Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1>O.CC(C)=O>[CH3:9][O:10][C:11]1[CH:17]=[CH:16][C:14]([NH:15][C:5]2[C:4]([NH:15][C:14]3[CH:16]=[CH:17][C:11]([O:10][CH3:9])=[CH:12][CH:13]=3)=[N:3][C:2](=[O:1])[C:7](=[O:8])[CH:6]=2)=[CH:13][CH:12]=1
Reactant: Oc1cccnc1O
Reactant: COc1ccc(N)cc1
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(NC2=CC(=O)C(=O)N=C2Nc2ccc(OC)cc2)cc1
Reaction time: 2 h
Yield: 32 %

Procedure:
2,3-dihydroxypyridine (0.0027 mol), p-methoxyaniline (0.0054 mol); and NaIO3 (0.0009 mol) were dissolved in 160 ml of water/acetone (80:1, v/v) solvent. The reaction mixture was stirred for 2 hours, and maintained still overnight. It was then filtered, and recrystallized with chloroform. The final product was 5,6-di(p-methoxyphenylamino)-2,3-pyridindione in a red powder. The yield was 32%-50%.
Reaction SMILES: [CH3:1][S:2][CH:3]([C:9]1[CH:14]=[C:13]([CH:15]=O)[CH:12]=[CH:11][C:10]=1[O:17][CH3:18])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[S:19]1[CH2:23][C:22](=[O:24])[NH:21][C:20]1=[O:25].N1CCCCC1.Cl>C(O)C>[CH3:1][S:2][CH:3]([C:9]1[CH:14]=[C:13]([CH:15]=[C:23]2[S:19][C:20](=[O:25])[NH:21][C:22]2=[O:24])[CH:12]=[CH:11][C:10]=1[O:17][CH3:18])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: O=C1CSC(=O)N1
Reactant: CCOC(=O)C(SC)c1cc(C=O)ccc1OC
Agent: Cl
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)C(SC)c1cc(C=C2SC(=O)NC2=O)ccc1OC
Temperature: 0 °C
Yield: 60.1 %

Procedure:
Ethyl 2-methylthio-2-(5-formyl-2-methoxyphenyl)acetate (7.50 g, 28.0 mmol), thiazolidine-2,4-dione (3.94 g, 33.6 mmol), piperidine (2.80 mL, 28.3 mmol) and ethanol (100 mL) were mixed and refluxed for 14 hours. After allowed to stand for cooling, concentrated hydrochloric acid was added under cooling with ice and stirring to make the reaction mixture acidic. Ice water was added thereto and the mixture was stirred for 30 minutes. The precipitated crystals were collected by filtration, washed with ethanol and water, and then dried to obtain 6.18 g (60%) of the title compound as yellow crystals.
Reaction SMILES: [H-].[Na+].[S:3]1[CH:7]=[CH:6][S:5][C:4]1=[C:8]1[C:13](=[O:14])[CH2:12][CH2:11][NH:10][C:9]1=[O:15].[CH3:16]I>CN(C)C=O>[CH3:16][N:10]1[CH2:11][CH2:12][C:13](=[O:14])[C:8](=[C:4]2[S:5][CH:6]=[CH:7][S:3]2)[C:9]1=[O:15]
Reactant: CI
Reactant: O=C1CCNC(=O)C1=C1SC=CS1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCC(=O)C(=C2SC=CS2)C1=O
Reaction time: 0.17 h
Yield: 59.5 %

Procedure:
Sodium hydride (60% dispersion in oil) (226 mg) is suspended in N,N-dimethylformamide (10 ml), and to the suspension is added dropwise a solution of 3-(1,3-dithiol-2-ylidene)-2,4-dioxopiperidine (1.0 g) (which is prepared in Example 13) in N,N-dimethylformamide (100 ml) while cooling at 0° to 5° C. The mixture is stirred for 10 minutes at the same temperature, and to the mixture is added dropwise methyl iodide (861 mg), and the mixture is stirred at 0° to 2° C. for 1.5 hour. After distilling off the solvent under reduced pressure, the residue is purified by silica gel column chromatography (solvent, n-hexane:ethyl acetate=1:1), and recrystallized from ethyl acetate-isopropyl ether to give 1-methyl-3-(1,3-dithiol-2-ylidene)-2,4-dioxopiperidine (634 mg, 59.5%) as pale yellow needles. m.p. 148.5°-153° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([OH:10])[CH:5]=[C:4]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH:3]=1.N1C=CC=CC=1.[O:24](S(C(F)(F)F)(=O)=O)[S:25]([C:28]([F:31])([F:30])[F:29])(=O)=[O:26]>C(Cl)Cl>[F:29][C:28]([F:31])([F:30])[S:25]([O:10][C:6]1[CH:5]=[C:4]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH:3]=[C:2]([Cl:1])[C:7]=1[CH:8]=[O:9])(=[O:26])=[O:24]
Reactant: O=Cc1c(O)cc(OC2CCCCO2)cc1Cl
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=Cc1c(Cl)cc(OC2CCCCO2)cc1OS(=O)(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
To a mixture of 6-chloro-2-hydroxy-4-(tetrahydro-pyran-2-yloxy)benzaldehyde (10.5 g, 40.9 mmol) and pyridine (14.6 mL, 0.20 mol) in DCM (150 mL) cooled at −10˜0° C. was added Tf2O (10.3 mL, 61.2 mmol) dropwise. The reaction mixture was stirred at 0° C. for an additional 2 h and quenched with cold brine (40 mL). The resulting mixture was extracted with EtOAc (2×50 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (EtOAc: PE=1:200) to give the title compound as a yellow oil (10.5 g. Yield: 66%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[NH2:19][C@H:20]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21]1>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:19][C@H:20]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21]2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Reactant: Fc1cnc(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(Cl)ncc2F)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.7 %

Procedure:
To a mixture of 2,4-dichloro-5-fluoro-pyrimidine (1.75 g, 10.48 mmol) and iPr2NEt (3.27 mL, 18.78 mmol) in THF (50 mL) was added tert-butyl (3S)-3-aminopyrrolidine-1-carboxylate (1.83 mL, 10.48 mmol) in THF (2 mL). The resulting solution was allowed to stir at room temperature for 2 hours. The mixture was concentrated to dryness, diluted with dichloromethane and washed with water. The organic layer was dried over Na2SO4 and concentrated in vacuo to afford 3.41 g of 7a, as a white foamy solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][CH2:8][CH3:9])=[C:4]([C:10]([O:12]CC)=[O:11])[CH:3]=1>[OH-].[Na+].C(O)C>[CH3:1][C:2]1[O:6][C:5]([CH2:7][CH2:8][CH3:9])=[C:4]([C:10]([OH:12])=[O:11])[CH:3]=1
Reactant: CCCc1oc(C)cc1C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCc1oc(C)cc1C(=O)O

Procedure:
Saponification of 0.5 g of the ester was carried out by refluxing 12 hours in 10 ml of 25% aqueous sodium hydroxide and 5 ml of ethanol. Acidification precipitated the crude acid which was purified by sublimination to give 5-methyl-2-propyl-3-furoic acid, mp 91°-102° C.
Reaction SMILES: [CH3:1][C:2]1[C:25]([O:26][CH3:27])=[CH:24][C:5]2[C:6](=[O:23])[N:7]3[CH2:22][CH2:21][CH2:20][C@H:8]3[C@H:9](O)[N:10](C(OCC(Cl)(Cl)Cl)=O)[C:4]=2[C:3]=1[O:28][CH3:29]>C1COCC1.CCOC(C)=O>[CH3:1][C:2]1[C:25]([O:26][CH3:27])=[CH:24][C:5]2[C:6](=[O:23])[N:7]3[CH2:22][CH2:21][CH2:20][CH:8]3[CH:9]=[N:10][C:4]=2[C:3]=1[O:28][CH3:29]
Reactant: COc1cc2c(c(OC)c1C)N(C(=O)OCC(Cl)(Cl)Cl)[C@@H](O)[C@@H]1CCCN1C2=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc2c(c(OC)c1C)N=CC1CCCN1C2=O
Yield: 94.4 %

Procedure:
10% Cd/Pb couple (1.34 g; 10.7 mmol Cd) was added to a rapidly stirring solution of 193 (1 g; 2.14 mmol) in a mixture of THF (15 ML) and 1 N NH4OAc (15 mL). After 3.5 hours the reaction was diluted with EtOAc (150 mL). The solution was dried over anhydrous MgSO4 and the solids were filtered and rinsed with EtOAc (50 mL). Removal of excess solvent yielded the product (194) as a white glass (554 mg, 2.021 mmol, 94%). 1H NMR (270 MHz, CDCl3) (mixture of imine and methyl ether forms) δ 7.72 (imine, d, J=4.39, 1H), 7.29 (s, 1H), 3.90 (s, 3H), 3.88-3.51 (m, 3H+2H+1H), 2.37-2.04 (m, 4H), 2.22 (s, 3H); 13C NMR (67.8 MHz, CDCl3) δ 164.65, 161.41, 156.79, 153.47, 133.87, 126.29, 124.27, 105.71, 60.98, 55.80, 55.70, 53.71, 46.70, 29.52, 29.34, 24.13, 9.33.
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:39]=[CH:38][C:8]([C:9]([NH:11][C:12]2[CH:17]=[C:16]([C:18]3[CH:27]=[C:26]4[C:21]([CH2:22][CH2:23][N:24](C(OC(C)(C)C)=O)[CH2:25]4)=[CH:20][CH:19]=3)[N:15]3[N:35]=[CH:36][CH:37]=[C:14]3[N:13]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].F[C:41](F)(F)C(O)=O>C(Cl)Cl>[OH:1][C:2]([C:5]1[CH:39]=[CH:38][C:8]([C:9]([NH:11][C:12]2[CH:17]=[C:16]([C:18]3[CH:27]=[C:26]4[C:21]([CH2:22][CH2:23][NH:24][CH2:25]4)=[CH:20][CH:19]=3)[N:15]3[N:35]=[C:36]([CH3:41])[CH:37]=[C:14]3[N:13]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(-c3cc(NC(=O)c4ccc(C(C)(C)O)cc4)nc4ccnn34)cc2C1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(-c3ccc4c(c3)CNCC4)n2n1
Reaction time: 0.5 h

Procedure:
tert-Butyl 7-(5-(4-(2-hydroxypropan-2-yl)benzamido)pyrazolo[1,5-a]pyrimidin-7-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate from Step A was dissolved in CH2Cl2 (2 ml). Trifluoroacetic acid (1 ml) was then added at 0° C. The mixture was stirred for 30 minutes at that temperature before being concentrated in vacuo. Residual trifluoroacetic acid was removed azeotropically with toluene twice. The residue was then dissolved in acetonitrile before being purified by preparatory HPLC (20-35% MeCN/H2O gradient+0.01% TFA) to give the titled compound as a white powder. 1H NMR (400 MHz, DMSO-d6) δ=11.22 (s, 1 H), 9.11 (br. s., 2 H), 8.01 (d, J=8.6 Hz, 2 H), 7.99-7.89 (m, 3 H), 7.62 (d, J=8.6 Hz, 2 H), 7.49 (d, J=8.1 Hz, 1 H), 6.40 (s, 1 H), 4.43 (br. s., 2 H), 3.47 (d, J=7.3 Hz, 2 H), 3.16-3.07 (m, 2 H), 2.40 (s, 3 H), 1.46 (s, 6 H); ESI-MS: m/z 442.2 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][C:10]2([O:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:15]>>[NH2:15][CH2:11][C:10]1([OH:12])[CH2:13][CH2:14][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9]1
Reactant: N
Reactant: c1ccc(CN2CCC3(CO3)C2)cc1
Product: NCC1(O)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
9.7 g (51.3 mmol) of 5-benzyl-5-aza-1-oxaspiro[2,4]heptane (U.S. Pat. No. 4,508,724) are added dropwise to 50 ml of ammonia solution (25%) and the mixture is stirred overnight at room temperature. The batch is then concentrated and the residue is distilled.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[S:7]1(=[O:17])=[O:16].[N:18]1[CH:23]=[CH:22][CH:21]=[N:20][C:19]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[N:18]1[CH:23]=[CH:22][CH:21]=[N:20][C:19]=1[N:24]1[CH2:29][CH2:28][N:27]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[C:10](=[O:11])[C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[S:7]2(=[O:17])=[O:16])[CH2:26][CH2:25]1
Reactant: O=C1c2ccccc2S(=O)(=O)N1CCCCBr
Reactant: c1cnc(N2CCNCC2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2S(=O)(=O)N1CCCCN1CCN(c2ncccn2)CC1

Procedure:
0.02 mol of 2-(4-bromobutyl)-1,2-benzoisothiazol-3-(2H)one 1,1-dioxide and 0.02 mol of 1-(2-pyrimidinyl) piperazine are stirred with 0.02 mol of K2CO3 in 150 ml of absolute dimethylformamide (DMF) for 1 hour at 100° C. The mixture is then concentrated. Water is added to the residue and the organic substance is taken up in methylene chloride (CH2CL2). The dried CH2CL2 phase is added to a silica gel column and eluted with CH2CL2 /CH3OH (95:5).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]2[N:15]([CH3:25])[C:16]([CH2:19][C:20]([O:22]CC)=[O:21])=[CH:17][CH:18]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]2[N:15]([CH3:25])[C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:17][CH:18]=2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1ccc(CCNS(=O)(=O)c2ccc(F)cc2)n1C
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(CCNS(=O)(=O)c2ccc(F)cc2)ccc1CC(=O)O

Procedure:
0.5 g (1.3 mmol) of ethyl [2-(2-(4-fluorobenzenesulphonylamino)-ethyl)-1-methylpyrrol-5-yl]acetate are stirred into 4.5 ml of 1N of sodium hydroxide solution overnight at ambient temperature. The mixture is then extracted with ethylene chloride and the aqueous phase is acidified with 1N hydrochloric acid. The precipitate obtained is suction filtered and dried.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[O:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].Cl[CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1>>[N:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:31]=[CH:32][C:23]=1[CH2:22][N:8]1[C:9]([O:10][C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]1=[O:19]
Reactant: Cc1cc(C)cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: ClCc1ccc2ccccc2n1
Product: Cc1cc(C)cc(Oc2c(C(C)C)c(=O)[nH]c(=O)n2Cc2ccc3ccccc3n2)c1
Yield: 33.5 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and 2-chloromethyl quinoline were reacted by the same way with the example 1 to obtain the titled compound (139 mg, yield: 33.5%).
Reaction SMILES: [C:1]12([CH:7]3[CH2:8][CH2:9][CH:4]1[C:5](=[O:10])[CH2:6]3)[CH2:3][CH2:2]2.C(O)(=[O:13])C>>[C:1]12([CH:4]3[CH2:9][CH2:8][CH:7]1[C:6](=[O:13])[C:5]3=[O:10])[CH2:3][CH2:2]2
Reactant: CC(=O)O
Reactant: O=C1CC2CCC1C21CC1
Product: O=C1C(=O)C2CCC1C21CC1
Temperature: 25 °C

Procedure:
A solution of spiro[bicyclo[2.2.1]heptane-7,1′-cyclopropan]-2-one (rac), 8.6 g (synthesis: N. J. Turro, JACS, 1980, 102, 6056) in acetic acid, 38 ml, was treated at RT with SeO2 (16.15 g) and the suspension was then heated at reflux for 12 h. The reaction mixture was cooled to RT, filtered and the filter cake was washed with ethyl acetate. The filtrate was made basic with 3N aqueous NaOH and more AcOEt was added. The layers were separated, the organic layer was dried over Na2SO4, filtered and evaporated. The residue was purified by flash chromatography (heptane/AcOEt: 100% to 90%) to give spiro[bicyclo[2.2.1]heptane-7,1′-cyclopropane]-2,3-dione, (2.5 g) as a yellow solid. MS (ESI): 168 (M+NH4)+.
Reaction SMILES: [C:1]([O:9][CH3:10])(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C([N-]C(C)C)(C)C.[Li+].[CH2:19]([O:26][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[C:29]([CH3:35])[CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[CH3:10][O:9][C:1](=[O:8])[CH:2]([CH:31]([C:30]1[CH:33]=[CH:34][C:27]([O:26][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:28][C:29]=1[CH3:35])[OH:32])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCC(=O)OC
Reactant: Cc1cc(OCc2ccccc2)ccc1C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCC(C(=O)OC)C(O)c1ccc(OCc2ccccc2)cc1C

Procedure:
In analogy to the procedure described in example 125 a], methyl heptanoate was deprotonated with lithium diisopropylamide and reacted with 4-benzyloxy-2-methyl-benzaldehyde in tetrahydrofuran to obtain 2-[(4-benzyloxy-2-methyl-phenyl)-hydroxy-methyl]-heptanoic acid methyl ester as a mixture of two diastereomeric racemates as light yellow oil.
Reaction SMILES: [CH:1]([OH:4])([CH3:3])[CH3:2].[C:5](Cl)(=[O:9])[C:6]([Cl:8])=[O:7]>>[CH:1]([O:4][C:5](=[O:9])[C:6]([Cl:8])=[O:7])([CH3:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)O
Product: CC(C)OC(=O)C(=O)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Isopropanol (158 μL, 2.1 mmol, 1.0 eq.) was added dropwise over 5 minutes to oxalyl chloride (350 μL, 4.14 mmol 2.0 eq.) at 0° C., and the resulting mixture was stirred at room temperature for 2 hours. The excess oxalyl chloride was removed by rotary evaporation (40° C., 50 mmHg) and used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:46]=[CH:45][C:7]([CH2:8][NH:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([NH:20][C@H:21]([C:25]([N:27]3[CH2:44][CH2:43][CH2:42][C@H:28]3[C:29]([NH:31][CH:32]([CH:39]([CH3:41])[CH3:40])[C:33](=[O:38])[C:34]([F:37])([F:36])[F:35])=[O:30])=[O:26])[CH:22]([CH3:24])[CH3:23])=[O:19])=[CH:14][CH:13]=2)=[O:11])=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:46]=[CH:45][C:7]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([NH:20][C@H:21]([C:25]([N:27]3[CH2:44][CH2:43][CH2:42][C@H:28]3[C:29]([NH:31][CH:32]([CH:39]([CH3:40])[CH3:41])[C:33](=[O:38])[C:34]([F:37])([F:35])[F:36])=[O:30])=[O:26])[CH:22]([CH3:24])[CH3:23])=[O:19])=[CH:16][CH:17]=2)=[O:11])=[CH:6][CH:5]=1
Reactant: CC(C)C(NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)c1ccc(C(=O)NCc2ccc([N+](=O)[O-])cc2)cc1)C(C)C)C(=O)C(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)C(NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)c1ccc(C(=O)NCc2ccc(N)cc2)cc1)C(C)C)C(=O)C(F)(F)F
Yield: 96.5 %

Procedure:
A solution of 3(RS)-[[4-[(4-nitrobenzyl)aminocarbonyl]phenylcarbonyl]-L-valyl-L-prolyl]amino -1,1,1-trifluoro-4-methyl-2-oxopentane (50 mg) in methanol (10 ml) was hydrogenated over 10% palladium on carbon (10 mg) at 4 atmosphere pressure of hydrogen for 2 hours. The catalyst was removed by filtration and the liltrate was evaporated under reduced pressure to give 3(RS)-[[4-[(4aminobenzyl)aminocarbonyl]phenylcarbonyl]-L-valyl-L-prolyl]amino-1,1,1-trifluoro-4-methyl-2-oxopentane (46 mg).
Reaction SMILES: [C:1](Cl)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[NH:11]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>>[C:1]([N:11]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: C1CCCNCC1
Reactant: CCCCCCCC(=O)Cl
Product: CCCCCCCC(=O)N1CCCCCC1
Yield: 67.9 %

Procedure:
In a manner similar to that described in Example 1, octanoyl chloride (16.26 g, 0.1M) was treated with hexahydro-1H-azepine (9.92 g, 0.1M). Work up and distillation of the residue gave 15.3 g (68%) of product, b.p. 122/0.8 mm.
Reaction SMILES: [CH2:1]([C:5]1[S:22][C:8]2[N:9]=[C:10]3[CH:17]=[CH:16][C:15]([C:18]([O:20]C)=[O:19])=[CH:14][N:11]3[C:12](=[O:13])[C:7]=2[CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH-:23].[Na+]>C(O)C>[CH2:1]([C:5]1[S:22][C:8]([NH:9][C:10]2[N:11]=[CH:14][C:15]([C:18]([OH:20])=[O:19])=[CH:16][CH:17]=2)=[C:7]([C:12]([OH:23])=[O:13])[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc2c(=O)n3cc(C(=O)OC)ccc3nc2s1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: CCCCc1cc(C(=O)O)c(Nc2ccc(C(=O)O)cn2)s1

Procedure:
A mixture of 2-butyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxylic acid, methyl ester (Example 8), 0.94 g (0.00297 mol), 35 ml of 1 N sodium hydroxide and 25 ml of ethanol is refluxed for fifty-five minutes. The resulting solution is evaporated to dryness, and the residue is dissolved in hot water, filtered, cooled and acidified with glacial acetic acid. The precipitate is separated, washed with water and dried to give 0.7 g of 6-[(5-butyl-3-carboxy-2-thienyl)amino]-3-pyridinecarboxylic acid; mp 217° C. (dec) after recrystallization from glacial acetic acid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:19][C:20]1[N:21]=[C:22]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)[S:23][C:24]=1[CH2:25][CH2:26]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:26][CH2:25][C:24]3[S:23][C:22]([C:28]4[CH:29]=[CH:30][C:31]([C:34]([F:37])([F:35])[F:36])=[CH:32][CH:33]=4)=[N:21][C:20]=3[CH3:19])[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Cn1ccc2ccc(O)cc21
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCO
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCOc1ccc2ccn(CC(=O)OC(C)(C)C)c2c1

Procedure:
In analogy to the procedure described in example 3 c], (6-hydroxy-indol-1-yl)-acetic acid tert-butyl ester (example 6 b]) was reacted with 2-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethanol (example 5 c]) in the presence of triphenylphosphine and di-tert-butyl azodicarboxylate to yield (6-{2-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-indol-1-yl)-acetic acid tert-butyl ester as light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21](O)=[O:22])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[NH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([NH:31]O)=[NH:30])=[CH:27][N:26]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21]4[O:22][N:31]=[C:29]([C:28]5[CH:33]=[CH:34][C:25]([NH2:24])=[N:26][CH:27]=5)[N:30]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)cc3)nc12
Reactant: N=C(NO)c1ccc(N)nc1
Product: Nc1ccc(-c2noc(-c3cnn4c(C(F)(F)F)cc(-c5ccc(Cl)cc5)nc34)n2)cn1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.4) (171 mg, 0.5 mmol) and 6-amino-N-hydroxy-nicotinamidine (example B.4) (114 mg, 0.75 mmol) according to general procedure II. Obtained after flash chromatography on silica gel (ethyl acetate/heptane) and further purification by crystallization (dichloromethane/hexane) as a yellow solid (81 mg, 36%). MS (ISP) 458.1 [(M+H)+]; mp 253° C.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([OH:12])=O)[C:4]=2[CH:3]=[CH:2]1.Cl.CN(C)CCCN=C=NCC.O.N1(O)C2C=CC=CC=2N=N1.[Cl:36][C:37]1[CH:38]=[C:39]([CH:44]=[CH:45][C:46]=1[O:47][CH:48]([CH3:50])[CH3:49])[C:40]([NH:42]O)=[NH:41]>CN(C=O)C.O>[Cl:36][C:37]1[CH:38]=[C:39]([C:40]2[N:42]=[C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[C:9]4[C:4]=3[CH:3]=[CH:2][NH:1]4)[O:12][N:41]=2)[CH:44]=[CH:45][C:46]=1[O:47][CH:48]([CH3:50])[CH3:49]
Reactant: CC(C)Oc1ccc(C(=N)NO)cc1Cl
Reactant: O=C(O)c1cccc2[nH]ccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2noc(-c3cccc4[nH]ccc34)n2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.7 %

Procedure:
Under an atmosphere of nitrogen a mixture of 1H-indole-4-carboxylic acid (3.88 g, 24.05 mmol), (3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride (4.61 g, 24.05 mmol) and benzotriazol-1-ol hydrate (3.68 g, 24.05 mmol) in anhydrous DMF (61.4 ml) was stirred at ambient temperature for about 1 h. To the reaction mixture a solution of 3-chloro-N-hydroxy-4-isopropoxybenzamidine (5.0 g, 21.87 mmol) in DMF (11.51 ml) was added. The mixture was stirred and heated at about 140° C. for about 2 h. The mixture was cooled to ambient temperature and poured into water (IL). The product was partitioned between ethyl acetate and the aqueous phase. The organic layer washed with 1N HCl (4×150 mL), 1N NaOH (2×150 mL) and water (2×300 mL), dried over MgSO4 and filtered. The solvent was removed under reduced pressure and the crude product was purified by elution through Florisil with heptane/ethyl acetate (2:1) to give 3-(3-chloro-4-isopropoxyphenyl)-5-(1H-indol-4-yl)-1,2,4-oxadiazole (2.76 g, 35.7%). LCMS (Table 1, Method b) Rt=2.69 min, m/z 354.17 (M+H)+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:20]4[C:15](=[N:16][CH:17]=[C:18]([C:21](=[O:23])[CH3:22])[N:19]=4)[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:24][Mg+].[Br-]>C1COCC1>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:20]4[C:15](=[N:16][CH:17]=[C:18]([C:21]([OH:23])([CH3:24])[CH3:22])[N:19]=4)[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(C)(O)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 3.8 %

Procedure:
To a solution of 1-(3-quinolin-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)-ethanone (100 mg, 0.33 mmol) in THF was added MeMgBr (0.260 mL, 0.362 mmol, 1.4M in toluene/THF) at 0° C. The reaction was allowed to stir for 16 hours at room temperature. The LC-MS showed a 1:1 ratio (ketone:alcohol), so another equivalent of the MeMgBr was added and the reaction was stirred for an additional 16 hours. The crude reaction was concentrated and purified by a reverse-phase C-18 preparative eluting of ACN—H2O with 0.1% acetic acid HPLC to give 2-(3-quinolin-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)-propan-2-ol (4 mgs, 4% yield).