Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:5]2.[NH:18]1[CH2:22][CH2:21][CH2:20][C:19]1=[O:23].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd]>[O:23]=[C:19]1[CH2:20][CH2:21][CH2:22][N:18]1[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:5]2
Reactant: CC(C)(C)OC(=O)n1ccc2cc(I)ccc21
Reactant: O=C1CCCN1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)n1ccc2cc(N3CCCC3=O)ccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 61.9 %

Procedure:
To a stirred mixture of tert-butyl 5-iodo-1H-indole-1-carboxylate (1.5 g, 4.3 mmol), Xant Phos (0.25 g, 0.43 mmol) and 2-pyrrolidinone (0.74 g, 8.7 mmol) in anhydrous dioxane (15 mL), cesium carbonate (2.8 g, 8.7 mmol) was added and the contents were stirred for 5 minutes. Tris(dibenzylideneacetone)-dipalladium (0)chloroform adduct (0.452 g, 0.437 mmol) was added and the reaction mixture was stirred at 110-115° C. for 6 h. The reaction mixture was cooled to room temperature and filtered over celite and filtrate was extracted with ethyl acetate. The organic layer was concentrated in vacuo and the residue was purified by flash column chromatography to yield tert-butyl 5-(2-oxopyrrolidin-1-yl)-1H-indole-1-carboxylate (0.80 g, 61%); MS: 301 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH:16](N)=O>O>[N:11]1([C:8]2[CH:7]=[C:3]3[C:2](=[CH:10][CH:9]=2)[N:1]=[CH:16][NH:6][C:4]3=[O:5])[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: NC=O
Reactant: NC(=O)c1cc(-n2ccnc2)ccc1N
Solvent: O
Product: O=c1[nH]cnc2ccc(-n3ccnc3)cc12
Temperature: 160 °C

Procedure:
A mixture of 2-amino-5-(1-imidazolyl)benzamide (12.0 g) and formamide (30 ml) was heated at 160° C. for 3 hours. The mixture was cooled and added to water. The precipitate was filtered off and washed with water to give 6-(1-imidazolyl)-3,4-dihydroquinazolin-4-one (7.5 g); NMR Spectrum: (CD3SOCD3) 7.15 (s, 1H), 7.80 (s, 1H), 7.90 (s, 1H), 8.13 (m, 2H), 8.26 (d, 1H), 8.41 (s, 1H);
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][C:9]1[CH:14]=[CH:13][C:12](/[C:15](/[C:22]2[NH:27][C:26](=[O:28])[C:25]([Cl:29])=[CH:24][CH:23]=2)=[CH:16]\[CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:11][CH:10]=1.C(=O)(O)[O-].[Na+]>>[Cl:29][C:25]1[C:26](=[O:28])[NH:27][C:22](/[C:15](/[C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:5](=[O:7])[CH3:6])=[CH:10][CH:11]=2)=[CH:16]/[CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:23][CH:24]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(/C(=C\C2CCCC2)c2ccc(Cl)c(=O)[nH]2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(=O)Nc1ccc(/C(=C\C2CCCC2)c2ccc(Cl)c(=O)[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 38 %

Procedure:
Acetic anhydride (5 mL) was added to 6-[(E)-1-(4-aminophenyl)-2-cyclopentylethenyl]-3-chloropyridin-2(1H)-one (173 mg), and the mixture was stirred at room temperature for 15 minutes. Saturated aqueous sodium bicarbonate was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1→0:1). This was powdered with ethyl acetate, and filtration operation gave the title compound as a light yellow powder (75 mg, 38%).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].C([N:14](CC)CC)C.S(Cl)(Cl)=O>O1CCCC1>[Br:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:14])=[O:6]
Reactant: O=C(O)c1cccc(Br)c1F
Reactant: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: NC(=O)c1cccc(Br)c1F
Reaction time: 1 h
Yield: 46.9 %

Procedure:
To a solution of 3-bromo-2-fluorobenzoic acid (3.77 g, 17.2 mmol) in dry tetrahydrofuran (200 ml) was added triethylamine (4.77 ml, 34.4 mmol) and thionyl chloride (1.69 ml, 21.5 mmol). The reaction mixture was stirred for 1 h and then quenched with ammonia in methanol (10 ml, saturated). After an additional hour of stirring the mixture was evaporated and the crude product was purified by flash column chromatography (ethyl acetate/isooctane 1:1) to give the title compound (1.76 g). MS m/z (rel. intensity, 70 eV) 219 (M+, 26), 217 (M+, 26), 203 (62), 201 (70), 94 (bp).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@@H:2]([C:20]([NH:22][CH2:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])=[O:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C@@H:2]([C:20]([NH:22][CH2:23][C:24]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:25])=[O:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]([CH3:16])=[CH:17][CH:18]=1)(=[O:11])=[O:10]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)OCc2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@@H](N)C(=O)NCC(=O)OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A 1 g portion of Boc-(D)-Arg(Tos)-Gly-OBn (1.74 mmol) was dissolved in 10 mL of CH2Cl2, cooled to 0° C. and treated with 10 mL of TFA. The solution was stirred at 0° C. for 3 h. Solvent and excess TFA were evaporated thoroughly to give the title compound as an oil which was used directly in Example 10.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][C:11]1[C:19]([CH3:20])=[C:18]([CH3:21])[C:17]([CH3:22])=[C:16]2[C:12]=1[CH2:13][C:14](=[N:24]O)[C:15]2=[O:23].C(N(CC)CC)C>ClCCl>[CH3:10][C:11]1[C:19]([CH3:20])=[C:18]([CH3:21])[C:17]([CH3:22])=[C:16]2[C:12]=1[CH2:13][CH:14]([NH:24][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:15]2=[O:23]
Reactant: Cc1c(C)c(C)c2c(c1C)CC(=NO)C2=O
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(C)c(C)c2c(c1C)CC(NC(=O)c1ccccc1)C2=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Benzoyl chloride (1.635 g) is added dropwise to 4,5,6,7-tetramethyl-indan-1,2-dione 2-oxime (2.53 g) and triethylamine (2.25 g) in anhydrous dichloromethane (60 ml) at 0° C. The reaction mixture is stirred at room temperature for 1.5 hours after which the solid product is filtered off and allowed to stir with water (150 ml), refiltered and dried. The organic filtrate is washed with 1M HCl, 10% brine, saturated sodium bicarbonate solution, 10% brine and treated with magnesium sulphate. After filtration, the solvent is removed in vacuo and the product triterated with diethyl ether, filtered and dried.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH:4]=[CH2:5].[NH2:7][CH2:8][CH2:9][CH:10]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[O:12][C:11]1([CH3:21])[CH3:20]>CO>[CH3:20][C:11]1([CH3:21])[CH:10]([CH2:9][CH2:8][N:7]([CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:6])[CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:6])[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[O:12]1
Reactant: C=CC(=O)OC
Reactant: CC1(C)Oc2ccccc2CC1CCN
Solvent: CO
Product: COC(=O)CCN(CCC(=O)OC)CCC1Cc2ccccc2OC1(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4.74 g (55 mmol) of acrylic acid methyl ester are added at room temperature to a solution of 5.13 g (25 mmol) of 3-(2-aminoethyl)-2,2-dimethyl-chroman in 50 ml of methanol. The mixture is stirred for 16 hours at room temperature and then concentrated by evaporation in vacuo, yielding 9.43 g (100% of the theoretical yield) of N-[2-(2,2-dimethylchroman-3-yl)-ethyl]-N,N-bis(2-methoxycarbonylethyl)-amine in the form of a light-yellow oil which is further used in that form.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:14]([F:17])([F:16])[F:15])[CH:3]=1.[H][H]>[Pd].C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:14]([F:15])([F:16])[F:17])[CH:3]=1
Reactant: COC(=O)/C=C/c1ccc(Cl)cc1C(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)CCc1ccc(Cl)cc1C(F)(F)F
Yield: 99.2 %

Procedure:
A mixture of (E)-methyl 3-(4-chloro-2-(trifluoromethyl)phenyl)acrylate (5 g) and palladium on charcoal (10%, dry, 2 g) in ethyl acetate (50 ml) was stirred under balloon hydrogen pressure for 3 hours. After filtration, filtrate was concentrated to give methyl 3-(4-chloro-2-(trifluoromethyl)-phenyl)propanoate (5 g).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:3]=1[CH2:4][NH:5][CH2:6][CH3:7].Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)=[O:18]>>[F:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][O:19][C:17](=[O:18])[N:5]([CH2:4][C:3]2[CH:8]=[C:9]([C:12]([F:13])([F:14])[F:15])[CH:10]=[CH:11][C:2]=2[Br:1])[CH2:6][CH3:7])=[CH:26][CH:25]=1
Reactant: CCNCc1cc(C(F)(F)F)ccc1Br
Reactant: O=C(Cl)OCc1ccc(F)cc1
Product: CCN(Cc1cc(C(F)(F)F)ccc1Br)C(=O)OCc1ccc(F)cc1

Procedure:
Prepared according to the procedure described in Example 56, Step 2, using the following starting materials: (2-bromo-5-trifluoromethyl-benzyl)-ethyl-amine and 4-fluorobenzyl chloroformate.
Reaction SMILES: [C:1]([O:6][CH2:7][CH:8]=[O:9])(=[O:5])[CH2:2][CH2:3][CH3:4].CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.[SH:25][CH2:26][C:27](O)=[O:28]>C(Cl)Cl>[C:1]([O:6][CH2:7][CH:8]1[S:25][CH2:26][C:27](=[O:28])[O:9]1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)CS
Reactant: CCCC(=O)OCC=O
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: ClCCl
Product: CCCC(=O)OCC1OC(=O)CS1
Reaction time: 16 h
Yield: 44 %

Procedure:
To a well-stirred suspension of 24 (1.3 g, 10 mmol) and CSA (116 mg, 0.50 mmol) in dry DCM (10 ml) was slowly added a solution of mercaptoacetic acid (2.76 g, 2.08 ml, 30 mmol) in dry DCM (5 ml). The reaction was left at room temperature for 16 hours with stirring. The reaction mixture was diluted with DCM (20 ml) and successively washed with: concentrated NaHCO3 (3×30 ml) and brine (2×30 ml), dried, filtered and evaporated to afford 25 (0.9 g, 4.4 mmol, 44%) as a colorless syrup.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[N:20]1[N:24]2[CH:25]=[CH:26][CH:27]=[N:28][C:23]2=[C:22]([C:29](O)=[O:30])[CH:21]=1.C1C=CC2N(O)N=NC=2C=1.O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:19][C:2]([F:1])([F:18])[C:3]1[CH:4]=[CH:5][C:6]([S:9]([N:12]2[CH2:17][CH2:16][N:15]([C:29]([C:22]3[CH:21]=[N:20][N:24]4[CH:25]=[CH:26][CH:27]=[N:28][C:23]=34)=[O:30])[CH2:14][CH2:13]2)(=[O:10])=[O:11])=[CH:7][CH:8]=1
Reactant: O=C(O)c1cnn2cccnc12
Reactant: O=S(=O)(c1ccc(C(F)(F)F)cc1)N1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1cnn2cccnc12)N1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 106.1 %

Procedure:
To a solution of 1-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine (may be prepared as described in Description 1) (200 mg, 0.680 mmol) in DMF (5 ml) was added pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (111 mg, 0.680 mmol), HOBT.H2O (104 mg, 0.680 mmol) and HBTU (258 mg, 0.680 mmol). Finally DIPEA (0.356 ml, 2.039 mmol) was added and the reaction mixture was stirred at rt for 20 hours. Solvent was removed by evaporation, the crude partitioned between DCM (50 ml) and saturated aq. sodium bicarbonate (50 ml), the DCM layer collected, dried (hydrophobic frit) and evaporated. MDAP purification yielded the title compound (317 mg) as an off-white solid.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([O:14][C:13]([C:12]1[CH:11]=[CH:10][C:9]([CH2:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[CH:17][CH:16]=1)=[O:15])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)Cc1ccc(C(=O)O)cc1
Product: CC(C)(C)OC(=O)Cc1ccc(C(=O)OCc2ccccc2)cc1

Procedure:
In a manner similar to Example 7(a), by reaction of 3 g (12.7 mmol) of 4-(tert-butoxycarbonylmethyl)benzoic acid prepared in Example 29(a) with 1.6 ml (14 mmol) of benzyl bromide, 3.2 g (77%) of the benzyl ester are obtained in the form of a slightly yellow oil.
Reaction SMILES: [CH:1]1([N:7]2[C:11](=[O:12])[CH2:10][CH:9]([C:13](O)=[O:14])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B.C1COCC1>C(Cl)Cl>[CH:1]1([N:7]2[CH2:8][CH:9]([CH2:13][OH:14])[CH2:10][C:11]2=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C1CC(=O)N(C2CCCCC2)C1
Agent: B
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C1CC(CO)CN1C1CCCCC1
Temperature: 0 °C
Yield: 65.4 %

Procedure:
Place 2-methylene-succinic acid (12.0 g, 92.2 mmol) and cyclohexylamine (9.15 g, 92.2 mmol) and heat to 160° C. for hours. Cool to give 18.8 g (96%) of 1-cyclohexyl-5-oxo-pyrrolidine-3-carboxylic acid. Charge a flask with 1-cyclohexyl-5-oxo-pyrrolidine-3-carboxylic acid (16.2 g, 76.7 mmol), add methylene chloride (20 mL) and cool to 0° C. Slowly add borane in THF (1M, 115.1 mL, 115.1 mmol) and stir for two hours at 0° C. Quench the reaction with ice and extract with methylene chloride. Dry over sodium sulfate, filter, and concentrate. Purify by silica gel (1-5% methanol in methylene chloride) to yield 9.9 g (65%) of the title compound: Mass spectrum (apci) m/z=198.1 (M+H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]#[C:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1)(=O)C.Cl>CO.O>[N:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:27]=[CH:28][C:19]=1[C:18]#[C:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[OH:10]
Reactant: CC(=O)Oc1ccccc1C#Cc1ccc2ccccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Oc1ccccc1C#Cc1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.4 %

Procedure:
Potassium carbonate (0.48 g, 3.48 mmol, 2.0 eq.) was added to a stirred solution of 2-(quinolin-2-ylethynyl)phenyl acetate (0.50 g, 1.74 mmol, 1.0 eq.) in a 1:1 mixture of methanol-water (10 mL). The resulting mixture was stirred at r.t. for 3 h. The reaction was poured onto water (50 mL) and the pH was adjusted to 7.0 by careful addition of aqueous hydrochloric acid (10%). The mixture was extracted with ethyl acetate (3×25 mL). The combined organic extracts were washed with brine (25 mL), dried over sodium sulfate and were concentrated under reduced pressure yielding the product (0.42 g, 95%) as a pale yellow solid; 1H NMR (500 MHz, DMSO-d6) δ 6.87 (t, J=7.5 Hz, 1H, Ar), 6.97 (d, J=8.0 Hz, 1H, Ar), 7.30 (t, J=8.0 Hz, 1H, Ar), 7.50 (d, J=7.5 Hz, 1H, Ar), 7.63 (t, J=7.5 Hz, 1H, Ar), 7.69 (d, J=8.5 Hz, 1H, Ar), 7.81 (t, J=7.0 Hz, 1H, Ar), 8.00 (d, J=7.0 Hz, 1H, Ar), 8.01 (d, J=7.0 Hz, 1H, Ar), 8.40 (d, J=8.5 Hz, 1H, Ar), 10.23 (s, 1H, OH).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-])=O)[C:7](=[O:14])[N:6]([CH:15]([CH3:17])[CH3:16])[C:5]2=[O:18].CC(O)=O.[Cl:23][C:24]1[C:29]([CH:30]=O)=[C:28]([O:32][CH3:33])[N:27]=[CH:26][CH:25]=1>CO>[Cl:23][C:24]1[CH:25]=[CH:26][N:27]=[C:28]([O:32][CH3:33])[C:29]=1[C:30]1[NH:11][C:10]2=[CH:9][C:8]3[C:7](=[O:14])[N:6]([CH:15]([CH3:17])[CH3:16])[C:5](=[O:18])[C:4]=3[CH:3]=[C:2]2[N:1]=1
Reactant: CC(C)N1C(=O)c2cc(N)c([N+](=O)[O-])cc2C1=O
Reactant: COc1nccc(Cl)c1C=O
Solvent: CC(=O)O
Solvent: CO
Product: COc1nccc(Cl)c1-c1nc2cc3c(cc2[nH]1)C(=O)N(C(C)C)C3=O
Temperature: -50 °C
Reaction time: 16 h
Yield: 41.8 %

Procedure:
To a suspension of 5-amino-2-isopropyl-6-nitroisoindoline-1,3-dione (0.37 g) in 250 mL of MeOH was added 5 mL of AcOH. The resulting solution was degassed with argon and then charged with 10% Pd/C (0.12 g, 50% wet) and hydrogenated at 40 psi of hydrogen for 16 h. Another 2 mL of AcOH was added to the mixture and then solids were filtered off. The filtrate was cooled to −50° C. and a solution of 4-chloro-2-methoxynicotinaldehyde (0.31 g, 1.78 mmol) in 200 mL of MeOH was added dropwise under inert atmosphere. The resulting solution was allowed to warm up to rt and stirred for 16 h. Solvent was evaporated and the oily residue was purified by column chromatography (7.5% MeOH in dichloromethane) to give title compound as a solid (0.23 g, 29.3%). 1H NMR (500 MHz, CDCl3) δ 8.18 (s, 1H), 8.12 (d, 1H), 8.03 (s, 1H), 7.90 (d, 1H), 6.92 (d, 1H), 6.75 (d, 1H), 5.39 (s, 2H), 4.56 (p, 1H), 3.72 (s, 3H), 3.61 (s, 3H), 1.50 (d, 6H). ESI MS: m/z 371.1 (M+1).
Reaction SMILES: [H-].[Na+].[OH:3][C@H:4]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)[C@@H:5]1[N:9]([CH3:10])[C:8](=[O:11])[CH2:7][C@@H:6]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:23]I.O>CN(C=O)C>[CH3:23][O:3][C@H:4]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)[C@@H:5]1[N:9]([CH3:10])[C:8](=[O:11])[CH2:7][C@@H:6]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CI
Reactant: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1[C@H](O)c1cccs1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CO[C@H](c1cccs1)[C@H]1[C@@H](c2ccccc2)CC(=O)N1C
Reaction time: 0.5 h
Yield: 46.1 %

Procedure:
To a slurry of NaH (60%, 32 mg, 1.0 mmol) in DMF (15 mL) was added (±)-(4R*,5R*)-5-((1S)-hydroxy-2-thienylmethyl)-1-methyl-4-phenylpyrrolidin-2-one (Example 5 step 1, 250 mg, 0.9 mmol). The resulting mixture was stirred for 30 min, then methyl iodide (0.08 mL, 1.3 mmol) was added. After 2 h water was added and the resulting mixture was extracted with EtOAc, dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (EtOAc) to give (±)-(4R*,5R*)-5-((1S*)-methoxy-2-thienylmethyl)-1-methyl-4-phenylpyrrolidin-2-one (125 mg, 46%) as a white solid: mp 101-102° C.; TLC (EtOAc/hex) Rf 0.50.
Reaction SMILES: [C:1]([N:5]1[C:13]2[CH2:12][CH2:11][C:10]([CH3:18])([C:14]([O:16]C)=[O:15])[CH2:9][C:8]=2[C:7]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>C1COCC1>[C:1]([N:5]1[C:13]2[CH2:12][CH2:11][C:10]([CH3:18])([C:14]([OH:16])=[O:15])[CH2:9][C:8]=2[C:7]([C:19]2[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=2)=[N:6]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)C1(C)CCc2c(c(-c3ccncc3)nn2C(C)(C)C)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1(C(=O)O)CCc2c(c(-c3ccncc3)nn2C(C)(C)C)C1
Temperature: 80 °C

Procedure:
To methyl 1-tert-butyl-5-methyl-3-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxylate (1.1 g, 3.5 mmol) in THF (20 mL) was added LiOH (1 M, 10 mL, 10 mmol) and the reaction was heated at 80° C. for overnight. After removal of THF, HCl (1 N) was added until pH˜4 to 5. The product precipitated as white solid and was collected by filtration (1.0 g). LC-MS found 314.19 (M+H)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:13](O)[CH3:14])[CH:5]=[C:6]([CH3:12])[C:7]=1[O:8][C:9](=[O:11])[CH3:10].OS([O-])(=O)=O.[K+].C(C1C=CC=C(O)C=1O)(C)(C)C>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([CH3:12])[C:7]=1[O:8][C:9](=[O:11])[CH3:10])[CH:13]=[CH2:14]
Reactant: CC(=O)Oc1c(C)cc(C(C)O)cc1C
Agent: CC(C)(C)c1cccc(O)c1O
Agent: O=S(=O)([O-])O
Agent: [K+]
Product: C=Cc1cc(C)c(OC(C)=O)c(C)c1
Temperature: 187.5 °C
Yield: 81.8 %

Procedure:
(36.6 g, 0.30 mol) of 2,6-dimethylphenol are mixed in an Hastelloy C autoclave with 0.315 mol of acetic anhydride and 9 mols of hydrogen flouride. The temperature is raised to 50° C. and the reaction runs for 3 hours. After extraction and wash, 47.4 g of a gray to purple solid mass of 3,5-dimethyl4-hydroxyacetophenone is obtained. This solid is then esterified by refluxing with 4 mols of acetic anhydride for 19 hours. After removal of acetic acid and acetic anhydride by vacuum distillation the 3,5-dimethyl-4-acetoxyacetophenone is flash distilled to yield 47.7 g of a slightly yellow liquid. 0.1 mol of the 3,5-dimethyl-4-acetoxyacetophenone, 1.2 g of 5% Pd/C as catalyst and 100 ml ethanol are mixed in an autoclave and the autoclave is charged with hydrogen gas at a pressure of 215-220 mm Hg and the reaction is run for about 21/2 hours at a temperature of about 25°-30° C. Additional catalyst is added as needed. The catalyst is then removed and the ethanol evaporated to yield 21.5 g of a colorless oil which is (3,5-dimethyl-4-acetoxyphenyl)ethanol. 0.168 mol of (3,5-dimethyl-4-acetoxyphenyl)ethanol is added to a flask with 0.35 g KHSO4 and 0.5 g t-butyl catechol. The flask is heated to 185 to 190° C. at 1.5 to 2.0 mm Hg. A colorless liquid is distilled. After the addition of 0.15 g of t-butyl catechol, and redistillation, 26.1 g of 3,5- dimethyl-4-acetoxystyrene monomer is produced. The compound has a boiling point of 90°-91° C. at 0.5 mm of Hg and the yield is 81.8%.
Reaction SMILES: BrC1C=CC(N/[N:9]=[CH:10]/[CH:11]=[N:12]/[NH:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[F:21])=C(F)C=1>C1(C)C=CC=CC=1.FC(F)(F)S([O-])(=O)=O.[Cu+2].FC(F)(F)S([O-])(=O)=O>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([N:13]2[N:9]=[CH:10][CH:11]=[N:12]2)=[C:15]([F:21])[CH:16]=1
Reactant: Fc1cc(Br)ccc1N/N=C/C=N/Nc1ccc(Br)cc1F
Agent: [Cu+2]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: Cc1ccccc1
Product: Fc1cc(Br)ccc1-n1nccn1
Reaction time: 8 h
Yield: 73.9 %

Procedure:
Copper (II) trifluoromethanesulfonate (218 mg, 0.60 mmol) was added to a slurry of (1E,2E)-ethanedial bis[(4-bromo-2-fluorophenyl)hydrazone](2.61 g, 6.04 mmol) in toluene (25 mL). The reaction was heated to reflux and stirred at this temperature overnight. The reaction was allowed to cool and was filtered through celite, and the filter pad was washed with EtOAc (100 mL). The combined filtrates were washed with 1 N aq HCl (3×100 mL), water (100 mL), and brine (100 mL) and then dried (MgSO4), filtered and concentrated. The crude product was purified via flash chromatography using a Varian SF25-40 g column and an eluent of EtOAc in hexanes (0-50%) to afford the title compound as a yellow solid (1.08 g, 73.9%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.44 (ddd, 1 H) 7.47-7.54 (m, 1 H) 7.76 (t, 1 H) 7.90 (s, 2 H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1C=O.[CH3:10][O:11][CH:12]([O:15][CH3:16])[CH2:13][NH2:14]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[N:14]=[CH:13][CH:12]([O:15][CH3:16])[O:11][CH3:10]
Reactant: COC(CN)OC
Reactant: O=Cc1ccccc1Br
Solvent: Cc1ccccc1
Product: COC(C=Nc1ccccc1Br)OC

Procedure:
2-bromobenzaldehyde (18.4 g, 0.1 mol) and 2,2-dimethoxyethanamine (11.55 g, 0.11 mol) in 200 mL of toluene was heated to reflux for 4 hr. The reaction mixture was evaporated under vacuum to give an oil of 2-bromo-N-(2,2-dimethyoxyethylidene)aniline which was used for the next step without purification. The oil was dropped into 50 mL of concentrated H2SO4 and the mixture was heated to 130-140° C. for 30 mins, then the reaction mixture was poured into 500 mL if ice-water and adjust to pH˜8 with 5N sodium hydroxide solution. The aqueous solution was extracted with DCM (250 mLX5) and washed with water (3×50 mL). The combined organic layer was washed with brine, dried over Na2SO4 and the solvent was evaporated under vacuum. The crude solid was purified with silica gel to give 8-bromoisoquinoline (2.2 g, two steps 10.6%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11](O)=O.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[N:18]1([C:11]2[C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[S:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=2)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1
Reactant: Nc1ccccc1Sc1ccccc1C(=O)O
Reactant: C1CNCCN1
Product: c1ccc2c(c1)N=C(N1CCNCC1)c1ccccc1S2

Procedure:
simultaneously conducting cyclization and chlorination reactions of 2-(2-aminophenylthio)benzoic acid which is expressed by Formula 7 in an organic solvent in the presence of a halogenating agent and a base, and continuously reacting a resulting compound with piperazine without separation, to produce 11-piperazinyl-dibenzo[b,f][1,4]thiazepine expressed by Formula 4; and