Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:8](O)[CH2:9][OH:10].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH2:2]([CH:1]1[O:10][CH2:9][CH2:8][O:7]1)[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: OCCO
Reactant: CCCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCCCCC1OCCO1
Temperature: 25 °C

Procedure:
30 g (0.29 mole) of hexanol, 31 g (0.5 mol) of ethylene glycol, 100 mg of p-toluenesulfonic acid (p-Ts) in 100 ml of benzene are placed in 250 ml round-bottomed flask equipped with a Dean-Stark trap, a condenser and a mechanical stirrer. The mixture is heated to reflux until no more water has separated from the benzene phase. The mixture is then cooled to room temperature, washed with 100 ml of 5% sodium bicarbonate, 100 ml of saturated NaCl solution, and finally water. The solution is dried over sodium sulfate. After removing the solvent, the oil is fractionated. A yield of 19.6 g of colorless oil (46%) is obtaind nD20 =1.4554.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[Br:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Br)=[CH:14][CH:13]=1>>[Br:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][O:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: BrCc1ccc(Br)cc1
Product: O=[N+]([O-])c1cccc(OCc2ccc(Br)cc2)c1
Yield: 94.8 %

Procedure:
3-Nitro-phenol (1.00 g, 7.189 mmol) was treated with 4-bromo-benzyl bromide (1.976 g, 7.90 mmol) following the procedure of 189a providing the tile compound (2.1 g, 97%).
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][C:6]([CH3:29])([CH3:28])[CH2:7][N:8]1[C:25](=[S:26])[N:11]2[C:12]3[CH:13]=[C:14]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)[O:15][C:16]=3[CH:17]=[C:10]2[C:9]1=[O:27])C.O>C(O)(C(F)(F)F)=O>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:14]2[O:15][C:16]3[CH:17]=[C:10]4[C:9](=[O:27])[N:8]([CH2:7][C:6]([CH3:28])([CH3:29])[CH2:5][C:4]([OH:30])=[O:3])[C:25](=[S:26])[N:11]4[C:12]=3[CH:13]=2)=[CH:19][CH:20]=1
Reactant: CCOC(=O)CC(C)(C)CN1C(=O)c2cc3oc(-c4ccc(Cl)cc4)cc3n2C1=S
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)(CC(=O)O)CN1C(=O)c2cc3oc(-c4ccc(Cl)cc4)cc3n2C1=S
Temperature: 90 °C
Yield: 83.4 %

Procedure:
Compound 10 (1.21 grams, 2.3 mmol) was dissolved in TFA (33 ml), water (11 ml) was added thereto, and the resulting mixture was heated at 90° C. for 16 hours. The product was filtered and washed with ethanol to give Compound 11 (800 mg, 83% yield) as an orange solid.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:12]=[CH:11][C:10]2[C:6](=[CH:7][N:8]([CH3:13])[N:9]=2)[C:5]=1[C@@H:14]1[CH2:16][C@H:15]1[CH2:17][NH2:18].C(N(CC)CC)C.[C:26](OC(=O)C)(=[O:28])[CH3:27]>O1CCCC1.C(=O)([O-])O.[Na+]>[F:3][C:4]1[CH:12]=[CH:11][C:10]2[C:6](=[CH:7][N:8]([CH3:13])[N:9]=2)[C:5]=1[C@@H:14]1[CH2:16][C@H:15]1[CH2:17][NH:18][C:26](=[O:28])[CH3:27]
Reactant: Cn1cc2c([C@@H]3C[C@H]3CN)c(F)ccc2n1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NC[C@@H]1C[C@H]1c1c(F)ccc2nn(C)cc12
Yield: 98.4 %

Procedure:
A solution of 1-[(1R,2R)-2-(5-fluoro-2-methyl-2H-indazol-4-yl) cyclopropyl]methanamine dihydrochloride (258 mg, 0.883 mmol) and triethylamine (615 μL, 4.415 mmol) in tetrahydrofuran (9 mL) was stirred at room temperature for 20 min. To the reaction solution was added acetic anhydride (125 μL, 1.325 mmol) under ice-cooling, and the mixture was stirred under ice-cooling for 15 min. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate=0/100→5/95) to give the title compound (227 mg, yield 98%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=[O:14])[C:7]3[S:8][CH:9]=[CH:10][C:11]=3[C:12](=[O:13])[C:2]1=2.[OH-].[Na+].C1(C)C=CC(S(O[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])(=O)=O)=CC=1>[Zn].C(O)C>[CH2:5]([O:14][C:6]1[C:7]2[S:8][CH:9]=[CH:10][C:11]=2[C:12]([O:13][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH3:27])=[C:2]2[S:1][CH:5]=[CH:4][C:3]=12)[CH2:4][CH2:3][CH2:2][CH2:12][CH2:11][CH2:7][CH3:6]
Reactant: O=C1c2ccsc2C(=O)c2ccsc21
Reactant: CCCCCCCCOS(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: CCO
Product: CCCCCCCCOc1c2ccsc2c(OCCCCCCCC)c2ccsc12
Yield: 62 %

Procedure:
1.0 g (4.5 mmol) of benzo[1,2-b:4,5-b′]dithiophene-4,8-dione was mixed with 0.65 g (10 mmol) of zinc dust in a flask. Then, 4 ml of ethanol and 15 ml of 20% NaOH was added and the mixture was refluxed for 1 h. 4.3 mL octyl p-toluenesulfonate was added in portions with stirring until the color changed to red. The resulting precipitate was filtered, the filtrate was diluted with 100 mL water and extracted with 100 mL chloroform. The organic extraction was dried with anhydrous sodium sulfate and evaporated in vacuo. Column chromatography on silica gel using dichloromethane and hexanes mixed solvents yielded the pure title compound as a white solid (1.24 g, 62%). 1HNMR (CDCl3): δ0.88-0.91 (6H, t, J=7 Hz), 1.31-1.38 (16H, m), 1.54-1.58 (4H, m), 1.84-1.89 (4H, m), 4.26-4.29 (4H, J=7 Hz), 7.36-7.37 (2H, d, J=6 Hz), 7.47-7.48 (2H, d, J=6 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[O:9][CH3:10].[N:11]([O-])=O.[Na+].O.O.[Sn](Cl)Cl>Cl.O>[CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][NH2:11])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: O=N[O-]
Reactant: COc1cc(N)ccc1C
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: COc1cc(NN)ccc1C
Temperature: -5 °C
Yield: 52.2 %

Procedure:
A stirred mixture of 100.0 g (0.73 mole) of 4-methyl-3-methoxyaniline in 800 mL of concentrated hydrochloric acid was cooled to -5° C. A solution of 501.5 g (0.73 mole) of sodium nitrite in 250 mL of water was added slowly while maintaining the temperature of the reaction mixture below 0° C. The resultant mixture was stirred at -5° C. for 30 minutes. A cold solution of 330.0 g (1.46 mole) of tin (II) chloride dihydrate in 360 mL of concentrated hydrochloric acid was added over one hour. After complete addition the resultant mixture was allowed to warm to room temperature. A solid precipitate formed and was collected by filtration and stirred in 200 mL of water. This mixture was neutralized with 50% aqueous sodium hydroxide, and extracted with toluene. The extract was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to yield 58.0 g of 4-methyl-3-methoxyphenylhydrazine as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.I[CH2:13][CH3:14].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:13]([O:11][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][C:6]=1[C:8](=[O:10])[CH3:9])[CH3:14]
Reactant: CC(=O)c1cc(F)ccc1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1ccc(F)cc1C(C)=O

Procedure:
5′-Fluoro-2′-hydroxyacetophenone (9.38 g, 61 mmole), iodoethane (7.3 ml, 91 mmole) and K2CO3 (12.6 g, 91 mmole) in acetone (100 ml) was stirred at 60° C. overnight. The mixture was filtered, evaporated, dissolved in hexane/ethyl acetate, washed with 2M NaOH (2×20 ml) and water, dried (MgSO4) and evaporated to give 2′-ethoxy-5′-fluoroacetophenone. A solution of mCPBA )19.3 g, 112 mmole) in CH2Cl2 (500 ml) was dried with MgSO4. 2′-Ethoxy-5′-fluoro-acetophenone (10.2 g, 56 mmole) was added and the mixture was stirred for 3 days. More mCPBA (5 g, 29 mmole) and MgSO4 was added and stirring was continued for 2 days. The mixture was filtered, diluted with ethyl acetate, washed with 2 M NaOH (2×70 ml), NH4Cl (sat, 50 ml), dried (MgSO4) and evaporated. The residue (10.45 g,) was dissolved in ethanol (100 ml). KOH (8.9 g, 160 mmole) was dissolved in water (50 ml). The solutions were combined and stirred for 1 h. The mixture was washed with diethyl ether/hexane 2×(50+25 ml), acidified with HCl (konc), extracted with ethyl acetate (3×100 ml), dried (MgSO4) and evaporated. The residue (8.22 g) was dissolved in CH2Cl2 (100 ml). Triethylamine 11.7 ml, 84 mmole) and bromomethyl methyl ether (6.45 ml, 79 mmole) were added and the solution was refluxed for 2 hrs. More triethylamine 11.7 ml, 84 mmole) and bromomethyl methyl ether (6.45 ml, 79 mmole) were added and refluxing was continued overnight. The solution was evaporated, CH2Cl (200 ml) was added and the solution was washed with water, 2M NaOH and NH4Cl. Drying (MgSO4) and evaporation provided 4.0 g of 1-ethoxy-4-fluoro-2-methoxymethoxybenzene. This compound was reacted in a manner analogous to Example 39 to give (+,−)-N-(cis-2-(3-ethoxy-6-fluoro-2-methoxymethoxyphenyl)-cyclopropyl)-N′-(5-chloropyrid-2-yl)-urea. Finally deprotection with 2 M HCl in dioxane gave the titled compound. 1NMR (250 MHz, DMSO-D6) δ 1.04-1.14 (m, 1H), 1.41-1.56 (m+t, 4H), 1.96-2.06 (m, 1H), 3.05-3.15 (m, 1H), 4.06-4.19 (m, 2H), 6.64 (t, 1H), 6.94 (dd, 1H), 7.19 (d, 1H), 7.82 (dd, 1H), 8.10 (d, 1H), 8.61 (br.s, 1H), 9.08 (br.s, 1H), 9.57 (br.s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[O:10][CH3:11].[CH2:12]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]1>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH2:13][CH2:12][C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]2=3)=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: c1ccc2c(c1)CCc1ccccc1C2
Reactant: COc1cc(C=O)ccc1F
Product: COc1cc(C=C2c3ccccc3CCc3ccccc32)ccc1F
Yield: 49 %

Procedure:
Following procedures essentially as described in Example 28 and using 4-fluoro-3-methoxybenzaldehyde (1.59 g, 10.3 mmol), dibenzosuberane (1.94 g, 10 mmol, provides 1.66 g of title compound in 49% yield as a light tan oil that slowly crystallized. HPLC shows 93% purity.
Reaction SMILES: [Na+].[C:2]([O:5][CH2:6][C:7]1[CH2:14][S:13][CH:12]2[N:9]([C:10](=[O:16])[CH:11]2[NH2:15])[C:8]=1[C:17]([O-:19])=[O:18])(=[O:4])[CH3:3].Cl[CH2:21][O:22][C:23](=[O:36])[C@H:24]([CH:33]([CH3:35])[CH3:34])[NH:25]C(OC(C)(C)C)=O>CN(C)C=O.C(OCC)(=O)C>[NH2:25][CH:24]([CH:33]([CH3:35])[CH3:34])[C:23]([O:22][CH2:21][O:18][C:17]([C:8]1[N:9]2[CH:12]([S:13][CH2:14][C:7]=1[CH2:6][O:5][C:2](=[O:4])[CH3:3])[CH:11]([NH2:15])[C:10]2=[O:16])=[O:19])=[O:36]
Reactant: CC(=O)OCC1=C(C(=O)[O-])N2C(=O)C(N)C2SC1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCCl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)OCC1=C(C(=O)OCOC(=O)C(N)C(C)C)N2C(=O)C(N)C2SC1
Reaction time: 72 h

Procedure:
A suspension of 5 grams of 3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt and 8.5 grams of N-tert-butoxycarbonyl-L-valine chloromethyl ester, which is prepared by the general procedure described in W. German Offen. 2,236,620, are mixed in 100 ml of dimethyl formamide and stirred for 72 hours. The mixture is diluted with ethyl acetate, washed with water with aqueous bicarbonate and again with water. The organic layer is dried over magnesium sulfate, filtered, and evaporated to dryness to give 3-[(acetyloxy)-methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0 oct-2-ene-2-carboxylic acid N-tert-butoxycarbonyl-2-amino-3-methylbutyryloxymethyl ester from which the amine protecting group is removed by standard procedures to give the title product.
Reaction SMILES: Cl[O-:2].[Na+].[C:4]([C:7]1[C:8]([CH3:23])=[C:9]2[C:14](=[C:15]([CH3:17])[CH:16]=1)[S:13](=[O:19])(=[O:18])[CH2:12][C:11]([CH3:21])([CH3:20])[C:10]2=[O:22])(=[O:6])C>O1CCOCC1.O>[C:4]([C:7]1[C:8]([CH3:23])=[C:9]2[C:14](=[C:15]([CH3:17])[CH:16]=1)[S:13](=[O:19])(=[O:18])[CH2:12][C:11]([CH3:20])([CH3:21])[C:10]2=[O:22])([OH:6])=[O:2]
Reactant: [O-]Cl
Reactant: CC(=O)c1cc(C)c2c(c1C)C(=O)C(C)(C)CS2(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(C(=O)O)c(C)c2c1S(=O)(=O)CC(C)(C)C2=O
Temperature: 30 °C
Yield: 84 %

Procedure:
17.8 Grams (about 15 mmol) of a 6.4 wt % sodium hypochlorite aqueous solution was placed in a 100-ml three-necked round-bottomed flask, and cooled to 15~20° C., and then a solution of 1.26 g (4.26 mmol) of 6-acetyl-3,3,5,8-tetramethylthiochroman-4-one-1,1-dioxide in 8 ml of dioxane was gradually added. The mixture was stirred at 15~20° C. with external cooling for 30 minutes, and then stirred at room temperature (temperature-increased to about 30° C.) for 3 hours. The reaction mixture was diluted with about 50 ml of water and washed with chloroform twice. A sodium sulfate aqueous solution was added to an aqueous layer to decompose excess hypochlorite, and then the aqueous solution was neutralized and acidified with a 5 wt % hydrochloric acid aqueous solution to give a white solid. The solid was extracted with ethyl acetate, and an organic layer was washed with diluted hydrochloric acid and with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 1.06 g (yield 84%) of 6-carboxy-3,3,5,8-tetramethylthiochroman-4-one-1,1-dioxide in the form of a white solid.
Reaction SMILES: Br[CH:2]([CH2:19][CH3:20])[C:3]([NH:5][C:6]1[S:7][C:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:9][N:10]=1)=[O:4].[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>CN(C)C=O>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][C:8]1[S:7][C:6]([NH:5][C:3](=[O:4])[CH:2]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH2:19][CH3:20])=[N:10][CH:9]=1
Reactant: CCC(Br)C(=O)Nc1ncc(Cc2ccccc2Cl)s1
Reactant: C1CCNCC1
Solvent: CN(C)C=O
Product: CCC(C(=O)Nc1ncc(Cc2ccccc2Cl)s1)N1CCCCC1

Procedure:
2-Bromo-N-[5-(2-chloro-benzyl)-thiazol-2-yl]-butyramide (37 mg, 0.10 mmol) was dissolved in 0.5 mL of N,N-dimethylformamide containing piperidine (170 mg, 2.0 mmol). The reaction vessel was sealed and then subjected to microwave irradiation for 5 minutes at 80° C. The crude mixture was evaporated to dryness and purified by reverse-phase preparative liquid chromatography (31 mg, 0.082, 82%). ESI-MS m/z calc. 377.1. found 378.2 (M+1)+ Retention time 2.21 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]1([O:25][CH3:26])[CH2:8][CH2:7][C:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:12]=2)([CH:9]=[O:10])[CH2:5][CH2:4]1.[BH4-].[Na+].O>COCCOC>[CH3:26][O:25][C:3]1([O:2][CH3:1])[CH2:8][CH2:7][C:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH:20]3[CH2:21][CH2:22][CH2:23][CH2:24]3)[CH:12]=2)([CH2:9][OH:10])[CH2:5][CH2:4]1
Reactant: COc1ccc(C2(C=O)CCC(OC)(OC)CC2)cc1OC1CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(C2(CO)CCC(OC)(OC)CC2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-formylcyclohexan-1-one dimethyl ketal (0.24 g, 0.66 mmol) in 1,2-dimethoxy-ethane (5 mL) under an argon atmosphere was added sodium borohydride (0.05 g, 1.3 mmol) and the mixture was stirred at room temperature for 0.75 h. Water was added, the mixture was partitioned between ether and water, was extracted twice with ether, the organic exact was dried (,potassium carbonate) and evaporated to an oil (0.19 g, 79%).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[CH3:21][C@H:22]1[NH:27][C@@H:26]([CH3:28])[CH2:25][N:24]([C:29]([C:31]2[C:32]([CH3:38])=[C:33]([CH:36]=O)[NH:34][CH:35]=2)=[O:30])[CH2:23]1>C(O)C.N1CCCCC1>[CH3:28][C@H:26]1[NH:27][C@@H:22]([CH3:21])[CH2:23][N:24]([C:29]([C:31]2[C:32]([CH3:38])=[C:33]([CH:36]=[C:11]3[C:10]4[C:14](=[CH:15][CH:16]=[CH:17][C:9]=4[C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:19])[F:20])[CH:4]=4)[NH:13][C:12]3=[O:18])[NH:34][CH:35]=2)=[O:30])[CH2:25]1
Reactant: O=C1Cc2c(cccc2-c2cccc(C(F)(F)F)c2)N1
Reactant: Cc1c(C(=O)N2C[C@@H](C)N[C@@H](C)C2)c[nH]c1C=O
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(C(=O)N2C[C@@H](C)N[C@@H](C)C2)c[nH]c1C=C1C(=O)Nc2cccc(-c3cccc(C(F)(F)F)c3)c21
Temperature: 25 °C
Reaction time: 72 h
Yield: 27 %

Procedure:
To a solution of 4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one (69.3 mg, 0.25 mmol) and 4-[(cis)-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 3-{4-((cis)-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrol-2-ylmethylene}-4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (34.3 mg, 27%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[CH:16]([NH2:18])[CH3:17].[CH3:19][O:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=1[S:29](Cl)(=[O:31])=[O:30].C(N(CC)C(C)C)(C)C>ClCCl>[CH3:19][O:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=1[S:29]([NH:18][CH:16]([C:10]1[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=1[C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])[CH3:17])(=[O:30])=[O:31]
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC)c1
Reactant: CC(N)c1cc(F)ccc1-c1ccc(F)cc1F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(S(=O)(=O)NC(C)c2cc(F)ccc2-c2ccc(F)cc2F)c(OC)c1
Temperature: 25 °C
Yield: 72.9 %

Procedure:
A stirred solution of 1-(2′,4,4′-trifluoro-1,1′-biphenyl-2-yl)ethylamine (0.71 g, 2.84 mmol) in dichloromethane (5 mL) was treated with 2,4-dimethoxybenzenesulfonyl chloride (0.71 g, 3.0 mmol), and N,N-diisopropylethylamine (0.77 g, 6.0 mmol). The reaction was stirred at room temperature for twelve hours, and the solvent was evaporated in vacuo to a crude oil. The crude oil was purified by preparative liquid chromatography on a Biotage® 40 Mi column of pre-packed silica gel (90 g), eluting with a gradient of between 5% and 50% methyl tert-butyl ether in hexane at a flow rate of 40 mL/min to afford, after evaporation of the solvent, a colorless oil. Crystallization of the colorless oil from ethyl acetate-hexane yielded the title compound (0.93 g, 2.07 mmol, 73%) as a homogeneous, colorless, crystalline solid, m.p. 192-194° C.;
Reaction SMILES: [C:1]([CH:5]1[O:11][CH:10]2[CH:7]([C:8](=[O:26])[N:9]2[C:12](=[C:23]([CH3:25])[CH3:24])[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[NH:6]1)([O:3][CH3:4])=[O:2].N1C=CC=CC=1.[C:33]1([CH2:39][C:40](Cl)=[O:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>O1CCCC1>[C:1]([CH:5]1[O:11][CH:10]2[C:7]([C:40](=[O:41])[CH2:39][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:8](=[O:26])[N:9]2[C:12](=[C:23]([CH3:24])[CH3:25])[C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14])[NH:6]1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)C1NC2C(=O)N(C(C(=O)OCc3ccccc3)=C(C)C)C2O1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COC(=O)C1NC2(C(=O)Cc3ccccc3)C(=O)N(C(C(=O)OCc3ccccc3)=C(C)C)C2O1
Temperature: -20 °C
Yield: 107 %

Procedure:
To a solution of 32.6 g of benzyl α-(3ξ-carbomethoxy-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate in 750 ml of tetrahydrofuran is dropwise added a solution of 9.5 ml of pyridine and 15.1 ml of phenylacetyl chloride in 144 ml of tetrahydrofuran over a period of 15 minutes while maintaining the temperature at -20° C. and stirring under nitrogen atmosphere. The mixture is stirred for 55 minutes, poured into 700 ml of ice water, stirred for 5 minutes and extracted with ethyl acetate. The extract is washed with an aqueous solution of sodium hydrogencarbonate and water, dried on sodium sulfate, and evaporated under reduced pressure to yield 46.4 g of benzyl α-(3ξ-carbomethoxy-2-phenylacetyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate as crude product in 107% yield.
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].[N:9]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:14][CH2:13][CH2:12][CH:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10]1.CI>C1COCC1>[CH3:1][C:11]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][CH2:14][N:9]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:10]1
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)C1CCCN(C(=O)OC(C)(C)C)C1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C1(C)CCCN(C(=O)OC(C)(C)C)C1
Temperature: -50 °C
Reaction time: 2 h
Yield: 72.1 %

Procedure:
To a cold (−78° C.) solution of lithium diisopropylamide (LDA) (23.3 mmol) in THF (10 mL) under an argon atmosphere was added dropwise a solution of 1-tert-butyl 3-ethyl 1,3-piperidinedicarboxylate (3.0 g, 11.6 mmol) in THF (5 mL), then stirred at −50° C. for 2 hrs. To the resulting mixture was added a solution of MeI (1.98 g, 14 mmol) in THF at −50° C. The reaction mixture was allowed to warm to room temperature, and quenched with saturated aqueous NH4Cl solution. The mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and water. The organic phase was separated, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (hexane:ethyl acetate, 9:1) to give 1-tert-butyl 3-ethyl 3-methyl-1,3-piperidinedicarboxylate as a pale yellow oil (2.27 g, yield; 72%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][NH:9][CH3:10]>C1COCC1>[CH3:8][N:9]([CH3:10])[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CNC
Reactant: Clc1ncccn1
Solvent: C1CCOC1
Product: CN(C)c1ncccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-chloropyrimidine (5 g, 43.65 mmol) in dry THF (50 ml) is saturated with gaseous dimethylamine. The mixture is stirred at ambient temperature for 1 hour followed by evaporation of solvent. The residue is partitioned between water and ethyl acetate. The aqueous phase is extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and evaporated to leave the product as a brownish oil. Yield 5.07 g (94%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N:15]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19])[CH:12]=[CH:11][C:10]=1[CH:24]=[CH:25][C:26]1[S:30][C:29]([CH:31]=O)=[CH:28][CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33]([C:35]1[C:36](=[C:46]([C:49]#[N:50])[C:47]#[N:48])[O:37][C:38]([CH3:45])([C:41]([F:44])([F:43])[F:42])[C:39]=1[CH3:40])#[N:34]>C(O)C.O1CCCC1>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N:15]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19])[CH:12]=[CH:11][C:10]=1[CH:24]=[CH:25][C:26]1[S:30][C:29]([CH:31]=[CH:40][C:39]2[C:38]([CH3:45])([C:41]([F:44])([F:42])[F:43])[O:37][C:36](=[C:46]([C:47]#[N:48])[C:49]#[N:50])[C:35]=2[C:33]#[N:34])=[CH:28][CH:27]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=O)s2)c(OCc2ccccc2)c1
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C(F)(F)F
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=CC3=C(C#N)C(=C(C#N)C#N)OC3(C)C(F)(F)F)s2)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 19 h
Yield: 84 %

Procedure:
In 10 ml of ethanol and 2 ml of tetrahydrofuran were dissolved 730 mg (1.63 mmol) of 5-[2-(2-benzyloxy-4-dibutylaminophenyl)vinyl]thiophene-2-carboaldehyde and 380 mg (1.5 mmol) of 2-(3-cyano-4,5-dimethyl-5-trifluoromethyl-2(5H)-furanylidene)propanedinitrile. The mixture was stirred at room temperature for 19 hours and further stirred with heating at 50° C. for 6 hours. The solvent was evaporated off and the residue was washed with ethanol to give 860 mg of a dark reddish brown crystal (yield: 94.0%; mp: 184-185° C.)