Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@H:5]([CH:7]([CH3:9])[CH3:8])[NH2:6].C(N(CC)CC)C.[O:18]1[CH2:22][CH2:21][CH2:20][CH:19]1[C:23](Cl)=[O:24]>O1CCCC1>[CH3:2][O:3][C:4](=[O:10])[C@H:5]([CH:7]([CH3:9])[CH3:8])[NH:6][C:23]([CH:19]1[CH2:20][CH2:21][CH2:22][O:18]1)=[O:24]
Reactant: O=C(Cl)C1CCCO1
Reactant: COC(=O)[C@@H](N)C(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)[C@@H](NC(=O)C1CCCO1)C(C)C

Procedure:
617 g (3.68 mol) of (S)-valine methyl ester hydrochloride were suspended in about 2.2 l of tetrahydrofuran and 745 g (7.38 mol) of triethylamine were added. 451 g (3.35 mol) of tetrahydrofuran-2-carbonyl chloride in 200 ml of THF were added dropwise with stirring, the reaction temperature rising to about 65° C. After completion of the addition, the mixture was stirred at room temperature for a further 12 hours. The precipitate was filtered off with suction and thoroughly washed with tetrahydrofuran, and the combined organic phases were evaporated. The residue was dissolved in ether to remove excess (S)-valine methyl ester, shaken with water and dried in the customary manner. Vacuum distillation yields N-(2-tetrahydrofuroyl)-(S)-valine methyl ester (formula V with X=S, n=1, R=CH(CH3)2 and R'=CH3) as a colorless liquid, b.p. 98°-103° C./0.01 torr, yield: 611 g (80%).
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][CH:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=2)[C:8]([CH3:13])([CH3:12])[CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.N1C=CN=C1.CN(C)C=O.[CH:34]([Si:37](Cl)([CH:41]([CH3:43])[CH3:42])[CH:38]([CH3:40])[CH3:39])([CH3:36])[CH3:35]>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([Br:21])=[CH:19][CH:20]=2)[C:8]([CH3:13])([CH3:12])[CH2:9][CH2:10][O:11][Si:37]([CH:41]([CH3:43])[CH3:42])([CH:38]([CH3:40])[CH3:39])[CH:34]([CH3:36])[CH3:35])=[CH:22][CH:23]=1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: CC(C)(CCO)C(Cc1ccc(Br)cc1)Cc1ccc(Br)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)[Si](OCCC(C)(C)C(Cc1ccc(Br)cc1)Cc1ccc(Br)cc1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
A mixture of 4-(4-bromobenzyl)-5-(4-bromophenyl)-3,3-dimethylpentan-1-ol (0.974 g, 2.34 mmol) and 1,3-diaza-2,4-cyclopentadiene (0.351 g, 5.15 mmol) in a reaction container was deaerated, and the air inside the reaction container was replaced with argon. N,N-dimethylformamide (12 mL) and triisopropylsilyl chloride (0.68 g, 3.51 mmol) were then added to the mixed liquid. The thus obtained mixed liquid was stirred overnight at room temperature, and a sufficient amount of water was added to halt the reaction. The organic layer was separated from the mixed liquid, and the water layer was extracted with diethyl ether. The thus obtained organic layer was washed with a saturated saline solution and then dried using anhydrous magnesium sulfate. The organic layer was then filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:diethyl ether=50:1), yielding the title compound (4j) (1.16 g, 1.94 mmol) as a light yellow liquid in a yield of 83%.
Reaction SMILES: [CH2:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11](O)=[O:12])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.CN(C=O)C>ClCCl>[CH2:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[CH:11]=[O:12])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccccc1CCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=Cc1ccccc1CCc1ccccc1
Temperature: -70 °C
Reaction time: 1.5 h
Yield: 74 %

Procedure:
A mixture of 2-phenethylbenzoic acid (11.3 g), oxalyl chloride (5.2 ml), DMF (0.2 ml) and dichloromethane (100 ml) was stirred for 1.5 hours. The solvent was evaporated, diglyme (75 ml) added and the mixture cooled to -70° C. Lithium tri-(tert-butoxy)aluminium hydride (100 ml, 0.5M solution in diglyme) was added dropwise over 45 minutes maintaining the reaction temperature below -60° C. The reaction was stirred at -70° C. for 1 hour and poured into a 2N HCl and ice mixture. The mixture was extracted with iso-hexane (3×100 ml). The extracts were washed with saturated aqueous sodium hydrogen carbonate, water and brine, dried (MgSO4), filtered and evaporated. The residue was purified by MPLC eluting with dichloromethane/ iso-hexane (1: 1) to give 2-(phenethyl)benzaldehyde (7.77 g).
Reaction SMILES: [OH:1][N:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[CH2:8]([Mg]Cl)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl-].[NH4+]>ClCCl.O=[Mn]=O>[CH2:8]([CH:3]1[CH2:4][O:5][CH2:6][CH2:7][N:2]1[OH:1])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: ON1CCOCC1
Reactant: Cl[Mg]Cc1ccccc1
Agent: O=[Mn]=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: ON1CCOCC1Cc1ccccc1
Reaction time: 1 h
Yield: 34.1 %

Procedure:
Activated MnO2 (1.29 g, 14.8 mmol) was added to a solution of N-hydroxymorpholine (0.50 g, 4.95 mmol) in dichloromethane (25 mL) at 0° C. and the mixture was stirred for 1 h. The reaction mixture was filtered through a pad of Celite™ and Na2SO4. The filtrate was added dropwise to a solution of benzylmagnesium chloride (2.0 M in tetrahydrofuran, 4.95 mL, 9.90 mmol) at −10° C. The reaction mixture was stirred at 0° C. for 0.5 h and then saturated aqueous ammonium chloride solution (25 mL) and dichloromethane (25 mL) were added. The aqueous phase was separated and extracted with dichloromethane (2×30 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The crude product was subjected to flash chromatography on SiO2 eluting with 25% diethyl ether in hexanes to give the title compound (0.326 g, 34%) as a white crystalline solid.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21]>CS(C)=O.C(OCC)(=O)C.CN(C)CCN(C)C>[CH3:21][O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: COCCOCCBr
Agent: CN(C)CCN(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COCCOCCOc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.9 %

Procedure:
Phenol (15.0 g, 0.159 mol), potassium carbonate (26.4 g, 0.191 mol, 1.2 eq) and tetramethylethylenediamine (0.92 g, 7.95 mmol, 0.05 eq) were dissolved in DMSO (100 mL) and stirred at r.t. for 30 minutes. Then 1-bromo-2-(2-methoxyethoxy)ethane (30.56 g, 0.166 mol, 1.04 eq) was added, the solution heated to 90° C. for 18 h and cooled to r.t. The reaction mixture was diluted with ethyl acetate (600 mL), washed with 1M potassium hydroxide (3×300 mL), dried (Na2SO4) and concentrated in vacuo to afford the title compound (16.50 g, 52%) as an orange oil. 1H NMR (500 MHz, (CD3)2CO) δ: 7.27 (dt, J=8.5 Hz, 1 Hz, 2H), 6.94 (dd, J=8 Hz, 1 Hz, 2H), 6.92 (dt, J=8 Hz, 1 Hz, 1H), 4.12 (t, J=5 Hz, 2H), 3.80 (t, J=5 Hz, 2H), 3.64 (t, J=5 Hz, 2H), 3.50 (t, J=5 Hz, 2H), 3.29 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[C:4]([F:10])[C:3]=1B1OC(C)(C)C(C)(C)O1.Br[C:21]1[N:26]=[C:25]([C:27]([O:29][CH3:30])=[O:28])[CH:24]=[CH:23][C:22]=1[F:31].CCN(C(C)C)C(C)C.O1CCOCC1>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.O>[F:10][C:4]1[CH:5]=[C:6]([S:8][CH3:9])[CH:7]=[C:2]([F:1])[C:3]=1[C:21]1[N:26]=[C:25]([C:27]([O:29][CH3:30])=[O:28])[CH:24]=[CH:23][C:22]=1[F:31]
Reactant: CSc1cc(F)c(B2OC(C)(C)C(C)(C)O2)c(F)c1
Reactant: COC(=O)c1ccc(F)c(Br)n1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc(F)c(-c2c(F)cc(SC)cc2F)n1
Temperature: 120 °C
Yield: 40.4 %

Procedure:
In a sealed tube, a mixture of 2-[2,6-difluoro-4-(methylthio)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.00 g, 3.49 mmol), methyl 6-bromo-5-fluoropyridine-2-carboxylate (1.23 g, 5.24 mmol) and DIPEA (1.83 mL, 10.5 mmol) in a mixed solvent of 1,4-dioxane (15 mL) and water (0.51 mL) was stirred and flushed with nitrogen bubbles for 5 min. before bis(tri-tert-butylphosphine)palladium (360 mg, 0.70 mmol) was added. The reaction mixture was heated at 120° C. for 30 min. After cooling, the reaction mixture was filtered, and the filter was washed with THF. The filtrate was concentrated and then purified by silica gel column chromatography using CombiFlash® (0 to 20% EtOAc in hexanes) to give the sub-title compound as powder (442 mg, 40%). LCMS calc. for C14H11F3NO2S (M+H)+: m/z=314.1. Found: 314.2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[S:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)=[O:9])=[CH:4][CH:3]=1.[Br:22]N1C(=O)CCC1=O.C(#N)N(C)C>C(Cl)(Cl)(Cl)Cl>[Br:22][CH2:21][C:18]1[CH:17]=[CH:16][C:15]([C:12]2[S:11][C:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=3)=[O:9])=[CH:14][CH:13]=2)=[CH:20][CH:19]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccc(C(=O)c3ccc(Br)cc3)s2)cc1
Solvent: CN(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(c1ccc(Br)cc1)c1ccc(-c2ccc(CBr)cc2)s1
Yield: 84.7 %

Procedure:
0.5 g of (4-bromophenyl)-(5-p-tolyl-thiophen-2-yl)-methanone and 262 mg of N-bromosuccinimide in 20 ml of carbon tetrachloride are held at reflux for 19 hrs. after the addition of a spatula tip of azaisobutyronitrile, concentrated and the residue is chromatographed on silica gel (methylene chloride/hexane). 517 mg of [5-(4-bromomethyl-phenyl)-thiophen-2-yl]-4-bromophenyl-methanone, m.p. 184° C. (decomposition), are isolated.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([C:17]([OH:19])=O)=[C:10]2[O:13][CH:14]([CH3:16])[CH3:15])=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.CN(C=O)C.[CH:31]([NH2:34])([CH3:33])[CH3:32]>C1COCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([C:17]([NH:34][CH:31]([CH3:33])[CH3:32])=[O:19])=[C:10]2[O:13][CH:14]([CH3:15])[CH3:16])=[CH:5][CH:4]=1
Reactant: CC(C)N
Reactant: COc1ccc2ccc(C(=O)O)c(OC(C)C)c2c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc2ccc(C(=O)NC(C)C)c(OC(C)C)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
To a room temperature solution of 7-methoxy-1-(1-methylethoxy)-2-naphthalenecarboxylic acid (200 0.77 mmol) in 5 mL of THF is added oxalyl chloride (0.08 mL, 0.92 mmol) followed by DMF (0.015 mL). The solution is stirred at room temperature for 2 hours. Isopropylamine (0.39 mL) is added and the reaction mixture is stirred at room temperature overnight. The reaction mixture is diluted with ethyl acetate and washed with 1N HCI, saturated NaHCO3, and brine. The organic layer is dried over MgSO4, filtered, and concentrated in vacuo. The crude product is chromatographed on silica gel eluting with hexane:ethyl acetate (2:1) to provide 7-methoxy-1-(1-methylethoxy)-N-(1-methylethyl)-2-naphthalenecarboxamide in 72% yield; mp 62°-64° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[C:10]([CH3:18])[CH:9]=2)=[CH:4][CH:3]=1.Cl[C:20]1[S:21][C:22]2[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:23]=2[N:24]=1.Cl.O1CCOCC1>C(O)CCC>[F:29][C:27]1[CH:26]=[CH:25][C:23]2[N:24]=[C:20]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([C:8]4[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[C:10]([CH3:18])[CH:9]=4)=[CH:6][CH:7]=3)[S:21][C:22]=2[CH:28]=1
Reactant: Fc1ccc2nc(Cl)sc2c1
Reactant: COC(=O)c1ccc(-c2ccc(N)cc2)cc1C
Agent: Cl
Solvent: CCCCO
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2ccc(Nc3nc4ccc(F)cc4s3)cc2)cc1C
Temperature: 65 °C
Yield: 58.2 %

Procedure:
As shown in Reaction Scheme 7, a mixture of methyl 4′-amino-3-methylbiphenyl-4-carboxylate (0.34 g, 1.40 mmol) and 2-chloro-6-fluoro-1,3-benzothiazole (0.26 g, 1.40 mmol) in n-butanol (4 mL) was heated to 60-70° C., and then 4N HCl in 1,4-dioxane (0.16 mL, 0.63 mmol) was added dropwise with stirring. The reaction mixture was heated at 90° C. for 18 h. Upon cooling to rt, the reaction mixture was concentrated in vacuo. The residue was triturated with ethanol and collected by filtration, yielding 0.32 g (58%) of the title compound as a pale yellow solid. LC/MS m/z 393.3 (MH+), retention time 4.02 min. 1H NMR (400 MHz, CD2Cl2) δ 2.62 (s, 3H), 3.95 (s, 3H), 7.05 (t, 1H), 7.39-7.60 (m, 4H), 7.65 (s, 4H), 7.96 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:11][C:12]1[S:13][CH:14]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:16]=1.N1C=CC=CC=1.O>C1COCC1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:11][C:12]1[S:13][CH:14]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:16]=1)=[O:5]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: CCOC(=O)c1csc(N)n1
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)c1csc(NC(=O)c2ccccc2Cl)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.2 %

Procedure:
1.07 g of o-chlorobenzoyl chloride was added to a solution in which 1.00 g of ethyl 2-amino-1,3-thiazole-4-carboxylate and 0.69 g of pyridine were dissolved in THF, under ice cooling. Then, after the reaction mixture was stirred at room temperature for 1 hr, it was poured into water and extracted with ethyl acetate. The organic layer was washed with an aqueous 2N-hydrochloric acid solution and dried on anhydrous magnesium sulfate. After distilling off the solvent, the crude product obtained was washed with a mixed solvent of hexane and t-butyl methyl ether to obtain 1.52 g of the aimed ethyl 2-(2-chlorobenzoyl)amino-1,3-thiazole-4-carboxylate.
Reaction SMILES: O[CH:2]1[C:10]2[C:5](=[C:6]([C:11]3[O:15][C:14]([C:16]4[CH:17]=[CH:18][C:19]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH:23]=4)[C:21]#[N:22])=[N:13][CH:12]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.S(Cl)(Cl)=O.C(NCC)(C)C.[CH2:38]([CH2:40][NH2:41])[OH:39]>C(Cl)Cl>[OH:39][CH2:38][CH2:40][NH:41][CH:2]1[C:10]2[C:5](=[C:6]([C:11]3[O:15][C:14]([C:16]4[CH:17]=[CH:18][C:19]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH:23]=4)[C:21]#[N:22])=[N:13][CH:12]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: NCCO
Reactant: CC(C)Oc1ccc(-c2ncc(-c3cccc4c3CCC4O)o2)cc1C#N
Agent: CCNC(C)C
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC(C)Oc1ccc(-c2ncc(-c3cccc4c3CCC4NCCO)o2)cc1C#N
Temperature: 25 °C
Reaction time: 3 h
Yield: 62 %

Procedure:
Prepared using General Procedure 14. To a stirring solution of 5-(5-(1-hydroxy-2,3-dihydro-1H-inden-4-yl)oxazol-2-yl)-2-isopropoxybenzonitrile 56 (50 mg, 0.1 mmol) in DCM (3 mL) was added thionyl chloride (25 mg, 0.21 mmol) at 0° C. The reaction mixture was stirred at room temperature for 3 h. The solvent was evaporated and the crude chloride re-dissolved in dimethyl acetamide (3 mL). Isopropyl ethylamine (40.8 mg, 0.316 mmol) and ethanolamine (19.3 mg, 0.31 mmol) were added and the reaction mixture heated at 70° C. overnight. The reaction mixture was quenched with NaHCO3 and extracted with EA. The combined organic extracts were washed with brine and then dried over MgSO4. The product was purified by chromatography (10% MeOH/DCM) to afford 25 mg (60%) of 5-(5-(1-(2-hydroxyethylamino)-2,3-dihydro-1H-inden-4-yl)oxazol-2-yl)-2-isopropoxybenzonitrile 57. LCMS-ESI (m/z) calculated for C24H25N3O3: 403.5; found 404.1 [M+H]+, tR=2.41 min. 1H NMR (400 MHz, DMSO) δ 8.18 (t, J=2.3 Hz, 1H), 8.08 (dd, J=9.0, 2.3 Hz, 1H), 7.70 (d, J=7.7 Hz, 1H), 7.44 (d, J=17.4 Hz, 1H), 7.42-7.32 (m, 1H), 7.30-7.11 (m, 2H), 4.70 (dt, J=12.2, 6.1 Hz, 2H), 4.39 (s, 1H), 3.40 (t, J=5.0 Hz, 2H), 3.18-2.95 (m, 2H), 2.93-2.75 (m, 1H), 2.73-2.54 (m, 2H), 2.38-2.16 (m, 1H), 1.98-1.78 (m, 1H), 1.15 (d, J=6.0 Hz, 61-1). 13C NMR (101 MHz, CDCl3) δ 161.35, 159.17, 151.04, 146.60, 139.78, 132.16, 127.43, 125.59, 125.07, 123.99, 120.49, 116.10, 113.90, 103.77, 72.60, 62.95, 61.51, 48.70, 33.27, 31.29, 29.91, 22.02.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]([CH2:24][OH:25])([CH2:22][OH:23])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:12]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:33]1([CH2:39][CH2:40][CH2:41][CH2:42]Br)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.O>CN(C)C=O>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]([CH2:22][OH:23])([CH2:24][OH:25])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:42][CH2:41][CH2:40][CH2:39][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[C:13]([C:18]([F:20])([F:19])[F:21])[CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(CO)(CO)CCc1ccc(O)c(C(F)(F)F)c1
Reactant: BrCCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NC(CO)(CO)CCc1ccc(OCCCCc2ccccc2)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 103.8 %

Procedure:
Compound 3-6 (350 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (255 mg) and 4-phenylbutylbromide (235 mg) were added, and the mixture was stirred at 80° C. for 6 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (490 mg) as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].N1C=CC=CC=1.[CH2:22]([O:29][C:30](Cl)=[O:31])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>C1C=CC=CC=1>[C:30](=[O:31])([O:29][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[O:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)=[CH:10][CH:11]=1
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: CCCCCCCOC(=O)Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCCCCCCOC(=O)Oc1ccc(-c2ccc(C#N)cc2)cc1

Procedure:
0.976 G. of 4'-cyano-4-hydroxy-biphenyl are dissolved in 10 ml. of absolute pyridine and reacted with 1.07 g. of chloroformic acid n-heptyl ester as in Example 1. The 1.8 g. of yellow oil obtained according to the procedure described in Example 1 is dissolved in benzene and chromatographed on 90 g. of silica gel. Benzene elutes 1.782 g. of colorless crystals which are recrystallized from ether-hexane up to constant melting point and clearing point. The pure 4'-cyano-4-biphenylyl n-heptyl carbonate obtained melts at 50.2°-50.5° and has a clearing point of 65.2°. UV (EtOH): ε 270 = 25900.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])=[O:12]>C(O)C>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[NH:13][C:11](=[O:12])[CH2:10][NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccccc1NC(=O)CCl
Reactant: NCc1ccccc1
Solvent: CCO
Product: COc1ccccc1NC(=O)CNCc1ccccc1

Procedure:
To ethanol (100 mL) add benzylamine (35 g, 0.33 mol) and 2-chloro-N-(2-methoxyphenyl)acetamide (22 g, 0.11 mol). Stir and heat the reaction at 50° C. Monitor the progress of the reaction by thin-layer chromatography. Upon completion of the reaction remove the precipiate that has formed by suction filtration and discard. Evaporate the filtrate and partition the residue between ethyl acetate and 2N NaOH(aq). Separate the organic layer and dry it over Na2SO4. Remove the drying agent by filtration and remove the solvent in vacuo. Chromatograph the residue on silica gel (400 g) using hexane/EtOAc (3/1) as eluent to obtain the title compound.
Reaction SMILES: Br[CH:2]([CH3:16])[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[S:12][C:11](=[O:13])[N:10]([CH3:14])[C:9]=2[CH:15]=1)=O.[NH2:17][C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=1>C(#N)C>[CH3:16][C:2]1[N:19]2[CH:20]=[CH:21][C:22]([CH3:24])=[CH:23][C:18]2=[N:17][C:3]=1[C:5]1[CH:6]=[CH:7][C:8]2[S:12][C:11](=[O:13])[N:10]([CH3:14])[C:9]=2[CH:15]=1
Reactant: CC(Br)C(=O)c1ccc2sc(=O)n(C)c2c1
Reactant: Cc1ccnc(N)c1
Solvent: CC#N
Product: Cc1ccn2c(C)c(-c3ccc4sc(=O)n(C)c4c3)nc2c1
Yield: 63.4 %

Procedure:
A solution of 5-(2-bromopropionyl)-3-methyl-2-benzothiazolinone (3.0 g) and 2-amino-4-methylpyridine (3.24 g) in acetonitrile (100 ml) was refluxed for 8 hours. The reaction mixture was concentrated to about a half volume and poured into a mixture of water and ethyl acetate. The resulitng mixture was acidified to PHO.5 with 10% hydrochloric acid. The precipitate was collected by filtration and washed successively with water and ethyl acetate. The resulting precipitate was added to a mixture of ethyl acetate, tetrahydrofuran and water, and the mixture was adjust to pH 7.0 with 20% aqueous potassium carbonate solution. The separated organic alyer was washed with brine, dried over magnesium sulfate and evaporated in vacuo to afford a crystalline residue. The residue was recrystallized from a mixture of ethyl acetate and tetrahydrofuran to give 5-(3,7-dimethylimidazo-[1,2-a]pyridin-2-yl)-3-methyl-2-benzothiazolinone (1.96 g).
Reaction SMILES: Cl[C:2](=[O:9])[CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].[Br:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17]([CH3:22])([CH3:21])[C:16](=[O:23])[CH:15]=[C:14]2[OH:24]>ClCCCl.C(Cl)Cl>[C:2]([O:24][C:14]1[C:13]2[C:18](=[CH:19][CH:20]=[C:11]([Br:10])[CH:12]=2)[C:17]([CH3:22])([CH3:21])[C:16](=[O:23])[CH:15]=1)(=[O:9])[CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6]
Reactant: CC1(C)C(=O)C=C(O)c2cc(Br)ccc21
Reactant: COC(=O)CCC(=O)Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: COC(=O)CCC(=O)OC1=CC(=O)C(C)(C)c2ccc(Br)cc21
Yield: 85 %

Procedure:
Methyl 4-chloro-4-oxobutyrate (0.107 mL, 0.873 mmol) was added to a solution of 6-bromo-4-hydroxy-1,1-dimethylnaphthalen-2(1H)-one (0.212 g, 0.794 mmol), TEA (0.121 mL, 0.873 mmol) in 1,2-dichloroethane (3 mL). The mixture was diluted with DCM, washed with water, washed with NaHCO3, and dried over MgSO4. The crude product was purified by flash chromatography using EtOAc/hexane to afford 7-bromo-4,4-dimethyl-3-oxo-3,4-dihydronaphthalen-1-yl methyl succinate in 85% yield. 1H-NMR (300 MHz, CDCl3) δ ppm 7.74 (1H, d, J=2.0 Hz), 7.59 (1H, dd, J=8.4, 2.1 Hz), 7.36 (1H, d, J=8.5 Hz), 6.20 (1H, s), 3.73 (3H, s), 3.01 (2H, t, J=6.0 Hz), 2.80 (2H, t, J=6.0 Hz), 1.48 (6H, s). MS m/z: 381.
Reaction SMILES: I[C:2]1[C:7]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[C:4]([CH3:23])[N:3]=1.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:26]=1B(O)O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:26]=1[C:2]1[C:7]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[C:4]([CH3:23])[N:3]=1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Reactant: OB(O)c1c(Cl)cccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3c(Cl)cccc3Cl)c2cc1OC
Temperature: 80 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
4-[(2-Iodo-6-methyl-3-pyridyl)oxy]-6,7-dimethoxyquinoline (compound 116) (84 mg), 2,6-dichlorophenylboronic acid (191 mg), and tetrakistriphenylphosphine palladium (12 mg) were dissolved in toluene (1 ml) to prepare a solution. A saturated aqueous sodium hydrogencarbonate solution (1 ml) was added to the solution, and the mixture was stirred at 80° C. for 3 hr. The reaction solution was filtered, the solvent was then removed by distillation under the reduced pressure, and the residue was purified by column chromatography using methanol-chloroform to give the title compound (79 mg, yield 90%).