=[C:7]([C:5]1[NH:1][C:2](=[O:6])[NH:3][CH:4]=1)[CH2:8][CH2:9][CH3:10]
Reactant: CCCC(=O)Cl
Reactant: O=c1[nH]cc[nH]1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CCCC(=O)c1c[nH]c(=O)[nH]1
Reaction time: 2 h

Procedure:
In 10 ml of dichloromethane is placed 1.0 g of 1,3-dihydro-2H-imidazol-2-one, 1.28 g of butyryl chloride and 4.8 g of aluminum chloride. The mixture is refluxed and stirred for 2 hours after which it is poured into water. The precipitate is collected, washed with water, and recrystallized from ethanol:water, to give the title compound, m.p. 268°-270° C.
Reaction SMILES: [CH3:1]SCCC(Cl)=O.[CH3:8][S:9][CH2:10][CH2:11][C:12]([N:14]=[C:15]=[S:16])=[O:13].[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][C:28]=1[O:29][CH3:30])[N:25]=[CH:24]N=[C:22]2[O:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[C:34]([F:39])[CH:33]=1.C1(C)C=CC=CC=1>C(O)C>[CH3:8][S:9][CH2:10][CH2:11][C:12]([N:14]=[C:15]=[S:16])=[O:13].[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][C:28]=1[O:29][CH3:30])[N:25]=[CH:24][CH:1]=[C:22]2[O:31][C:32]1[CH:38]=[CH:37][C:35]([NH:36][C:15]([NH:14][C:12](=[O:13])[CH2:11][CH2:10][S:9][CH3:8])=[S:16])=[C:34]([F:39])[CH:33]=1
Reactant: CSCCC(=O)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)c(F)c3)c2cc1OC
Agent: CSCCC(=O)N=C=S
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)CCSC)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
3-(Methylsulfanyl)propanoyl isothiocyanate was prepared using commercially available 3-(methylsulfanyl)propanoyl chloride (80 mg) as a starting compound according to the description of the literature. 3-(Methylsulfanyl)propanoyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-fluoroaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (43 mg, yield 57%).