Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8]([S:10][CH3:11])[N:7]=[C:6]([C:12]2[S:16][C:15]([C:17](=[O:19])[CH3:18])=[CH:14][CH:13]=2)[CH:5]=1)[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:30][C:31]([F:38])([F:37])[C:32](OCC)=[O:33].Cl>C1COCC1.O>[CH2:1]([O:3][C:4]1[N:9]=[C:8]([S:10][CH3:11])[N:7]=[C:6]([C:12]2[S:16][C:15]([C:17](=[O:19])[CH2:18][C:32](=[O:33])[C:31]([F:38])([F:37])[F:30])=[CH:14][CH:13]=2)[CH:5]=1)[CH3:2]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CCOc1cc(-c2ccc(C(C)=O)s2)nc(SC)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1cc(-c2ccc(C(=O)CC(=O)C(F)(F)F)s2)nc(SC)n1
Temperature: -78 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
1-[5-(6-Ethoxy-2-methylsulfanyl-pyrimidin-4-yl)-thiophen-2-yl]-ethanone (210 mg, 0.71 mmol) was dissolved in anhydrous THF (7 mL) and cooled to −78° C. under nitrogen atmosphere. A solution of lithium bis(trimethylsilyl)amide (0.71 mL, 1.0 M) in THF was added. The reaction mixture was stirred at −20° C. under nitrogen atmosphere for 1 h. The reaction mixture was then cooled to −78° C. To this reaction mixture was added ethyl trifluoroacetate (170 μL, 1.43 mmol). The vigorously stirred solution was allowed to warm to ambient temperature overnight. The reaction mixture was poured into 20 mL of ice and water and was brought to pH=3˜4 by adding 10% HCl aqueous solution. The mixture was then extracted with diethyl ether (20 mL×3) three times. The ether layer was separated and dried with anhydrous MgSO4 and concentrated in vacuo to give crude product 1-[5-(6-ethoxy-2-methylsulfanyl-pyrimidin-4-yl)-thiophen-2-yl]-4,4,4-trifluoro-butane-1,3-dione (272 mg, 98% yield). 1H-NMR (CDCl3): δ 7.81 (m, 1H), 7.68 (m, 1H), 6.70 (s, 1H), 6.47 (s, 1H), 4.47 (q, J=7.1 Hz, 2H), 2.61 (s, 3H), 1.41 (t, J=7.1 Hz, 3H).
Reaction SMILES: Cl[C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].[OH:12][C:13]1[CH:18]=[CH:17][C:16]([SH:19])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O>[NH2:4][C:3]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:2]=1[S:19][C:16]1[CH:17]=[CH:18][C:13]([OH:12])=[CH:14][CH:15]=1
Reactant: Nc1cc([N+](=O)[O-])ccc1Cl
Reactant: Oc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1cc([N+](=O)[O-])ccc1Sc1ccc(O)cc1
Temperature: 0 °C

Procedure:
A solution of 2-Chloro-5-nitroaniline (3 g, 17.4 mmole), 4-hydroxythiophenol (2.4 g, 19.0 mmol), cesium carbonate (12.35 g, 38 mmol) in dimethylformamide (35 ml) was heated at 100° C. for 16 hours. Afterwards ice water (200 mL) was added to the solution and to the resultant slurry was added ethyl acetate (200 ml). The layers were separated and the organic layer was washed with 10% sodium bicarbonate and 10% sodium chloride, dried over anhydrous sodium sulfate. The drying agent was filtered and solvent was removed under vacuum leaving a yellow oil. The oil was purified by silica gel chromatography eluting with methylene chloride/methanol (97:3), to provide a yellow solid (4-(2-Amino-4-nitro-phenylsulfanyl)-phenol) (2.1g, 46%).
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:14](Br)[CH:15]=[CH2:16].C(=O)([O-])[O-:19].[K+].[K+]>CC(C)=O>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([OH:13])=[C:11]([O:19][CH2:14][CH:15]=[CH2:16])[CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C([O-])[O-]
Reactant: C=CCBr
Reactant: Oc1ccc(C2CCCCC2)cc1
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cc(C2CCCCC2)ccc1O
Yield: 94.1 %

Procedure:
A solution of 4-cyclohexylphenol (10 g), allyl bromide (13.74 g) and potassium carbonate (9.42 g) in acetone (150 mL) was kept at reflux for 10-12 h. The solution was cooled, filtered and concentrated under reduced pressure to provide 4-cyclohexyl allyloxyphenol (12.4 g). This product was used as such for Step C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]3[NH:14][C:15](=[O:22])[N:16]([CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])[C:12]=3[CH:11]=[C:10]([C:23]([O:25]C)=[O:24])[CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+:28].[ClH:29]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]3[NH:14][C:15](=[O:22])[N:16]([CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])[C:12]=3[CH:11]=[C:10]([C:23]([OH:25])=[O:24])[CH:9]=2)=[CH:4][CH:3]=1.[Cl-:29].[Na+:28]
Reactant: COC(=O)c1cc(-c2ccc(F)cc2)c2[nH]c(=O)n(CC(C)(C)O)c2c1
Reactant: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(O)Cn1c(=O)[nH]c2c(-c3ccc(F)cc3)cc(C(=O)O)cc21
Product: [Cl-]
Temperature: 100 °C
Yield: 982.1 %

Procedure:
To a solution of methyl 7-(4-fluorophenyl)-3-(2-hydroxy-2-methylpropyl)-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylate (80.0 mg, 0.223 mmol) in MeOH (0.446 mL) was added sodium hydroxide (0.446 mL, 1M, 0.446 mmol). Reaction heated in the microwave at 100° C. for 15 min. More sodium hydroxide (0.446 mL, 1M, 0.446 mmol) added and heated an additional 20 min in the microwave at 100° C. HCl (0.446 mL, 2M in ether, 0.892 mmol) was added and the reaction mixture was concentrated to give the title compound with four equivalents of sodium chloride (128 mg): LC-MS [M+1]=345.3.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[N:15]1([C:21]2[N:22]=[N:23][CH:24]=[CH:25][N:26]=2)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([C:7]([N:18]2[CH2:17][CH2:16][N:15]([C:21]3[N:22]=[N:23][CH:24]=[CH:25][N:26]=3)[CH2:20][CH2:19]2)=[O:8])[CH:10]=1.[N:23]1[CH:24]=[CH:25][N:26]=[C:21]([N:15]2[CH2:16][CH2:17][N:18]([C:7]([C:6]3[CH:10]=[CH:2][CH:3]=[CH:4][C:5]=3[C:11]([F:14])([F:13])[F:12])=[O:8])[CH2:19][CH2:20]2)[N:22]=1
Reactant: O=C(Cl)c1cc(F)ccc1C(F)(F)F
Reactant: c1cnc(N2CCNCC2)nn1
Product: O=C(c1cc(F)ccc1C(F)(F)F)N1CCN(c2nccnn2)CC1
Product: O=C(c1ccccc1C(F)(F)F)N1CCN(c2nccnn2)CC1
Yield: 67 %

Procedure:
Compound 4 is prepared from 5-fluoro-2-trifluoromethyl-benzoyl chloride and intermediate 5a according to synthesis method 2 under the operating conditions described for example 3 (67% yield).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][C:40]([O:42][CH3:43])=[O:41].[CH2:44](N(CC)CC)C.[C:51]1(C)[C:52]([S:57](Cl)(=[O:59])=[O:58])=[CH:53][CH:54]=[CH:55][CH:56]=1>ClCCl.CN(C1C=CN=CC=1)C>[S:57]([O:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][C:40]([O:42][CH3:43])=[O:41])([C:52]1[CH:51]=[CH:56][C:55]([CH3:44])=[CH:54][CH:53]=1)(=[O:58])=[O:59]
Reactant: COC(=O)CCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: CCN(CC)CC
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)CCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
To a stirred solution of methyl 1-hydroxy-3,6,9,12,15,18,21,24,27,30,33,36-dodecaoxanonatriacontan-39-oate (265a)(1.2 g, 1.897 mmol) in dichloromethane (9.48 mL) at 0° C. was added triethylamine (0.529 mL, 3.79 mmol), toluene sulfonylchloride (0.542 g, 2.84 mmol) and DMAP (0.023 g, 0.190 mmol). The mixture was stirred for one hour at 0° C. and then three hours at ambient temperature, after which it was quenched with water and extracted twice with dichloromethane. The organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Purification by silica gel chromatography (5% MeOH/CH2Cl2) gave methyl 1-(tosyloxy)-3,6,9,12,15,18,21,24,27,30,33,36-dodecaoxanonatriacontan-39-oate (265b)(1.0 g, 67%) as a light yellow oil. 1H NMR (400 Hz, CDCl3): δ 7.80 (d, J=8.4 Hz, 2H), 7.35 (d, J=8.0 Hz, 2H), 4.16 (t, J=4.8 Hz, 2H), 3.75 (t, J=6.4 Hz, 2H), 3.69 (s, 3H), 3.64 (m, 46H), 2.60 (t, J=6.4 Hz, 2H), 2.45 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([C:6]([NH:8][C:9]2[C:10]([NH:16][C:17]([O:19][CH:20]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[O:18])=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=2)=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:41](Cl)(=[O:43])[CH3:42].CO>C(Cl)Cl>[C:41]([NH:15][C:12]1[CH:11]=[C:10]([NH:16][C:17]([O:19][CH:20]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[C:21]2[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=2)=[O:18])[C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:34][CH:33]=2)=[CH:14][CH:13]=1)(=[O:43])[CH3:42]
Reactant: Nc1ccc(NC(=O)c2ccc(Cl)cc2)c(NC(=O)OC(c2ccncc2)C2CCNCC2)c1
Reactant: CC(=O)Cl
Solvent: CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1ccc(NC(=O)c2ccc(Cl)cc2)c(NC(=O)OC(c2ccncc2)C2CCNCC2)c1
Reaction time: 16 h
Yield: 76.6 %

Procedure:
A solution of N1-(4-chlorobenzoyl)-N2-[1-(4-pyridyl)piperidin-4-ylmethoxycarbonyl]-1,2,4-benzenetriamine (40 mg, 0.08 mmol) in 5 mL of CH2Cl2 was treated with pyridine (1 mL) and acetyl chloride (0.006 mL, 0.09 mmol). After 16 h, the mixture was treated with MeOH (1 mL) and then concentrated. The residue was partitioned between EtOAc and NaOH (aq). The organic layer was dried (MgSO4), concentrated, and purified by chromatography (17:3 CH2Cl2:MeOR), affording 32 mg (76%) of the title compound.
Reaction SMILES: [CH2:1]([SH:4])[CH2:2][SH:3].Cl[CH2:6][C:7]([C:9](=[N:15][O:16][CH3:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=O>>[S:3]1[C:7]([C:9](=[N:15][O:16][CH3:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][S:4][CH2:1][CH2:2]1
Reactant: SCCS
Reactant: CCOC(=O)C(=NOC)C(=O)CCl
Product: CCOC(=O)C(=NOC)C1=CSCCS1
Yield: 22.3 %

Procedure:
Ethane-1,2-dithiol (20.6 g.) was allowed to react with ethyl 2-chloroacetyl-2-methoxyiminoacetate (41.4 g.) in a similar manner to that of Example A-(i) to give ethyl 2-(2,3-dihydro-1,4-dithiin-6-yl)-2-methoxyiminoacetate (syn isomer, 11 g.), white crystals, mp. 65° to 67° C.
Reaction SMILES: [CH3:1][C:2](CC)=O.C(=O)([O-])[O-].[K+].[K+].C(I)C.[OH:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[O:22][C:21]([CH3:29])([CH3:28])[CH2:20][C:19]2=[O:30]>>[CH2:1]([O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[O:22][C:21]([CH3:28])([CH3:29])[CH2:20][C:19]2=[O:30])[CH3:2]
Reactant: COc1cc2c(cc1O)C(=O)CC(C)(C)O2
Reactant: CCC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCI
Product: CCOc1cc2c(cc1OC)OC(C)(C)CC2=O
Yield: 95 %

Procedure:
In 100 ml of methyl-ethyl-ketone 4.45 g (20 millimoles) of 6-hydroxy-7-methoxy-2,2-dimethyl-4-chromanone are dissolved, whereupon 4.1 g (30 millimoles) of potassium carbonate and 4.7 g (2.4 ml, 30 millimoles) of ethyl iodide are added and the reaction mixture is refluxed for 5 hours. The precipitated inorganic salt is filtered off, washed twice with 20 ml of acetone each and the solvent is removed. The residue is crystallized from 90% ethanol. Thus 4.75 g of the desired compound are obtained, yield 95%. Mp.: 86°-87° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:9])=[N:4][C:5]([Cl:8])=[CH:6][N:7]=1.[Cl:10][C:11]1[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=1>>[Cl:10][C:11]1[S:15][C:14]([S:16]([NH:9][C:3]2[C:2]([Br:1])=[N:7][CH:6]=[C:5]([Cl:8])[N:4]=2)(=[O:18])=[O:17])=[CH:13][CH:12]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: Nc1nc(Cl)cnc1Br
Product: O=S(=O)(Nc1nc(Cl)cnc1Br)c1ccc(Cl)s1

Procedure:
Prepared by the method of Example 1 using 3-bromo-6-chloro-2-pyrazinamine and 5-chloro-2-thienylsulphonyl chloride.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[N:8]2)[CH:2]=1.C(Cl)(=O)C([Cl:18])=O>ClCCl.CN(C)C=O>[ClH:18].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:11]=[C:10]([C:12]([Cl:18])=[O:14])[CH:9]=[N:8]2)[CH:2]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cnn(-c2cccnc2)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cl
Product: O=C(Cl)c1cnn(-c2cccnc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4.00 g (21.15 mmol) of 1-(pyridin-3-yl)-1H-pyrazole-4-carboxylic acid were initially charged in approx. 100 ml of dichloromethane, and admixed with 2 drops of dimethylformamide under argon. 7.783 g (61.32 mmol) of oxalyl chloride were added dropwise and, after the end of the addition, the mixture was stirred at room temperature for 1 hour. The solution was concentrated, and the residue was admixed with approx. 10 ml of toluene and concentrated. This gave a colourless solid which was converted further immediately.
Reaction SMILES: B1([O-])OO1.[OH2:5].[OH2:6].O.O.[Na+].[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=1[NH2:18]>C(O)(=O)C>[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=1[N+:18]([O-:6])=[O:5]
Reactant: Nc1c(F)cccc1Br
Reactant: O
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1c(F)cccc1Br
Temperature: 55 °C
Reaction time: 3 h
Yield: 29.5 %

Procedure:
To a suspension of sodium perborate tetrahydrate (135.374 g., 886.4 mmol) in 500 mL acetic acid at 55° C. was added dropwise a solution of 2-bromo-6-fluoro-phenylamine (33.685 g., 177.271 mmol) in 70 mL acetic acid over 1 hour. The reaction mixture was stirred at 55° C. for an additional 3 hours, then cooled to 0° C. in an ice bath. Insoluble materials were removed by filtration through a plug of celite, which was rinsed with 100 mL acetic acid. The combined acetic acid fractions were added to 3 L ice water with stirring to give a waxy solid which was removed by filtration. The crude solid was dissolved in 250 mL ethyl acetate, washed three times with 200 mL of 10% aqueous hydrogen chloride, 200 mL saturated sodium bicarbonate and 100 mL brine. The solution was concentrated in vacuo to give 11.51 g of 1-bromo-3-fluoro-2-nitro-benzene as a red oil,
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15][N:16]1[CH2:20][CH2:19][CH:18]([CH2:21][C:22](O)=[O:23])[CH2:17]1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1.C1(N=C=NC2CCCCC2)CCCCC1.OC1C2N=NNC=2C=CC=1.C(N(C(C)C)CC)(C)C>ClCCl>[O:23]=[C:22]([N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)[CH2:21][CH:18]1[CH2:19][CH2:20][N:16]([CH2:15][CH2:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:3]2[CH2:4][CH2:5][CH2:6][CH2:7][C:2]2=[O:1])[CH2:17]1
Reactant: C1CCNC1
Reactant: O=C(O)CC1CCN(CCc2ccccc2N2CCCCC2=O)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CC1CCN(CCc2ccccc2N2CCCCC2=O)C1)N1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7 %

Procedure:
To (1-{2-[2-(2-oxopiperidin-1-yl)phenyl]ethyl}pyrrolidin-3-yl)acetic acid a14-1 (115 mg, 0.348 mmol, 1 eq) and pyrrolidine (32 μl, 0.382 mmol 1.1 eq) in dichloromethane (5 ml) are added dicyclohexylcarbodiimide (79 mg, 0.82 mmol, 1.1 eq), hydroxybenzotriazole (52 mg, 0.382 mmol, 1.1 eq) and diisopropylethylamine (131 μl, 0.731 mmol, 2.1 eq). The reaction mixture is stirred overnight at room temperature, then filtered and concentrated under reduced pressure. The residue is purified by reverse phase chromatography (gradient: CH3CN/H2O/NH4OH from 30/70/0.1 to 60/40/0.1) to afford 9 mg of 1-[2-(2-{3-[2-oxo-2-(pyrrolidin-1-yl)ethyl]pyrrolidin-1-yl}ethyl)phenyl]piperidin-2-one 86 as a yellow oil.
Reaction SMILES: [O:1]1[CH2:6][C:5](=O)[CH2:4][C:3](=[O:8])[CH2:2]1.[I:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[CH3:18])[CH:13]=O.[NH2:19]/[C:20](/[CH3:26])=[CH:21]\[C:22]([O:24][CH3:25])=[O:23]>CO>[I:9][C:10]1[CH:11]=[C:12]([CH:13]2[C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]([CH3:26])[NH:19][C:5]3[CH2:6][O:1][CH2:2][C:3](=[O:8])[C:4]2=3)[CH:15]=[CH:16][C:17]=1[CH3:18]
Reactant: O=C1COCC(=O)C1
Reactant: Cc1ccc(C=O)cc1I
Reactant: COC(=O)/C=C(/C)N
Solvent: CO
Product: COC(=O)C1=C(C)NC2=C(C(=O)COC2)C1c1ccc(C)c(I)c1
Yield: 45.5 %

Procedure:
The product from Example 11B (0.34 g, 3.0 mmol), the product from Example 54A (0.74 g, 3.0 mmol) and methyl 3-aminocrotonate (0.35 g, 3.0 mmol) in methanol (8 mL) were processed as described in Example 68A to provide the title compound (0.60 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@:9]1([CH3:24])[C@H:13]([CH2:14][F:15])[CH2:12][N:11]([C@@H](C2C=CC=CC=2)C)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[C].[Pd].[H][H]>[C:1]([O:5][C:6]([NH:8][C@:9]1([CH3:24])[C@H:13]([CH2:14][F:15])[CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: C[C@H](c1ccccc1)N1C[C@@H](CF)[C@@](C)(NC(=O)OC(C)(C)C)C1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@]1(C)CNC[C@H]1CF

Procedure:
To a solution of (3R,4R)-3-(tert-butoxycarbonylamino)-4-fluoromethyl-3-methyl-1-[(1R)-1-phenylethyl]pyrrolidine (250 mg, 0.743 mmol) in ethanol (10 mL) was added 10% palladium-carbon catalyst (containing 52.8% water, 250 mg), and the suspension was stirred in an oil bath at 40° C. for 1.5 hours in hydrogen gas atmosphere. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure to obtain 169 mg (98%) of the crude target compound as a colorless transparent syrup substance.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.CN(C=O)C.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:34]([CH3:40])[CH2:35][C:36](=[O:39])[NH:37][N:38]=2)=[CH:29][C:28]=1O>O.C(O)(=O)C>[CH3:40][CH:34]1[C:33]([C:30]2[CH:31]=[CH:32][C:27]3[N:26]=[C:6]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)[O:8][C:28]=3[CH:29]=2)=[N:38][NH:37][C:36](=[O:39])[CH2:35]1
Reactant: CC1CC(=O)NN=C1c1ccc(N)c(O)c1
Reactant: O=C(O)c1cccs1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC1CC(=O)NN=C1c1ccc2nc(-c3cccs3)oc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.6 g (0.02 mol) thiophene-2-carboxylic acid, 3.3 g (0.02 mol) 1,1′carbonyldiimidazole and 50 ml DMF are combined and the mixture is stirred for 30 min at RT, then 4.4 g (0.02 mol) 6-(4-amino-3-hydroxy-phenyl)-5-methyl-4,5-dihydro-2H-pyridazin-3-one are added and the mixture is stirred for 4 h at 60° C. The reaction mixture is diluted with water and acidified with glacial acetic acid, the precipitated solid is filtered off, washed with water and isopropanol and then dried. The solid obtained is heated to 130° C. with 60 g polyphosphoric acid for 30 min, then poured onto ice water and then extracted with chloroform. The org. phase is washed with water, dried on magnesium sulphate and the solv. is eliminated by rotary evaporation i.V. The residue is stirred with acetone/diethyl ether, filtered off and then recrystallised from isopropanol/dioxane.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:4])=[O:3].F[C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[C:14]([I:21])[CH:13]=1>CS(C)=O.C(OCC)(=O)C>[I:21][C:14]1[CH:13]=[C:12]([N:8]2[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH2:7]2)[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=1
Reactant: O=[N+]([O-])c1cc(F)cc(I)c1
Reactant: CS(=O)(=O)N1CCNCC1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)N1CCN(c2cc(I)cc([N+](=O)[O-])c2)CC1
Temperature: 130 °C

Procedure:
1-(methylsulfonyl)piperazine (627 mg, 3.82 mmol) was added to a solution of 1-fluoro-3-iodo-5-nitrobenzene (510 mg, 1.91 mmol) in dimethylsulfoxide (2 mL). The reaction was heated to 130° C. for 60 minutes in the microwave reaction, then allowed to cool to room temperature. The reaction mixture was diluted with ethyl acetate (30 mL) and washed with 1:1 water:brine (3×30 mL). The organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate/hexanes) provided 1-(3-iodo-5-nitrophenyl)-4-(methylsulfonyl)piperazine as a bright yellow foam. 1H NMR (400 MHz, CDCl3) δ 8.04 (s, 1H), 7.70 (s, 1H), 7.51 (s, 1H), 3.42 (s, 8H), 2.87 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[Mg].Cl[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:18][CH2:19][C:20]([CH3:23])([CH3:22])[N:21]=2)=[C:13](OC)[CH:12]=1.[Cl-:26].[NH4+]>C1COCC1>[Cl:26][C:16]1[CH:11]=[CH:12][C:13]([C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=2)=[C:14]([C:17]2[O:18][CH2:19][C:20]([CH3:23])([CH3:22])[N:21]=2)[CH:15]=1
Reactant: COc1cc(Cl)ccc1C1=NC(C)(C)CO1
Reactant: Cc1ccc(Br)cc1
Reactant: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc(Cl)cc2C2=NC(C)(C)CO2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A THF solution (450 ml) of 46.0 g of 4-bromotoluene was dropwise added to 6.38 g of magnesium in a nitrogen stream. After heating under reflux for 40 min, the reaction mixture was dropwise added at room temperature to a THF solution (260 ml) of 30 g of 2-(4-chloro-2-methoxyphenyl)-4,4-dimethyloxazoline. The mixture was stirred at room temperature for 2 hr and then cooled, and an aqueous ammonium chloride was added thereto. The mixture was extracted with ethyl acetate, and the extract was washed with a dilute sodium hydroxide solution and a saline solution, dried over anhydrous magnesium sulfate and then concentrated to prepare 38 g of the title compound in a crude form.
Reaction SMILES: C(NCC)C.[OH:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O.[C:16](#[N:20])[CH2:17][C:18]#[N:19].O>CN(C=O)C>[NH2:20][C:16]1[O:6][CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:17]=1[C:18]#[N:19]
Reactant: O=C(CO)c1ccccc1
Reactant: N#CCC#N
Solvent: O
Solvent: CN(C)C=O
Solvent: CCNCC
Product: N#Cc1c(-c2ccccc2)coc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Add 3.78 ml (36.7 mmol) diethylamine dropwise to a mixture of 10 g (73.4 mmol) hydroxyacetophenone and 4.852 g (73.4 mmol) malononitrile in 24 ml DMF with cooling at RT. Stir the dark mixture for 2 h at RT and then add slowly to water (200 ml), with stirring and cooling. Continue stirring the precipitate for 30 min at approx. 10° C., filter with suction, suspend in water twice more, and filter with suction again. Dry the residue at high vacuum to constant weight. 10.99 g (81.2% of theor.) of the target compound is obtained as a yellowish-brown solid.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][CH2:16][CH:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1.[C:26]1(=[O:32])[O:31][C:29](=[O:30])[CH2:28][CH2:27]1>ClC(Cl)C>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([S:12]([NH:15][CH2:16][CH:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:26](=[O:32])[CH2:27][CH2:28][C:29]([OH:31])=[O:30])[CH:23]=3)[CH2:18]2)(=[O:14])=[O:13])=[CH:10][CH:11]=1
Reactant: O=S(=O)(NCC1Cc2ccccc2C1)c1ccc(Cl)cc1
Reactant: O=C1CCC(=O)O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: O=C(O)CCC(=O)c1ccc2c(c1)CC(CNS(=O)(=O)c1ccc(Cl)cc1)C2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.7 %

Procedure:
Suspended in 35 ml of dichloroethane were 6.82 g (51.2 mmol) of anhydrous aluminum chloride, and 4.26 g (13.3 mmol) of 2-[(4-chlorophenyl)sulfonylaminomethyl]indane prepared in Referential Example 1 were added thereto. While chilling with ice water, 2.07 g (20.6 mmol) of succinic anhydride were added to this suspension in small portions. Thereafter, the mixture was stirred at room temperature for 1.5 hours, and the liquid reaction mixture was poured into ice water. A crystal deposited was collected by filtration, washed with water and then recrystallized from acetic acid to obtain 4.75 g of a colorless crystal. Yield: 85%.