Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:4][N:3]=1.C(OCC)(=O)C.[BH4-].[Na+].[Cl-].[NH4+]>C(O)C.[C].[Pd].C(Cl)Cl>[NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1nccc(-c2cccs2)c1[N+](=O)[O-]
Agent: [Pd]
Agent: [BH4-]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1nccc(-c2cccs2)c1N
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.1 %

Procedure:
To a solution of 2-amino-3-nitro-4-(2-thienyl)pyridine (2.06 g, 9.3 mmol) and 10% palladium-carbon (466 mg) in ethanol (130 ml)-ethyl acetate (65 ml), a 1 M aqueous sodium borohydride solution was added at 0° C. The mixture was stirred at 0° C. for 1 hour and then poured into a 5% aqueous ammonium chloride solution (43 ml). The mixture was filtered through celite, and the filtrate was diluted with water (500 ml) and extracted three times with ethyl acetate (250 ml). The solution was dried over sodium sulfate and then evaporated under reduced pressure to remove the solvent. The residue was purified by column chromatography (methylene chloride:ethanol=19:1 to 93:7) to give 2,3-diamino-4-(2-thienyl)pyridine (Rf 0.24/methylene chloride:ethanol=9:1) (1.46 g, yield 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:3]=1[CH2:4][O:5][C:6]1[N:11]2[N:12]=[C:13]([CH3:18])[C:14]([C:15](O)=[O:16])=[C:10]2[CH:9]=[C:8]([CH3:19])[CH:7]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[C:47]([O:51][C:52](=[O:61])[NH:53][C:54]([CH2:59][NH2:60])([CH3:58])[CH2:55][CH2:56][CH3:57])([CH3:50])([CH3:49])[CH3:48].C(N(CC)C(C)C)(C)C>O1CCCC1>[C:47]([O:51][C:52](=[O:61])[NH:53][C:54]([CH3:58])([CH2:55][CH2:56][CH3:57])[CH2:59][NH:60][C:15]([C:14]1[C:13]([CH3:18])=[N:12][N:11]2[C:6]([O:5][CH2:4][C:3]3[C:20]([F:24])=[CH:21][CH:22]=[CH:23][C:2]=3[Cl:1])=[CH:7][C:8]([CH3:19])=[CH:9][C:10]=12)=[O:16])([CH3:48])([CH3:49])[CH3:50]
Reactant: CCCC(C)(CN)NC(=O)OC(C)(C)C
Reactant: Cc1cc(OCc2c(F)cccc2Cl)n2nc(C)c(C(=O)O)c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(C)(CNC(=O)c1c(C)nn2c(OCc3c(F)cccc3Cl)cc(C)cc12)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.8 %

Procedure:
A solution of 26 mg (0.074 mmol) of 7-(2-chloro-6-fluorobenzyloxy)-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carboxylic acid (Example 137A) in 3 ml of tetrahydrofuran was admixed with 17 mg (0.09 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 14 mg (0.09 mmol) of 1-hydroxybenzotriazole, 21 mg (0.096 mmol) of rac-(1-aminomethyl-1-methylbutyl)carbamic acid tert-butyl ester from Example 152A and 0.039 ml (0.222 mmol) of N,N-diisopropylethylamine. The mixture was stirred at room temperature for a further 18 hours. The reaction mixture was then heated to 60° C. for 3 hours. After concentration under reduced pressure, the residue was partitioned between dichloromethane and water. The organic phase was removed and concentrated under reduced pressure, which gave 40 mg (99% yield) of the target compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[CH3:14])[C:5]([NH:7][CH:8]1[CH2:10][CH2:9]1)=[O:6].[F:15][C:16]1[CH:17]=[CH:18][C:19]([N+:25]([O-:27])=[O:26])=[C:20]([CH:24]=1)[C:21](O)=[O:22]>>[F:15][C:16]1[CH:17]=[CH:18][C:19]([N+:25]([O-:27])=[O:26])=[C:20]([CH:24]=1)[C:21]([NH:1][C:2]1[CH:3]=[C:4]([C:5]([NH:7][CH:8]2[CH2:9][CH2:10]2)=[O:6])[CH:11]=[CH:12][C:13]=1[CH3:14])=[O:22]
Reactant: Cc1ccc(C(=O)NC2CC2)cc1N
Reactant: O=C(O)c1cc(F)ccc1[N+](=O)[O-]
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(F)ccc1[N+](=O)[O-]

Procedure:
Using an analogous procedure to that described paragraph (A) in the portion of Example 1 which is concerned with the preparation of starting materials, 3-amino-N-cyclopropyl-4-methylbenzamide was reacted with 5-fluoro-2-nitrobenzoic acid to give 5-fluoro-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-nitrobenzamide; NMR Spectrum: (DMSOd6) 0.58 (m, 2H), 0.69 (m, 2H), 2.30 (s, 3H), 2.85 (m, 1H), 7.31 (m, 1H), 7.61 (m, 2H), 7.76 (m, 1H), 7.94 (s, 1H), 8.26 (m, 1H), 8.40 (m, 1H), 10.25 (s, 1H); Mass Spectrum: M−H+ 356.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[CH:12]1[C:21]2[C:20](=[O:22])[CH2:19][CH2:18][CH2:17][C:16]=2[N:15]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[C:14](=[O:33])[NH:13]1)[C:7]#[N:8].[CH3:34][S:35](Cl)(=[O:37])=[O:36].O>O1CCCC1>[Cl:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[CH:12]1[C:21]2[C:20](=[O:22])[CH2:19][CH2:18][CH2:17][C:16]=2[N:15]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:31])([F:32])[F:30])[CH:24]=2)[C:14](=[O:33])[N:13]1[S:35]([CH3:34])(=[O:37])=[O:36])[C:7]#[N:8]
Reactant: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)CCC3)c(Cl)c1
Reactant: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1Cl
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Sodium hydride (60% in mineral oil, 14 mg, 0.36 mmol) is added to a solution of 3-chloro-4-(2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4,5,6,7,8-octahydroquinazolin-4-yl)-benzonitrile (example 56, 60 mg, 0.13 mmol) in tetrahydrofuran (3 mL), and the mixture is stirred at room temperature for 20 min. Methanesulfonyl chloride (21 μL, 0.27 mmol) is added, and the mixture is stirred at room temperature over night. Water is added, and the mixture is extracted with dichloromethane. The phases are separated, and the organic phase is concentrated under reduced pressure. The residue is purified by preparative HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 40 mg; ESI mass spectrum [M+H]+=524; Retention time HPLC: 0.70 min (X012_S01).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][C:9]([O:11]C(C)(C)C)=[O:10])[C:3]1=[O:16].C(O)(C(F)(F)F)=O>ClCCl>[CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][C:9]([OH:11])=[O:10])[C:3]1=[O:16]
Reactant: CN1CCCN(CC(=O)OC(C)(C)C)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCCN(CC(=O)O)C1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 1012.6 %

Procedure:
To a solution of 0.090 g (0.39 mmol) of tert-butyl (3-methyl-2-oxotetrahydropyrimidin-1(2H)-yl)acetate from step B above in 4 mL of anhydrous dichloromethane was added 1 mL of TFA. The resulting mixture was stirred at ambient temperature for 6 h then evaporated to dryness in vacuo to afford the title compound as an off-white gum (0.68 g, 99%). LC-MS: m/z (ES) 173 (MH)+.
Reaction SMILES: [CH:1]1([N:4]([CH3:24])[C:5]2[N:9]=[C:8]([CH:10]=[CH:11][C:12]3[N:22]=[C:15]4[C:16]([CH3:21])=[N:17][CH:18]=[C:19]([CH3:20])[N:14]4[N:13]=3)[N:7]([CH3:23])[N:6]=2)[CH2:3][CH2:2]1>[Pd].CO>[CH:1]1([N:4]([CH3:24])[C:5]2[N:9]=[C:8]([CH2:10][CH2:11][C:12]3[N:22]=[C:15]4[C:16]([CH3:21])=[N:17][CH:18]=[C:19]([CH3:20])[N:14]4[N:13]=3)[N:7]([CH3:23])[N:6]=2)[CH2:3][CH2:2]1
Reactant: Cc1ncc(C)n2nc(C=Cc3nc(N(C)C4CC4)nn3C)nc12
Agent: [Pd]
Solvent: CO
Product: Cc1ncc(C)n2nc(CCc3nc(N(C)C4CC4)nn3C)nc12
Temperature: 25 °C
Reaction time: 14 h
Yield: 64.8 %

Procedure:
A mixture of N-cyclopropyl-5-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)vinyl)-N,1-dimethyl-1H-1,2,4-triazol-3-amine (23 mg, 70.9 μmol, Eq: 1.00) and palladium on carbon 10% (7.55 mg, 7.09 μmol, Eq: 0.1) in methanol (3.5 ml) was stirred for 14 hours at 25° C. under hydrogen atmosphere. Palladium was filtered off, the crude material was applied on silica gel and purified by column chromatography using ethy acetate/methanol (0-10% methanol) as eluent to give N-cyclopropyl-5-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)ethyl)-N,1-dimethyl-1H-1,2,4-triazol-3-amine (15 mg, 64.8%) as white waxy solid
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:4]([CH3:6])([CH3:5])[CH:3]1[C:7]([OH:9])=[O:8].C(=O)([O-])[O-].[K+].[K+].[C:17]([CH:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:21]=1)#[N:18]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:10])[C:4]([CH3:6])([CH3:5])[CH:3]1[C:7]([O:9][CH:19]([C:17]#[N:18])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:21]=1)=[O:8]
Reactant: N#CC(Br)c1cccc(Oc2ccccc2)c1
Reactant: CC1(C)C(C(=O)O)C1(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: Cc1ccccc1
Product: CC1(C)C(C(=O)OC(C#N)c2cccc(Oc3ccccc3)c2)C1(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 2,2,3,3-tetramethylcyclopropane carboxylic acid (7.8g, 0.055M), potassium carbonate (3.8g, 0.0275M) water (40 mls), tetrabutylammonium bromide (1.5g, 10 mole %), alpha-cyano-3-phenoxybenzyl bromide (14.4g, 0.05 mole) and toluene (50 ml) was stirred at 25° C for 5 hours. The aqueous phase was separated and the toluene layer washed twice with 5% potassium carbonate solution and twice with water. The solution was filtered through a pad of silica-gel (3g) and evaporated to leave a pale-yellow oil (17.4g; purity = 92%). Recrystallisation of this material from hexane gave pure alpha-cyano-3-phenoxybenzyl 2,2,3,3-tetramethylcyclopropane carboxylate, melting point 50°-51° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([OH:16])[C:8]([F:15])([F:14])[C:9](OCC)=[O:10].O.[NH2:18][NH2:19].O>CCO>[F:14][C:8]([F:15])([CH:7]([OH:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[C:9]([NH:18][NH2:19])=[O:10]
Reactant: CCOC(=O)C(F)(F)C(O)c1ccccn1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)C(F)(F)C(O)c1ccccn1
Reaction time: 16 h

Procedure:
To stirring solution of 0.96 g (4.1 mmol) of ethyl 3-(2-pyridyl)-3-hydroxy-2,2-difluoropropanoate, prepared as described by Hallinan and Fried, Tetrahedron Lett., 25, 2301 (1984), in 8 mL of EtOH was added 0.41 g (8.2 mmol) of hydrazine hydrate. After 16 hours, a yellow precipitate had formed. To the reaction was added H2O. The precipitate was filtered and washed with a minimum of H2O. The yield of product was 0.44 g (49%) after drying in a steam cabinet. Analysis calculated for C8H9N3O2F2 (M.W. 217.18): C, 44.24; H, 4.18; N, 19.35. Found: C, 44.07; H, 4.16; N, 19.05.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([NH:18][CH2:19][CH2:20][O:21][CH3:22])=[C:16]([S:23]([C:26]([F:29])([F:28])[F:27])(=[O:25])=[O:24])[C:15]([C:30]#[N:31])=[N:14]1.[H-].[Na+].I[CH3:35].[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[Cl:12][C:4]1[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:13]1[C:17]([N:18]([CH2:19][CH2:20][O:21][CH3:22])[CH3:35])=[C:16]([S:23]([C:26]([F:29])([F:27])[F:28])(=[O:24])=[O:25])[C:15]([C:30]#[N:31])=[N:14]1
Reactant: COCCNc1c(S(=O)(=O)C(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCCN(C)c1c(S(=O)(=O)C(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-5-(2-methoxyethylamino)-4-trifluoromethylsulfonylpyrazole (1.5g, 2.9 mmol) in tetrahydrofuran at 20° C. under nitrogen, was added sodium hydride (0.38 g, 60% in oil, 9.4 mmol), and stirred for 0.5 hour. Iodomethane (1.68 g, 11.7 mmol) was added and the mixture stirred for 15 hours at 20° C., then heated to 40° C. for 8 hours. The mixture was added to ethyl acetate and saturated ammonium chloride solution. The organic layer was washed with water and brine, dried (sodium sulfate), evaporated and chromatographed on silica gel eluting with heptane-ethyl acetate (9:1) to give 1-(2,6-dichloro-4-trifluoromethylphenyl-3-cyano-5-[N-(2-methoxyethyl)-N-methylamino]-4-trifluoromethylsulfonylpyrazole as a white solid (Compound number 2-3, 0.78 g), mp 75° C.
Reaction SMILES: [C:1]([CH2:4]P(=O)(OCC)OCC)(=[O:3])[NH2:2].CC(C)([O-])C.[K+].[CH2:19]([O:22][C:23]([N:25]1[CH2:29][C@H:28]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:27][C@H:26]1[CH2:38][CH2:39][N:40]1[CH:44]=[C:43]([CH:45]=O)[N:42]=[CH:41]1)=[O:24])[CH:20]=[CH2:21]>O1CCCC1.C(OCC)(=O)C.O>[CH2:19]([O:22][C:23]([N:25]1[CH2:29][C@H:28]([O:30][Si:31]([C:34]([CH3:36])([CH3:37])[CH3:35])([CH3:33])[CH3:32])[CH2:27][C@H:26]1[CH2:38][CH2:39][N:40]1[CH:44]=[C:43]([CH:45]=[CH:4][C:1](=[O:3])[NH2:2])[N:42]=[CH:41]1)=[O:24])[CH:20]=[CH2:21]
Reactant: CCOP(=O)(CC(N)=O)OCC
Reactant: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CCn1cnc(C=O)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CCn1cnc(C=CC(N)=O)c1
Reaction time: 1 h
Yield: 52.5 %

Procedure:
To a solution of diethyl carbamoylmethylphosphonate (12.7 g) and potassium tert-butoxide (13.9 g) in tetrahydrofuran (400 ml) were added a solution of (2R,4R)-1-allyloxycarbonyl-4-tert-butyldimethylsilyloxy-2-{2-(4-formylimidazol-1-yl)ethyl}pyrrolidine (24 g) in tetrahydrofuran (50 ml) at 45° C. After stirring for 1 hour, to the reaction mixture were added water (3 ml). Evaporation of the solvent gave a residue, which was dissolved in a mixture of ethyl acetate (500 ml) and water (50 ml). The organic layer was separated, washed in turn with water (50 ml×2) and brine (50 ml×2), and dried over magnesium sulfate. Evaporation of the solvent gave an oil, which was chromatographed on silica gel (500 ml) eluting with a mixture of dichloromethane and methanol (10:1) to give (2R,4R)-1-allyloxycarbonyl-4-tert-butyl-dimethylsilyloxy-2-[2-{4-(2-carbamoylethenyl)imidazol-1-yl}ethyl]pyrrolidine (13.87 g).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[O:9]=[C:10]1[C@@H:16]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:15][CH2:14][C:13]2[CH:25]=[CH:26][CH:27]=[CH:28][C:12]=2[NH:11]1>CCOC(C)=O>[Br:1][C:26]1[CH:27]=[CH:28][C:12]2[NH:11][C:10](=[O:9])[C@@H:16]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:23])[CH3:21])[CH2:15][CH2:14][C:13]=2[CH:25]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCc2ccccc2NC1=O
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CCc2cc(Br)ccc2NC1=O
Yield: 103.9 %

Procedure:
23.5 g of N-bromosuccinimide (136 mmol) are introduced, at AT, as 4 portions over 3 days, into a 2 l three-necked flask, with stirring and under an argon atmosphere, containing 1.5 l of EtOAc and 8.47 g of 2a (103.0 mmol). The medium is left stirring for an additional overnight period, and washed with 500 ml of HCl (0.5N), 500 ml of a saturated aqueous solution of NaHCO3 and 500 ml of water. The organic phase is dried over MgSO4, filtered and then evaporated to dryness. 38 g of brown foam are obtained. The product is purified by chromatography on a silica cartridge (600 g), elution being carried out with heptane/EtOAc (70/30). 20.46 g of expected product 10a (white solid) are recovered.
Reaction SMILES: Cl.[N:2]1([CH2:8][C:9]23[CH2:17][CH:13]4[CH2:14][CH:15]([CH2:16]2)[C:11]([NH2:18])([CH2:12]4)[CH2:10]3)[CH2:7][CH2:6][S:5][CH2:4][CH2:3]1.Cl[CH2:20][C:21]([N:23]1[CH2:27][CH2:26][CH2:25][C@H:24]1[C:28]#[N:29])=[O:22].C([O-])([O-])=O.[K+].[K+]>CS(C)=O.CCOC(C)=O>[N:2]1([CH2:8][C:9]23[CH2:17][CH:13]4[CH2:12][C:11]([NH:18][CH2:20][C:21]([N:23]5[CH2:27][CH2:26][CH2:25][C@H:24]5[C:28]#[N:29])=[O:22])([CH2:10]2)[CH:15]([CH2:14]4)[CH2:16]3)[CH2:7][CH2:6][S:5][CH2:4][CH2:3]1
Reactant: N#C[C@@H]1CCCN1C(=O)CCl
Reactant: NC12CC3CC1CC(CN1CCSCC1)(C3)C2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#C[C@@H]1CCCN1C(=O)CNC12CC3CC1CC(CN1CCSCC1)(C3)C2
Reaction time: 3 h
Yield: 35.3 %

Procedure:
To a stirred solution of the hydrochloride salt (0.17 g, 0.51 mmol) obtained in step II above in DMSO (2.0 mL) at room temperature under nitrogen atmosphere was added (2S)-1-(chloroacetyl)pyrrolidine-2-carbonitrile (0.09 g, 0.52 mmol) and K2CO3 (0.35 g, 2.55 mmol. After stirring the reaction mixture for 3 h, it was diluted with EtOAc and washed with water and brine, dried over Na2SO4 and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain (2S)-1-{N-[2-(thiomorpholin-4-ylmethyl)hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrile as an off-white solid (0.07 g) in 35% yield. m/z (M+1) 389; 1H NMR (CDCl3) 300 MHz δ 4.83-4.75 (m, 1H), 3.90-3.45 (m, 4H), 2.85-2.70 (m, 4H), 2.70-2.60 (m, 4H), 2.48-2.35 (m, 2H), 2.35-2.15 (m, 4H), 2.0-1.75 (m, 4H), 1.68-1.40 (m, 5H), 1.38-1.25 (m, 1H).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([I:20])=[C:7]([C:11]([I:19])=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[C:13]=1[I:14])[C:8]([OH:10])=[O:9])(=[O:3])[CH3:2].[OH-].[K+:22]>O>[C:16]([NH:15][C:12]1[C:11]([I:19])=[C:7]([C:6]([I:20])=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[C:13]=1[I:14])[C:8]([O-:10])=[O:9])(=[O:18])[CH3:17].[K+:22]
Reactant: CC(=O)Nc1c(I)c(NC(C)=O)c(I)c(C(=O)O)c1I
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Nc1c(I)c(NC(C)=O)c(I)c(C(=O)[O-])c1I
Temperature: 60 °C

Procedure:
A suspension of 3,5-diacetylamino-2,4,6-triiodobenzoic acid (0.5 g, 0.81 mmol) in water (5 ml) was heated to 60° C. and an aqueous solution of KOH prepared by dissolving KOH (46 mg, 0.81 mmol) in water (2 ml) was added. A solution of 0.5N KOH was added dropwise to the suspension to adjust it to pH 7. Water was removed under reduced pressure to give a residue which was washed twice with ethanol and dried under reduced pressure.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].[C:11]([NH:18][C@H:19]([C:29]([OH:31])=[O:30])[CH2:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C(N(CC)CC)C.[I-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[O:8]1[CH2:9][CH2:10][N:5]([C:3]([CH2:2][O:31][C:29](=[O:30])[C@H:19]([CH2:20][O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:18][C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])=[O:4])[CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Reactant: O=C(CCl)N1CCOCC1
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)OCC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
O-Benzyl-L-serine (10.0 g, 51.3 mmol), di-tert-butyl-dicarbonate (11.2 g, 51.4 mmol) and 1 N sodium hydroxide (103 mL, 103 mmol) are stirred together in 100 mL of dioxane at room temperature for 16 hours. The mixture is concentrated in vacuo, taken up in water, acidified to pH 1 with 6 N HCl and extracted with ethyl acetate. The organic layer is washed with water, then brine, and dried over anhydrous magnesium sulfate. The mixture is filtered and concentrated in vacuo to give BOC-O-benzyl-L-serine as an oil. 4-(2-Chloroacetyl)morpholine (1.22 g, 7.48 mmol) is added to a solution of BOC-O-benzyl-L-serine (2.20 g, 7.46 mmol), triethylamine (0.75 g, 7.43 mmol) and sodium iodide (0.11 g, 0.73 mmol) in 5 mL of N,N-dimethylformamide and the mixture stirred at room temperature for 2 hours. The mixture is diluted with ethyl acetate, washed with water, then with brine, and dried over anhydrous magnesium sulfate. The mixture is filtered and concentrated in vacuo to give a yellow oil. The oil is chromatographed on silica gel with hexane:ethyl acetate:methanol (35:60:5) to give BOC-O-benzyl-L-serine morpholinocarbonylmethyl ester as a colorless oil. HCl gas is bubbled through a solution of the carbamate ester (1.72 g, 4.08 mmol) in methylene chloride (50 mL) for 5 minutes and the mixture is stirred at room temperature for 3 hours. The resulting mixture is concentrated in vacuo to yield O-benzyl-L-serine morpholinocarbonylmethyl ester as a foam.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]1([C@H:17]2[CH2:21][N:20]([C:22](=[O:27])[C:23]([F:26])([F:25])[F:24])[CH2:19][C@@H:18]2[CH2:28][OH:29])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl-].[NH4+]>ClCCl.C(N(CC)CC)C>[C:11]1([C@H:17]2[CH2:21][N:20]([C:22](=[O:27])[C:23]([F:25])([F:26])[F:24])[CH2:19][C@@H:18]2[CH:28]=[O:29])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(N1C[C@H](CO)[C@@H](c2ccccc2)C1)C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=C[C@H]1CN(C(=O)C(F)(F)F)C[C@@H]1c1ccccc1
Temperature: -25 °C
Reaction time: 0.25 h

Procedure:
A 7.18 g portion of DMSO was dissolved in 30 ml of dichloromethane, and a 10 ml dichloromethane solution of 4.0 ml oxalyl chloride was added thereto while keeping the internal temperature at −60° C. or less. After stirring for 15 minutes, a 40 ml dichloromethane solution of 6.28 g of [(3R,4S)-4-phenyl-1-(trifluoroacetyl)pyrrolidin-3-yl]methanol was added thereto while keeping the inner temperature at −60° C. and stirred for 15 minutes. A 19.3 ml portion of triethylamine was added to the reaction solution while keeping the internal temperature at −50° C. or less, and then the internal temperature was allowed to warm to −25° C. over 30 minutes or more, and this was further stirred at −25° C. for 20 minutes. Under ice-cooling, the reaction solution was added to saturated ammonium chloride aqueous solution to quench the reaction, and extracted with diethyl ether. The organic layer was washed with water and saturated brine in that order and dried with anhydrous sodium sulfate. By concentrating under a reduced pressure, (3R,4S)-4-phenyl-1-(trifluoroacetyl)pyrrolidine-3-carbaldehyde was obtained as a crude product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:18][C:19]1[C:23]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([CH3:30])[CH:25]=2)=[CH:22][NH:21][N:20]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:20]3[N:21]=[CH:22][C:23]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([CH3:30])[CH:25]=4)=[C:19]3[N:18]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(Cl)c(Cl)c1
Reactant: Cc1cc(-c2c[nH]nc2N)ccn1
Product: Cc1cc(-c2cnn3c(C(F)(F)F)cc(-c4ccc(Cl)c(Cl)c4)nc23)ccn1
Yield: 47.3 %

Procedure:
Reaction of 1-(3,4-dichloro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (143 mg, 0.5 mmol), prepared from commercially available 3,4-dichloro-acetophenone according to general procedure A, and 3-amino-4-(2-methyl-4-pyridinyl)-pyrazole [see part synthesis of amino-pyrazole derivatives] (87 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (100 mg, 47%). MS (ISP) 423.0 [(M+H)+]; mp 275° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3]>C(Cl)CCC>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]2[CH2:16][CH2:15][N:14]([CH2:6][CH2:5][CH2:10][CH3:9])[CH2:13][CH2:12]2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1cccc(C2CCNCC2)c1
Solvent: CCCCCl
Product: CCCCN1CCC(c2cccc(S(C)(=O)=O)c2)CC1

Procedure:
Beginning with 4-(3-methanesulfonyl-phenyl)piperidine and n-BuCl. MS m/z (rel. intensity, 70 eV) 295 (M+, 3), 252 (bp), 130 (5), 115 (3), 70 (8).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([SH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)#[N:13]>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)=[N:13][C:7](=[O:9])[C:6]=2[CH:10]=1
Reactant: O=C(O)c1cc(Br)ccc1S
Reactant: N#Cc1ccccn1
Solvent: c1ccncc1
Product: O=c1nc(-c2ccccn2)sc2ccc(Br)cc12
Yield: 46.1 %

Procedure:
5-Bromo-2-mercaptobenzoic acid (4.10 g, 17.6 mmol), 2-cyanopyridine (1.70 g, 16.3 mmol) and pyridine (50.0 ml) were refluxed for 9 hrs as described in Example 9. After cooling, the precipitated crystals were collected and recrystallized from hexane-chlorobenzene to give the titled compound (2.40 g, 45%).