Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][CH2:4][CH2:5][CH3:6].[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1O>>[CH3:14][CH:9]([NH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:1][C:2]=1[OH:7])[CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCC(C)=O
Reactant: Nc1ccccc1O
Product: CCCCC(C)Nc1ccccc1O
Reaction time: 5.33 h

Procedure:
The same procedure as in Example 3 was repeated except for using 145 mL (121 g; 1.2 mol) of 2-hexanone in place of 100 mL of acetone, to conduct the reaction. As a result, it was confirmed that the rate of conversion of o-aminophenol was 93%, the selectivity to the N-monoalkylated compound (molar ratio of the monoalkylated compound to a sum of the mono- and di-alkylated compounds) was 41%, and the oxygen absorption initiation time as an index of determining an oxidation-inhibiting property thereof was 320 min.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][OH:11].[N+:12]([C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1)([O-:14])=[O:13]>N1C=CC=CC=1>[N+:12]([C:15]1[CH:23]=[CH:22][C:18]([C:19]([CH:2]([NH2:1])[CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:10][O:11][C:19](=[O:20])[C:18]2[CH:17]=[CH:16][C:15]([N+:12]([O-:14])=[O:13])=[CH:23][CH:22]=2)=[O:20])=[CH:17][CH:16]=1)([O-:14])=[O:13]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: NCCc1ccccc1CO
Solvent: c1ccncc1
Product: NC(Cc1ccccc1COC(=O)c1ccc([N+](=O)[O-])cc1)C(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.3 %

Procedure:
1-Amino-2-(2-hydroxymethylphenyl)ethane (10.2 g) was dissolved in 40 ml of pyridine, and with stirring under ice cooling, 25 g of 4-nitrobenzoyl chloride was added gradually. The mixture was stirred at room temperature for 4 hours and then at 50° C. for 1 hour, and poured into ice water. The crystals precipitated were washed in water, dried, and recrystallized from tetrahydrofuran-benzene to afford 24.3 g of 1-(4-nitrobenzoyl)-amino-2-[2-(4-nitrobenzoyloxymethyl)phenyl]ethane having a melting point of 168.2° to 169.7° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:29][CH3:30])=[C:5]([O:27][CH3:28])[C:6]2[N:12](C(OCC(Cl)(Cl)Cl)=O)[C@@H:11](O)[C@@H:10]3[CH2:22][CH2:23][CH2:24][N:9]3[C:8](=[O:25])[C:7]=2[CH:26]=1>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3]1[C:4]([O:29][CH3:30])=[C:5]([O:27][CH3:28])[C:6]2[N:12]=[CH:11][CH:10]3[CH2:22][CH2:23][CH2:24][N:9]3[C:8](=[O:25])[C:7]=2[CH:26]=1
Reactant: COc1cc2c(c(OC)c1OC)N(C(=O)OCC(Cl)(Cl)Cl)[C@@H](O)[C@@H]1CCCN1C2=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc2c(c(OC)c1OC)N=CC1CCCN1C2=O
Reaction time: 0.67 h
Yield: 95.2 %

Procedure:
10% Cd/Pb couple (1.25 g, 10 mmol Cd) was added to a rapidly stirring solution of the Troc-carbamate, 119 (1.00 g, 2.1 mmol) in a mixture of THF (13 mL) and 1N NH4OAc (B mL). Upon addition, the reaction mixture went cloudy. After 40 minutes, TLC showed the reaction to be complete and the reaction mixture was diluted with EtOAc (200 mL). The solution was dried over anhydrous MgSO4 and the solids were filtered and rinsed with EtOAc (50 mL). Evaporation of the solvent yielded the product as a yellow glass (0.581 g, 2.0 mmol). 1H NMR (270 MHz, CDCl3) δ 7.73 (d, 1H, J=4.57 Hz), 7.08 (s, 1H), 4.0-3.4 (m, 12H), 2.4-1.8 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=O)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[ClH:27].Cl.[NH2:29][CH2:30][CH2:31][O:32][NH2:33].N1C=CC=CC=1>C(O)C>[ClH:27].[ClH:27].[NH2:29][CH2:30][CH2:31][O:32][N:33]=[C:17]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:16][CH2:15][CH2:14][N:11]1[CH2:12][CH2:13][CH:8]([C:6](=[O:7])[C:5]2[CH:25]=[CH:26][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:9][CH2:10]1
Reactant: NCCON
Reactant: O=C(CCCN1CCC(C(=O)c2ccc(F)cc2)CC1)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: NCCON=C(CCCN1CCC(C(=O)c2ccc(F)cc2)CC1)c1ccccc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
A mixture of 4-[4-(4-fluorobenzoyl)-1-piperdinyl]-1-phenyl-1-butanone (5.00 g), O-(2-aminoethyl)hydroxylamine dihydrochloride (2.21 g), 3 equivalents of pyridine, and absolute ethanol (75 ml) was stirred at 60° C., overnight, under nitrogen. The reaction mixture was evaporated, toluene was added and evaporated. The reaction mixture was partitioned between 10% sodium hydroxide solution and ethyl acetate. The layers were separated and the aqueous phase extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. The residue was purified by flash chromatography (180:19:1 dichloromethane/methanol/ammonium hydroxide). The appropriate fractions were collected and evaporated. The residue was dissolved in absolute ethanol and treated with ethereal hydrogen chloride. Diethyl ether was added. The precipitate was collected and recrystallized twice from absolute ethanol/ether to give 2.3 g (34%) of product, mp 110°-115° C. (dec).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[N:6][C:7]=1[CH3:8].C[Li].C([Li])(C)(C)C.N1([CH:34]=[O:35])CCCCC1>O1CCCC1>[CH3:8][C:7]1[C:2]([CH:34]=[O:35])=[CH:3][CH:4]=[C:5]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[N:6]=1
Reactant: Cc1nc(NCc2ccc(C(F)(F)F)cc2)ccc1Br
Reactant: O=CN1CCCCC1
Agent: [Li]C
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: Cc1nc(NCc2ccc(C(F)(F)F)cc2)ccc1C=O
Temperature: 78 °C
Reaction time: 2 h

Procedure:
(5-Bromo-6-methyl-pyridin-2-yl)-(4-trifluoromethyl-benzyl)-amine (34, 1.7 g, 4.93 mmol) was dissolved in tetrahydrofuran (40 mL) and cooled at 78° C. under a nitrogen atmosphere. To this mixture was added methyllithium (1.6 M in diethyl ether, 5.91 mmol) dropwise over 20 minutes. After the addition of methyllithium was completed, the reaction mixture was stirred at −78° C. for 2 hours. To this mixture was added tert-butyllithium (1.7 M in pentane, 10.85 mmol) and the mixture was stirred for 4 hours. The reaction mixture was maintained at −78° C., and 1-piperidinecarboxaldehyde (0.60 mL, 5.42 mmol) was added dropwise. The reaction was allowed to stir at −78° C. for an additional 2 hours and warming to 25° C. was achieved from the slow evaporation of the dry ice/acetone cooling bath. The reaction was quenched with ice cold saturated sodium chloride and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and filtered. Concentration under reduced pressure afforded an orange oil (35, 1.4 g, 4.93 mmol).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH2:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16](N1C=CN=C1)(N1C=CN=C1)=[S:17]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]=[C:16]=[S:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CN=C=S)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.1 %

Procedure:
To a solution of 1-(t-butyloxycarbonyl)-4-(aminomethyl)piperidine (2.14 g) in N,N-dimethylformamide (20 ml) was added 1,1′-thiocarbonyldiimidazole (1.87 g), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was poured into ice water (100 ml), and extracted with ethyl acetate (100 ml). The extract was washed successively with 0.5M hydrochloric acid, 1M aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=4/1) to give [1-(t-butyloxycarbonyl)piperidin-4-yl]methyl isothiocyanate (1.64 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19])#[N:2].[CH3:20][C:21](C)([O-:23])[CH3:22].[K+].C(C1OC1)Br>CC(N(C)C)=O>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH2:20][CH:21]1[CH2:22][O:23]1)#[N:2]
Reactant: CC(C)(C)[O-]
Reactant: N#Cc1ccccc1CCCCc1ccccc1O
Agent: BrCC1CO1
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: N#Cc1ccccc1CCCCc1ccccc1OCC1CO1
Yield: 89 %

Procedure:
Following a procedure similar to that described in Example 1(a), 634 mg of 2-[4-(2-cyanophenyl)butyl]phenol (prepared as described in Preparation 11), 283 mg of potassium t-butoxide and 345 mg of epibromohydrin were reacted in 6 ml of dimethylacetamide. The crude product, extracted as described in Example 1, was purified as described in Example 1, to give 690 mg (yield 89%) of the title compound as an oil.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].C([Li])CCC.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>O1CCCC1>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][C:22]([OH:25])([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(C#C[Si](C)(C)C)CC1
Temperature: -40 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To a cooled (-40° C.) solution of trimethylsilylacetylene (34 ml 241 mmol) in anhydrous tetrahydrofuran (400 ml) under an atmosphere of nitrogen was added slowly n-butyl lithium (96 ml of a 2.5. M solution in hexanes, 241 mmol). After addition the mixture was stirred at -40° C. for 1 hour then cooled to -78° C. To this mixture was added via a cannula a solution of 1-tert-butyloxycarbonyl-4-piperidone (40 g, 201 mmol) in anhydrous tetrahydrofuran (250 ml). After addition the mixture was stirred at -78° C. for 1 hour, the cooling bath removed and the mixture stirred at room temperature for 72 hours. The reaction was quenched by the addition of saturated aqueous ammonium chloride (300 ml), stirred for a further 10 minutes and poured into water (500 ml) and extracted with ethyl acetate (3×300 ml). The combined organic solutions were washed with water (500 ml), brine (300 ml), dried (MgSO4) and evaporated to afford the title compound (55 g, 92%); mp 75° C.; δH (250 MHz, CDCl3) 0.19 (9H, s), 1.48 (9H, s), 1.63-1.74 (2H, m), 1.80-1.92 (2H, m), 3.18-3.28 (2H, m), 3.71-3.84 (2H, m); mlz (ES) 298 (M+ +1).
Reaction SMILES: [C:1]([NH:7][NH:8][C:9]([NH:11][C@H:12]([C:16]([O:18][CH3:19])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])(=O)[CH2:2][CH2:3][CH:4]=[CH2:5].O.C([O-])(O)=O.[Na+]>O=P(Cl)(Cl)Cl>[CH2:2]([C:1]1[O:10][C:9]([NH:11][C@H:12]([C:16]([O:18][CH3:19])=[O:17])[CH:13]([CH3:15])[CH3:14])=[N:8][N:7]=1)[CH2:3][CH:4]=[CH2:5]
Reactant: C=CCCC(=O)NNC(=O)N[C@H](C(=O)OC)C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: C=CCCc1nnc(N[C@H](C(=O)OC)C(C)C)o1
Temperature: 0 °C

Procedure:
Methyl N-[(2-pent-4-enoylhydrazino)carbonyl]-L-valinate (from Step 3) was heated at 80° C. for 2 h in POCl3 (0.1 M solution). The mixture was cooled at 0° C. and water was carefully added. Solid NaHCO3 was added until the mixture reached pH 7, then the mixture was extracted with EtOAc and the organic layer dried over Na2SO4 to obtain a pale yellow oil. 1H NMR (400 MHz, DMSO-d6) δ: 8.42 (d, J 15.7, 1H), 5.88-5.78 (m, 1H), 5.08 (d, J 17.2, 1H), 5.01 (d, J 10.3, 1H), 4.04 (dd, J 7.1, 14.2, 1H), 3.64 (s, 3H), 2.75 (t, J 7.3, 2H), 2.39 (m, 2H), 2.13-2.06 (m, 1H), 0.94 (d, J 3.9, 3H), 0.92 (d, J 3.9, 3H). MS (ES+) C12H19N3O3 requires: 253 found: 254 (M+H+).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[Cl:23][C:24]1[C:32]2[N:31]=[C:30]3[N:33]([C:37]4[C:38]([CH3:46])=[N:39][C:40]([O:44][CH3:45])=[N:41][C:42]=4[CH3:43])[CH2:34][CH2:35][CH2:36][N:29]3[C:28]=2[C:27]([CH:47]([OH:50])[CH2:48][CH3:49])=[CH:26][CH:25]=1>CS(C)=O.C(#N)C.C(=O)([O-])O.[Na+]>[Cl:23][C:24]1[C:32]2[N:31]=[C:30]3[N:33]([C:37]4[C:38]([CH3:46])=[N:39][C:40]([O:44][CH3:45])=[N:41][C:42]=4[CH3:43])[CH2:34][CH2:35][CH2:36][N:29]3[C:28]=2[C:27]([C:47](=[O:50])[CH2:48][CH3:49])=[CH:26][CH:25]=1
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(C)nc(OC)nc1C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CS(C)=O
Product: CCC(=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(C)nc(OC)nc1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.1 %

Procedure:
Dess-Martin reagent (207 mg, 0.487 mmol) was added to a stirred solution of 1-[9-chloro-1-(2-methoxy-4,6-dimethylpyrimidin-5-yl)-1,2,3,4-tetrahydropyrimido [1,2- a]benzimidazol-6-yl]propan-1-ol (178 mg, 0.443 mmol) in dimethyl sulfoxide (1.0 mL) and acetonitrile (3.0 mL) at 0 ° C., and the mixture was stirred at 0 ° C. for 30 min. The mixture was diluted with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the title compound as a yellow solid (172 mg, 0.430 mmol, 97%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=[CH:5]2.C(N(CC)CC)C.Cl[Si:24]([C:37]([CH3:40])([CH3:39])[CH3:38])([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:40][C:37]([Si:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=[CH:5]2)([CH3:38])[CH3:39]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1cccc2cc(O)ccc12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc2cc(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 6-hydroxy-1-naphthalenecarboxylic acid, methyl ester (1.01 g, 5 mmol), triethylamine (1.55 mL, 6 mmol) and N,N-dimethyl-4-pyridineamine (0.30 g, 2.5 mmol) in CH2Cl2 (25 mL) is treated with a solution of chloro(1,1-dimethylethyl)diphenylsilane (1.55 mL, 6 mmol) in CH2Cl2 (10 mL) and stirred at room temperature overnight. The mixture is washed with saturated aqueous NaHCO3, dried (Na2SO4) and solvent is evaporated off under reduced pressure to give a residue, which is purified by column chromatography (SiO2; hexane/CH2Cl2 1:1) to afford the title compound as an oil.
Reaction SMILES: Cl.O1CCOCC1.C(O[C:13](=O)[N:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[N:25]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[O:38][C:39]([F:42])([F:41])[F:40])[N:26]=[CH:27][C:28]=2[CH:29]2[CH2:31][CH2:30]2)=[CH:18][C:17]=1[CH3:43])C)(C)(C)C>C(Cl)Cl>[CH:29]1([C:28]2[CH:27]=[N:26][N:25]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[O:38][C:39]([F:42])([F:40])[F:41])[C:24]=2[CH2:23][O:22][C:19]2[CH:20]=[CH:21][C:16]([NH:14][CH3:13])=[C:17]([CH3:43])[CH:18]=2)[CH2:31][CH2:30]1
Reactant: Cc1cc(OCc2c(C3CC3)cnn2-c2ccccc2OC(F)(F)F)ccc1N(C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CNc1ccc(OCc2c(C3CC3)cnn2-c2ccccc2OC(F)(F)F)cc1C
Reaction time: 2 h
Yield: 96.9 %

Procedure:
HCl/dioxane (4 N, 3.7 mL) is added to a solution of {4-[4-cyclopropyl-2-(2-trifluoromethoxy-phenyl)-2H-pyrazol-3-ylmethoxy]-2-methyl-phenyl}-methyl-carbamic acid tert-butyl ester (1.92 g, 3.71 mmol) in methylene chloride (40 mL) at room temperature. After 2 h of stirring, the mixture is concentrated and worked up with ethyl acetate and saturated aqueous sodium bicarbonate. The organic layers are washed with brine and dried over sodium sulfate to provide 1.50 g (97%) of the title compound as an oil. MS m/e 418.0 (M+1).
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:14][CH2:15][CH:16]([OH:18])[CH3:17].[C:19](OC(=O)C)(=[O:21])[CH3:20]>N1C=CC=CC=1>[C:19]([O:18][CH:16]([CH2:15][CH2:14][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:12][C:13]=2[CH:1]=1)[CH3:17])(=[O:21])[CH3:20]
Reactant: CC(O)CCc1ccc2c(c1)Cc1ccccc1-2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC(C)CCc1ccc2c(c1)Cc1ccccc1-2
Yield: 90 %

Procedure:
To 4.72 grams of 4-(2-fluorenyl)-butan-2-ol were added 1.74 grams of pyridine and 2.24 grams of acetic anhydride and the mixture was heated to reflux for 25 hours. An excess of acetic anhydride and pyridine was removed by evaporation, the residue was subjected to a silica gel column chromatography, the column was eluted with a 4:1 mixture of n-hexane and ethyl acetate, and the resulting crystals were recrystallized from n-hexane to give 5 grams of 4-(2-fluorenyl)-butan-2-ol acetate, white crystals, m.p. 63°-64.5° C.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22](Br)=[C:21]([CH2:26][C:27]3[S:28][C:29]([C:32]4[O:33][CH:34]=[CH:35][CH:36]=4)=[CH:30][N:31]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:37][O:38][C:39](=[O:41])[CH3:40])(=[O:3])[CH3:2].[CH:42]1(B(O)O)[CH2:44][CH2:43]1.F[B-](F)(F)F.C1([PH+](C2CCCCC2)C2CCCCC2)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([CH:42]3[CH2:44][CH2:43]3)=[C:21]([CH2:26][C:27]3[S:28][C:29]([C:32]4[O:33][CH:34]=[CH:35][CH:36]=4)=[CH:30][N:31]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:37][O:38][C:39](=[O:41])[CH3:40])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Br)c(Cc3ncc(-c4ccco4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC([PH+](C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(C3CC3)c(Cc3ncc(-c4ccco4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 19.9 %

Procedure:
The bromide 58 (300 mg, 0.46 mmol) was added to a microwave reaction tube containing cyclopropylboronic acid (86.9 mg, 1.01 mmol), palladium(II) acetate (31 mg, 46 μmol), tricyclohexylphosphonium tetrafluoroborate (68 mg, 0.18 mmol) and cesium carbonate (601 mg, 1.84 mmol) in dioxaone (5 mL). The capped reaction tube was placed in a microwave reactor and the mixture irradiated at 150° C. for 25 min. After dilution with EtOAc, the organic layer was washed with water and brine prior to drying over anhydrous MgSO4. After filtration and concentration under reduced pressure, the residue was purified by silica column chromatography to provide the cyclopropane 60 (56 mg, 20%) as a yellow oil. MH+612.
Reaction SMILES: [C:1]([C:4]1[C:8]([CH3:9])=[C:7]([Cl:10])[S:6][C:5]=1[Cl:11])(=[O:3])[CH3:2].[N:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.O.C(=O)(O)[O-].[Na+]>COCCOC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[C:1]([C:4]1[C:8]([CH3:9])=[C:7]([Cl:10])[S:6][C:5]=1[Cl:11])(=[O:3])[CH3:2].[C:1]([C:4]1[C:8]([CH3:9])=[C:7]([C:15]2[CH:16]=[CH:17][N:12]=[CH:13][CH:14]=2)[S:6][C:5]=1[C:15]1[CH:16]=[CH:17][N:12]=[CH:13][CH:14]=1)(=[O:3])[CH3:2]
Reactant: OB(O)c1ccncc1
Agent: Cl[Pd]Cl
Agent: CC(=O)c1c(Cl)sc(Cl)c1C
Agent: O=C([O-])O
Solvent: COCCOC
Solvent: O
Product: CC(=O)c1c(-c2ccncc2)sc(-c2ccncc2)c1C

Procedure:
3-Acetyl-2,5-dichloro-4-methylthiophene was prepared according the method of Eric C. Bigham, U.S. Pat. No. 4,110,342 (1978). To a stirred solution of 3-acetyl-2,5-dichloro-4-methylthiophene (593 mg, 2.84 mmol) in DME (15 mL) were added 4-pyridineboronic acid (0.87 g, 7.09 mmol). water (5 mL), sodium bicarbonate (1.76 g, 20.9 mmol) and bis(triphenylphosphine)-palladium(II)chloride (0.2 g, 0.28 mmol) at room temperature under nitrogen. The mixture was heated at reflux temperature for 8 hours. After cooling, 4-pyridineboronic acid (0.3 g, 2.44 mmol), sodium bicarbonate (0.6 g, 7.14 mmol) and bis(triphenylphosphine)-palladium(II)chloride (0.1 g, 0.14 mmol) were added to the reaction mixture. The mixture was heated at reflux temperature for additional 3 hours. After cooling, the reaction mixture was filtered through celite pad. The filtrate was extracted with ethyl acetate (100 mL×2), and the combined organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo. The resulting residue was purified by flash chromatography eluting with hexane-ethyl acetate (1:2) to provide the title product as a solid. Recrystallized from ethyl acetate gave the title product (468 mg, 56% yield).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9])=[O:4].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:22].Cl.C(N(CC)CC)C>C(#N)C>[CH3:11][O:10][C:8]([C:7]1[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=1[NH:5][C:3](=[O:4])[CH2:2][N:26]1[CH2:27][CH2:28][N:23]([C:21](=[O:22])[C:20]2[CH:29]=[CH:30][C:31]([O:32][CH3:33])=[C:18]([O:17][CH3:16])[CH:19]=2)[CH2:24][CH2:25]1)=[O:9]
Reactant: COC(=O)c1ccccc1NC(=O)CCl
Reactant: COc1ccc(C(=O)N2CCNCC2)cc1OC
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1ccccc1NC(=O)CN1CCN(C(=O)c2ccc(OC)c(OC)c2)CC1

Procedure:
10.06 Grams of methyl o-(α-chloroacetylamino)benzoate, 15.2 g of N-(3,4-dimethoxybenzoyl)piperzine.monohydrochloride and 16 g of triethylamine were suspended in 55 ml of acetonitrile, and the mixture was reacted at 49°-50° C. for 4 hours. After completion of the reaction, the reaction mixture was ice-cooled, and the crystals formed were collected by filtration. Recrystallized from ethanol to obtain 14.68 g of o-methoxycarbonyl-α-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]acetanilide in the form of colorless needle-like crystals. Melting point: 167.5°-169.0° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.Cl[C:20]1[S:21][C:22]([CH:26]=[O:27])=[C:23]([Cl:25])[N:24]=1.O>O1CCCC1>[Cl:25][C:23]1[N:24]=[C:20]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=2)[S:21][C:22]=1[CH:26]=[O:27]
Reactant: O=Cc1sc(Cl)nc1Cl
Reactant: NCc1ccc(Cl)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=Cc1sc(NCc2ccc(Cl)cc2)nc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.2 %

Procedure:
To a solution of p-chlorobenzylamine (61, 283 mg, 2.00 mmol) and N,N-Diisopropylethylamine (0.697 mL) in tetrahydrofuran (20 mL) was slowly added 2,4-Dichloro-thiazole-5-carbaldehyde (93, 364 mg, 2.00 mmol) in tetrahydrofuran (10 mL) at room temperature. The reaction was stirred at room temperature overnight. The reaction mixture was poured into iced water, extracted with ethyl acetate, washed with brine, and dried over sodium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexane to provide the compound as a yellow solid (94, 0.3 g, 50%). MS (ESI) [M−H+]=286.97.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[S:14][C:15]([C:22]#[N:23])=[C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])[N:17]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[S:14][C:15]([C:22]#[N:23])=[C:16]([C:18]([CH3:19])([CH3:21])[CH3:20])[N:17]=1)=[O:9]
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: CC(C)(C)c1nc(N)sc1C#N
Product: CC(C)(C)c1nc(NC(=O)c2cc(Cl)ccc2O)sc1C#N
Yield: 63.4 %

Procedure:
Using 5-chlorosalicylic acid and 2-amino-5-cyano-4-[(1,1-dimethyl)-ethyl]thiazole as the raw materials, the same operation as the Example 16 gave the title compound.