Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:14]([OH:16])=[O:15])[C:10]([CH3:13])([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(Cl)Cl.[CH2:20](O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(Cl)CCl>CN(C)C1C=CN=CC=1.C(OCC)C>[C:4]([O:3][C:1]([NH:8][C@H:9]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:14]([O:16][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:15])=[O:2])([CH3:6])([CH3:7])[CH3:5]
Reactant: OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)OCc1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 2-dram vial containing a small stirbar was charged with Boc-tert-leucine (10a) (10 mg, 0.04 mmol), CH2Cl2 (1 mL), 4-dimethylaminopyridine (2 mg, 0.02 mmol, 0.5 equiv), benzyl alcohol (20 μL, 0.2 mmol, 5 equiv), and EDC (20 mg, 0.1 mmol, 2.5 equiv). The solution was stirred at room temperature for 3 h, and then diluted with 10 mL of diethyl ether. The mixture was washed with water (2×10 mL), saturated aqueous NaHCO3 (10 mL), and brine (10 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue can be further purified by flash column chromatography on silica gel (7:1 hexanes/Et2O). Both the crude and purified samples were analyzed by chiral HPLC analysis: (AD-H, 1 mL/min, 5% IPA/hexanes, 210 nm): tR(major)=9.08 min, tR(minor)=15.80 min.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]3[N:22]=[CH:23][C:24]([C:25](O)=O)=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[OH:28][NH:29][C:30](=[NH:41])[C:31]1[CH:36]=[CH:35][C:34]([S:37](=[O:40])(=[O:39])[NH2:38])=[CH:33][CH:32]=1>>[CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:19])[F:20])[N:15]3[N:22]=[CH:23][C:24]([C:25]4[O:28][N:29]=[C:30]([C:31]5[CH:36]=[CH:35][C:34]([S:37]([NH2:38])(=[O:39])=[O:40])=[CH:33][CH:32]=5)[N:41]=4)=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:9])([F:10])[F:11]
Reactant: N=C(NO)c1ccc(S(N)(=O)=O)cc1
Reactant: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)O)c3n2)ccc1C(F)(F)F
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(-c4nc(-c5ccc(S(N)(=O)=O)cc5)no4)c3n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 5-(3-methyl-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.8) (195 mg, 0.5 mmol) and N-hydroxy-4-sulfamoyl-benzamidine [CAS-No. 4476-10-2] (161 mg, 0.75 mmol) according to general procedure II. Obtained after purification by flash chromatography (ethyl acetate/heptane) and crystallization (dichloromethane) as a yellow solid (200 mg, 70%). MS (ISN) 567.2 [(M−H)−]; mp 273° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:19])[CH2:14][C@H:13]2[CH3:26])=[N:4][N:3]=1.[C:27]1([CH3:36])[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:26][C@H:13]1[N:12]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([C:30]3[CH:31]=[CH:32][C:27]([CH3:36])=[CH:28][CH:29]=3)=[N:3][N:4]=2)[CH2:17][CH2:16][N:15]([C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:19])[CH2:14]1
Reactant: C[C@@H]1CN(C(=O)c2ccccc2)CCN1c1nnc(Cl)c2ccccc12
Reactant: Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2nnc(N3CCN(C(=O)c4ccccc4)C[C@H]3C)c3ccccc23)cc1
Temperature: 100 °C
Yield: 86.3 %

Procedure:
Compound 20 was prepared as described generally in synthetic Method D. Substrate JK-5 was prepared as described in detail in Example 11. To a reaction flask was added (R)-(4-(4-chlorophthalazin-1-yl)-3-methylpiperazin-1-yl)(phenyl)methanone (JK-5) (200 mg, 0.54 mmol), p-tolyl boronic acid (111 mg, 0.82 mmol, 1.5 eq), and Pd(PPh3)4 (31 mg, 0.027 mmol, 0.05 eq). The flask was fitted with a reflux condenser and purged with nitrogen. Toluene (5.4 mL) and aqueous Na2CO3 (2 M, 0.54 mL, 2 eq) were added and the reaction was heated to 100° C. overnight. The reaction was then cooled to rt and diluted with 75 mL of ethyl acetate. The organic phase was washed with 1×10 mL of sat. NaHCO3 solution, 1×10 mL of H2O, and 1×10 mL of sat. NaCl solution. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. Purification by column chromatography (60% ethyl acetate in hexanes) afforded 197 mg (86%) of (R)-(3-methyl-4-(4-p-tolylphthalazin-1-yl)piperazin-1-yl)(phenyl)methanone 20 MS (M+H)+=423.3.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@@H:4]([NH2:12])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)C(C)C)(C)C.C([O:25][C:26](=O)/[CH:27]=[C:28](/[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=1)\[CH2:29]Br)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C@@H:4]([N:12]1[CH2:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=2)=[CH:27][C:26]1=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Reactant: CCOC(=O)/C=C(\CBr)Oc1cccc(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2cccc(F)c2)=CC1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 38.7 %

Procedure:
To a stirred solution of (S)-2-amino-3-cyclohexyl-propionic acid methyl ester (2.03 g, 0.011 mol) in N,N-dimethylformamide (10 mL) was added N,N-diisopropylethylamine (6.38 g, 0.049 mol) slowly at room temperature, under nitrogen. The resulting mixture was stirred for 5 min and then treated with (E)-4-bromo-3-(3-fluoro-phenoxy)-but-2-enoic acid ethyl ester (3.00 g, 0.010 mol) and the reaction mixture was heated at 110° C.-120° C. for 16 h. After this time, ice water was added and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (silica gel (100-200 mesh)) afforded (S)-3-cyclohexyl-2-[4-(3-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (1.40 g, 35%) as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[CH3:2].[H-].[Na+].[C:17]1([CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]Br)[C:26]=2[O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:14])[C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([O:24][CH2:23][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:26]=2[O:38][CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)=[CH:8][CH:7]=1)[CH3:2]
Reactant: CCOC(=O)C(=O)c1ccc(O)cc1
Reactant: BrCCCCCCc1cccc(OCc2ccccc2)c1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)c1ccc(OCCCCCCc2cccc(OCc3ccccc3)c2OCc2ccccc2)cc1
Reaction time: 0.25 h
Yield: 60.1 %

Procedure:
A solution of 4-hydroxy-alpha-oxobenzeneacetic acid ethyl ester (0.97 g) in dimethylformamide (12 mL) was treated with 55% sodium hydride (0.22 g), stirred for 15 minutes and then 1,2-bis-(phenylmethoxy)-3-(6-bromohexyl)benzene (2.27 g) was added and rinsed in with dimethylformamide (3 mL). The mixture was stirred overnight at room temperature and worked up as in Example 20. The residual oil was purified by HPLC (ethyl acetate-hexane; 1:9) and crystallized from diethyl ether-hexane to provide 1.7 g of 4-[6-[2,3-bis-(phenylmethoxy)phenyl]hexyloxy]-alpha-oxobenzeneacetic acid ethyl ester, mp 39°-42° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])O.[Na+:16].S([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1>[Na+:16].[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=S([O-])c1cccc(Cl)c1
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 7.1 %

Procedure:
A solution of 3-chlorobenzenesulfonyl chloride (3.0 g) in dioxane (40 mL) was treated with a mixture of sodium hydrogen carbonate (2.7 g), sodium sulfite (3.6 g) and water (20 mL), and the resulting mixture was stirred at 75° C. for 30 minutes. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was triturated with ethanol to afford the title compound as a white solid (0.20 g).
Reaction SMILES: [C:1]1([CH:7]([O:24][C:25]2[CH:49]=[CH:48][C:28]([C:29]([C:31]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[N:33]([CH2:40][CH2:41][CH2:42][C:43]([O:45]CC)=[O:44])[CH:32]=3)=[O:30])=[CH:27][CH:26]=2)[CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].C(O)(=O)C>C(O)C>[C:1]1([CH:7]([O:24][C:25]2[CH:49]=[CH:48][C:28]([C:29]([C:31]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[N:33]([CH2:40][CH2:41][CH2:42][C:43]([OH:45])=[O:44])[CH:32]=3)=[O:30])=[CH:27][CH:26]=2)[CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])[CH2:14][CH2:15]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCCn1cc(C(=O)c2ccc(OC(CCN3CCN(c4ccccc4OC)CC3)c3ccccc3)cc2)c2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccccc1N1CCN(CCC(Oc2ccc(C(=O)c3cn(CCCC(=O)O)c4ccccc34)cc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.8 %

Procedure:
Ethyl 4-{3-{4-{1-phenyl-3-[4-(2-methoxyphenyl) piperazin-1-yl]propoxy}benzoyl}indol-1-yl}butanoate (1.89 g) obtained in Step 3 was dissolved in ethanol (20 ml). Potassium hydroxide (0.80 g) was added to the resultant solution and stirred for 3 hours at room temperature. After adding acetic acid (2 ml) to the reaction mixture, the solvent was distilled off. Water was added thereto, followed by extraction with ethyl acetate. The resultant extract was washed with brine and dried. The solvent was distilled off. The residue was purified by silica gel column chromatography (methylene chloride: methanol=40:1), obtaining 1.68 g of 4-{3-{4-{1-phenyl-3-[4-(2-methoxyphenyl)piperazin-1-yl] propoxy}benzoyl}indol-1-yl}butanoic acid as amorphous powder.
Reaction SMILES: C([O:5][C:6](=[O:23])[CH:7]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])CCC.C(=O)([O-])[O-].[Na+].[Na+]>CO>[C:12]([O:11][C:9]([NH:8][CH:7]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[C:6]([OH:23])=[O:5])=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: CCCCOC(=O)C(NC(=O)OC(C)(C)C)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)NC(C(=O)O)c1ccc(O)cc1

Procedure:
A solution of 0.5 g. (1.5 mmol). of N-t-butoxycarbonyl-2-(4-hydroxyphenyl)glycine n-butyl ester in 20 ml. of methanol and 30 ml. of 5% aqueous sodium carbonate was heated at reflux for 30 minutes. The solvent was removed in vacuo and the aqueous residue was extracted with ethyl acetate. The aqueous phase was acidified to pH 3.0 with phosphoric acid and again extracted with ethyl acetate. The extract was dried (Na2SO4) and concentrated to give N-t-butoxycarbonyl-2-(4-hydroxyphenyl)glycine, m.p. 112°-114° (methanol-water).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:3]=1[NH:4][CH2:5][C:6]1[C:7]([O:14]CC2C=CC(OC)=CC=2)=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:3]=1[NH:4][CH2:5][C:6]1[C:7](=[O:14])[NH:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1
Reactant: COc1ccc(COc2nc(SC)ncc2CNc2ccc(Cl)cc2Cl)cc1
Solvent: O=C(O)C(F)(F)F
Product: CSc1ncc(CNc2ccc(Cl)cc2Cl)c(=O)[nH]1
Yield: 33 %

Procedure:
A solution of 5 g (11.5 mmol) of 5-(2,4-dichloroanilinomethyl)-4-(4-methoxy-benzyloxy)-2-methylthiopyrimidine in 30 ml of trifluoroacetic acid was heated at reflux for 20 minutes, cooled and evaporated. The product was purified by flash chromatography on silica gel using ethyl acetate/isohexane in a ratio of 1:2 as eluent. Product-containing fractions were combined and evaporated to give 1.2 g (24%) of 5-[2,4-dichloroanilinomethyl]-2-methylthio-3H-pyrimidin-4-one as a pale yellow solid. [Mass spectrum (ESI) MH+ =316].
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)([O-])=O.O>C(OCC)(=O)C>[NH2:1][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1cccc2ccccc12
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1cccc2ccccc12
Reaction time: 0.5 h
Yield: 62 %

Procedure:
86.6 mg (0.50 mmol) of 1-nitronaphthalene (17), 270 μL (15 mmol) of distilled water and stainless steel balls (50 pieces) were placed in the vessel of the planetary ball mill, which was then closed, and agitated by operating the planetary ball mill for 12 hours at 800 rpm (reversed every 30 minutes). After the lapse of 12 hours, 10 mL of ethyl acetate was added to the vessel of the planetary ball mill to provide a solution containing the reaction mixture, which was then filtered with celite. The operation was repeated 5 times to provide a filtrate, which was then concentrated, thereby providing 44.3 mg (0.31 mmol) of 1-aminonaphthalene (18). The yield was 62%. The conversion yield was 100%, but the isolated yield was lowered since the product was partially distilled off under reduced pressure. The reaction is expressed by the following scheme.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[O:13]C(=O)[NH:11][CH:10]1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1.[OH-].[Na+]>C(O)C>[NH2:11][CH:10]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1)[CH:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])[OH:13]
Reactant: O=C1NC(Cc2ccc(C(F)(F)F)cc2)C(c2ccc(F)cc2F)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1F
Yield: 69.9 %

Procedure:
To a solution of (4RS,5SR)-5-(2,4-difluorophenyl)-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one (3.5 g, 9.8 mmol) in ethanol (60 ml) was added 8N aqueous sodium hydroxide solution (6.1 ml, 49 mmol) and the mixture was heated under reflux for 6 hrs. The reaction solution was concentrated, diluted with water (300 ml) and extracted with ethyl acetate (300 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give (1RS,2SR)-2-amino-1-(2,4-difluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (2.27 g, 70%).
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].[CH3:16][CH:17]([CH2:23][CH3:24])[C:18](=[O:22])[C:19](O)=[O:20]>>[CH2:8]([O:7][C:3]([O:4][CH2:5][CH3:6])([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[CH2:2][NH:1][C:19](=[O:20])[C:18](=[O:22])[CH:17]([CH3:16])[CH2:23][CH3:24])[CH3:9]
Reactant: CCC(C)C(=O)C(=O)O
Reactant: CCOC(CN)(OCC)c1cccnc1
Product: CCOC(CNC(=O)C(=O)C(C)CC)(OCC)c1cccnc1

Procedure:
In a manner analogous to Example 1, by condensing 3-(2-amino-1,1-diethoxyethyl)pyridine with 3-methyl-2-oxopentanoic acid there is obtained rac-N-[2,2-diethoxy-2-(3-pyridyl)ethyl]-3-methyl-2-oxovaleramide as an amorphous, colorless solid. Subsequent acidic hydrolysis to rac-3-methyl-2-oxo-N-[(3-pyridylcarbonyl)methyl]valeramide hydrochloride (beige, crystalline solid, melting point 158°-159°) and ring closure gives rac-3-(1-methylpropyl)-5-(3-pyridyl)-2(1H)-pyrazinone as a yellow solid, melting point 146°-148° (from acetonitrile). The conversion into rac-2-chloro-3-(1-methylpropyl)-5-(3-pyridyl)pyrazine is also effected analogously to Example 1. Hydrazinolysis to rac-2-hydrazino-3-(1-methylpropyl)-5-(3-pyridyl)pyrazine in the form of beige crystals, melting point 166°-167° (from ethanol/water) and subsequent condensation with diethyl malonate gives ethyl rac-8-(1-methylpropyl)-6-(3-pyridyl)-s-triazolo[4,3-a]pyrazine-3-acetate, MS: 335 (M)+, which is converted by saponification into the above acid, MS: 267 (M-CO 2)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH2:18][CH:19]3[CH2:21][CH2:20]3)=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([OH:15])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:53][C@@H:54]1[CH2:59][CH2:58][CH2:57][CH2:56][C@H:55]1[OH:60]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([O:17][CH2:18][CH:19]3[CH2:21][CH2:20]3)=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([NH:53][C@@H:54]2[CH2:59][CH2:58][CH2:57][CH2:56][C@H:55]2[OH:60])=[O:15])=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnc(OCC2CC2)c(-c2ccc(Cl)cc2)c1
Reactant: N[C@@H]1CCCC[C@H]1O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(OCC2CC2)c(-c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.2 %

Procedure:
5-(4-Chloro-phenyl)-6-cyclopropylmethoxy-nicotinic acid (21.5 g, 0.071 mol) was dissolved in DMF (655 mL). To the solution was added TBTU (25 g, 0.078 mol), N,N-diisopropylethyl amine (60.5 mL, 0.35 mol) and (1R,2R)-2-amino-cyclohexanol (11.8 g, 0.078 mol). The reaction mixture was stirred for 16 h at room temperature. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica (n-heptane/ethyl acetate gradient) to yield 21.7 g of the title compound as a white solid, MS (ISP) 401.2 (M+H)+.
Reaction SMILES: S(Cl)(Cl)=O.[N+:5]([C:8]1[CH:46]=[CH:45][C:11]([CH2:12][O:13][C:14](=[O:44])[CH:15]([N:17]2[C@H:20]([S:21][C:22]([S:24][CH2:25][CH2:26][NH:27][C:28]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=3)=[O:29])=[S:23])[C@@H:19]([O:41][CH3:42])[C:18]2=[O:43])O)=[CH:10][CH:9]=1)([O-:7])=[O:6].[C:47]1([P:53]([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.[N+](C1C=CC(COC(=O)C(N2[C@H](SC(SCCNC(OCC3C=CC([N+]([O-])=O)=CC=3)=O)=S)[C@@H](OC)C2=O)Cl)=CC=1)([O-])=O>O1CCCC1.C(N(CC)CC)C>[N+:5]([C:8]1[CH:9]=[CH:10][C:11]([CH2:12][O:13][C:14](=[O:44])[C:15]([N:17]2[C@H:20]([S:21][C:22]([S:24][CH2:25][CH2:26][NH:27][C:28]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=3)=[O:29])=[S:23])[C@@H:19]([O:41][CH3:42])[C:18]2=[O:43])=[P:53]([C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[C:60]2[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=2)=[CH:45][CH:46]=1)([O-:7])=[O:6]
Reactant: CO[C@H]1C(=O)N(C(O)C(=O)OCc2ccc([N+](=O)[O-])cc2)[C@@H]1SC(=S)SCCNC(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CO[C@H]1C(=O)N(C(Cl)C(=O)OCc2ccc([N+](=O)[O-])cc2)[C@@H]1SC(=S)SCCNC(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CO[C@H]1C(=O)N(C(C(=O)OCc2ccc([N+](=O)[O-])cc2)=P(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H]1SC(=S)SCCNC(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
Analogously to Example 24, 0.12 ml of thionyl chloride and 0.23 ml of triethylamine in 0.23 ml of absolute tetrahydrofuran are added to a solution of 640 mg of 2-[(3S,4R)-4-(2-p-nitrobenzyloxycarbonylaminoethylthiothiocarbonylthio)-3-methoxy-2-oxoazetidin-1-yl]-2-hydroxyacetic acid p-nitrobenzyl ester in 4.5 ml of absolute tetrahydrofuran. After reacting and working up, 0.54 g of triphenylphosphine is added to the crude 2-[(3S,4R)-4-(2-p-nitrobenzyloxycarbonylaninoethylthiothiocarbonylthio)-3-methoxy-2-oxoazetidin-1-yl]-2-chloroacetic acid p-nitrobenzyl ester, obtained as intermediate, in 1.15 ml of absolute tetrahydrofuran. After working up and chromatography over silica gel, the title compound is obtained.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:9]=1[O:10][CH3:11])=[O:4].[OH-].[K+]>O.CO>[CH3:11][O:10][C:9]1[CH:8]=[C:7]([C:12]([F:14])([F:15])[F:13])[S:6][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1sc(C(F)(F)F)cc1OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc(C(F)(F)F)sc1C(=O)O
Yield: 88.4 %

Procedure:
A solution of 2 g (14 mmole) of methyl-3-methoxy-5-trifluoromethyl-2-thiophenecarboxylate, 2 g (28 mmole) of KOH in a mixture of 15 mL water and 50 mL of methanol was refluxed for 2 hr. The reaction mixture was partitioned with ether and dilute aqueous HCl. The organic phase was separated, dried over MgSO4, filtered and concentrated to give 2.8 g (87%) of a colorless solid. mp 131-132° C. 1H NMR (300 MHz, CDCl3): δ 7.2 (s, 1H); 4.1 (s, 3H). Anal. Calc'd for C7H5F3O3S: C, 37.17; H, 2.23; S, 14.18. Found: C, 36.96; H, 2.19; S, 14.08.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[NH:14][N:15]([C:18]3[CH:27]=[N:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)[C:16](=[O:17])[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:31]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH3:31])[N:15]([C:18]3[CH:27]=[N:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)[C:16](=[O:17])[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]n(-c3cnc4ccccc4n3)c(=O)c2C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c2c(c(=O)n1-c1cnc3ccccc3n1)CN(C(=O)OC(C)(C)C)CC2
Reaction time: 0.17 h
Yield: 63 %

Procedure:
To a solution of 3-oxo-2-quinoxalin-2-yl-1,2,3,4,6,7-hexahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (prepared according to the method of Example 75, Step A, 250 mg, 0.68 mmol) in dimethylformamide (2 mL) at 0° C. with stirring under nitrogen was added sodium hydride (60% dispersion in mineral oil, 41 mg, 1.02 mmol). After 10 min, iodomethane (51 μL, 0.82 mmol) was added. This mixture was allowed to stir at 0° C. for 2 h, quenched by addition of saturated aqueous sodium bicarbonate and extracted with ethyl acetate (4×). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (40% ethyl acetate/hexanes) to give 164 mg (63%) of the title compound of Example 75, Step B as a yellow foam. 1H NMR (CDCl3, 250 MHz) δ9.71 (s, 1H), 8.15 (dd, 1H), 8.02 (m, 1H), 7.80-7.70 (c, 2H), 4.29 (s, 2H), 4.14 (t, 2H), 3.79 (s, 3H), 2.72-2.67 (c, 2H), 1.50 (s, 9H); MS (APCI) 382 (MH+).
Reaction SMILES: C([O:4][C:5]1[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:7]([OH:9])=O)(=O)C.[F:14][C:15]([F:25])([F:24])[C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1>>[F:14][C:15]([F:24])([F:25])[C:16]1[CH:17]=[CH:18][C:19]([CH2:20][NH:21][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[OH:4])=[CH:22][CH:23]=1
Reactant: CC(=O)Oc1ccccc1C(=O)O
Reactant: NCc1ccc(C(F)(F)F)cc1
Product: O=C(NCc1ccc(C(F)(F)F)cc1)c1ccccc1O

Procedure:
This compound was obtained as a white solid starting from acetylsalicyclic acid and 4-trifluoromethylbenzylamine using the same procedure described in example 5.