Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][CH3:9].C(N(CC)CC)C.Cl.Cl[C:19]([C:21]1[CH:22]=[N:23][C:24]([NH:27][C:28](=[O:30])[CH3:29])=[CH:25][CH:26]=1)=[O:20]>CN(C)C=O>[C:28]([NH:27][C:24]1[CH:25]=[CH:26][C:21]([C:19]([NH:1][CH2:2][CH:3]2[CH2:7][CH2:6][CH2:5][N:4]2[CH2:8][CH3:9])=[O:20])=[CH:22][N:23]=1)(=[O:30])[CH3:29]
Reactant: CCN1CCCC1CN
Reactant: CC(=O)Nc1ccc(C(=O)Cl)cn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN1CCCC1CNC(=O)c1ccc(NC(C)=O)nc1
Temperature: 50 °C
Yield: 59.9 %

Procedure:
A mixture of 12.8 g (0.1 mole) of 2-aminomethyl-1-ethyl pyrrolidine and 22.2 g (0.11 mole) of triethylamine was added at a temperature ≤20°C, to a solution of 23.5 g (0.1 mole) of 3-chlorocarbonyl-6-acetamido pyridine hydrochloride (itself prepared starting from 6-acetamido nicotinic acid) in 250 ml of anhydrous dimethylformamide. After the completion of the addition, the mixture was heated to 50°C for 1 hour then dimethylformamide was eliminated under reduced pressure. The oily residue was triturated with 200 ml of water and 100 ml of ether. The so-obtained base crystallized and there were obtained 17.4 g of 2-(6-acetamido nicotinamidomethyl)-1-ethyl pyrrolidine in the form of beige crystals melting (Kofler) at 162°-163°C. This compound was deacetylated according to the above described method and there were finally obtained 9.8 g of 2-(6-amino nicotinamidomethyl)-1-ethyl pyrrolidine, melting (Kofler) at 136°C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:13]([CH2:14][CH2:15]OS(C)(=O)=O)[CH2:12][N:11]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)[C:10](=[O:28])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:29]([S-:31])[CH3:30].[Na+].CCOC(C)=O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[C@@H:13]([CH2:14][CH2:15][S:31][CH2:29][CH3:30])[CH2:12][N:11]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)[C:10](=[O:28])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(=O)N(c2cccc(Cl)c2)C[C@@H]1CCOS(C)(=O)=O
Reactant: CC[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCSCC[C@H]1CN(c2cccc(Cl)c2)C(=O)CN1C(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
To a solution of the mesylate from Step F (3.6 g, 8.3 mmol) in 100 mL of DMF at 0° C. was added sodium ethanethiolate (1.4 g, 16.6 mmol). After 2 hours, the reaction was poured into EtOAc, washed with sat. NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the crude product which was used in the next step without further purification.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][CH2:26][C:27]1[C:28]([F:44])=[C:29]([O:34][C:35]2[CH:36]=[C:37]([CH:40]=[C:41]([Cl:43])[CH:42]=2)[C:38]#[N:39])[C:30]([Cl:33])=[CH:31][CH:32]=1.[CH3:45][C:46]([O:49][C:50]([NH:52][C:53]1[CH:54]=[CH:55][CH:56]=[C:57]2[C:61]=1[NH:60][C:59]([C:62](O)=[O:63])=[CH:58]2)=[O:51])([CH3:48])[CH3:47].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][NH:25][C:62]([C:59]2[NH:60][C:61]3[C:57]([CH:58]=2)=[CH:56][CH:55]=[CH:54][C:53]=3[NH:52][C:50](=[O:51])[O:49][C:46]([CH3:47])([CH3:45])[CH3:48])=[O:63])=[C:28]([F:44])[C:29]=1[O:34][C:35]1[CH:36]=[C:37]([C:38]#[N:39])[CH:40]=[C:41]([Cl:43])[CH:42]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: CC(C)(C)OC(=O)Nc1cccc2cc(C(=O)O)[nH]c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cccc2cc(C(=O)NCc3ccc(Cl)c(Oc4cc(Cl)cc(C#N)c4)c3F)[nH]c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.4 %

Procedure:
HATU (0.055 g, 0.145 mmol) was added to a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.030 g, 0.096 mmol), 7-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-1H-indole-2-carboxylic acid (0.026 g, 0.096 mmol) and DIPEA (0.025 mL, 0.145 mmol) in DMF (1 mL). The mixture was stirred at RT overnight then extracted with water and ethyl acetate. The organic layer was separated, dried over sodium sulfate, and concentrated. The residue was purified by column chromatography (hexane/EtOAc) to give the title compound (0.027 g, 44%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.59 (s, 1H), 9.32 (s, 1H), 9.07 (t, 1H), 7.81 (s, 1H), 7.67-7.77 (m, 1H), 7.44-7.57 (m, 3H), 7.39 (t, 1H), 7.27 (d, 1H), 7.17 (d, 1H), 6.96 (t, 1H), 4.57 (d, 2H), 1.5 (s, 9H). MS: m/z 569 (M).
Reaction SMILES: [CH2:1]([C:4]1[CH2:5][CH:6]([OH:9])[CH2:7][CH:8]=1)[CH:2]=[CH2:3].N1C=CC=CC=1.[Cl:16]/[C:17](/[C:27]([F:30])([F:29])[F:28])=[CH:18]\[C@@H:19]1[C@H:21]([C:22](Cl)=[O:23])[C:20]1([CH3:26])[CH3:25]>C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.C1(C)C=CC=CC=1>[Cl:16]/[C:17](/[C:27]([F:28])([F:29])[F:30])=[CH:18]\[C@@H:19]1[C@H:21]([C:22]([O:9][CH:6]2[CH2:7][CH:8]=[C:4]([CH2:1][CH:2]=[CH2:3])[CH2:5]2)=[O:23])[C:20]1([CH3:26])[CH3:25]
Reactant: C=CCC1=CCC(O)C1
Reactant: CC1(C)[C@H](/C=C(\Cl)C(F)(F)F)[C@@H]1C(=O)Cl
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: C=CCC1=CCC(OC(=O)[C@H]2[C@@H](/C=C(\Cl)C(F)(F)F)C2(C)C)C1
Yield: 78.3 %

Procedure:
To a mixture of (RS)-3-(2-propenyl)-3-cyclopenten-1-ol (115 mg), 2,6-di-tert-butyl-4-methylphenol (5 mg), pyridine (100 mg) and toluene (10 ml), (IRS)-cis-3-(Z-2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarbonyl chloride (239 mg) was added under ice-cooling. The resulting reaction mixture was further allowed to react for 8 hours at room temperature. Then the reaction mixture was subjected to the same post-treatment as in Example 1 to afford 250 mg of (RS)-3-(2-propenyl)-3-cyclopenten-1-yl (IRS)-cis-3-(Z-2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylate (Compound No. 35). Yield 77% nD25 1.4713
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([NH2:12])[C:8]([NH2:11])=[CH:9][CH:10]=1)(=[O:4])=[O:3].[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18](=O)[C:19](O)=[O:20]>>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:8](=[CH:9][CH:10]=1)[NH:11][C:19](=[O:20])[C:18]([C:14]1[S:13][CH:17]=[CH:16][CH:15]=1)=[N:12]2)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(N)c(N)c1
Reactant: O=C(O)C(=O)c1cccs1
Product: CS(=O)(=O)c1ccc2[nH]c(=O)c(-c3cccs3)nc2c1

Procedure:
The quinoxalin-2-one of the present example is prepared with 4-Methanesulfonyl-benzene-1,2-diamine and (thiophen-2-yl)oxo-acetic acid via the method described in Example 12 to afford 6-Methanesulfonyl-3-thiophen-2-yl-1H-quinoxalin-2-one.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8](O)=[C:7]([O:13][CH3:14])[C:6]=1[O:15][CH3:16])(=[O:3])[CH3:2].[CH2:17](Cl)[C:18](=[CH2:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([CH2:19][C:18]([CH3:20])=[CH2:17])=[C:7]([O:13][CH3:14])[C:6]=1[O:15][CH3:16])(=[O:3])[CH3:2]
Reactant: COc1c(O)cc(C)c(OC(C)=O)c1OC
Reactant: C=C(C)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C)Cc1cc(C)c(OC(C)=O)c(OC)c1OC
Yield: 84 %

Procedure:
A suspension (200 ml) of 4-acetoxy-2,3-dimethoxy-5-methylphenol (26 g), methallyl chloride (13 ml) and potassium carbonate (18 g) in N,N-dimethylformamide was stirred under an atmosphere of argon at 65° C. for 15 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=4:1) to obtain the title compound (27 g, 84%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([CH3:9])[C:5](I)=[CH:4][N:3]=1.[C:11]([Si:13]([CH3:16])([CH3:15])[CH3:14])#[CH:12].C(N(CC)C(C)C)(C)C>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([CH3:9])[C:5]([C:12]#[C:11][Si:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][N:3]=1
Reactant: Cc1c(I)cnc(Cl)c1F
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1c(C#C[Si](C)(C)C)cnc(Cl)c1F
Temperature: 60 °C
Yield: 0.1 %

Procedure:
A mixture of 2-chloro-3-fluoro-5-iodo-4-methyl-pyridine (2960 mg, 10.9 mmol), ethynyltrimethylsilane (1.89 mL, 13.1 mmol), N,N-diisopropylethylamine (3.80 mL, 21.8 mmol), dichlorobis(triphenylphosphine)palladium(II) (390 mg, 0.545 mmol), and cuprous iodide (104 mg, 0.55 mmol) in dioxane (40 mL) was heated at 60° C. for 2 hours. The reaction mixture was filtered through a short plug of silica, rinsed with 50 mL of ethyl acetate/heptane (1:1), and the filtrate was evaporated in vacuo to provide an orange oil that was purified by flash chromatography (12 g, Silica, 0-20% ethyl acetate in heptane). Desired fractions were combined and evaporated in vacuo to afford the title compound as a pale yellow oil, (2.35 mg, 89%). 1H NMR (400 MHz, CDCl3) δ 8.21 (s, 1H), 2.40 (d, J=1.9 Hz, 3H), 0.28 (s, 11H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:10]1[C:14](=[O:15])[N:13]([CH2:16][CH2:17][CH3:18])[N:12]=[N:11]1.CC1C=CC(S(O)(=O)=O)=CC=1.[O:30]1[CH:34]=[CH:33][CH2:32][CH2:31]1.N>O1CCOCC1.CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:31]2[CH2:32][CH2:33][CH2:34][O:30]2)=[CH:4][C:3]=1[N:10]1[C:14](=[O:15])[N:13]([CH2:16][CH2:17][CH3:18])[N:12]=[N:11]1
Reactant: CCCn1nnn(-c2cc(O)c(Cl)cc2Cl)c1=O
Reactant: C1=COCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Solvent: CO
Solvent: C1COCCO1
Product: CCCn1nnn(-c2cc(OC3CCCO3)c(Cl)cc2Cl)c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.1 %

Procedure:
To a stirred solution of 1.0 g (0.0035 mole) of 1-(2,4-dichloro-5-hydroxyphenyl)-1,4-dihydro-4-propyl-5H-tetrazol-5-one (Example 10, Step A) and 0.05 g (0.00026 mole) of 4-methylphenylsulfonic acid in 40 mL of p-dioxane was added slowly 0.88 g (0.0126 mole) of dihydrofuran in 20 mL of p-dioxane. The mixture was stirred at room temperature for approximately 18 hours, and an additional 0.88 g of dihydrofuran was added. The mixture was stirred at room temperature for an additional 48 hours. One mL of methanol saturated with ammonia was added to the mixture and stirring was continued for a short period of time. The reaction mixture was evaporated under reduced pressure to leave a residue. The residue was purified by column chromatography on silica gel, eluting with methylene chloride, to yield 0.58 g of 1-[2,4-dichloro-5-(2-tetrahydrofuranyloxy)phenyl]-1,4-dihydro-4-propyl-5H-tetrazol-5-one as a solid, mp 89°-90° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[CH3:12][CH:13](O)[CH:14]=[CH2:15].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>COC(OC)(C)C>[CH2:12]([CH:7]1[CH2:6][C:5]2[C:9](=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=2)[C:8]1=[O:11])[CH:13]=[CH:14][CH3:15]
Reactant: C=CC(C)O
Reactant: O=C1CCc2ccc(Br)cc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: O
Product: CC=CCC1Cc2ccc(Br)cc2C1=O
Yield: 78 %

Procedure:
A solution of 10.0 g of 6-bromo-1-indanone, 9.79 ml of 3-buten-2-ol and 100 mg of p-toluenesulfonic acid in 100 ml of 2,2-dimethoxypropane was boiled under reflux for 71 hours on a water separator filled with molecular sieve (0.4 nm, 2 mm pearl shaped). The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/diethyl ether 1:1). In addition to 3.07 g of educt, there were obtained 9.86 g (78%) of (RS)-2-(2-buten-1-yl)-6-bromo-1-indanone as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][CH2:14][CH3:15])=[C:11]([C:16](Cl)=[O:17])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH:19]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][CH2:14][CH3:15])=[C:11]([C:16]([NH:25][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:17])[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCCc1c(C(=O)Cl)cnn1-c1ccc(Cl)cc1
Reactant: NC1CCCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCc1c(C(=O)NC2CCCCC2)cnn1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 1-(4-chlorophenyl)-5-propyl-pyrazole-4-carbonyl chloride (commercially available, 302 mg, 1.07 mmol) in DCM (5 ml) was added 1 drop of DMF followed by cyclohexylamine (306 μL, 2.68 mmol). The reaction mixture was stirred at room temperature for two hours then stopped.
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:21])=[C:6]([CH:10]=[C:11]2[C:15](=[O:16])[NH:14][N:13]=[C:12]2[O:17][CH:18]([CH3:20])[CH3:19])[NH:7][C:8]=1[CH3:9])([OH:3])=[O:2].CN(C=O)C.C(Cl)(=O)C(Cl)=O.[CH3:33][N:34]([CH2:36][CH2:37]O)[CH3:35]>ClCCl>[CH3:33][N:34]([CH3:35])[CH2:36][CH2:37][O:2][C:1]([C:4]1[C:5]([CH3:21])=[C:6]([CH:10]=[C:11]2[C:15](=[O:16])[NH:14][N:13]=[C:12]2[O:17][CH:18]([CH3:19])[CH3:20])[NH:7][C:8]=1[CH3:9])=[O:3]
Reactant: Cc1[nH]c(C=C2C(=O)NN=C2OC(C)C)c(C)c1C(=O)O
Reactant: CN(C)CCO
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1[nH]c(C=C2C(=O)NN=C2OC(C)C)c(C)c1C(=O)OCCN(C)C
Reaction time: 24 h

Procedure:
A mixture of 4-[(4-carboxy-3,5-dimethylpyrrol-2-yl)methylene]-3-isopropoxy-2-pyrazolin-5-one (200 mg, 0.68 mmol) in dichloromethane (20 ml) and a drop of DMF, was treated with oxalyldichloride (0.2 ml). The stirring was continued for 24 h and a solution of dimethylaminoethanol (0.6 g, 6.7 mmol) in dichloromethane (5 ml) was added. The stirring was continued for 24 h. The solvent was evaporated to dryness, the solid residue was treated with NaHCO3 (5%) and extracted with dichloromethane. The solid obtained after elimination of the solvent was recrystallized from n-heptane.
Reaction SMILES: [C:1]1(=[O:20])[N:5]([CH2:6][C:7](=O)[CH2:8][CH2:9][C:10](=O)[CH2:11][CH3:12])[C:4](=[O:15])[C:3]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:2]12.Cl.[CH3:22][O:23][C:24](=[O:27])[CH2:25][NH2:26].C([O-])(=O)C.[Na+]>C1(O)CCCCC1>[CH3:22][O:23][C:24]([CH2:25][N:26]1[C:10]([CH2:11][CH3:12])=[CH:9][CH:8]=[C:7]1[CH2:6][N:5]1[C:4](=[O:15])[C:3]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:2]2[C:1]1=[O:20])=[O:27]
Reactant: CCC(=O)CCC(=O)CN1C(=O)c2ccccc2C1=O
Reactant: COC(=O)CN
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: OC1CCCCC1
Product: CCc1ccc(CN2C(=O)c3ccccc3C2=O)n1CC(=O)OC

Procedure:
6.8 g (0.025 mol) of 7-phthalimido-3,6-heptanedione, 3.5 g (0.028 mol) of glycine methyl ester hydrochloride and 2.3 g (0.028 mol) of sodium acetate are stirred in 150 ml of cyclohexanol at 60° C. for 13 hours and the mixture is worked up as in Example 22.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[CH:17][N:18]3[CH3:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]C(C)(C)C.[C:29]1([S:35](F)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[C:17]([S:35]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:37])=[O:36])[N:18]3[CH3:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(=O)(F)c1ccccc1
Reactant: Cn1ccc2c(N3CCN(C(=O)OC(C)(C)C)CC3)cccc21
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: Cn1c(S(=O)(=O)c2ccccc2)cc2c(N3CCN(C(=O)OC(C)(C)C)CC3)cccc21
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
To a −75° C. solution of 4-(1-methyl-1H-indol-4-yl)-piperazine-1-carboxylic acid tert-butyl ester compound 3-1 (330 mg, 1.05 mmol) in THF (25 mL) was slowly added t-BuLi (1.2 mL, 2.1 mmol). The reaction mixture was stirred for 30 minutes at −75° C. then warmed in an ice bath for 15 min. The reaction was re-cooled to −75° C. and benzenesulfonyl fluoride was added (0.2 mL, 1.6 mmol). The reaction was stirred cold for 1.5 h at which time the ice bath was removed and the reaction was allowed to warm to room temperature (45 min.). The reaction was quenched with a saturated solution of ammonium chloride (55 mL) and extracted with ethyl acetate (3×20 mL). The combined ethyl acetate layers were washed with brine (25 mL), dried (MgSO4), filtered and concentrated to afford a yellow oil. The oil was chromatographed over silica eluting with hexanes/ethyl acetate (4:1) to afford 190 mg (40%) of 4-(2-benzenesulfonyl-1-methyl-1H-indol-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (3-2).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[BrH:11].Br.[NH+]1C=CC=CC=1.O>C(O)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH2:9][Br:11]
Reactant: CC(=O)c1ccccc1C
Reactant: Br
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccccc1C(=O)CBr
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3.0 g of 2'-methylacetophenone in 60 ml of acetic acid was added successively 9.7 ml of 47% hydrobromic acid and 8.6 g of pyridinium hydrobromide perbromide, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and a saturated sodium carbonate solution, and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was removed under reduced pressure to give 5.4 g of the title compound as a colorless oily material.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:17][OH:18]>C(O)C.N1C=CC=CC=1>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:17][OH:18])=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1ccc(Br)cc1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: ON=C(c1ccccc1)c1ccc(Br)cc1
Yield: 94 %

Procedure:
A mixture of 4-bromobenzophenone (10.0 g, 0.0383 mol) and hydroxylamine hydrochloride (13.3 g, 0.192 mol) was heated in a mixture of ethanol (250 mL) and pyridine (50 mL) at reflux for 2 hours under an atmosphere of nitrogen. The solvents were removed under the reduced pressure and the residue was partitioned between water (300 mL) and dichloromethane (300 mL). The water phase was further extracted with dichloromethane twice (180 mL each) and the combined organic extracts were dried over magnesium sulfate. The solvent was removed under the reduced pressure and the residue was purified by flash chromatography on silica gel using ethyl acetate/n-heptane (1:9) as mobile phase to yield (4-bromophenyl)(phenyl)methanone oxime as a white solid (9.93 g, 0.036 mol): 1H NMR (DMSO-d6, 400 MHz) 7.66 (d, 1H), 7.57(d, 1H), 7.33 (m, 7H) TLC (ethyl acetate/heptane 1:5) Rf 0.38.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[O:5][CH:6]1[CH2:10][CH2:9][N:8]([C:11](Cl)=[O:12])[CH2:7]1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:23]([N:25]([CH2:30][CH3:31])[CH2:26][CH2:27][CH2:28][NH2:29])[CH3:24].O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[O:5][CH:6]1[CH2:10][CH2:9][N:8]([C:11]([NH:29][CH2:28][CH2:27][CH2:26][N:25]([CH2:30][CH3:31])[CH2:23][CH3:24])=[O:12])[CH2:7]1
Reactant: CCN(CC)CCCN
Reactant: O=C(Cl)N1CCC(Oc2cccc(Cl)c2)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCN(CC)CCCNC(=O)N1CCC(Oc2cccc(Cl)c2)C1
Temperature: 0 °C
Reaction time: 78 h

Procedure:
A stirred solution, 13 g (0.05 mole) of 3-(3-chlorophenoxy)-1-pyrrolidinecarbonyl chloride in 100 ml of chloroform was treated with 25 mg of ice and 12.8 g of sodium carbonate after 5 min. This mixture was treated with 7.15 g (0.055 mole) of N,N-diethyl-1,3-propanediamine dropwise and allowed to stir for 78 hours. The reaction mixture was transferred to a separatory funnel and enough water was added to form two distinct phases. The organic phase (chloroform) was separated and washed with 50 ml of water; the organic portion was extracted with 50 ml of 3N hydrochloric acid, separated and washed with 2×25 ml of water. All the aqueous portions were combined and the pH adjusted to neutral with 3N sodium hydroxide and extracted with 4×30 ml of chloroform. The extract was combined, washed with water, dried over magnesium sulfate and concentrated on a rotary vacuum to a pale yellow oil (12 g). The oil was dissolved in chloroform, treated with 1.5 g of charcoal and filtered hot. This was then slurried with 25 g of silica gel and filtered. The chloroform was discarded and the silica gel washed with methanol to give, after concentrating, 4 g of pale yellow oil. This was dissolved in ethyl ether and filtered through celite.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([CH2:11][C@@H:12]([OH:17])[CH2:13][C:14](O)=[O:15])#[N:10].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.S(=O)(=O)(O)O>[CH2:1]([O:8][C:14](=[O:15])[CH2:13][C@H:12]([OH:17])[CH2:11][C:9]#[N:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: N#CC[C@@H](O)CC(=O)O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC#N
Product: N#CC[C@@H](O)CC(=O)OCc1ccccc1
Yield: 71.6 %

Procedure:
Benzylalcohol (216 g, 2 eq.) and conc. sulfuric acid (5 g) were added to (R)-4-cyano-3-hydroxybutyric acid (1.0 mol) dissolved in acetonitrile (500 ml) and refluxed for 5 hours. The reaction mixture was neutralized with sodium carbonate and filtered. The filtrate was concentrated in vacuo to afford (R)-4-cyano-3-hydroxybutyric acid benzyl ester (157 g, 92%) which was purified by column chromatography on a silica gel.
Reaction SMILES: ClCCl.[O:4]=[C:5]1[NH:9][C:8](=[O:10])[CH:7]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:21][CH3:22])=[C:16]([CH:20]=2)[C:17]([OH:19])=O)[S:6]1.C(Cl)(=O)OCC.[F:29][C:30]([F:40])([F:39])[C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH2:36])=[CH:33][CH:32]=1>C(N(CC)CC)C>[O:4]=[C:5]1[NH:9][C:8](=[O:10])[CH:7]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:21][CH3:22])=[C:16]([CH:20]=2)[C:17]([NH:36][CH2:35][C:34]2[CH:33]=[CH:32][C:31]([C:30]([F:29])([F:39])[F:40])=[CH:38][CH:37]=2)=[O:19])[S:6]1
Reactant: COc1ccc(CC2SC(=O)NC2=O)cc1C(=O)O
Reactant: NCc1ccc(C(F)(F)F)cc1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CC2SC(=O)NC2=O)cc1C(=O)NCc1ccc(C(F)(F)F)cc1
Reaction time: 0.17 h
Yield: 59.5 %

Procedure:
To 49 mL of dichloromethane were added 6.30 g of triethylamine and 7.00 g of 5-[(2,4-dioxothiazolidin-5-yl) methyl]-2-methoxybenzoic acid. After 2.71 g of ethyl chlorocarbonate were added, the mixture was stirred for 10 minutes. Further, 4.59 g of 4-trifluoromethylbenzylamine were added and the mixture was stirred for 1 hour. After washed the reaction mixture with water, solvent was distilled off and to the residue were added 109 mL of water and 33 mL of ethanol, to which solution 2 mol/L hydrochloric acid was added dropwise to adjust to pH 2.0. The precipitated crystals were collected by filtration and washed with water to obtain 10.25 g of crude crystals. By recrystallizing 10.25 g of crude crystals twice from 90% ethanol, 6.49 g of 5-[(2,4-dioxothiazolidin-5-yl) methyl]-2-methoxy-N-[[4-(trifluoromethyl)phenyl]methyl] benzamide (KRP-297) were obtained (yield 61.3%).
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:26][N:27]([CH3:35])[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:4][N:5](S(C2C=CC=CC=2)(=O)=O)[C:6]=1[C:7]1[C:8]([C:13]([F:16])([F:15])[F:14])=[N:9][CH:10]=[CH:11][CH:12]=1.[OH-].[Na+]>O1CCCC1.CO>[F:1][C:2]1[C:3]([CH2:26][N:27]([CH3:35])[C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[CH:4][NH:5][C:6]=1[C:7]1[C:8]([C:13]([F:15])([F:16])[F:14])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2ccccc2)c(-c2cccnc2C(F)(F)F)c1F)C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(Cc1c[nH]c(-c2cccnc2C(F)(F)F)c1F)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
To a solution of tert-butyl ({4-fluoro-1-(phenylsulfonyl)-5-[2-(trifluoromethyl)pyridin-3-yl]-1H-pyrrol-3-yl}methyl)methylcarbamate (938 mg) in tetrahydrofuran (4 mL) and methanol (1 mL) was added a 8 mol/L aqueous sodium hydroxide solution (0.6 mL) at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane:ethyl acetate=4:1) to give the title compound as a yellow oil (yield 423 mg, 62%).