Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][CH2:2][C:3]([OH:5])=[O:4].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:18]1[C:22]2[CH:23]=[CH:24][C:25]([C:27](O)([CH2:29][CH3:30])[CH3:28])=[CH:26][C:21]=2[O:20][CH2:19]1>C1C=CC=CC=1>[O:18]1[C:22]2[CH:23]=[CH:24][C:25]([C:27]([S:1][CH2:2][C:3]([OH:5])=[O:4])([CH3:28])[CH2:29][CH3:30])=[CH:26][C:21]=2[O:20][CH2:19]1
Reactant: O=C(O)CS
Reactant: CCC(C)(O)c1ccc2c(c1)OCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCC(C)(SCC(=O)O)c1ccc2c(c1)OCO2
Yield: 35.4 %

Procedure:
50 ml of benzene, 1.29 g of mercaptoacetic acid and a catalytic amount of p-toluenesulfonic acid monohydrate were added to 2.27 g of 2-(1,3-benzodioxol-5-yl)-2-butanol (crude oil). The obtained mixture was heated under reflux for 11 hours and cooled, followed by the addition of benzene. The obtained mixture was washed with water, followed by the addition of a 1N aqueous solution of sodium hydroxide. The alkaline layer was separated, washed with ethyl acetate, acidified with concentrated hydrochloric acid and extrated with chloroform. The organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled to remove the solvent. The residue was purified by silica gel column chromatography (chloroform) to obtain 1.11 g of the title compound as a colorless oil.
Reaction SMILES: COC[O:4][C:5]1[C:6]([CH3:14])=[C:7](B(O)O)[CH:8]=[CH:9][CH:10]=1.[CH3:15][C:16]1[CH:17]=[C:18]([CH:23]=[C:24]([CH3:34])[C:25]=1OS(C(F)(F)F)(=O)=O)[C:19]([O:21][CH3:22])=[O:20].C(=O)([O-])[O-].[K+].[K+]>CO.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>[OH:4][C:5]1[C:6]([CH3:14])=[C:7]([C:25]2[C:24]([CH3:34])=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=2[CH3:15])[CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)c1cc(C)c(OS(=O)(=O)C(F)(F)F)c(C)c1
Reactant: COCOc1cccc(B(O)O)c1C
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: CO
Product: COC(=O)c1cc(C)c(-c2cccc(O)c2C)c(C)c1

Procedure:
In a manner similar to that of Example 11(d), by reaction of 1.5 g (7.6 mmol) of 3-methoxymethoxy-2-methylbenzene-1-boronic acid (described in Example 11(c)) with 2 g (6.4 mmol) of methyl 3,5-dimethyl-4-trifluoromethanesulphonyloxybenzoate, 7.7 mL of 2.0M potassium carbonate solution and 370 mg (0.32 mmol) of tetrakis(triphenylphosphine)palladium, followed by deprotection in methanol, the desired product is obtained in the form of a white solid (m.p.=149° C.; m=1.34 g; Y=67%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:10]([CH:21]([CH3:23])[CH3:22])[C:9]1=[O:24])C1C=CC=CC=1>C1COCC1>[CH:21]([CH:10]1[C:9](=[O:24])[NH:8][CH2:13][CH2:12][N:11]1[C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])([CH3:23])[CH3:22]
Reactant: CC(C)[C@@H]1C(=O)N(Cc2ccccc2)CCN1C(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)C1C(=O)NCCN1C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 58.7 %

Procedure:
To a three-necked bottle containing THF (10 mL) was bubbled with NH3 (gas) at −78° C. for 5 mins. Then Na (300 mg, 13.0 mmol) was added to the mixture slowly at −78° C. After stirring for 30 min, (R)-tert-butyl 4-benzyl-2-isopropyl-3-oxopiperazine-1-carboxylate (700 mg, 2.11 mmol) was added dropwise at −78° C. The mixture was stirred at −78° C. for 30 min. The mixture was quenched with sat. aq. NH4Cl (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, concentrated and purified by preparative TLC with petroleum ether/EtOAc 1/1 to afford tert-butyl 2-isopropyl-3-oxopiperazine-1-carboxylate (300 mg, 59% yield) as a white solid. The product was found to be a racemic mixture. The cause of racemization was not investigated. LC-MS m/z 187.1 [M−56+H]+, 265.1 [M+Na]+. 1H NMR (CDCl3 400 MHz): δ 6.29 (s, 1H), 4.55-3.99 (m, 2H), 3.51-3.36 (m, 1H), 3.32-3.12 (m, 2H), 2.34-2.29 (m, 1H), 1.46 (s, 9H), 1.09 (d, J=6.8 Hz, 3H), 0.99 (d, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C@H:4](/[CH:5]=[CH:6]/[C:7]([O:9][CH3:10])=[O:8])[C@H:3]1[C:11](Cl)=[O:12].[C:15]([OH:19])([CH3:18])([CH3:17])[CH3:16]>C1C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:14])[C@H:4](/[CH:5]=[CH:6]/[C:7]([O:9][CH3:10])=[O:8])[C@H:3]1[C:11]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:12]
Reactant: CC(C)(C)O
Reactant: COC(=O)/C=C/[C@@H]1[C@@H](C(=O)Cl)C1(C)C
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Product: COC(=O)/C=C/[C@@H]1[C@@H](C(=O)OC(C)(C)C)C1(C)C

Procedure:
Using the procedure of Example 3, 2.7 g of (1R,trans) 2,2-dimethyl-3-[(E)-3-methoxy-3-oxo-1-propenyl]-cyclopropane-1-carboxylic acid chloride in 12.5 ml of benzene and 1.23 ml of tert.-butanol were reacted to obtain 1.05 g of tert.-butyl (1R,trans) 2,2-dimethyl-3-[(E)-3-methoxy-3-oxo-1-propenyl]-cyclopropane-1-carboxylate melting at 67° C. with a specific rotation of [α]D20 =+75.5°±2° (c=0.5% in chloroform).
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH2:5][CH2:4][N:3]1[C:7](Cl)=[O:8].[C:10]1([CH2:16][O:17][C:18]([C:20]2([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:10]1([CH2:16][O:17][C:18]([C:20]2([NH:26][C:7]([N:3]3[CH2:4][CH2:5][NH:6][C:2]3=[O:1])=[O:8])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)=[O:19])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(Cl)N1CCNC1=O
Reactant: NC1(C(=O)OCc2ccccc2)CCCCC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C1NCCN1C(=O)NC1(C(=O)OCc2ccccc2)CCCCC1
Temperature: 60 °C
Reaction time: 96 h
Yield: 82.2 %

Procedure:
1.38 g (9.3 mmol) of 2-oxo-1-imidazolidinecarbonyl chloride was added to a solution of 2.17 g (9.3 mmol) of 1-aminocyclohexanecarboxylic acid phenylmethyl ester and 1.04 g (10 mmol) of triethylamine in 100 ml of chloroform, and the mixture was stirred at 60° C. for 4 days. The reaction solution was successively washed with water, a 10% aqueous potassium hydrogensulfate solution, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and the mixture was dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained crystal was washed with diethyl ether to obtain 2.64 g (82%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH3:24])[S:11]([C:14]2[CH:18]=[C:17]([C:19](=O)[CH:20]([CH3:22])[CH3:21])[S:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.Cl.[NH2:26][OH:27].C([O-])(=O)C.[Na+]>C(O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH3:24])[S:11]([C:14]2[CH:18]=[C:17]([C:19](=[N:26][OH:27])[CH:20]([CH3:22])[CH3:21])[S:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1
Reactant: NO
Reactant: CC(C)C(=O)c1cc(S(=O)(=O)N(C)CCc2ccc(F)cc2)cs1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)C(=NO)c1cc(S(=O)(=O)N(C)CCc2ccc(F)cc2)cs1
Temperature: 25 °C

Procedure:
To a mixture solution of 5-isobutyrylthiophene-3-sulfonic acid [2-(4-fluorophenyl)-ethyl]-methyl-amide (the compound of Preparation Example 88) (30 mg) in ethanol (2 mL) and water (1 mL) was added hydroxylamine.hydrochloride (11 mg) and sodium acetate (13 mg). After heating and refluxing for 12 hours, the reaction solution was cooled to room temperature. The solution was diluted with water and extracted with ethyl acetate. This solution was washed with saturated sodium chloride water. The crude product that was obtained after drying with anhydrous sodium sulfate and removing the solvent by evaporation was purified by silica gel column chromatography (ethyl acetate/hexane), the title compound (a pale yellow viscous oily substance) (29 mg) was obtained as a mixture where (E):(Z)=1:1.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][C:11]=1[N+:18]([O-])=O)[CH3:2].B.C1COCC1.O.C1COCC1>C1COCC1>[NH2:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[O:3][CH2:1][CH3:2])=[C:11]([NH2:18])[CH:12]=1
Reactant: CCOc1ccccc1-c1ccc(C#N)cc1[N+](=O)[O-]
Agent: B
Solvent: O
Solvent: C1CCOC1
Product: CCOc1ccccc1-c1ccc(CN)cc1N
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 2′-ethoxy-2-nitrobiphenyl-4-carbonitrile (500 mg, 1.86 mmol) in THF (80 mL) was added a solution of BH3.THF (5.6 mL, 10% wt. in THF, 5.6 mmol) at 0° C. over 30 min. The reaction mixture was stirred at 0° C. for 3 h and then at room temperature for 15 h. The reaction solution was chilled to 0° C., and a H2O/THF mixture (3 mL) was added. After being agitated at room temperature for 6 h, the volatiles were removed under reduced pressure. The residue was dissolved in EtOAc (100 mL) and extracted with 1N HCl (2×100 mL). The aqueous phase was basified with 1N NaOH solution to pH 1 and extracted with EtOAc (3×50 mL). The combined organic layers were washed with water (50 mL), dried over Na2SO4, filtered, and evaporated. After drying under vacuum, 4-aminomethyl-2′-ethoxy-biphenyl-2-ylamine was isolated as a brown oil (370 mg, 82%). 1H NMR (300 MHz, DMSO-d6) δ 7.28 (dt, J=7.2 Hz, J=1.8 Hz, 1H), 7.09 (dd, J=7.2 Hz, J=1.8 Hz, 1H), 7.05 (d, J=7.5 Hz, 1H), 6.96 (dt, J=7.2 Hz, J=0.9 Hz, 1H), 6.83 (d, J=7.5 Hz, 1H), 6.66 (d, J=1.2 Hz, 1H), 6.57 (dd, J=7.5 Hz, J=1.5 Hz, 1H), 4.29 (s, 2H), 4.02 (q, J=6.9 Hz, 2H), 3.60 (s, 2H), 1.21 (t, J=6.9 Hz, 3H); HPLC ret. time 1.54 min, 10-100% CH3CN, 5 min gradient; ESI-MS 243.3 m/z (MH+).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH:11]1[O:16][CH2:15][CH2:14][N:13]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=2)=[O:18])[CH2:12]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][CH2:9][CH2:10][CH:11]1[O:16][CH2:15][CH2:14][N:13]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=2)=[O:18])[CH2:12]1
Reactant: CC(C)(C)OC(=O)NCCC1CN(C(=O)OCc2cc(Cl)cc(Cl)c2)CCO1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCC1CN(C(=O)OCc2cc(Cl)cc(Cl)c2)CCO1

Procedure:
A mixture comprising of 3,5-dichlorobenzyl 2-(2-((tert-butoxycarbonyl)amino)ethyl)morpholine-4-carboxylate (step 1)(500 mg, 1.154 mmol) and trifluoroacetic acid (3556 μl, 46.2 mmol) in DCM (3.8 ml) was stirred for 1 hour at room temperature. The resulting mixture was concentrated under reduced pressure and the crude product was diluted with EtOAc. The mixture was washed with sat. NaHCO3 and the organic portion was separated, dried over MgSO4, filtered and concentrated under reduced pressure to afford the title compound;
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:14][CH2:15][CH3:16])(=[O:13])[CH2:9][C:10]([O-:12])=O.[K+].[Cl-].[Mg+2].[Cl-].[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1C(Cl)=O>C(#N)C>[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:10](=[O:12])[CH2:9][C:8]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: O=C(Cl)c1ccco1
Agent: [Cl-]
Agent: [K+]
Agent: [Mg+2]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)c1ccco1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 71.8 %

Procedure:
Triethylamine (11.7 mL, 84.3 mmol) was added dropwise to a suspension of potassium ethyl malonate (13.4 g, 78.5 mmol) in acetonitrile (80 mL) at 10° C., followed by portionwise addition of anhydrous magnesium chloride (9.12 g, 95.8 mmol). The reaction mixture was warmed to room temperature and stirred for 2.5 h. The resulting white slurry was cooled to 0° C. and furan-2-carbonyl chloride (5.0 g, 38.3 mmol) in acetonitrile (20 mL) was added dropwise over a period of 20 min. The mixture was allowed to stir at ambient temperature overnight. The solvent was evaporated in vacuo and the residue was azeotroped with toluene (10 mL) then dissolved in toluene, cooled to between 0 and 5° C. and acidified with 13% aqueous hydrochloric acid (50 mL). After stirring for 15 min the aqueous phase was separated and the organic phase was washed with 13% aqueous hydrochloric acid (2×50 mL) followed by water (2×25 mL) and concentrated in vacuo to afford the crude compound. Purification by flash column chromatography over silica gel (100-200 mesh) using 5% ethyl acetate in petroleum ether as eluent afforded ethyl 3-(2-furyl)-3-oxo-propanoate (5.01 g, 72%) as a pale yellow liquid.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17])[C:10](O)=[O:11]>O1CCOCC1>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17])[C:10]([Cl:3])=[O:11]
Reactant: O=S(Cl)Cl
Reactant: COc1cc(C(=O)O)ccc1[N+](=O)[O-]
Solvent: C1COCCO1
Product: COc1cc(C(=O)Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Thionyl chloride 3.7 mL, (50 mmol) was added drop wise, at room temperature, to a stirred solution of 3-methoxy-4-nitro-benzoic acid (1.0 g, 5.07 mmol) in 15 mL of dioxane under a nitrogen atmosphere. After the addition was complete, the reaction was allowed to stir at room temperature for 1 hr. The reaction flask was then fitted with a distillation head, and excess thionyl chloride and about ½ of the solvent was removed by distillation in a 120° C. oil bath. The remaining solvent was removed by rotary evaporation, and the residue was taken up in 20 mL toluene and again about 1 of the solvent was removed by distillation. The remaining solution was then cooled to 0° C., and the white solid which precipitated, was collected by suction filtration, and rinsed with 1-1 Et2O-hexane. 1H-NMR (400 MHz, CDCl3) δ7.87 (d, J=7.83 Hz, 1H), 7.82 (d, J=7.83 Hz, 1H), 7.77 (s, 1H), 4.04 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1>>[F:18][C:17]1[C:12]2[N:13]([C:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([C:29]4[CH:28]=[CH:27][CH:26]=[C:25]([C:24]([F:35])([F:34])[F:23])[CH:30]=4)[CH:3]=3)=[CH:10][N:11]=2)[CH:14]=[CH:15][C:16]=1[C:19]([OH:22])([CH3:21])[CH3:20]
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4cccc(C(F)(F)F)c4)c3)cnc2c1F
Yield: 4 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol and 3-trifluoromethylbenzeneboronic acid were coupled in the same way as in Example 30 to give 2-[8-fluoro-3-(2-fluoro-3′-trifluoromethylbiphenyl-5-yl)imidazo[1,2-α]pyridin-7-yl]propan-2-ol as an off-white solid (7 mg, 4%): m/z (ES+) 433 [MH+].
Reaction SMILES: [CH2:1]([NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[CH:8][C:7]=1[N+:16]([O-])=O)[CH2:2][CH2:3][CH3:4].[C:19](O)(=O)[CH2:20][OH:21]>>[CH2:1]([N:5]1[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=[C:19]1[CH2:20][OH:21])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)CO
Reactant: CCCCNc1c([N+](=O)[O-])cnc2ccccc12
Product: CCCCn1c(CO)nc2cnc3ccccc3c21
Yield: 78.3 %

Procedure:
Using the general method of Example 1, N-butyl-3-nitro-4-quinolinamine (9.8 g, 0.04 mole, Example 122) was hydrogenated then reacted with glycolic acid (9.1 g, 0.12 mole) to provide 8.0 g of the desired product as a solid. A small sample was recrystallized from ethyl acetate to provide pure material, m.p. 146-149° C. Analysis: Calculated: %C, 70.6; %H, 6.7; %N, 16.5; Found: %C, 70.3; %H, 6.7; %N, 16.3.
Reaction SMILES: [CH3:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C[N:12](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>[CH3:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:12])=[O:5]
Reactant: Cc1ncccc1C(=O)O
Reactant: 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: Cc1ncccc1C(N)=O
Reaction time: 8 h
Yield: 76.3 %

Procedure:
To a solution of 2-methylnicotinic acid (0.537 mg, 3.9 mmol) in 20 mL of DMF at 0° C. was added HATU (1.56 g, 4.1 mmol) followed by the dropwise addition of DIPEA (0.72 ml, 4.1 mmol). NH3 (g) was then bubbled into the solution for 15 mins. The reaction was allowed to stir overnight. The resulting paste was filtered and rinsed with cold DMF and discarded. The mother liquor was concentrated and purified by normal phase chromatography using CH2Cl2/7 N NH3 in MeOH: 93/7 as eluent. Yielded a white solid (405 mg, 76%). 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.34 (s, 9 H), 1.36 (d, J=6.64 Hz, 3H), 2.56 (s, 3 H), 4.32-4.40 (m, 1 H), 7.15-7.19 (m, J=8.20 Hz, 1 H), 7.68 (d, J=8.20 Hz, 1 H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[F:25])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=3[F:25])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccc(Cl)cc1)C(CCCCCO)c1cc(F)ccc1F
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccc(Cl)cc1)C1(c2cc(F)ccc2F)CCCCC1

Procedure:
In toluene (20 ml) was dissolved 6-[(4-chlorophenyl)sulfonyl]-6-(2,5-difluorophenyl)-1-hexanol (200 mg, 0.514 mmol). After addition of cyanomethylenetri-n-butylphosphorane (500 mg, 2.07 mmol), the resulting mixture was heated under reflux for 4 days under an argon atmosphere. The reaction mixture was allowed to cool down and then concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography (hexane:ethyl acetate=20:1) to yield a white solid. The resulting solid was washed with hexane/methylene chloride, whereby the title compound (97 mg, 51%) was obtained as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](OC(F)(F)F)[CH:5]=[CH:4][C:3]=1[NH2:13].C[Al](C)C.C[O:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]([F:33])([F:32])[F:31])=[CH:24][N:23]=1)=O.Cl>C1(C)C=CC=CC=1.ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:13][C:20]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]([F:33])([F:32])[F:31])=[CH:24][N:23]=1)=[O:19]
Reactant: Nc1ccc(OC(F)(F)F)cc1Cl
Reactant: COC(=O)c1ccc(OCC(F)(F)F)cn1
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C(Nc1ccccc1Cl)c1ccc(OCC(F)(F)F)cn1
Temperature: 85 °C
Reaction time: 0.5 h

Procedure:
2-Chloro-4-trifluoromethoxy-phenylamine (2.0 g, 9.29 mmol) in toluene (50 mL) was added to trimethylaluminum (2.0 M 4.65 mL) then 5-(2,2,2-Trifluoro-ethoxy)-pyridine-2-carboxylic acid methyl ester 3 (1.1 g, 4.65 mol) was added and the mixture was heated to 80-90° C. for 2 h. The reaction was cooled down and 1N HCl solution (10 mL) was added to be acidic. Dichloromethane (100 mL) was then added and the organic phase was further washed with water (100 mL) and dried over sodium sulfate. The solvent was removed and the residue was mixed with ether (50 mL) and stirred for 0.5 h. The solid was filtered and dried to give 5-(2,2,2-Trifluoro-ethoxy)-pyridine-2-carboxylic acid (2-chloro-phenyl)-amide 4 as a solid. Yield: 1.0 g, 71%.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]3[O:31][CH2:30][CH2:29][O:28][C:25]=3[CH:26]=2)[N:21]=[CH:20][N:19]=1>CC(O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:18]2[C:27]3[C:22](=[CH:23][C:24]4[O:31][CH2:30][CH2:29][O:28][C:25]=4[CH:26]=3)[N:21]=[CH:20][N:19]=2)=[CH:4][CH:3]=1
Reactant: Clc1ncnc2cc3c(cc12)OCCO3
Reactant: Clc1ccc2c(c1)NCC2
Solvent: c1ccncc1
Solvent: CC(C)O
Product: Clc1ccc2c(c1)N(c1ncnc3cc4c(cc13)OCCO4)CC2
Yield: 87 %

Procedure:
To 6-chloroindoline (52 mg, 0.339 mmol) and pyridine (23.3 mg, 0.294 mmol) in i-PrOH (3 mL) was added 4-chloro-6,7-(ethylenedioxy)quinazoline (65 mg, 0.284 mmol). The mixture was heated to reflux under dry N2(g) for 16 hours and then concentrated in vacuo. The residue was partitioned between CHCl3 and saturated aqueous NaHCO3, and the organic phase was washed with brine, dried over Na2SO4(s), and concentrated in vacuo. The residue was flash chromatographed on silica using 30% acetone/hexanes to afford 84 mg of 4-(6-chloro-2,3-dihydro-indol-1-yl)-7,8-dihydro-[1,4]dioxino [2,3-g]quinazoline as its free-base (M.P. 209°-211° C.; GC/MS: 339 (M+); anal. RP18-HPLC RT: 5.02 min).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]2[O:9][C:10]3[CH2:16][CH2:15][CH2:14][CH2:13][C:11]=3[N:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.CS([C:21]1[N:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[N:22]=1)(=O)=O.C(=O)([O-])[O-].O>CN(C=O)C>[CH3:30][O:29][C:23]1[CH:24]=[C:25]([O:27][CH3:28])[N:26]=[C:21]([O:1][C:2]2[C:3]([C:8]3[O:9][C:10]4[CH2:16][CH2:15][CH2:14][CH2:13][C:11]=4[N:12]=3)=[N:4][CH:5]=[CH:6][CH:7]=2)[N:22]=1
Reactant: Oc1cccnc1-c1nc2c(o1)CCCC2
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OC)nc(Oc2cccnc2-c2nc3c(o2)CCCC3)n1

Procedure:
0.12 g 2-(3-hydroxy-2-pyridyl)-4,5,6,7-tetrahydrobenzoxazole, 0.12 g 2-methanesulfonyl-4,6-dimethoxypyrimidine and 0.21 g pottasium carbonate were suspended in 3 ml DMF, and the resulting suspension was subjected to a reaction for 2 hours at 60° C. After completing the reaction, the suspension reacted was added with water and then extracted with ethyl acetate. The extract was then washed with saturated saline solution. The organic layer obtained was dried with anhydrous magnesium sulfate, and the solvent used was removed by distillation under reduced pressure. The residue obtained was purified by using silica gel column chromatography, affording the objective substance in an amount of 0.18 g.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1(N=C=NC2CCCCC2)CCCCC1.ON1C2N=CC=CC=2N=N1>C(Cl)Cl>[C:21]1([NH:20][C:17](=[O:19])[C@H:9]([CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: Nc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.9 %

Procedure:
To a stirred solution of N-BOC-L-phenylalanine (20 g, 75.4 mmol) in methylene chloride (200 mL) is added aniline (7.0 mL, 75.4 mmol), dicyclohexylcarbodiimide (15.5 g, 75.4 mmol), and 1-hydroxy-7-azabenzotriazole (10.3 g, 75.4 mmol). The mixture is stirred at room temperature overnight. The solid is filtered away and the filtrate is washed with 5% citric acid (50 mL), a saturated solution of sodium bicarbonate (50 mL), and brine (50 mL). The organic phase is dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield a light brown solid. The solid is recrystalized from ethyl acetate to afford N-BOC-L-phenylalanine-N-phenylamide as a white solid (11 g).
Reaction SMILES: C(OC([N:8]([CH2:22][CH2:23][CH2:24][CH:25]=[CH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:9]1[CH:10]=[C:11]([CH:19]=[CH:20][CH:21]=1)[C:12](C1NC=CN=1)=[O:13])=O)(C)(C)C.[OH-].[Na+].[NH2:39][CH2:40][CH:41]([OH:44])[CH2:42][OH:43]>C(Cl)(Cl)Cl>[CH2:22]([NH:8][C:9]1[CH:10]=[C:11]([CH:19]=[CH:20][CH:21]=1)[C:12]([NH:39][CH2:40][CH:41]([OH:44])[CH2:42][OH:43])=[O:13])[CH2:23][CH2:24][CH:25]=[CH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCCCCCC=CCCCN(C(=O)OC(C)(C)C)c1cccc(C(=O)c2ncc[nH]2)c1
Reactant: NCC(O)CO
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCC=CCCCNc1cccc(C(=O)NCC(O)CO)c1
Temperature: 40 °C
Reaction time: 24 h

Procedure:
To a mixture containing 4.3 g. of [N-(t-butyloxycarbonyl)-3-(4-pentadecenylamino)benzoyl]imidazole, 50 ml. of chloroform, and 50 ml. of 5 N sodium hydroxide is added 1.1 g. of 3-amino-1,2-propanediol. The mixture is vigorously stirred for 24 hours, the layers are separated, and the chloroform solution is washed once with 50 ml. of 1 N sodium hydroxide. The solvent is evaporated and the residue is heated for 30 minutes at 40° C. in 50 ml. of anhydrous trifluoroacetic acid. The solvent is again evaporated and the resulting oil is crystallized from acetone to yield the product as light yellow crystals.