Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1.Br[CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[C:23](=[O:26])([O-])[O-:24].[K+].[K+]>C(O)C>[C:4]([O:24][C:23]([N:1]1[CH2:6][CH2:5][CH:4]([CH:7]2[CH2:12][CH2:11][N:10]([CH2:14][CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:9][CH2:8]2)[CH2:3][CH2:2]1)=[O:26])([CH3:7])([CH3:5])[CH3:3]
Reactant: BrCCCc1ccccc1
Reactant: C1CC(C2CCNCC2)CCN1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(C2CCN(CCCc3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 10.98 g (45.52 mM) of 4,4′-bi-piperidine and 9.06 g (45.5 mM) of 1-bromo-3-phenylpropane in 150 ml of ethanol was added 18.9 g (137 mM) of potassium carbonate and the mixture was stirred at room temperature for one day. This reaction mixture was filtered and the solvent was removed from the filtrate under reduced pressure. The residue was dissolved in 100 ml of tetrahydrofuran, and after 11.9 g (54.6 mM) of di-tert-butyl dicarbonate was added, the mixture was stirred at room temperature for 6 hours. This reaction mixture was poured in aqueous solution of sodium hydroxide and extracted with 3 portions of ethyl acetate. The pooled organic layer was dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1 to 1/1 ethyl acetate) to provide the title compound.
Reaction SMILES: C([O:5][C:6](=[O:16])[CH2:7][NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)(C)(C)C.C(O)(C(F)(F)F)=O.O>C(Cl)Cl>[C:12]1([CH3:15])[CH:13]=[CH:14][C:9]([NH:8][CH2:7][C:6]([OH:16])=[O:5])=[CH:10][CH:11]=1
Reactant: Cc1ccc(NCC(=O)OC(C)(C)C)cc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(NCC(=O)O)cc1
Reaction time: 96 h
Yield: 54.5 %

Procedure:
A solution of crude p-tolylamino-acetic acid tert-butyl ester (200 mmol) in DCM (600 mL) was cooled to 0° C. and treated with TFA (150 mL). The reaction mixture was allowed to reach RT and stirred for 4 d. Water (200 mL) was added, the layers were separated and the aqueous layer was extracted with DCM (4×200 mL). The aqueous layer was adjusted to pH 8 by addition of saturated NaHCO3 solution and extracted with ethyl acetate (4×200 mL). The combined organic layers were dried with Na2SO4 and the solvents were removed in vacuo to give the crude acid (18 g) which was used in the next step without further purification.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:35])=[C:7]([C:9]2[NH:13][C:12](=[O:14])[N:11]([C:15]3[CH:32]=[CH:31][C:18]([C:19]([NH:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]([F:30])[F:29])[CH:23]=4)=[O:20])=[C:17]([O:33][CH3:34])[CH:16]=3)[N:10]=2)[CH:8]=1.[CH:36]1([C:39](Cl)=[O:40])[CH2:38][CH2:37]1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:35][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:39]([CH:36]2[CH2:38][CH2:37]2)=[O:40])=[CH:8][C:7]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:32]=[CH:31][C:18]([C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]([F:30])[F:29])[CH:23]=3)=[O:20])=[C:17]([O:33][CH3:34])[CH:16]=2)[N:10]=1
Reactant: O=C(Cl)C1CC1
Reactant: COc1cc(-n2nc(-c3cc(CN)ccc3Cl)[nH]c2=O)ccc1C(=O)Nc1cccc(C(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc(-n2nc(-c3cc(CNC(=O)C4CC4)ccc3Cl)[nH]c2=O)ccc1C(=O)Nc1cccc(C(F)F)c1
Yield: 26.4 %

Procedure:
The title compound was prepared by following the procedure as described for step-2 of Intermediate-30 by using 4-(3-(5-(aminomethyl)-2-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(3-(di flu oromethyl)phenyl)-2-methoxybenzamide (Intermediate-39, 0.050 g, 0.10 mmol), cyclopropane carbonyl chloride (0.016 g, 0.15 mmol), DIPEA (2.0 mL) and THF (2 mL) to afford 0.015 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 0.68 (d, J=8.7 Hz, 4H), 1.60 (m, 1H), 3.95 (s, 3H), 4.34 (d, J=5.4 Hz, 2H), 7.05 (m, 1H), 7.29 (d, J=7.9 Hz, 1H), 7.41-7.55 (m, 4H), 7.65 (d, J=9.0 Hz, 1H), 7.74 (s, 1H), 7.82 (d, J=8.7 Hz, 2H), 8.07 (s, 1H), 8.72 (m, 1H), 10.33 (s, 1H); MS (m/z): 566.29 (M−H)−.
Reaction SMILES: Cl.[F:2][C:3]([F:13])([F:12])[C:4]1[S:8][C:7]([C:9](=[NH:11])[NH2:10])=[N:6][CH:5]=1.[Br:14][C:15]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:16]=1[CH:17]=O.O=[C:25]([CH3:32])[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>>[Br:14][C:15]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:16]=1[CH:17]1[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:25]([CH3:32])[NH:10][C:9]([C:7]2[S:8][C:4]([C:3]([F:2])([F:12])[F:13])=[CH:5][N:6]=2)=[N:11]1
Reactant: CCOC(=O)CC(C)=O
Reactant: O=Cc1ccc(F)cc1Br
Reactant: N=C(N)c1ncc(C(F)(F)F)s1
Agent: Cl
Product: CCOC(=O)C1=C(C)NC(c2ncc(C(F)(F)F)s2)=NC1c1ccc(F)cc1Br
Yield: 22.9 %

Procedure:
5-(trifluoromethyl)thiazole-2-carboximidamide hydrochloride (0.93 g, 4 mmol) was reacted with 2-bromo-4-fluorobenzaldehyde (0.81 g, 4 mmol) and ethyl 3-oxobutanoate (0.55 g, 4.2 mmol) according to the procedure as described in Example 1, Step A to give the title compound as a yellow solid (0.45 g, 23%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]#[CH:13])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C([Li:18])CCC>C1COCC1>[C-:1]#[C-:2].[Li+:18].[Li+:18].[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([C:12]#[CH:13])=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: [Li]CCCC
Agent: C#Cc1ccc(CCCCC)cc1
Solvent: C1CCOC1
Product: [C-]#[C-]
Product: [Li+]
Temperature: -78 °C

Procedure:
4-n-pentylphenylacetylene (0.9 g) was introduced into a flask, THF (30 ml) was added thereto, and the mixture was cooled to −78° C. with stirring. n-butyllithium (1.6 M hexane solution, 12.5 ml) was added thereto. The mixture was stirred for 30 minutes while maintaining the internal temperature at −78° C., to obtain a THF solution of lithium acetylide of 4-n-pentyl phenylacetylene (the compound (d1)), and the resulting solution was transferred into a dripping funnel under a nitrogen stream.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1)=O.[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:18][CH:17]=1.C1CCN2C(=NCCC2)CC1.Cl>C(#N)C.CCN(CC)CC>[F:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[C:23](=[O:25])[O:24][CH2:2][C:3]=2[C:5]2[CH:6]=[CH:7][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:9][CH:10]=2)=[CH:20][CH:21]=1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: CS(=O)(=O)c1ccc(C(=O)CBr)cc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: C1CCC2=NCCCN2CC1
Product: CS(=O)(=O)c1ccc(C2=C(c3ccc(F)cc3)C(=O)OC2)cc1
Reaction time: 0.75 h
Yield: 68.2 %

Procedure:
To the product of Step 1 (216 mg) dissolved in acetonitrile (4 mL) was added Et3N (0.26 mL), followed by 4-fluorophenylacetic acid (102 mg). After 1.5 h at room temperature 0.23 mL of DBU was added. The reaction mixture was stirred for another 45 min and then treated with 5 mL of 1N HCl. The product was extracted with EtOAc, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography (40% EtOAc in hexane) to yield 150 mg of the title compound as a solid.
Reaction SMILES: Cl.[OH:2][CH:3]([CH3:11])[CH2:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]1[C:21](O)=[O:22].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl>CN(C=O)C.C(N(CC)CC)C>[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]1[C:21]([N:8]1[CH2:9][CH2:10][CH:5]([CH2:4][CH:3]([OH:2])[CH3:11])[CH2:6][CH2:7]1)=[O:22]
Reactant: CC(O)CC1CCNCC1
Reactant: O=C(O)c1cc2ccccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(O)CC1CCN(C(=O)c2cc3ccccc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 233 mg of tert-butyl 4-(2-hydroxy propyl)piperidine-1-carboxylate in 4 mL of ethyl acetate was added 3 mL of 4M HCl/EtOAc, followed by stirring at room temperature for 2 hours. The reaction liquid was concentrated under reduced pressure to obtain 4-(2-hydroxypropyl)piperidine hydrochloride. To a solution of the 4-(2-hydroxypropyl)piperidine hydrochloride and 155 mg of indole-2-carboxylic acid in 5 mL of DMF were added 0.15 mL of triethylamine, 190 mg of 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride and 130 mg of 1-hydroxybenzotriazole, followed by stirring at room temperature for 1 day. 0.5M aqueous hydrochloric acid was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed with 0.5M aqueous sodium hydroxide solution and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography [chloroform:methanol=1:0-10:1], and then solidified using diisopropyl ether to obtain 49 mg of 1-[1-(1H-indol-2-ylcarbonyl)piperidin-4-yl]propan-2-ol as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C:8]2[N:9]=[C:10](O)[C:11]3[CH2:16][O:15][CH2:14][C:12]=3[N:13]=2)[CH:7]=1.C([O-])(O)=O.[Na+].O=P(Cl)(Cl)[Cl:26]>C(Cl)Cl>[Cl:26][C:10]1[C:11]2[CH2:16][O:15][CH2:14][C:12]=2[N:13]=[C:8]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[F:18])[N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nc(-c2cc(Cl)ccc2F)nc2c1COC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Fc1ccc(Cl)cc1-c1nc(Cl)c2c(n1)COC2
Temperature: 25 °C
Yield: 73 %

Procedure:
A suspension of 2-(5-chloro-2-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidin-4-ol (100 mg, 0.36 mmol, 1 eq) in POCl3 (5 ml) was stirred under reflux for 1 h. The solution was then cooled to room temperature and concentrated under reduced pressure to give a white solid which was dissolved in dry methylene chloride. The solution was cooled to 0° C. and ice was added followed by sat. NaHCO3. The organic layer was separated, washed with brine, dried (MgSO4), filtered and evaporated in vacuo to provide a crude white solid which was purified by flash column chromatography (1:9 EtOAc:Hexane) to give 4-Chloro-2-(5-chloro-2-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidine (78 mg, 73%) as a white solid.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH2:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:11]1[N:16]=[CH:15][C:14]2[C:17](=[C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([F:31])[CH:29]=4)[NH:24][C:23]3=[O:32])[O:18][CH:19]([CH2:20][CH3:21])[C:13]=2[CH:12]=1.O>O1CCOCC1>[CH2:20]([CH:19]1[C:13]2[CH:12]=[C:11]([NH:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[N:16]=[CH:15][C:14]=2[C:17](=[C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([F:31])[CH:29]=3)[NH:24][C:23]2=[O:32])[O:18]1)[CH3:21]
Reactant: CCC1OC(=C2C(=O)Nc3ccc(F)cc32)c2cnc(Cl)cc21
Reactant: NCCN1CCOCC1
Solvent: O
Solvent: C1COCCO1
Product: CCC1OC(=C2C(=O)Nc3ccc(F)cc32)c2cnc(NCCN3CCOCC3)cc21
Temperature: 100 °C
Reaction time: 1 h
Yield: 14.1 %

Procedure:
A solution of 2-morpholin-4-yl-ethylamine (177 mg, 1.51 mmol) in 3 mL of dioxane is treated with 3-(6-Chloro-1-ethyl-1H-furo[3,4-c]pyridin-3-ylidene)-5-fluoro-1,3-dihydro-indol-2-one (100 mg, 0.30 mmol) in one portion. The reaction mixture is heated at 100° C. until no starting material remained. The reaction mixture is treated with water (10 mL) and heating is continued for 1 hr. The precipitate which formed is collected by filtration and washed with small amounts of water, EtOAc and ether. The solid obtained is dried under vacuum to give the title compound as a yellow solid (18 mg, 14%).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])C=[CH:2]1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Cl:26]Cl.[CH:28]([Cl:31])(Cl)Cl>>[Cl:26][C@H:2]1[C@H:28]([Cl:31])[C:4](=[O:5])[O:6][C:1]1=[O:7]
Reactant: O=C1C=CC(=O)O1
Reactant: ClC(Cl)Cl
Reactant: ClCl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: O=C1OC(=O)[C@@H](Cl)[C@@H]1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 65 %

Procedure:
A solution of maleic anhydride (10.6 g, 108 mmol) and benzoyl peroxide (5 mg, 0.02 mmol) in CHCl3 (250 mL) was saturated with chlorine gas and the resulting bright yellow solution was stirred for 5 h at rt. Residual chlorine was removed with a stream of nitrogen and the reaction mixture was partially concentrated. Four crops of the white, solid title product were obtained by filtration (11.9 g, 65% yield): mp 90-92° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[CH:15]=[CH:14][N:13]=[CH:12][C:11]=3[N:10]=[CH:9]2)=[N:6][CH:7]=1.[CH3:17][Mg+].[Br-].[Cl:20][C:21]1[C:29]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24].[NH4+].[Cl-]>C1COCC1>[Cl:20][C:21]1[C:29]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([N:13]1[CH:14]=[CH:15][C:16]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=3)[CH:9]=[N:10][C:11]=2[CH:12]1[CH3:17])=[O:24]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1Cl
Reactant: C[Mg+]
Reactant: Fc1ccc(-n2cnc3cnccc32)nc1
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1c2ncn(-c3ccc(F)cn3)c2C=CN1C(=O)c1cccc(C(F)(F)F)c1Cl
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 82.2 %

Procedure:
In a three-neck round-bottom flask equipped with a mechanic stirring, an internal thermal couple and an addition funnel, 1-(5-fluoropyridin-2-yl)-1H-imidazo[4,5-c]pyridine (70 g, 326 mmol) was suspended in THF (1.7 L) and then warmed to 50° C. to form a clear solution. The clear solution was cooled to −78° C. and a lot of solid precipitated out. Under N2, MeMgBr (3.0 mol/L in THF, 109 mL, 326 mmol) was added over 30 min while the internal temperature was maintained at <−70° C. After 20 min, the solution of Intermediate 12 (87 g, 359 mmol) in THF (100 mL) was added over 30 min with the internal temperature maintained at <−70° C. The rest of MeMgBr (3.0 mol/L in THF, 130 mL, 390 mmol) was then added over 30 min. The reaction was stirred at −78° C. for 1 hour. The cold bath was removed and the reaction solution was warmed to 0° C. With an ice/water bath, 2 mol/L HCl aqueous solution was slowly added to quench the reaction while the internal temperature was maintained at <5° C. Concentrated NH4Cl aqueous solution was then added until clear phase separation was obtained. The aqueous layer was extracted with EtOAc twice (300 mL). The organic layers were combined, dried over Na2SO4, and concentrated. The crude product was recrystallized from hot EtOAc (250 mL)/MTBE (500 mL). The precipitated solid was collected by filtration, washed with cold MTBE (500 mL) to afford Intermediate 245 as a white solid (117 g, 82%). MS-EI (m/z): [M+H]+ observed: 437.0.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2].[C:8](OC=C)(=[O:10])[CH3:9].[C]=O.[H][H]>CO.C(O)C.C(O)(=O)C>[C:1]([O:4][CH:5]([O:7][C:8](=[O:10])[CH3:9])[CH3:6])(=[O:3])[CH3:2]
Reactant: C=COC(C)=O
Reactant: CC(=O)OC(C)=O
Reactant: [H][H]
Agent: [C]=O
Solvent: CCO
Solvent: CC(=O)O
Solvent: CO
Product: CC(=O)OC(C)OC(C)=O

Procedure:
Therefore, in step (a) of the process of this invention, methanol is hydrocarbonylated to C2 compounds such as ethanol, acetaldehyde, methyl acetate and dimethylacetal, and the reaction mixture containing these compounds is then freed of ethanol, acetaldehyde, methyl acetate and dimethylacetal; concurrently, in step (b), methyl acetate is carbonylated to acetic anhydride which is then freed from the reaction mixture; the mixture of acetaldehyde and dimethylacetal separated in step (a) is reacted with acetic anhydride to form a vinyl acetate precursor ethylidene diacetate (hereunder referred to as ED) and methyl acetate (step (c)), or vinyl acetate, acetic acid and methyl acetate are produced directly and simultaneously (step (c) combined with step (d)); both the methyl acetate produced in the step (c) or the combination of steps (c) and (d) and the methyl acetate produced in the step (a) are carbonylated to acetic anhydride. The above cycle is repeated. When ED is synthesized as a precursor, it is thermally decomposed (step (d)) to vinyl acetate and acetic acid. In summary, this invention accomplishes simultaneous production of vinyl acetate, acetic acid and ethanol from methanol, carbon monoxide and hydrogen.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[C:14]2[N:18]([CH3:19])[C:17]3[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=3[S:15]2)[S:10][C:9]1=[S:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]1([CH3:36])[CH:30]=[CH:29][C:28]([S:31]([O:34]C)(=[O:33])=[O:32])=[CH:27][CH:26]=1.[CH3:37]N(C=O)C>CC(C)=O>[C:25]1([CH3:36])[CH:26]=[CH:27][C:28]([S:31]([O-:34])(=[O:32])=[O:33])=[CH:29][CH:30]=1.[CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[C:14]2[N:18]([CH3:19])[C:17]3[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=3[S:15]2)[S:10][CH2+:9]1[S:24][CH3:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: CN(C)C=O
Reactant: CN1C(=C2SC(=S)N(Cc3ccccc3)C2=O)Sc2ccccc21
Solvent: CC(C)=O
Product: CS[CH2+]1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 120 °C
Yield: 83 %

Procedure:
To a 200 mL flask was added 3-benzyl-5-(3-methylbenzothiazolin-2-ylidene)-2-thioxothiazolidin-4-one (5.00 g, 13.5 mmol), methyl p-toluenesulfonate (7.34 mL, 48.6 mmol) and anhydrous DMF(40 mL). After heating at 120° C. for 3 h, the mixture was allowed to cool to 60° C., transferred to a 1 L flask and diluted with acetone (400 mL). After cooling to room temperature, the precipitate was filtered under reduced pressure, washed first with acetone (50 mL) and then Et2O (100 mL), and dried under vacuum for 12 h to give the title product (6.25 g, 83%) as a yellow crystalline solid, which was used without further purification. 1H-NMR (CDCl3): δ 7.83 (1H, d), 7.75 (2H, m), 7.59–7.66 (2H, m), 7.50 (1H, m), 7.37–7.43 (5H, m), 7.06 (2H, d), 5.31 2H, s), 4.52 (3H, s), 3.22 (3H, s), 2.28 (3H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[OH-].[Na+].[CH3:13]I>CS(C)=O.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:13])[CH:6]=[CH:5]2
Reactant: CI
Reactant: Brc1ccc2[nH]ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Cn1ccc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 5-bromo-1H-indole (1.530 mmol) in dimethyl sulfoxide (10 mL) was treated with NaOH (2.295 mmol) and stirred at room temperature for 30 min. The solution was then treated with methyl iodide (4.59 mmol) and was stirred for 3 days at room temperature. The solution was diluted with water (100 mL) and was extracted with ethyl acetate. The combined organic phases were washed with water, washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The yellow oil was used without further purification. MS(ES)+ m/e 210/212 [M+H]+ (bromide isotope pattern).
Reaction SMILES: [NH:1]1C2(CCCCC2)[NH:4][CH2:3][C:2]1=[O:11].[O:12]1[CH2:22][CH:13]1[CH2:14][C:15]([O:17]CC(C)C)=O.O>C(O)C>[CH2:14]1[C:15](=[O:17])[N:4]([CH2:3][C:2]([NH2:1])=[O:11])[CH2:22][CH:13]1[OH:12]
Reactant: CC(C)COC(=O)CC1CO1
Reactant: O=C1CNC2(CCCCC2)N1
Solvent: O
Solvent: CCO
Product: NC(=O)CN1CC(O)CC1=O
Reaction time: 2 h

Procedure:
1 g of 2,2-dimethyl-4-imidazolidinone ((5); R4 =R5 =CH3) (8.76 mmoles) are heated at 165° C. (external temperature) for 1 h 30 min with 2 g 2-methylpropyl 3,4-epoxybutanoate ((4); X=isobutyl) (12.64 mmoles). 0.17 ml of water and 5 ml ethanol are added, and boiling is continued for a further 2 h. The mixture is cooled and filtered. Oxiracetam is obtained as a white crystalline powder, m.p. 167°-70° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]2[N:27](COCC[Si](C)(C)C)[CH:28]=[CH:29][N:30]=2)(=[O:19])=[O:18])=[CH:13][CH:12]=1.FC(F)(F)C(O)=O.CCOCC>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]1[CH:12]=[CH:13][C:14]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]2[NH:30][CH:29]=[CH:28][N:27]=2)(=[O:19])=[O:18])=[CH:15][CH:16]=1
Reactant: C[Si](C)(C)CCOCn1ccnc1-c1ccccc1S(=O)(=O)c1ccc(/C=C/c2ccc(F)cc2F)cc1
Solvent: CCOCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(c1ccc(/C=C/c2ccc(F)cc2F)cc1)c1ccccc1-c1ncc[nH]1
Reaction time: 16 h
Yield: 55.9 %

Procedure:
A solution of 2-[2-({4-[(E)-2-(2,4-difluorophenyl)vinyl]phenyl}sulfonyl)phenyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole (Step 2, 110 mg) in CH2Cl2 (5 mL) was treated with trifluoroacetic acid (5 mL) and the solution stirred for 16 h, then concentrated in vacuo and partitioned between saturated aqueous NaHCO3 (20 mL) and EtOAc (20 mL). The phases were separated and the organic phase dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica (eluant 75% EtOAc/isohexane) to afford a colourless oil, which solidified on treatment with Et2O. The solid was washed with 50% EtOAc/isohexane and dried, to afford the title compound as a white solid (47 mg). δH (500 MHz, d6 DMSO): 12.11 (1H, s), 8.25 (1H, t, J 4.6), 7.85 (1H, q, J 8.1), 7.77–7.71 (2H, m), 7.69 (2H, d, J 8.4), 7.58 (2H, d, J 8.4), 7.51 (1H, t, J 4.4), 7.39–7.29 (3H, m), 7.23 (1H, s), 7.15 (1H, td, J 2.5, 8.5), 6.94 (1H, s); m/z (ES+) 422 [MH+].
Reaction SMILES: Cl[C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])[CH2:10][C:6]=2[C:5]([F:23])=[C:4]([NH:24][C@H:25]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:26]([NH2:28])=[O:27])[N:3]=1.[CH3:33][N:34]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[N:35]1>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:21][O:20][C:13]1[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:12]=1[CH2:11][N:9]1[CH2:10][C:6]2[C:5]([F:23])=[C:4]([NH:24][C@H:25]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:26]([NH2:28])=[O:27])[N:3]=[C:2]([C:37]3[CH:36]=[N:35][N:34]([CH3:33])[CH:38]=3)[C:7]=2[C:8]1=[O:22]
Reactant: COc1ccc(CN2Cc3c(F)c(N[C@H](CC(C)C)C(N)=O)nc(Cl)c3C2=O)c(OC)c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc(CN2Cc3c(F)c(N[C@H](CC(C)C)C(N)=O)nc(-c4cnn(C)c4)c3C2=O)c(OC)c1
Yield: 43.8 %

Procedure:
A solution of (R)-2-(4-chloro-2-(2,4-dimethoxybenzyl)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)-4-methylpentanamide (83 mg, 0.179 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (111 mg, 0.536 mmol), and bis(triphenylphosphine)palladium chloride (12.53 mg, 0.018 mmol) in dioxane (2 mL) and saturated aq Na2CO3 (2 mL) was heated at 120° C. for 30 min. After filtering off the solid, the solvent was removed, and the residue was dissolved in MeOH and DCM and was purified by preparative HPLC. The fractions were collected and the solvent was stripped to dryness via rotary evaporation to yield the title compound (40 mg, 44%). [M+H] calc'd for C26H31FN6O4, 511. found, 511.