Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][CH2:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[CH:9][C:8]=1Br)/[CH:2]=[CH:3]/[CH3:4].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CC(O)=O.CC(O)=O.[Pd]>[CH:3]([CH:2]1[C:8]2[C:7](=[C:12]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:10][CH:9]=2)[CH2:6][O:5][CH2:1]1)=[CH2:4]
Reactant: C/C=C/COCc1c(Br)cccc1[N+](=O)[O-]
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC(=O)O
Product: C=CC1COCc2c1cccc2[N+](=O)[O-]

Procedure:
To a solution of 2-bromo-6-nitrobenzyl (2E)-but-2-en-1-yl ether (3.3 g, 11.19 mmol) in TEA (100 mL) was added P(o-Tol)3 (196 mg, 0.873 mmol) and Pd(OAC)2(1.0 g, 3.21 mmol), and the mixture was stirred at reflux for 16 h. Then the mixture was concentrated in vacuo, and the mixture was partitioned between water and EtOAc. The combined organic layers were washed with HCl (1N) and brine, dried and concentrated in vacuo. The residue was purified with silica gel cloumn chromatography to give 4-ethenyl-8-nitro-3,4-dihydro-1H-isochromene. 1H-NMR (400 MHz, CDCl3) δ 7.96 (d, J=8.0 Hz, 1H), 7.45 (d, J=8.0 Hz, 1H), 7.31 (t, J=8.0 Hz, 2H), 5.74˜5.82 (m, 1H), 5.14˜5.19 (m, 2H), 5.04 (d, J=4.0 Hz, 2H), 3.93˜3.98 (m, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[CH3:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[N:21]1[CH2:22][CH2:23][N:24]([C:8]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)=[O:10])[CH2:25][CH2:26]1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(N2CCN(C(=O)c3ccc([N+](=O)[O-])cc3)CC2)c(C)c1
Temperature: 25 °C
Yield: 102.7 %

Procedure:
4-Nitrobenzoic acid (2 g), 1-(2,4-dimethylphenyl)piperazine (2.28 g), and 1-hydroxybenzotriazole 1 hydrate (1.62 g) were dissolved in N,N-dimethylformamide (30 mL), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (2.31 g) was added, and the mixture was stirred at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. To the obtained residue was added ethyl acetate/diisopropyl ether and the insoluble material was collected by filtration to give [4-(2,4-dimethylphenyl)piperazin-1-yl](4-nitrophenyl)methanone (4.17 g). Then, ammonium chloride (3.71 g) and iron (2.68 g) were added to a solution of ethanol (61 mL) and water (17 mL), and the obtained [4-(2,4-dimethylphenyl)piperazin-1-yl](4-nitrophenyl)methanone (4.17 g) was added with stirring at 60° C.-70° C. After completion of the reaction, the insoluble material was filtered off, and the filtrate was concentrated. To the residue was added aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate, and the solvent was evaporated to give crude (4-aminophenyl) [4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (4.17 g). To the obtained crude (4-aminophenyl) [4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (1 g) were added itaconic acid (0.42 g), water (5 mL), 1,2-dimethoxyethane (2 mL) and acetic acid (5 mL), and the mixture was stirred with heating under reflux for 13 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. To the obtained residue was added ethyl acetate, and the precipitate was collected by filtration to give the title compound (508 mg).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10](OCC)=[O:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].C([Al+]C(C)C)(C)C.CO.S([O-])([O-])(=O)=O.[Na+].[Na+]>C(Cl)Cl.CCOCC.[Cl-].[Na+].O>[Si:1]([O:8][CH2:9][CH:10]=[O:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CO[Si](C)(C)C(C)(C)C
Agent: CC(C)[Al+]C(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCC=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 32.7g (0.15 mole) of ethyl t-butyldimethylsilyloxyacetate in 924 ml of methylene chloride a solution of 1M diisopropylaluminum hydride in methylene chloride is added dropwise with stirring at -78° C. over a period of 1/2 h. The mixture is stirred for 45 min and 100 ml of methanol is added dropwise. The mixture is diluted with 3 l of ether, 100 ml of brine and 70 g of sodium sulfate are added and the mixture is stirred at room temperature for 15 h. The solids are filtered, the filtrates are evaporated and the residue is distilled to give t-butyldimethylsilyloxyacetaldehyde, b.p. 65°-75° C. (14 mm/Hg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[CH:22])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.Br[C:24]1[CH:25]=[C:26]([S:30]([NH2:33])(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:15])([F:17])[F:16])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[C:22][C:24]4[CH:25]=[C:26]([S:30]([NH2:33])(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)cc3)nc12
Reactant: NS(=O)(=O)c1cccc(Br)c1
Product: NS(=O)(=O)c1cccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(Cl)cc4)nc23)c1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-3-ethynyl-7-trifluoromethyl pyrazolo[1,5-a]pyrimidine (example C.4) (161 mg, 0.5 mmol) and 3-bromo-benzenesulfonamide (118 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (133 mg, 56%). MS (ISP) 477.1 [(M+H)+]; mp 218-220° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][C@H:11]([CH3:21])[CH2:12][O:13][Si](C(C)(C)C)(C)C)[N:5]=[C:4]([C:22]([NH:24][CH2:25][CH:26]2[CH2:31][CH2:30][N:29]([CH2:32][C:33]3[S:37][C:36]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=4)=[N:35][CH:34]=3)[CH2:28][CH2:27]2)=[O:23])[CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][C@H:11]([CH3:21])[CH2:12][OH:13])[N:5]=[C:4]([C:22]([NH:24][CH2:25][CH:26]2[CH2:27][CH2:28][N:29]([CH2:32][C:33]3[S:37][C:36]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=4)=[N:35][CH:34]=3)[CH2:30][CH2:31]2)=[O:23])[CH:3]=1
Reactant: C[C@H](CO[Si](C)(C)C(C)(C)C)Oc1nc(C(=O)NCC2CCN(Cc3cnc(-c4ccccn4)s3)CC2)cc(N)c1C#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@H](CO)Oc1nc(C(=O)NCC2CCN(Cc3cnc(-c4ccccn4)s3)CC2)cc(N)c1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.6 %

Procedure:
The compound prepared in Example 209 (0.032 g) was suspended in tetrahydrofuran (10 mL) and aqueous tetrabutylammonium fluoride solution (1 mol/L; 0.103 mL) added dropwise to the reaction mixture. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The combined organics were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford the crude material, which was purified by preparative TLC, (eluant: 10% (9:1 methanol/concentrated ammonium hydroxide)/ethyl acetate) to furnish the title compound (0.020 g) having the following physical properties.
Reaction SMILES: C[N:2]([CH3:19])[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]([N:13]([CH2:17][CH3:18])[C:14](=[O:16])[CH3:15])[CH:10]=[CH:11][CH:12]=1)=O.N[C:21]1[C:25]([C:26]#[N:27])=C[NH:23][N:22]=1.P(=O)(O)(O)O>O.CO>[CH3:18][CH2:17][N:13]([C:14]([CH3:15])=[O:16])[C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:5]2[N:23]3[N:22]=[CH:21][C:25]([C:26]#[N:27])=[C:19]3[N:2]=[CH:3][CH:4]=2)[CH:8]=1
Reactant: N#Cc1c[nH]nc1N
Reactant: CCN(C(C)=O)c1cccc(C(=O)C=CN(C)C)c1
Agent: O=P(O)(O)O
Solvent: CO
Solvent: O
Product: CCN(C(C)=O)c1cccc(-c2ccnc3c(C#N)cnn23)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.4 %

Procedure:
N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-ethylacetamide (2.6 g, 0.01 mol) and 3-amino-4-cyanopyrazole (1.08 g, 0.01 mol) were dissolved in the mixture of water (35 cm3) and methanol (20 cm3). Phosphoric acid (85%) (0.67 cm3, 0.01 mol) was then added and the mixture was stirred at room temperature for about 4 hours. The reaction mixture was then cooled to about 5° C. and the crystalline product that formed was collected, washed with water and dried at about 60° C. to yield zaleplon (2.79 g, 91.5%) in 98.83% purity as determined by HPLC.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]([P:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]=[CH:11][CH:12]=1)=O.O.[NH2:28][NH2:29]>C(O)C>[NH:28]1[CH:3]=[CH:4][C:5]([C:7]2[CH:8]=[C:9]([P:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:10]=[CH:11][CH:12]=2)=[N:29]1
Reactant: NN
Reactant: CN(C)C=CC(=O)c1cccc(P(c2ccccc2)c2ccccc2)c1
Solvent: CCO
Solvent: O
Product: c1ccc(P(c2ccccc2)c2cccc(-c3cc[nH]n3)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
A solution of 1.8 g (5.1 mmol) of [3-(3-dimethylamino-1-oxoprop-2-en-yl)phenyl]diphenyl phosphane and 2.6 g (51 mmol) hydrazine monohydrate in 20 ml of ethanol is heated to boil under cover gas for 3 h. After cooling of the solution to room temperature, the solvent is removed in a vacuum. The remaining colorless oily residue is recrystallized from acetic acid ethyl ester. A colorless solid is obtained (yield: >70%).
Reaction SMILES: [Na].CN(C)C=O.Br[C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[OH:16])[CH:11]=[O:12].Cl.[CH2:18]([OH:22])[CH2:19][CH2:20][CH3:21]>[Cu]Cl>[CH2:18]([O:22][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[OH:16])[CH:11]=[O:12])[CH2:19][CH2:20][CH3:21]
Reactant: O=Cc1ccc(O)c(Br)c1
Reactant: CCCCO
Agent: Cl[Cu]
Agent: Cl
Agent: [Na]
Solvent: CN(C)C=O
Product: CCCCOc1cc(C=O)ccc1O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80 %

Procedure:
2.16 g (93.9 mmol) of sodium are dissolved in 15 ml of n-butanol at 110° C. for 3 hours. 20 ml of dimethylformamide are added at ambient temperature and then the medium is degassed several times. 3.4 g (34.1 mmol) of copper(I) chloride are added at ambient temperature and then the reaction medium is stirred for 10 minutes. 6.2 g (31 mmol) of 3-bromo-4-hydroxybenzaldehyde are added and then the reaction medium is stirred at 120° C. for 2 hours. The reaction mixture is cooled to ambient temperature and then the reaction is halted by the addition of 50 ml of a 2M hydrochloric acid solution. The medium is extracted with 250 ml of ethyl acetate. The solvents are evaporated and then the residue is filtered through a silica gel patch (2 cm): eluent heptane/ethyl acetate 8/2. After evaporation of the solvents, 5.55 g of orange oil are obtained. This oil is crystallized from pentane. 4.8 g of 3-butoxy-4-hydroxybenzaldehyde are obtained in the form of a brown solid after filtration.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[N:5][N:6]([CH2:8][N:9]2[C:14]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[S:17][C:13]=3[C:12](=[O:24])[N:11]([CH:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)[C:10]2=[O:38])[N:7]=1)[CH3:2].[ClH:39]>O1CCOCC1>[ClH:39].[CH2:1]([C:3]1[N:4]=[N:5][N:6]([CH2:8][N:9]2[C:14]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[S:17][C:13]=3[C:12](=[O:24])[N:11]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[C:10]2=[O:38])[N:7]=1)[CH3:2]
Reactant: CCc1nnn(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)n1
Agent: Cl
Solvent: C1COCCO1
Product: CCc1nnn(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)n1

Procedure:
According to the procedure described for compound B90 tert-butyl 4-{1-[(5-ethyl-2H-tetrazol-2-yl)methyl]-2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl}piperidine-1-carboxylate (290 mg, compound B75) is reacted with hydrogen chloride in 1,4-dioxane (5.0 ml, 6.8 M) to afford the title compound as a solid.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[Cl-].[Al+3].[Cl-].[Cl-].[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:1](=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=[O:5])=[CH:15][CH:14]=1
Reactant: O=C1CCC(=O)O1
Reactant: Fc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(O)CCC(=O)c1ccc(F)cc1
Yield: 74.5 %

Procedure:
50 gm of succinic anhydride and 133.3 gm of aluminum chloride was added to 79.6 gm of fluorobenzene, and the mixture was heated under reflux for 6 hours. After evaporating the surplus fluorobenzene, the residue was added to 2 l of 1% hydrochloric acid aqueous solution. The precipitate was collected by filtration, washed with water, and dried to obtain 73 gm of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[N:17]=[CH:16][CH:15]=[C:14]3[N:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH:26]=O)[CH2:21][CH2:20]2)=[CH:5][CH:4]=1.[CH3:30][CH2:31][CH2:32][NH:33][C@@H:34]1[CH2:39][C:38]2[S:40][C:41]([NH2:43])=[N:42][C:37]=2[CH2:36][CH2:35]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[N:17]=[CH:16][CH:15]=[C:14]3[N:19]2[CH2:20][CH2:21][N:22]([CH2:25][CH2:26][N:33]([CH2:32][CH2:31][CH3:30])[CH:34]3[CH2:35][CH2:36][C:37]4[N:42]=[C:41]([NH2:43])[S:40][C:38]=4[CH2:39]3)[CH2:23][CH2:24]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(COc2cccc3c(N4CCN(CC=O)CC4)ccnc23)cc1
Reactant: CCCN[C@H]1CCc2nc(N)sc2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCCN(CCN1CCN(c2ccnc3c(OCc4ccc(OC)cc4)cccc23)CC1)C1CCc2nc(N)sc2C1
Yield: 74.9 %

Procedure:
Compound 27 (1.0 g, 2.55 mmol) was treated with (−)-pramipexole (599 mg, 2.81 mmol) and NaBH(OAc)3 (973 mg, 4.59 mmol) by following procedure A. The reaction mixture was purified by silica gel column chromatography (EtOAc/MeOH, 9:1) to yield 1.12 g (75%) of compound (−)-28 as yellow solid. The 1H NMR of (−)-28 is similar to compound (±)-28.
Reaction SMILES: Br[C:2]1([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:12].[Cl:21][C:22]1[CH:30]=[C:29]2[C:25]([CH2:26][CH2:27][NH:28]2)=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:21][C:22]1[CH:30]=[C:29]2[C:25]([CH2:26][CH2:27][N:28]2[C:2]2([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)[C:10]3[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=3)[NH:4][C:3]2=[O:12])=[CH:24][CH:23]=1
Reactant: Clc1ccc2c(c1)NCC2
Reactant: O=C1Nc2cc(Cl)ccc2C1(Br)Cc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)N1CCc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.9 %

Procedure:
The mixture of rac-3-bromo-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (100 mg, 0.27 mmol) (from example 1c supra), 6-Chloro-2,3-dihydro-1H-indole (62 mg, 0.45 mmol) and K2CO3 (110 mg, 0.80 mmol) in DMF (1 mL) was stirred at room temperature overnight. Then water (10 mL) was added and the desired product was precipitated out. The crude product was purified by prep-HPLC to give 55 mg rac-6,6′-Dichloro-3′-(3-chloro-benzyl)-2,3,1′,3′-tetrahydro-[1,3′]biindolyl-2′-one. MS: [M+H]+=443
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH:4]([CH:5]=[C:6]([Br:14])[C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[CH:3]1[C:15](O)=[O:16].S(Cl)([Cl:21])=O>C(Cl)(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:18])[CH:4]([CH:5]=[C:6]([Br:14])[C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[CH:3]1[C:15]([Cl:21])=[O:16]
Reactant: O=S(Cl)Cl
Reactant: CC1(C)C(C=C(Br)c2ccc(Cl)cc2)C1C(=O)O
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)C(C=C(Br)c2ccc(Cl)cc2)C1C(=O)Cl
Yield: 48.4 %

Procedure:
59 g (0.2 mol) of 2,2-dimethyl-3-(2-bromo-2-(4-chloro-phenyl)-vinyl)-cyclopropanecarboxylic acid were dissolved in 500 ml of carbon tetrachloride, and 119 g of thionyl chloride were slowly added dropwise at 25° C., while stirring. The mixture was then heated to the reflux temperature for 4 hours. When the reaction period had ended, excess thionyl chloride and carbon tetrachloride were distilled off under a waterpump vacuum. The oil which remained was distilled. 33.7 g (53.8% of theory) of 2,2-dimethyl-3-(2-bromo-2-(4-chloro-phenyl)-vinyl)-cyclopropanecarboxylic acid chloride were obtained as a colorless liquid with a boiling point of 165°-166° C. under 8 mm Hg.
Reaction SMILES: O.[NH2:2][NH2:3].CS([C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][N:9]=1)(=O)=O>C(O)C>[NH:2]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][N:9]=1)[NH2:3]
Reactant: CS(=O)(=O)c1ccc(S(C)(=O)=O)nc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)c1ccc(NN)nc1
Temperature: 15 °C

Procedure:
1.7 ml (1.7 g, 34.0 mmol) hydrazine hydrate are added to 2.0 g (8.5 mmol) 2,5-bis-(methylsulfonyl)pyridine [Woods et al., J. Heterocycl. Chem. 1984, 21, 97-101] in 15 ml ethanol and the mixture is stirred under reflux for 4 h. For working up, the reaction solution is cooled to 15° C., the solid which has precipitated out is filtered off, the residue on the filter is washed with ethanol and diethyl ether and the product is dried in vacuo.
Reaction SMILES: C1C=CC=CC=1.[CH3:7][CH:8]1[CH2:13][CH2:12][CH2:11][N:10]([CH2:14][CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[OH:16])[CH2:9]1.[CH2:23]=[C:24]1[O:28][C:26](=[O:27])[CH2:25]1>C(N(CC)CC)C>[C:26]([O:16][CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:14][N:10]1[CH2:11][CH2:12][CH2:13][CH:8]([CH3:7])[CH2:9]1)(=[O:27])[CH2:25][C:24]([CH3:23])=[O:28]
Reactant: CC1CCCN(CC(O)c2ccccc2)C1
Reactant: C=C1CC(=O)O1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC(=O)CC(=O)OC(CN1CCCC(C)C1)c1ccccc1
Yield: 106.5 %

Procedure:
To 100 ml of benzene are added 9.5 g of 2-(3-methyl piperidino)-1-phenylethanol having a melting point of 70° C., 5 g of diketene and 0.1 ml of triethylamine, and the mixture is refluxed under heating for two hours. The reaction mixture is concentrated under reduced pressure to give 14 g of 2-(3-methylpiperidino)-1-phenylethyl acetoacetate as oily substance. To 150 ml of isopropanol are added 14 g of 2-(3-methylpiperidino)-1-phenylethyl acetoacetate, 6.5 g of m-nitrobenzaldehyde and 5 g of methyl β-aminocrotonate, and the mixture is refluxed under heating for 15 hours. The reaction mixture is concentrated under reduced pressure and the oily residue is dissolved in ethyl acetate. The ethyl acetate layer is washed with 1N-hydrochlroic acid, potassium carbonate and water, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The oily residue (25 g) is purified by column chromatography. The eluate is concentrated and the residue is dissolved in acetone, whereupon an ethanol solution of hydrogen chloride is added to crystallize. The precipitated crystals are collected by filtration and recrystallized from ethanol to give 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methylester-5-[2-(3-methylpiperidino)-1-phenyl]ester in the form of hydrochloride as crystals melting at 225° C.-226° C. (decomposition).
Reaction SMILES: C(OC([N:8]1[CH2:12][C:11]([F:14])([F:13])[CH2:10][CH:9]1[C:15]([O:17][CH2:18][CH:19]=[CH2:20])=[O:16])=O)(C)(C)C.[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24]>ClCCl>[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24].[CH2:18]([O:17][C:15]([CH:9]1[CH2:10][C:11]([F:14])([F:13])[CH2:12][NH:8]1)=[O:16])[CH:19]=[CH2:20]
Reactant: C=CCOC(=O)C1CC(F)(F)CN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CCOC(=O)C1CC(F)(F)CN1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
4,4-Difluoro-pyrrolidine-1,2-dicarboxylic acid 2-allyl ester 1-tert-butyl ester (Example 14c, 5.85 g, 20.09 mmol) was dissolved in a 5% solution of trifluoroacetic acid in dichloromethane and stirred at 25° C. for 16 h. The solvent was removed in vacuo and the crude 4,4-difluoro-pyrrolidine-2-carboxylic acid allyl ester (6.14 g, 20.09 mmol, 100% yield) was obtained as the trifluoroacetic acid salt, which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ: 2.75-2.86 (1H, m), 2.90-3.02 (1H, m), 3.76-3.93 (2H, m), 4.68-4.78 (3H, m), 5.33-5.39 (2H, m), 5.84-5.94 (1H, m).
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]([S:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH:12]2[CH2:18][CH2:17][CH2:16][CH2:15][NH:14][C:13]2=[O:19])=[CH:6][CH:5]=1.[OH-].[Na+]>CO.CC#N>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([S:20]([N:11]([CH2:10][C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:30])=[O:2])=[CH:9][CH:8]=2)[CH:12]2[CH2:18][CH2:17][CH2:16][CH2:15][NH:14][C:13]2=[O:19])(=[O:21])=[O:22])=[CH:24][CH:25]=1
Reactant: COC(=O)c1ccc(CN(C2CCCCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CO
Product: O=C(O)c1ccc(CN(C2CCCCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)cc1

Procedure:
rac-4-{[(4-Chloro-benzenesulfonyl)-(2-oxo-azepan-3-yl)-amino]-methyl}-benzoic acid methyl ester (0.95 g, 2.10 mmol) in a mixture of MeOH/CH3CN (50 ml, 1:1 v/v) was treated with 1 N NaOH (2.5 ml) for 24 h. Solvent was removed under reduced pressure and the residue dissolved in ethyl acetate and washed with 5% KHSO4/10% K2SO4 (2×). The aqueous washes were extracted with ethyl acetate and the combined organic fractions were washed with brine, dried (Na2 SO4), filtered, concentrated under reduced pressure and lyophilized from water/CH3CN: lyophilisate, 0.87 g; MS: m/e=435.2 (MH−)
Reaction SMILES: [OH-].[Na+:2].[O:3]=[C:4]1[CH2:8][CH2:7][C:6]([C:14]([O:16]CC)=[O:15])([C:9]([O:11]CC)=[O:10])[NH:5]1>C(O)C>[O:3]=[C:4]1[CH2:8][CH2:7][C:6]([C:9]([O-:11])=[O:10])([C:14]([O-:16])=[O:15])[NH:5]1.[Na+:2].[Na+:2]
Reactant: CCOC(=O)C1(C(=O)OCC)CCC(=O)N1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C1CCC(C(=O)[O-])(C(=O)[O-])N1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
2(c) 8.74 ml of a 1N aqueous solution of sodium hydroxide were added to a solution of 1.0 g of diethyl 2-oxopyrrolidine-5,5-dicarboxylate (prepared as described above) in 10 ml of ethanol, and the mixture was stirred at room temperature for 3 days. At the end of this time, the solvent was removed by distillation under reduced pressure, and the residual crystals were washed with acetone and dried to give 950 mg of sodium 2-oxopyrrolidine-5,5-dicarboxylate as a colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH:11]([CH2:16][CH2:17]CC)[CH2:12][C:13]([OH:15])=[O:14].[CH:20]([Mg]Br)(C)C>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH:11]([CH:16]([CH3:17])[CH3:20])[CH2:12][C:13]([OH:15])=[O:14]
Reactant: CCCCC(CC(=O)O)c1ccc(OC)cc1OC
Reactant: CC(C)[Mg]Br
Product: COc1ccc(C(CC(=O)O)C(C)C)c(OC)c1

Procedure:
Following a similar procedure to that described in Preparation 42a, but using isopropylmagnesium bromide instead of butylmagnesium bromide, the title compound was obtained as an oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][CH2:12][C:13]2([S:20]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[S:17][C:16](=[O:18])[NH:15][C:14]2=[O:19])=[CH:4][CH:3]=1.[Br:31][CH2:32][CH2:33][CH2:34]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][CH2:12][C:13]2([S:20]([C:23]3[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)(=[O:22])=[O:21])[S:17][C:16](=[O:18])[N:15]([CH2:34][CH2:33][CH2:32][Br:31])[C:14]2=[O:19])=[CH:4][CH:3]=1
Reactant: BrCCCBr
Reactant: COc1ccc(S(=O)(=O)C2(CCCC#Cc3ccc(Cl)cc3)SC(=O)NC2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)C2(CCCC#Cc3ccc(Cl)cc3)SC(=O)N(CCCBr)C2=O)cc1

Procedure:
The compound of Example 97 is reacted with 1,3-dibromopropane and potassium carbonate in DMF to give 5-[5-(4-chlorophenyl)pent-4-ynyl]-3-(3-bromopropyl)-5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione, and this is reacted with imidazole, sodium salt in DMF, and in the presence of a catalytic amount of potassium iodide to give the title compound as a light tan solid, mp 111-113° C.