Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:30]([NH2:32])=[O:31])[CH:17]=[C:18](B4OC(C)(C)C(C)(C)O4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].Br[C:34]1[CH:35]=[C:36]([CH:39]=[C:40]([CH:42]=[O:43])[CH:41]=1)[C:37]#[N:38].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[C:37]([C:36]1[CH:35]=[C:34]([C:18]2[CH:19]=[C:20]3[C:15](=[C:16]([C:30]([NH2:32])=[O:31])[CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:9]2[CH2:10][CH2:11][N:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])[CH2:7][CH2:8]2)[CH:41]=[C:40]([CH:42]=[O:43])[CH:39]=1)#[N:38]
Reactant: N#Cc1cc(Br)cc(C=O)c1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(B4OC(C)(C)C(C)(C)O4)cc23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(C#N)cc(C=O)c4)cc23)CC1
Temperature: 160 °C

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamide (46 mg, 0.1 mmol) in dioxane (2.0 mL, 0.7 mL) was added 3-bromo-5-formylbenzonitrile (68 mg, 0.3 mmol) and K2CO3 (83 mg, 0.6 mmol) in a microwave tube. The reaction mixture was degassed for 5 min before addition of tetrakis(triphenylphosphosphine) palladium (0) (11 mg, 0.01 mmol). The reaction was heated in a microwave for 20 min at 160° C. It was then purified by Gilson Preparatory HPLC to give 5-(3-cyano-5-formylphenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide.
Reaction SMILES: C(N(CC)CC)C.[N+:8]([C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[CH3:18])[NH2:14])([O-:10])=[O:9].[C:19]([C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)#[N:20]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:18][C:17]1[CH:16]=[CH:15][C:13]([NH:14][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][C:21]([C:19]#[N:20])=[CH:22][CH:23]=2)=[CH:12][C:11]=1[N+:8]([O-:10])=[O:9]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: Cc1ccc(N)cc1[N+](=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)c2ccc(C#N)cc2)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 5 h
Yield: 1237.4 %

Procedure:
Triethylamine (23 ml) was added to a suspension of 3-nitro-4-methylaniline (0.8 g), 4-cyanobenzoyl chloride (13.1 g), 4-dimethylaminopyridine (0.8 g) in methylene chloride (200 ml) which had been cooled to 0° C. The reaction mixture was allowed to warm to ambient temperature and was stirred for 5 hours. The mixture was partitioned between methylene chloride and 0.5M hydrochloric acid solution. The organic phase was dried over magnesium sulphate, filtered and evaporated to dryness. The residue was triturated under isohexane and the resulting solid was isolated and dried under vacuum at 55° C. to yield N-(4-methyl-3-nitrophenyl)-4-cyanobenzamide (18.3 g); NMR: 2.5 (s, 3H), 7.49 (d, 1H), 7.96 (m, 1H), 8.05 (d, 2H), 8.12 (d, 2H), 8.51 (d, 1H), 10.77 (s, 1H).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:18]2[NH:22][C:21]([C:23]([OH:25])=O)=[C:20]([CH3:26])[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.C[N:29](C)CCCN=C=NCC>CN(C)C=O.C(OCC)(=O)C>[CH:1]1([CH2:6][CH:7]([C:18]2[NH:22][C:21]([C:23]([NH2:29])=[O:25])=[C:20]([CH3:26])[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCN=C=NCCCN(C)C
Reactant: Cc1cc(C(CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)[nH]c1C(=O)O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(C(CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)[nH]c1C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
To a solution (5 mL) of 5-{2-cyclopentyl-1-[4-(methylsulfonyl)phenyl]ethyl}-3-methyl-1H-pyrrole-2-carboxylic acid (160 mg) in N,N-dimethylformamide were added under ice-cooling N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (125 mg) and 1-hydroxybenzotriazole-ammonia complex (100 mg). The reaction mixture was slowly warmed to room temperature, and stirred overnight. The reaction mixture was diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (155 mg, yield 97%) was obtained as colorless amorphous crystals from a fraction eluted with ethyl acetate-hexane (4:1, volume ratio). MS: 375 (MH+).
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[CH:5]([NH2:11])[CH2:4]2.[F:12][C:13]([F:26])([F:25])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1/[CH:20]=[CH:21]/[C:22](O)=[O:23]>>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[CH:5]([NH:11][C:22](=[O:23])/[CH:21]=[CH:20]/[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:13]([F:25])([F:26])[F:12])[CH2:4]2
Reactant: O=C(O)/C=C/c1ccccc1C(F)(F)F
Reactant: NC1CN2CCC1CC2
Agent: Cl
Product: O=C(/C=C/c1ccccc1C(F)(F)F)NC1CN2CCC1CC2

Procedure:
Prepared as a free base by a method analogous to that described in Example 1 from racemic 1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride and E-3-(2-trifluoromethylphenyl)propenoic acid; MS (ES+) 325 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[CH2:8][C:7]2[CH:17]=[CH:18][CH:19]=[CH:20][C:6]1=2)=[O:4].C(OCC)(OCC)O[CH2:23][CH3:24]>C(O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9]([O:16][CH2:23][CH3:24])=[CH:8][C:7]2[CH:17]=[CH:18][CH:19]=[CH:20][C:6]1=2)=[O:4]
Reactant: COC(=O)N1c2ccccc2CC(=O)c2ccccc21
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC1=Cc2ccccc2N(C(=O)OC)c2ccccc21
Temperature: 60 °C
Reaction time: 4 h
Yield: 96.7 %

Procedure:
A suspension of 10-oxo-10,11-dihydro-dibenzo[b,f]azepine-5-carboxylic acid methyl ester (15 g, 56 mmol) in ethanol (75 ml) is heated to 60° C. and a catalytic amount of p-toluene sulfonic acid (0.213 g, 1.1 mmol) is added. After addition of triethyl ortho-formate (8.73 g, 58.9 mmol) the solution is stirred at 60–70° C. for 4 hours. During this reaction the product precipitates as white crystals. The mixture is cooled to room temperature, filtered and dried to yield 16.0 g of pure title compound (97%).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].[CH3:10][O-:11].[Na+]>CO>[F:9][C:8]1[CH:7]=[CH:6][C:4]([NH2:5])=[CH:3][C:2]=1[O:11][CH3:10]
Reactant: Nc1ccc(F)c(F)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(N)ccc1F
Temperature: 110 °C

Procedure:
3,4-Difluoroaniline (2.6 g) was added to a 28% methanol solution of sodium methoxide, and the mixture was heated for 2 days at about 60° C. and for 4 days at 110° C. After distilled water (50 ml) was added to the reaction mixture, it was extracted with chloroform (50 ml). A chloroform layer was washed with distilled water (20 ml) and then dried over anhydrous magnesium sulfate. The dry chloroform layer was concentrated under reduced pressure to obtain the title compound (2.8 g) as a dark brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=1.[Br:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]=O>>[Br:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]1[C:3]2[C:4](=[O:10])[CH2:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2]=2[NH:1][C:2]2[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[C:3]1=2
Reactant: O=Cc1ccccc1Br
Reactant: CC1(C)CC(=O)C=C(N)C1
Product: CC1(C)CC(=O)C2=C(C1)NC1=C(C(=O)CC(C)(C)C1)C2c1ccccc1Br

Procedure:
3-Amino-5,5-dimethyl-2-cyclohexen-1-one was reacted with 2-bromobenzaldehyde in an analogous manner to that described in Example 1 to give 9-(2-bromophenyl)-3,4,6,7,9,10-hexahydro-3,3,6,6-tetramethyl-1,8(2H,5H)-acridinedione. Crystallization from dimethylformamide/water gave a yellow powder of melting point >285° C. (decomposition).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][N:6]=1)=[O:4].[H-].[Na+].[CH2:14](Br)[CH:15]=[CH2:16]>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:16][CH:15]=[CH2:14])=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(O)cn1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc(C(=O)OC)nc1
Reaction time: 0.5 h

Procedure:
4.7 g of 5-hydroxy-2-pyridinecarboxylic acid methyl ester is added to a stirred suspension of 1.30 g of sodium hydride (57% mineral oil dispersion) in 10 ml of dimethylformamide at room temperature while maintaining a nitrogen atmosphere. The mixture is stirred for 30 minutes and then is added a solution of 3.90 g of allyl bromide in 20 ml of dimethylformamide. The mixture is heated to 100° and maintained at 100° for 5 hours. Then the mixture is cooled, filtered and the filtrate evaporated to a residue. The residue is partitioned between water and methylene chloride, the layers are separated and the water layer is extracted with methylene chloride. The methylene layer is combined with the methylene extract, dried over anhydrous sodium sulfate and filtered. The filtrate is evaporated and the residue is distilled to yield 5-allyloxy-2-pyridinecarboxylic acid methyl ester boiling at 124°-130°/0.15 mm/Hg.
Reaction SMILES: [C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21](/[C:23](/[CH:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:24]\[C:25]([NH2:27])=[O:26])[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].O=O.[H][H]>>[C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21]([CH:23]([CH:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)[CH2:24][C:25]([NH2:27])=[O:26])[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:4])([CH3:5])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)C(=O)OCn1ccc2c(-c3cnn(/C(=C\C(N)=O)C4CCCC4)c3)ncnc21
Agent: O=O
Product: CC(C)(C)C(=O)OCn1ccc2c(-c3cnn(C(CC(N)=O)C4CCCC4)c3)ncnc21
Temperature: 25 °C

Procedure:
General screening procedure for asymmetric hydrogenation using the substrate, (Z)-(4-(1-(3-amino-1-cyclopentyl-3-oxoprop-1-enyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (10) to afford optically enriched product, (4-(1-(3-amino-1-cyclopentyl-3-oxopropyl]-1H-pyrazol-4-yl}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate ((R)-11 or (S)-11): A 300 mL-volume autoclave with glass vial (20 mL) was charged with the substrate (10), the catalyst (metal, ligand, and catalyst precursor), and oxygen-free solvent (4-6 mL) under nitrogen. This autoclave was charged with hydrogen gas to the desired pressure and stirred at room temperature or heated with oil bath. After hydrogen gas was released, the reaction mixture was concentrated under reduced pressure. The residue was purified by eluting through a silica gel pad using a mixture of ethyl acetate and methanol (v/v=9/1) to afford product, (4-(1-(3-amino-1-cyclopentyl-3-oxopropyl]-1H-pyrazol-4-yl}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate ((R)-11 or (S)-11), for chemical conversion (HPLC and chiral HPLC), LC/MS and NMR spectroscopy and enantiomeric excess (% ee by chiral HPLC) determination.
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[C:13]([Si:15]([CH3:18])([CH3:17])[CH3:16])#[CH:14].C(NC(C)C)(C)C>C1COCC1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:16][Si:15]([C:13]#[C:14][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1)([CH3:18])[CH3:17]
Reactant: C#C[Si](C)(C)C
Reactant: CCOC(=O)c1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)c1ccc(C#C[Si](C)(C)C)cc1
Yield: 73 %

Procedure:
A mixture of ethyl 4-bromobenzoate (1.5 g, 6.55 mmol), ethynyl trimethylsilane (965 mg, 9.82 mmol), diisopropylamine (1.39 g, 13.7 mmol), cuprous iodide(25 mg, 0.131 mmol), and bis(triphenylphosphine) palladium(II) chloride (184 mg, 0.262 mmol) was heated at 45° C. for 4 h in dry THF (10 ml) under argon atmosphere. The reaction was quenched by the addition of water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel flash column chromatography (eluent: hexane/ethyl acetate=100/1) to give ethyl 4-[(trimethylsilyl)ethynyl]benzoate (73%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:15]([CH3:31])([CH3:30])[CH2:14]2)[N:5]=[C:4]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][NH:39][C:40]2[N:45]=[C:44](Cl)[N:43]=[C:42]([NH:47][CH2:48][CH2:49][CH2:50][CH2:51][CH:52]3[CH2:57][C:56]([CH3:59])([CH3:58])[N:55]([O:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH3:68])[C:54]([CH3:70])([CH3:69])[CH2:53]3)[N:41]=2)[N:3]=1.[CH2:71]([CH2:73][NH2:74])[OH:72]>>[OH:72][CH2:71][CH2:73][NH:74][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:15]([CH3:31])([CH3:30])[CH2:14]2)[N:5]=[C:4]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][NH:39][C:40]2[N:45]=[C:44]([NH:74][CH2:73][CH2:71][OH:72])[N:43]=[C:42]([NH:47][CH2:48][CH2:49][CH2:50][CH2:51][CH:52]3[CH2:57][C:56]([CH3:59])([CH3:58])[N:55]([O:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH3:68])[C:54]([CH3:70])([CH3:69])[CH2:53]3)[N:41]=2)[N:3]=1
Reactant: CCCCCCCCON1C(C)(C)CC(CCCCNc2nc(Cl)nc(NCCCCCCNc3nc(Cl)nc(NCCCCC4CC(C)(C)N(OCCCCCCCC)C(C)(C)C4)n3)n2)CC1(C)C
Reactant: NCCO
Product: CCCCCCCCON1C(C)(C)CC(CCCCNc2nc(NCCO)nc(NCCCCCCNc3nc(NCCO)nc(NCCCCC4CC(C)(C)N(OCCCCCCCC)C(C)(C)C4)n3)n2)CC1(C)C

Procedure:
The title compound is prepared from the reaction of N,N'-bis{2-chloro-4-[N-(1-octyloxy-2,2,6,6-tetramethylpiperidin-4-yl)butylamino]-1,3,5-triazin-6-yl}-1,6-hexanediamine and ethanolamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[C:10](=[N:12]O)[CH2:9][CH2:8]2.[H][H]>O1CCCC1.CO.[Ni]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([NH2:12])[CH2:9][CH2:8]2
Reactant: COc1cccc2c1C(=NO)CC2
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cccc2c1C(N)CC2
Yield: 97 %

Procedure:
A mixture of 7-methoxy-indan-1-one oxime (CAS 908108-58-7, (E)-oxime 179899-16-2) (22.3 g, 126 mmol)) and Raney-Nickel (11.26 g) in tetrahydrofuran (570 mL) and methanol (570 mL) was hydrogenated at 100 bar hydrogen-pressure at 60° C. for 22 h. Filtered the catalyst off, washed with methanol and tetrahydrofuran, all volatiles were removed in vacuum to give the title compound as a brown oil (19.95 g, 97%, HPLC 0.4 min), MS (ISP) m/e=164.2 [(M+H)+].
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]([CH3:29])([CH3:28])[C@H:5]([NH:7][C:8]1[C:9]2[N:10]([CH:17]=[C:18]([C:20]3[CH:21]=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[CH:19]=2)[N:11]=[CH:12][C:13]=1[C:14](=[O:16])[NH2:15])[CH3:6].[OH-].[K+].Cl>CO.O>[C:14]([C:13]1[CH:12]=[N:11][N:10]2[CH:17]=[C:18]([C:20]3[CH:21]=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[CH:19]=[C:9]2[C:8]=1[NH:7][C@H:5]([CH3:6])[C:4]([CH3:29])([CH3:28])[C:3]([OH:30])=[O:2])(=[O:16])[NH2:15]
Reactant: COC(=O)C(C)(C)[C@@H](C)Nc1c(C(N)=O)cnn2cc(-c3ccc(OC)nc3)cc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(-c2cc3c(N[C@H](C)C(C)(C)C(=O)O)c(C(N)=O)cnn3c2)cn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82.9 %

Procedure:
(R)-methyl-3-((3-carbamoyl-6-(6-methoxypyridin-3-yl)pyrrolo[1,2-b]pyridazin-4-yl)amino)-2,2-dimethylbutanoate (125 mg, 0.304 mmol) was dissolved in MeOH (25 mL) and water (1.0 mL). Potassium hydroxide (256 mg, 4.56 mmol) was added and the reaction mixture was heated at reflux overnight. After completion, the reaction mixture was cooled to room temperature and MeOH was removed under reduced pressure. The crude mass obtained was acidified to pH 5 at 0° C. using 1.5N HCl and stirred at room temperature for 15 minutes to give a solid that was collected by vacuum filtration and dried to afford the title compound (100 mg, 0.252 mmol, 83% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 1.13-1.15 (d, J=8.4 Hz, 6H), 1.25-1.26 (d, J=6.4 Hz, 3H), 3.86 (s, 3H), 4.68 (m, 1H), 6.84-6.86 (d, J=8.4 Hz, 1H), 7.25 (s, 1H), 8.06-8.064 (d, J=2 Hz, 1H), 8.15-8.18 (d, J=12 Hz, 2H), 8.59 (s, 1H), 10.86-10.89 (d, J=10 Hz, 1H). [α]24.8=1.6 (c=0.1, MeOH)
Reaction SMILES: [F:1][CH:2]1[CH2:6][N:5]([C@@H](C2C=CC=CC=2)C)[CH2:4][C@@:3]1([CH3:22])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].[CH2:23]([O:30][C:31](Cl)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>ClCCl>[CH2:23]([O:30][C:31]([N:5]1[CH2:6][CH:2]([F:1])[C@:3]([CH3:22])([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:4]1)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C[C@H](c1ccccc1)N1CC(F)[C@](C)(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@]1(C)CN(C(=O)OCc2ccccc2)CC1F
Temperature: 60 °C
Reaction time: 20 h
Yield: 77 %

Procedure:
To a solution of tert-butyl (3S)-4-fluoro-3-methyl-1-[(1R)-1-phenylethyl]-pyrrolidine-3-carboxylate (isomer A) (2.15 g, 6.99 mmol) in dichloromethane (40 mL), benzyloxycarbonyl chloride (1.50 mL, 10.5 mmol) was added, and the mixture was stirred in an oil bath at 60° C. for 20 hours. After concentrating the reaction mixture under reduced pressure, the concentrate was purified by silica gel column chromatography (elusion by hexane:ethyl acetate, 12:1→2:1) to obtain 1.81 g (77%) of the title compound (isomer A) as a colorless oily substance.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[C:15](=[O:33])[N:16]([CH3:32])[C:17](=[O:31])[N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=4)[C:19]=3[CH3:20])=[C:12]([S:34](Cl)(=[O:36])=[O:35])[CH:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2].O.[NH3:39]>C(#N)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[C:15](=[O:33])[N:16]([CH3:32])[C:17](=[O:31])[N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=4)[C:19]=3[CH3:20])=[C:12]([S:34]([NH2:39])(=[O:36])=[O:35])[CH:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: Cc1c(-c2c(S(=O)(=O)Cl)cnn2-c2ccc(C#N)cc2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: N
Solvent: O
Solvent: CC#N
Product: Cc1c(-c2c(S(N)(=O)=O)cnn2-c2ccc(C#N)cc2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 0 °C

Procedure:
A suspension of the compound prepared in Example 204 (50.0 mg) in acetonitrile (20 ml) was cooled to 0° C. and thereto was added ammonia water (28%, 5.0 ml) dropwise and the mixture was stirred for another ten minutes. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford 1-(4-cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonamide (42.0 mg). UPLC/MS 531 (M+H)/0.87 min. (measurement condition 9)
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](Cl)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:21])(=O)C.[NH2:22][C:23]1[CH:33]=[CH:32][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][CH:24]=1.[OH-].[Na+]>ClCCl.CO>[CH2:30]([O:29][C:27]([C:26]1[CH:25]=[CH:24][C:23]([NH:22]/[C:13](=[C:6]2\[C:5](=[O:21])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[CH:10][CH:11]=3)/[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:33][CH:32]=1)=[O:28])[CH3:31]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CC(=O)N1C(=O)C(=C(Cl)c2ccccc2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)c1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 2 from 1-acetyl-3-(1-chloro-1-phenyl-methylidene)-2-indolinone and ethyl 4-aminobenzoate in dichloromethane and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([OH:10])=O.[C:11]([N:14]1[CH2:19][CH2:18][NH:17][CH:16]([CH2:20][N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[CH2:15]1)(=[O:13])[CH3:12].[ClH:26].[NH4+].[Cl-]>>[ClH:26].[C:11]([N:14]1[CH2:19][CH2:18][N:17]([C:8](=[O:10])[CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH:16]([CH2:20][N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[CH2:15]1)(=[O:13])[CH3:12]
Reactant: O=C(O)Cc1ccccn1
Reactant: CC(=O)N1CCNC(CN2CCCC2)C1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Product: CC(=O)N1CCN(C(=O)Cc2ccccn2)C(CN2CCCC2)C1

Procedure:
The compound was prepared by coupling of 2-pyridylacetic acid with 4-acetyl-2-(R,S)-[(1-pyrrolidinyl)methyl]piperazine; mp: (HCl salt) 127-130° C.; 1H NMR (free base, 200 MHz, CDCl3) δ1.4-1.7 (4 H, m), 2.0 (3 H, s), 2.2-3.2 (9 H, m), 3.4-4.8 (6 H, m), 6.8-7.5 (3 H, m), 8.4 (1 H, m); MS (FAB) 331 (M+H)+ ; Anal. Calcd. for C18H26N4O2.2HCl. 0.5 NH4Cl: C, 50.27; H, 7.03; N, 14.65. Found: C, 50.86; H, 6.47; N, 15.79.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2[CH:19]=[CH:18][C:11]3[C:12](O)=[N:13][S:14](=[O:16])(=[O:15])[C:10]=3[CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[F:20][C:21]([S:24]([C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=1)(=[O:26])=[O:25])([F:23])[F:22]>>[Cl:1][C:2]1[C:3]([C:8]2[CH:19]=[CH:18][C:11]3[C:12]([NH:33][C:30]4[CH:31]=[CH:32][C:27]([S:24]([C:21]([F:23])([F:20])[F:22])(=[O:26])=[O:25])=[CH:28][CH:29]=4)=[N:13][S:14](=[O:16])(=[O:15])[C:10]=3[CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S1(=O)N=C(O)c2ccc(-c3ncccc3Cl)cc21
Reactant: Nc1ccc(S(=O)(=O)C(F)(F)F)cc1
Product: O=S1(=O)N=C(Nc2ccc(S(=O)(=O)C(F)(F)F)cc2)c2ccc(-c3ncccc3Cl)cc21

Procedure:
The title compound was prepared by reacting the product of Example 1B (0.1521 g, 0.52 mmol) with 4-aminophenyl trifluoromethyl sulphone (0.1417 g, 0.63 mmol) using the procedure as described in Example 1C. MS (ESI+) m/z 454 (M-47)+; (ESI−) m/z 500 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 7.58 (dd, J=8.3, 4.6 Hz, 1H), 8.18 (m, 1H), 8.28 (m, 3H), 8.39 (m, 3H), 8.65 (d, J=8.1 Hz, 1H), 8.72 (dd, J=4.6, 1.5 Hz, 1H), 11.42 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([Br:7])[S:4][C:3]=1[C:8]([O:10]C)=[O:9].C[O-].[Na+].CO.Cl>O>[NH2:1][C:2]1[CH:6]=[C:5]([Br:7])[S:4][C:3]=1[C:8]([OH:10])=[O:9]
Reactant: COC(=O)c1sc(Br)cc1N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Nc1cc(Br)sc1C(=O)O
Temperature: 75 °C
Reaction time: 5 h
Yield: 69.4 %

Procedure:
A mixture of methyl 3-amino-5-bromothiophene-2-carboxylate (0.236 g, 1.00 mmol), sodium methoxide (0.162 g, 3.00 mmol), methanol (4.0 mL) and water (1.0 mL) was stirred at 75° C. for 5 h. The mixture was cooled in an ice-bath and conc. HCl (0.250 mL, 3.00 mmol) was added. The mixture was concentrated in vacuo to remove methanol. The residue was triturated with water, and the precipitate was collected by filtration and washed with water to afford the title compound (0.154 g, 69%) as a pale orange solid:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].[CH2:8]([O:15][C:16](ON1C(=O)CCC1=O)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CN(C=O)C>[CH2:8]([O:15][C:16]([NH:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: NCCCC(=O)O
Solvent: CN(C)C=O
Product: O=C(O)CCCNC(=O)OCc1ccccc1

Procedure:
Gamma-aminobutyric acid (1.03 g:0.010 mol) and N-benzyloxycarbonyloxysuccinimide (2.49 g:0.01 mol) in N,N'-dimethylformamide (10 ml) was stirred for 18 hours at 22° C. The resulting clear solution was concentrated and the residue was treated with water. The resulting oil yielded white crystals which were then dried to yield a residue which was purified on a silica gel column employing dichloromethane:methanol mixture (95:5) as an eluent to yield gamma-(benzyloxycarbonylamino)butyric acid.