Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].[CH:8]1([C:14]([O:16][CH:17]([O:21][C:22](ON2C(=O)CCC2=O)=[O:23])[CH:18]([CH3:20])[CH3:19])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>C(#N)C.O>[CH:8]1([C:14]([O:16][CH:17]([O:21][C:22]([NH:1][CH:2]([CH2:3][OH:4])[C:5]([OH:7])=[O:6])=[O:23])[CH:18]([CH3:19])[CH3:20])=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: CC(C)C(OC(=O)ON1C(=O)CCC1=O)OC(=O)C1CCCCC1
Reactant: N[C@H](CO)C(=O)O
Solvent: O
Solvent: CC#N
Product: CC(C)C(OC(=O)NC(CO)C(=O)O)OC(=O)C1CCCCC1
Yield: 9.4 %

Procedure:
Following the general procedure for the synthesis of acyloxyalkyl carbamates, D-serine (0.40 g, 3.80 mmol) and 1-(2,5-dioxoazolidinyloxycarbonyloxy)-2-methylpropyl cyclohexanecarboxylate (1.0 g, 2.93 mmol) were reacted in the acetonitrile/water mixture to provide 0.091 g (10% yield) of the title compound (34) as a white wax after work-up and mass-guided preparative HPLC purification. 1H NMR (CDCl3, 400 MHz): δ=6.58 (dd, 1H), 6.11 (dd, 1H), 4.42-4.31 (m, 1H), 4.11-3.92 (br dd, 2H), 2.38 (m, 1H), 2.11 (m, 1H), 1.97 (br d, 2H), 1.77 (br d, 2H), 1.6 (br d, 1H), 1.4 (q, 2H), 1.2 (br m, 3H), 0.99 (dd, 6H). MS (ESI) m/z 354.22 (M+Na)+; 330.21 (M−H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C@H:6]([NH:8][C:9]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([C:20]3[C:28]4[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=4)[N:22]([CH3:30])[N:21]=3)[N:18]=2)[N:13](COCC[Si](C)(C)C)[CH:12]=1)=[O:10])[CH3:7].FC(F)(F)C(O)=O.C(N)CN>ClCCl>[O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C@H:6]([NH:8][C:9]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([C:20]3[C:28]4[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=4)[N:22]([CH3:30])[N:21]=3)[N:18]=2)[NH:13][CH:12]=1)=[O:10])[CH3:7]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)c1ncco1
Solvent: ClCCl
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)c1ncco1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 40.5 %

Procedure:
In a round-bottomed flask, 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-oxazol-2-yl-ethyl)-amide (75 mg, 0.14 mmol) was dissolved in dichloromethane (0.7 ml) and trifluoroacetic acid (0.45 ml, 5.6 mmol) was added. The reaction mixture was stirred at room temperature for 2.5 h then concentrated. The residue was dissolved in dichloromethane (0.7 ml) and ethylenediamine (0.6 ml, 8.4 mmol) was added. The yellow solution was stirred at room temperature for 1 h then quenched with water and diluted with ethyl acetate. The resulting suspension was filtered, washed with hot water and ethyl acetate and dried under high vacuum to provide 23 mg (39%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-oxazol-2-yl-ethyl)-amide as a light yellow powder. MS: (M+H)+=406; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.95 (br. s., 1H), 9.13 (s, 1H), 8.66 (d, J=8.7 Hz, 1H), 8.51 (s, 1H), 8.47 (dd, J=9.1, 5.3 Hz, 1H), 8.11 (s, 1H), 7.69 (dd, J=9.6, 2.1 Hz, 1H), 7.24 (s, 1H), 7.02-7.11 (m, 1H), 5.48-5.60 (m, 1H), 4.15 (s, 3H), 1.66 (d, J=7.2 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([NH:15][C:16]3[C:25]([C:26]([NH:28][CH:29]([CH3:31])[CH3:30])=[O:27])=[CH:24][C:19]([C:20](OC)=[O:21])=[CH:18][C:17]=3[CH3:32])=[O:14])=[CH:11][C:10]([C:33]([F:36])([F:35])[F:34])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:37]([Sn](CCCC)(CCCC)C(OCC)=C)CCC.O>CN(C=O)C.C1(P([Pd](Cl)(Cl)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:20]([C:19]1[CH:24]=[C:25]([C:26]([NH:28][CH:29]([CH3:30])[CH3:31])=[O:27])[C:16]([NH:15][C:13]([C:12]2[N:8]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=3)[N:9]=[C:10]([C:33]([F:34])([F:36])[F:35])[CH:11]=2)=[O:14])=[C:17]([CH3:32])[CH:18]=1)(=[O:21])[CH3:37]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1cc(C)c(NC(=O)c2cc(C(F)(F)F)nn2-c2ncccc2Cl)c(C(=O)NC(C)C)c1
Agent: Cl[Pd](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1cc(C)c(NC(=O)c2cc(C(F)(F)F)nn2-c2ncccc2Cl)c(C(=O)NC(C)C)c1
Temperature: 80 °C

Procedure:
The title compound of Example 2, Step C (0.7 g, 1.3 mmol) was dissolved in DMF (10 mL) and treated with tributyl-(1-ethoxyvinyl)tin (0.47 g, 1.3 mmol) and bis(triphenyl-phosphino)palladium dichloride (50 mg). The mixture was heated at 80° C. for 4 hours. The mixture was poured into water (50 mL) and extracted with ether (3×50 mL). The combined organic layers were washed with water (50 mL) and saturated brine (50 mL). The mixture was dried over magnesium sulfate and concentrated under reduced pressure. The residue was filtered through a silica gel cartridge using dichloromethane as eluent. The appropriate fractions were pooled and evaporated. The residue (400 mg) was dissolved in acetone (20 mL) and treated with 1N hydrochloric acid (5 mL). After 1 hour at 25° C. the reaction mixture was partitioned between ethyl acetate (50 ml) and water (50 ml). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to chromatography on silica gel using ethyl acetate/hexanes (40:60) as eluent. Pooling appropriate fractions and evaporation of solvent provided the title compound, a compound of the invention, (150 mg) as a yellow solid, m.p.: 135–137° C. 1H NMR (CDCl3): δ 10.8 (NH), 8.42 (1H), 7.89 (1H), 7.87 (2H), 7.42 (1H), 7.31 (1H), 6.15 (1H), 4.21 (1H), 2.59 (3H), 2.27 (3H), 1.28 (6H).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]=O)[CH:21]=1>>[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)[CH:21]=1
Reactant: O=Cc1cccnc1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4cccnc4)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with pyridine-3-carbaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-(pyridin-3-ylmethyl)piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[NH:14][C:15]([NH2:24])=[C:16]2[C:20]([N:21]=1)=[N:19][C:18]([O:22][CH3:23])=[N:17]2)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][CH:34]1[CH2:38][CH2:37][CH2:36][O:35]1.O>CN(C)C=O>[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH2:33][CH:34]2[CH2:38][CH2:37][CH2:36][O:35]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCOc1nc2nc(OC)nc-2c(N)[nH]1
Reactant: BrCCC1CCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CCC3CCCO3)c2n1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A stirring mixture of 2-butoxy-8-methoxy-1H-purin-6-amine trifluoroacetate salt (200 mg) and potassium carbonate (236 mg) in dry N,N-dimethylformamide (2 ml) was heated with stirring at 60° C. for 1 h. 2-(2-Bromoethyl)tetrahydrofuran (122 mg) was added and the stirring mixture heated at 50° C. for 4 h. After allowing to cool, water was added and the mixture extracted three times with ethyl acetate. The combined extracts were washed with water then brine, dried by passing through a phase separation cartridge and stripped to give a brown oil. This was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid)-acetonitrile (containing 0.05% formic acid) as eluent (20-60%) and the appropriate fractions combined and evaporated to remove acetonitrile. The remaining aqueous mixture was made basic with saturated sodium hydrogen carbonate, extracted three times with dichloromethane and the combined extracts dried by passing through a phase separation cartridge then evaporated to afford the title compound as a clear oil, yield 122 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]([OH:10])=[O:9])=[CH:3][CH:2]=1.Cl[CH2:12][CH2:13][O:14][CH2:15][CH2:16]Cl>[OH-].[Na+].[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2([C:8]([OH:10])=[O:9])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:3][CH:2]=1
Reactant: ClCCOCCCl
Reactant: O=C(O)Cc1ccncc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Product: O=C(O)C1(c2ccncc2)CCOCC1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a mixture of pyridin-4-yl-acetic acid (930 mg, 6.0 mmol) and bis-(2-chloroethyl)ether 1.1 mL, 9.0 mmol) in 50% NaOH aq. solution (5 mL) is added benzyltriethylammonium chloride (680 mg, 3 mmol). The solution is heated to 60° C. and stirred at the temperature for 2 hours. After cooling down to rt, the aqueous layer is removed and the organic layer is neutralized with sat. NH4Cl aq. and extracted with Et2O. The combined organic phases are washed with H2O and dried over Na2SO4. Concentration under reduced pressure gives the title compound. The material is used in a next step without purification.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1(C)[CH2:11][CH2:10]1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:13]([O:21]C)(=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:1]([NH:5][S:6]([C:9]1([C:13](=[O:21])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:11][CH2:10]1)(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccccc1
Reactant: CC(C)(C)NS(=O)(=O)C1(C)CC1
Product: CC(C)(C)NS(=O)(=O)C1(C(=O)c2ccccc2)CC1
Yield: 66 %

Procedure:
This compound was obtained in 66% yield using the procedure described for the synthesis of N-tert-butyl-(1-methyl)cyclopropylsulfonamide except 1.2 equivalents of methyl benzoate was used as the electrophile. The compound was purified by column chromatography over SiO2 using 30% to 100% CH2Cl2 in hexane: 1H NMR (CDCl3) δ 1.31 (s, 9H), 1.52 (m, 2H), 1.81 (m, 2H), 4.16 (br s, 1H), 7.46 (m, 2H), 7.57 (m, 1H), 8.05 (d, J=8.5 Hz, 2H).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([Cl:4])=[O:3].[C:7]([O:11][O:12][C:13]([CH3:19])([CH3:18])[CH2:14][CH:15]([CH3:17])[OH:16])([CH3:10])([CH3:9])[CH3:8].[Cl-]>C(OC)(C)(C)C>[C:2]([Cl:4])(=[O:3])[C:1]([O:16][CH:15]([CH3:17])[CH2:14][C:13]([O:12][O:11][C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:18])[CH3:19])=[O:5]
Reactant: CC(O)CC(C)(C)OOC(C)(C)C
Reactant: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Solvent: COC(C)(C)C
Product: CC(CC(C)(C)OOC(C)(C)C)OC(=O)C(=O)Cl

Procedure:
A 250 mL three-neck flask equipped with a magnetic stirrer, a thermometer and an addition funnel was charged with 25.4 g (200 mmoles) of oxalyl chloride and 75 mL of methyl t-butyl ether (MTBE). Then to the resulting solution was added 20.6 g (100 mmoles) of 93% 3-t-butylperoxy-1,3-dimethylbutanol over a period of 30 minutes at 22°-28° C. The addition funnel was then replaced with a nitrogen gas tube and dry nitrogen gas was slowly bubbled through the reaction mass in order to remove HCl over a period of 4 hours at 25°-30° C. The MTBE, excess oxalyl chloride, and any remaining gas were removed in vacuo using a water aspirator. Obtained was 28.3 g (101% of theory, uncorrected) of a yellow liquid. An IR spectrum ofthe product showed no OH bands and showed carbonyl bands at 1800 cm-1 and 1760 cm-1. The assay of I-2, based upon hydrolyzable chloride content (theory, 12.63%; found, 12.37%), was 97.9% and the corrected yieldwas 98.6%.
Reaction SMILES: CCCCCC.[H-].C([Al+]CC(C)C)C(C)C.[CH3:17][O:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([O:29][CH3:30])=[CH:21][C:20]=1[CH2:31][CH2:32][CH2:33][C:34]#N.[OH2:36]>C(Cl)Cl>[CH3:17][O:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([O:29][CH3:30])=[CH:21][C:20]=1[CH2:31][CH2:32][CH2:33][CH:34]=[O:36]
Reactant: COc1cc(CCCC#N)c(OC)c2ccccc12
Reactant: O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCC
Solvent: ClCCl
Product: COc1cc(CCCC=O)c(OC)c2ccccc12
Reaction time: 2 h

Procedure:
20 ml of a 1.0M hexane solution of diisobutylaluminum hydride were added at -70° C. to a solution of 3.36 g of 4-(1,4-dimethoxy-2-naphthyl)butyronitrile [prepared as described in step (a) above] in 100 ml of dry methylene chloride, and the resulting mixture was stirred for 2 hours. At the end of this time, water was added to the reaction mixture, and the insoluble materials were filtered off with the aid of a Celite (trade name) filter aid. The methylene chloride layer which separated was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure, to give 2.96 g of the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[N:12][N:13]2C(OC(C)(C)C)=O)=[CH:9][CH:8]=1)=[O:5].[C:27]([C:31]1[CH:32]=[C:33]2[C:38](=O)[O:37][C:35](=[O:36])[C:34]2=[CH:40][CH:41]=1)([CH3:30])([CH3:29])[CH3:28]>C1COCC1.C(OCC)C>[NH:13]1[C:14]2[C:10](=[CH:9][CH:8]=[C:7]([NH:6][C:4](=[O:5])[C:3]3[CH:23]=[CH:24][CH:25]=[CH:26][C:2]=3[N:1]3[C:38](=[O:37])[C:33]4[C:34](=[CH:40][CH:41]=[C:31]([C:27]([CH3:29])([CH3:28])[CH3:30])[CH:32]=4)[C:35]3=[O:36])[CH:15]=2)[CH:11]=[N:12]1
Reactant: CC(C)(C)c1ccc2c(c1)C(=O)OC2=O
Reactant: CC(C)(C)OC(=O)n1ncc2ccc(NC(=O)c3ccccc3N)cc21
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)c1ccc2c(c1)C(=O)N(c1ccccc1C(=O)Nc1ccc3cn[nH]c3c1)C2=O
Reaction time: 72 h
Yield: 16.3 %

Procedure:
To a stirring solution of 2-amino-N-(1-Boc-6-indazolyl)benzamide (1 g, 2.8 mmol) in THF (30 mL) was added 4-t-butylphthalic anhydride (1.2 g, 5.9 mmol) and the solution was heated to reflux. After 72 h, the vessel was cooled and the volume was reduced to about 10 mL in vacuo. The mixture was diluted with diethyl ether (20 mL) and after sonication, a white solid was collected. This solid was processed by methods substatially equivalent to those described in Example 2-F to give 200 mg of N-(6-indazolyl)-2-(5-t-butyl-1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)benzamide.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][C:12]([CH:15]([O:18][C:19]3[CH:29]=[CH:28][C:22]([C:23]([O:25]CC)=[O:24])=[CH:21][CH:20]=3)[CH2:16][CH3:17])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[OH-].[Na+]>C(O)C>[F:30][C:2]([F:1])([F:31])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:14]=[CH:13][C:12]([CH:15]([O:18][C:19]3[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:28][CH:29]=3)[CH2:16][CH3:17])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1ccc(OC(CC)c2ccc(-c3ccc(C(F)(F)F)cc3)nc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCC(Oc1ccc(C(=O)O)cc1)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1

Procedure:
To a solution of 1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-propoxy-1-ol (280 mg, 1.0 mmol) in THF (2 mL) and toluene (4 mL) is added 1,1′-(azodicarbonyl)dipiperidine (ADDP, 376.8 mg, 1.49 mmol) at 0° C., followed by the addition of triphenylphosphine (391.6 mg, 1.49 mmol) and methyl 4-hydroxybenzoate (181.7 mg, 1.19 mmol). The reaction mixture is warmed up to room temperature and stirred overnight. The mixture is loaded on silica gel, eluted with hexanes with a gradient from 0% of ethyl acetate to 50% of ethyl acetate giving ethyl 4-{1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-propoxy}-benzoate (350 mg). The ester product is taken into ethanol (4 mL), treated with sodium hydroxide (5N aqueous, 1 mL) for 3 h at 40° C. The mixture is concentrated, diluted with ethyl acetate, acidified with 5 N HCl (1.1 mL), extracted with ethyl acetate. The organic layers are dried and concentrated giving 4-{1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-propoxy}-benzoic acid (345 mg).
Reaction SMILES: [CH3:1][CH:2]([OH:4])[CH3:3].Cl[C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]4[O:25][C:24]([NH:26][CH:27]([CH3:29])[CH3:28])=[N:23][N:22]=4)[CH:19]=3)[N:14](S(C3C=CC(C)=CC=3)(=O)=O)[CH:13]=2)[N:7]=1.[H-].[Na+]>>[CH:2]([O:4][C:10]1[CH:11]=[CH:6][N:7]=[C:8]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]4[O:25][C:24]([NH:26][CH:27]([CH3:29])[CH3:28])=[N:23][N:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[N:9]=1)([CH3:3])[CH3:1]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nccc(Cl)n3)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Reactant: CC(C)O
Agent: [H-]
Agent: [Na+]
Product: CC(C)Nc1nnc(-c2ccc3[nH]cc(-c4nccc(OC(C)C)n4)c3c2)o1
Temperature: 100 °C
Yield: 10.2 %

Procedure:
A glass microwave reaction vessel was charged with IPA (1 mL, 13.06 mmol) and 5-(3-(4-chloropyrimidin-2-yl)-1-tosyl-1H-indol-5-yl)-N-isopropyl-1,3,4-oxadiazol-2-amine (80 mg, 0.157 mmol), followed by the addition of 60% of NaH in mineral oil (15.72 mg, 0.393 mmol, Aldrich). The reaction was stirred and heated in a Initiator microwave reactor at 100° C. for 30 min, then the solvent was removed. The residue was purified with RP-HPLC (eluent: 10-50% MeCN in water with 0.1% TFA). The fractions containing the product were combined and concentrated to remove AcCN. The remaining mixture was neutralized with NH4OH and filtered and dried to give 5-(3-(4-isopropoxypyrimidin-2-yl)-1H-indol-5-yl)-N-isopropyl-1,3,4-oxadiazol-2-amine (6.0 mg, 0.016 mmol, 10.09%) as an off-white solid. MS (ESI, pos. ion) m/z: 379.1 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 11.99 (1H, br. s.), 9.00 (1H, s), 8.50 (1H, d, J=5.7 Hz), 8.30 (1H, s), 7.52-7.72 (3H, m), 6.60 (1H, d, J=5.9 Hz), 5.47-5.62 (1H, m), 3.67-3.81 (1H, m), 1.42 (6H, d, J=6.1 Hz), 1.23 (6H, d, J=6.5 Hz).
Reaction SMILES: O[C:2]1[C:3]([C:11]2([CH2:26][OH:27])[C:15]3[CH:16]=[N:17][CH:18]=[CH:19][C:14]=3[N:13]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:12]2=[O:25])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.OC1C(C2(CO)C3C(=NC=CC=3)N(CCCCC)C2=O)=CC2OCOC=2C=1>>[CH2:20]([N:13]1[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][C:15]=2[C:11]2([C:3]3=[CH:4][C:5]4[O:9][CH2:8][O:7][C:6]=4[CH:10]=[C:2]3[O:27][CH2:26]2)[C:12]1=[O:25])[CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCN1C(=O)C(CO)(c2cc3c(cc2O)OCO3)c2cnccc21
Agent: CCCCCN1C(=O)C(CO)(c2cc3c(cc2O)OCO3)c2cccnc21
Product: CCCCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2cnccc21

Procedure:
Following the procedure as described in EXAMPLE 1, and making non-critical variations using 3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1-pentyl-1,3-dihydro-2H-pyrrolo[3,2-c]pyridin-2-one to replace 3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1-pentyl-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one, the title compound was obtained: 1H NMR (300 MHz, CDCl3) δ 8.51 (br, 1H), 8.28 (br, 1H), 6.97-6.87 (m, 1H), 6.51 (s, 1H), 6.08 (s, 1H), 5.90-5.84 (m, 2H), 6.87 (d, 1H), 4.67 (d, 1H), 3.86-3.60 (m, 2H), 1.78-1.63 (m, 2H), 1.44-1.27 (m, 4H), 0.89 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 177.0, 156.0, 150.7, 149.6, 149.4, 143.1, 142.6, 117.7, 113.9, 102.6, 101.7, 93.9, 80.0, 56.7, 40.7, 28.9, 27.1, 22.2, 13.9; MS (ES+) m/z 353.4 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:7]([CH2:13][CH2:14][CH2:15][CH3:16])[C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])[O:5][CH:6]=1.ClC1C=CC=C(C(OO)=[O:25])C=1>C(Cl)Cl>[OH:25][C:6]1[O:5][C:4]([N:7]([CH2:13][CH2:14][CH2:15][CH3:16])[C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])=[N:3][C:2]=1[CH3:1]
Reactant: CCCCN(C(=O)C(C)C)c1nc(C)co1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCCN(C(=O)C(C)C)c1nc(C)c(O)o1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
4-methyl-2-(N-butyl isobutyramido)oxazole (15 g., 0.067 m.) in dry methylene chloride (100 c.c.) was cooled to 0° C during the addition of m-chloroperbenzoic acid (16 g., 0.023 m.) over 1 hour. The mixture was then stirred at room temperature for 40 hours. The precipitated m-chlorobenzoic acid was then filtered off and the filtrate evaporated to dryness. The residue was taken in ether (100 c.c.) and stirred with 5% aqueous sodium sulphite solution for 1 hour. The organic phase was then separated and washed successively with aqueous sodium carbonate (× 2) and water, and then dried and evaporated to give a brown oil, 13.9 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH:9]1[CH2:14][C:13](=O)[CH2:12][C:11](=[O:16])[CH2:10]1.C([O-])(=O)C.[NH4+:21]>C(O)C>[NH2:21][C:13]1[CH2:14][CH:9]([C:3]2[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=2[Cl:1])[CH2:10][C:11](=[O:16])[CH:12]=1
Reactant: [NH4+]
Reactant: Cc1ccc(Cl)c(C2CC(=O)CC(=O)C2)c1
Agent: CC(=O)[O-]
Solvent: CCO
Product: Cc1ccc(Cl)c(C2CC(=O)C=C(N)C2)c1
Yield: 97.1 %

Procedure:
A solution of 5-(2-chloro-5-methylphenyl)cyclohexane-1,3-dione (3.0 g) and ammonium acetate (2.9 g) in ethanol (50 ml) was refluxed for 13 hours. Under reduced pressure, the solvent was evaporated, and precipitated crystals were washed with water and toluene, and dried to give 1-amino-5-(2-chloro-5-methylphenyl)cyclohexen-3-one (2.9 g).
Reaction SMILES: [I:1]I.[Cl:3][C:4]([Cl:13])([Cl:12])[C:5]([C:7]1[NH:8][CH:9]=[CH:10][CH:11]=1)=[O:6].O>ClCCl.FC(F)(F)C([O-])=O.[Ag+]>[Cl:13][C:4]([Cl:3])([Cl:12])[C:5]([C:7]1[NH:8][CH:9]=[C:10]([I:1])[CH:11]=1)=[O:6]
Reactant: II
Reactant: O=C(c1ccc[nH]1)C(Cl)(Cl)Cl
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: O=C(c1cc(I)c[nH]1)C(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 5 h
Yield: 93.7 %

Procedure:
Iodine (1.2 g, 4.7 mmol) was added portion wise to a solution of 2,2,2-trichloro-1-(1H-pyrrol-2-yl)ethanone (1 g, 4.7 mmol) and silver trifluoroacetate (1.1 g, 5 mmol) in dry dichloromethane (24 mL), cooled to 0° C. The reaction mixture was allowed to warm up slowly to 18° C. (water bath) and stirred at the same temperature for 5 h. The solid was filtered, the organic phase washed with Na2S2O5 (5% aq. solution) until decoloration occurs and finally washed with H2O (1×20 mL). The organic phase was dried over Na2SO4 and filtered through a plough of SiO2 (hexane-EtOAc 4:1), to obtain compound 2,2,2-trichloro-1-(4-iodo-1H-pyrrol-2-yl)ethanone (IX) as an off-white solid (1.49 g, 94% yield).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:12]=[C:11]([CH3:13])[NH:10][N:9]=1.F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=1[C:24]([F:27])([F:26])[F:25].Cl>CN(C=O)C>[CH3:13][C:11]1[NH:10][N:9]=[C:8]([O:7][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=2[C:24]([F:25])([F:26])[F:27])[CH:12]=1
Reactant: O=[N+]([O-])c1ccc(F)c(C(F)(F)F)c1
Reactant: Cc1cc(O)n[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ccc([N+](=O)[O-])cc2C(F)(F)F)n[nH]1
Temperature: 60 °C
Yield: 60.6 %

Procedure:
Potassium carbonate (7.60 g, 55.0 mmol) was added to a solution of 3-hydroxy-5-methylpyrazole (4.90 g, 50.0 mmol) and 2-fluoro-5-nitrobenzotrifluoride (10.5 g, 50.0 mmol) in DMF (50 ml), and the mixture was stirred under heating at 60° C. for 4 hours. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid (100 ml) and extracted with ethyl acetate (50 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/3), to give a yellowish viscous substance of 5-methyl-3-(4-nitro-2-trifluoromethylphenyloxy)pyrazole (8.70 g, yield: 60.6%). 1H-NMR (CDCl3, TMS, ppm): δ 2.30 (d, J=0.5 Hz, 3H), 5.78 (d, J=0.5 Hz, 1H), 7.31 (d, J=9.2 Hz, 1H), 8.31 (dd, J=2.7 and 9.2 Hz, 1H), 8.57 (d, J=2.7 Hz, 1H), 10.05-10.50 (br s, 1H).
Reaction SMILES: CN(C)[C:3]1[N:8]=[C:7]([NH2:9])[C:6]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])=[CH:5][N:4]=1.S(O)(O)(=O)=O.[N:24]1(C(N)=N)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]1[C:3]1[N:8]=[C:7]([NH2:9])[C:6]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])=[CH:5][N:4]=1
Reactant: CN(C)c1ncc(-c2ccc(Cl)cc2Cl)c(N)n1
Reactant: N=C(N)N1CCCCC1
Agent: O=S(=O)(O)O
Product: Nc1nc(C2CCCCN2)ncc1-c1ccc(Cl)cc1Cl

Procedure:
This compound was prepared in an analogous manner to the compound of Example 76 from 1-piperidinecarboxamidine sulphate (Bader), mp. 169° C.