Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:13]2[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]2)=[C:7]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8]2.C(=O)([O-])[O-].[K+].[K+].[CH2:25](I)[CH2:26][CH3:27].O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:13]2[CH2:18][CH2:17][CH2:16][N:15]([CH2:25][CH2:26][CH3:27])[CH2:14]2)=[C:7]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8]2
Reactant: CCCI
Reactant: COc1ccc(C2CCCNC2)c2c1NC(=O)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCN1CCCC(c2ccc(OC)c3c2CC(=O)N3)C1
Reaction time: 1.5 h

Procedure:
A mixture of 2 g of the product of Example 1 in 40 ml of dimethylformamide, 3.39 g of potassium carbonate and 1.6 ml of propyl iodide was stirred under inert atmosphere for 90 minutes. After adding water, extracting with methylene chloride, washing with water, drying, evaporating to dryness under reduced pressure and purifying the residue by chromatography over silica (eluent: methylene chloride--methanol 9-1), 1.6 g of 1,3-dihydro-7-methoxy-4-(1-propyl-3-piperidinyl)-2H-indol-2-one melting at ≈120° C. were obtained.
Reaction SMILES: C([O:3][C:4](=[O:20])[CH2:5][CH:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11]1=[O:19])CCC)C.C(OC([N:28]1[C:36]2[C:31](=[C:32]([Cl:37])[CH:33]=[CH:34][CH:35]=2)[C:30]([CH2:38]O)=[CH:29]1)=O)(C)(C)C.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:37][C:32]1[CH:33]=[CH:34][CH:35]=[C:36]2[C:31]=1[C:30]([CH2:38][N:12]1[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:10]([CH2:6][CH2:5][C:4]([OH:3])=[O:20])[C:11]1=[O:19])=[CH:29][NH:28]2
Reactant: CC(C)(C)OC(=O)n1cc(CO)c2c(Cl)cccc21
Reactant: CCCC(CC(=O)OCC)n1c(=O)[nH]c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: C1CCOC1
Product: O=C(O)CCn1c(=O)n(Cc2c[nH]c3cccc(Cl)c23)c2ccccc21
Temperature: 0 °C
Yield: 7.5 %

Procedure:
3-(2-Oxo-2,3-dihydro-benzoimidazol-1-yl)-hexanoic acid ethyl ester (80 mg, 0.29 mmol), prepared as described above, 4-chloro-3-hydroxymethyl-indole-1-carboxylic acid tert-butyl ester (282 mg, 1 mmol) and triphenylphosphene (223 mg, 0.85 mmol) were combined in a reaction vial and THF (1 mL) was added. The mixture was stirred until complete solution was attained, then cooled to 0° C., and diisopropylazodicarboxylate (0.165 mL, 0.85 mmol) was added dropwise. The reaction mixture was heated in the microwave at 130° C. for 20 minutes, cooled, then diluted with THF (1 mL) and treated directly with the Amberlyst® resin (2.2 g, 2.95 mmol). This reaction mixture was agitated overnight and the resin was then filtered and washed with DMF (2×3 mL) and several portions of methanol. The product was eluted by treating the resin with a 20% solution of formic acid in methanol (2×3 mL) and washing with methanol (3 mL). The combined eluant and final wash was evaporated and redissolved in dichloromethane (1 mL). To this solution was added TFA (0.2 mL) and the reaction mixture was agitated for 1 h. The solvent was evaporated and the residue was purified by preparative HPLC using an acetonitrile/water/formic acid gradient providing the title compound (8 mg, 7%) LCMS (ESMS): m/z 412 (M+H+).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.C([O-])(=O)C.[Na+].Cl.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27]N)=[CH:23][CH:22]=1.O>C(O)(=O)C>[CH2:11]([O:10][C:8]([CH:5]1[CH2:6][C:7]2[C:25]3[C:24](=[CH:23][CH:22]=[C:21]([O:20][CH3:19])[CH:26]=3)[NH:27][C:2]=2[CH2:3][CH2:4]1)=[O:9])[CH3:12]
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: COc1ccc(NN)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C1CCc2[nH]c3ccc(OC)cc3c2C1
Yield: 68.4 %

Procedure:
A solution of ethyl 4-oxocyclohexanecarboxylate (3 g, 17.6 mmol) and sodium acetate (1.59 g, 19.4 mmol) in glacial acetic acid (36 mL) was degassed with nitrogen prior to addition of 4-methoxyphenylhydrazine hydrochloride (3.38 g, 19.4 mmol). The mixture was heated at reflux for 2 hours then cooled, poured into water and extracted with tert-butylmethyl ether. The organic phase was washed with 5% K2CO3, then water and finally brine. The organic layer was dried over sodium sulphate then solvent removed under reduced pressure and the residue purified by column chromatography to afford 3.29 g of the title compound.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][CH:9]=[C:10]2[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][C:11]2=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>[Pd].C(OCC)(=O)C>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]2[C:11](=[O:17])[CH2:12][CH2:13][CH2:14][C:15]2=[O:16])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: O=C1CCCC(=O)C1=CC=Cc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C1CCCC(=O)C1CCCc1ccccc1

Procedure:
A mixture of 6.8 g (30 mmol) of 2-(3-phenylpropenylidene)-1,3-cyclohexanedione from the preceding example, 0.7 g of 10% palladium on carbon, and 150 mL of ethyl acetate was stirred at room temperature, in an atmosphere of hydrogen, until gas uptake ceased. The catalyst was filtered with suction and the filtrate was concentrated in vacuo giving 6.7 g (97%) of the title dione as an off-white solid which was used without further purification.
Reaction SMILES: [CH3:1][CH2:2][O:3]CC.Br[C:7]1[CH:8]=[CH:9][C:10]2[O:14][CH2:13][C:12]([CH3:16])([CH3:15])[C:11]=2[CH:17]=1.C(=O)C.[NH4+].[Cl-]>C1COCC1>[CH3:15][C:12]1([CH3:16])[C:11]2[CH:17]=[C:7]([CH:2]([OH:3])[CH3:1])[CH:8]=[CH:9][C:10]=2[O:14][CH2:13]1
Reactant: CCOCC
Reactant: CC1(C)COc2ccc(Br)cc21
Agent: CC=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1ccc2c(c1)C(C)(C)CO2
Reaction time: 1.5 h
Yield: 682 %

Procedure:
A mixture of the precursor ether (0.21 g 0.9 mmol), Mg turnings (1.0 g 0.041 g at) and dry THF (2 mL) was heated (heat gun) under N2 until the mixture turned cloudy (ca 15 min). Dry THF (15 mL) was added to the mixture which was then heated to reflux. A solution of ether (42) (2.92 g, 12.9 mmol) in dry THF (25 mL) was added dropwise to the vigorously stirred mixture over a period of 0.75 hours. After vigorous stirring at reflux for 2.75 hours, another 0.25 g (0.010 g at) of Mg turnings were added. The new mixture was stirred at reflux for 0.75 hour and with no external heat for 0.5 hours. Upon cooling the mixture to -5° to -10° C. (ice-salt bath), a solution of freshly distilled acetaldehyde (2.0 g, 0.045 mol) in dry THF (20 mL) was added dropwise to the vigorously stirred mixture over a period of 0.7 hours. This reaction mixture was stirred in an ice-salt bath (-5° to -10° C.), for 1.5 hours, after which time a solution of acetaldehyde (0.9 g, 0.020 mol) in dry THF (5 mL) was added dropwise (over a period of about 0.2 h) and the new mixture was stirred 0.3 hours. With continued cooling (-5° to -10° C.), saturated aqueous NH4Cl (3 mL) was added and the excess Mg turnings were removed by filtration. Saturated aqueous NH4Cl (10 mL) and ether rinses (of glassware and Mg turnings, 60 mL) were added to the filtrate. After separating the organic layer, the aqueous phase (pH≥8) was acidified (pH 6.5 to 7) with saturated aqueous NH4Cl (15 mL) and 4% H2SO4 (14 mL). The aqueous solution was extracted with ether (5 ×40 mL) and ether (90 mL) was added to the combined organics. The organic solution was washed with saturated aqueous NaHCO3 (75 mL) and brine (50 mL). After drying (MgSO4) the solution, the solvent was removed, and the residual oil was chromatographed through a circular silica gel plate (4 mm) spun by a Chromatotron (Model 7924T, Harrison Research, 840 Moana Court, Palo Alto, Calif.). Half of the product was eluted with ether/petroleum ether (bp 50°-110° C.) 20:1, 8:1, and 4:1 and then the same solvent system was used to elute the other half. In both separations, the 4:1 ratio was required to elute the title compound. Concentration of the eluent in the desired fractions gave 1.18 g (44%) of the alcohol as a light yellow, viscous oil. TLC analysis (1:4 ether:petroleum ether, bp 50°-110° C.) indicated the compound was essentially pure.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:11]=[CH:10][C:9]([CH:12]([CH2:17][C:18]([OH:20])=[O:19])[CH2:13][C:14]([OH:16])=O)=[CH:8][C:5]=2[C:6]=1[CH3:7].C(O)(=O)C>C(OC(=O)C)(=O)C>[CH3:1][C:2]1[O:3][C:4]2[CH:11]=[CH:10][C:9]([CH:12]3[CH2:17][C:18](=[O:20])[O:19][C:14](=[O:16])[CH2:13]3)=[CH:8][C:5]=2[C:6]=1[CH3:7]
Reactant: Cc1oc2ccc(C(CC(=O)O)CC(=O)O)cc2c1C
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: Cc1oc2ccc(C3CC(=O)OC(=O)C3)cc2c1C

Procedure:
27.6 g (0.1 mol) of 3-(2,3-dimethyl-5-benzofuranyl)-glutaric acid are refluxed in 120 ml of acetic anhydride for one hour. The excess reagent and the acetic acid formed are then evaporated off in a rotary evaporator. The brownish residue is dissolved in ether, and hexane is added until crystallisation starts. The crystals are filtered off with suction, washed with ether/hexane and dried. The 3-(2,3-dimethyl-5-benzofuranyl)-glutaric anhydride thus obtained as pale sand-coloured crystals melts at 107°-110°, and after recrystallisation from methylene chloride/hexane, at 111°-112°.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[NH2:15][C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[C:18](Cl)[N:17]=1.C(N(C(C)C)CC)(C)C>CS(C)=O>[NH2:15][C:16]1[N:17]=[C:18]([NH:1][CH:2]2[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]2)[CH:19]=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23]
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCCC(Nc2ccc([N+](=O)[O-])c(N)n2)C1
Temperature: 120 °C

Procedure:
500 mg (2.11 mmol) of tert-butyl 3-aminopiperidine-1-carboxylate, 772 mg (4.22 mmol) of 2-amino-6-chloro-3-nitropyridine and 1.05 ml (6.34 mmol) of diisopropylethylamine were suspended in 18 ml of DMSO and heated in a microwave reactor at 120° C. for 45 min. The reaction mixture was purified by preparative RP-HPLC (Method 11). This gave 600 mg (81% of theory) of the product as a solid.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=2[N+:15]([O-])=O)=[CH:4][CH:3]=1.[H][H]>CO.[Pd]>[NH2:15][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:7]=1[O:6][C:5]1[CH:18]=[CH:19][C:2]([OH:1])=[CH:3][CH:4]=1)[C:11]#[N:12]
Reactant: N#Cc1ccc(Oc2ccc(O)cc2)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: N#Cc1ccc(Oc2ccc(O)cc2)c(N)c1
Yield: 99 %

Procedure:
The product of Example 152A (500 mg, 1.952 mmol) was hydrogenated in methanol (20 mL) with hydrogen (1 atmosphere, balloon) and 10% palladium on carbon (50 mg) for 30 minutes. The reaction was vacuum filtered through a 0.45□ PTFE membrane and the catalyst washed with methanol. The filtrate was concentrated by rotary evaporation under vacuum to provide the title compound as a pinkish-beige solid (437 mg, 99%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][NH:10][C:5]2=[CH:4][CH:3]=1.[H-].[Na+].[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([O:26][C:27]2[CH:32]=[C:31](Cl)[N:30]=[CH:29][N:28]=2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>CN(C=O)C.C(OCC)(=O)C>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([O:26][C:27]2[CH:32]=[C:31]([N:10]3[C:5]4[C:6](=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[CH2:8][CH2:9]3)[N:30]=[CH:29][N:28]=2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: Clc1ccc2c(n1)CCN2
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(Cl)ncn2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(N3CCc4nc(Cl)ccc43)ncn2)CC1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
20a (36 mg, 0.23 mmol) was dissolved in DMF (1.5 mL) with NaH (60% suspension, 9.6 mg, 0.24 mmol). 3a (75 mg, 0.24 mmol) was added slowly. The mixture was stirred at 90° C. for 8 h then cooled down to room temperature, diluted with ethyl acetate and washed with saturated NaHCO3. The organic layer was isolated, dried, filtered and evaporated. The residue was purified by preparative HPLC to afford 20-1, LCMS 432.1 (MH+). tR=5.21 (Method 5). EC50: 751 nM.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([F:9])=[CH:4][CH:3]=1.[Br:10]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>ClCCl>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][Br:10])[C:5]([F:9])=[CH:4][CH:3]=1
Reactant: Cc1nc(Br)ccc1F
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCl
Product: Fc1ccc(Br)nc1CBr
Temperature: 55 °C
Reaction time: 17 h
Yield: 54.9 %

Procedure:
To a solution of 6-bromo-3-fluoro-2-methylpyridine (0.5 gr, 2.63 mmol) in dichloromethane (5 ml) were added at room temperature N-bromosuccinimide (937 mg, 5.26 mmol) and azo-di-isobutyronitrile (86 mg, 0.526 mmol). After 17 h stirring at 55° C. the reaction mixture was quenched by the addition of water and the product was extracted into dichloromethane. The combined organic phases were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Column chromatography afforded 6-bromo-2-(bromomethyl)-3-fluoropyridine (388 mg) as a clear oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8]([NH:10][CH3:11])[N:7]=[C:6]([NH2:12])[N:5]=1)[CH3:2].[CH3:13][O:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([N:26]=[C:27]=[O:28])(=[O:25])=[O:24])=[O:16]>C(Cl)Cl>[CH2:1]([O:3][C:4]1[N:9]=[C:8]([NH:10][CH3:11])[N:7]=[C:6]([NH:12][C:27]([NH:26][S:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:15]([O:14][CH3:13])=[O:16])(=[O:24])=[O:25])=[O:28])[N:5]=1)[CH3:2]
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Reactant: CCOc1nc(N)nc(NC)n1
Solvent: ClCCl
Product: CCOc1nc(NC)nc(NC(=O)NS(=O)(=O)c2ccccc2C(=O)OC)n1
Reaction time: 1 h
Yield: 46.4 %

Procedure:
To a suspension of 0.8 g of 4-ethoxy-6-methylamino-1,3,5-triazin-2-amine in 25 ml of methylene chloride was added 1.14 g of 2-(methoxycarbonyl)benzenesulfonyl isocyanate. Dissolution of the suspension occurred, followed by precipitation of a solid. After 1 hour at ambient temperature, the solid was collected and dried giving 0.9 g of the title compound, m.p. 204°-206° C.
Reaction SMILES: OC(C(F)(F)F)=O.C([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[N:18][C:19]([NH:40][C@H:41]([CH3:45])[CH2:42][O:43][CH3:44])=[C:20]([N:25]3[CH2:30][CH2:29][CH:28]([O:31][C:32]4[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=4[F:39])[CH2:27][CH2:26]3)[N:21]=2)[CH2:16]1)C1C=CC=CC=1>C1COCC1.[OH-].[OH-].[Pd+2]>[F:39][C:33]1[CH:34]=[C:35]([F:38])[CH:36]=[CH:37][C:32]=1[O:31][CH:28]1[CH2:27][CH2:26][N:25]([C:20]2[N:21]=[C:22]3[CH2:23][CH2:24][NH:15][CH2:16][C:17]3=[N:18][C:19]=2[NH:40][C@H:41]([CH3:45])[CH2:42][O:43][CH3:44])[CH2:30][CH2:29]1
Reactant: COC[C@@H](C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCN(Cc1ccccc1)C2
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: COC[C@@H](C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCNC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (R)-6-benzyl-2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-(1-methoxypropan-2-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (161.4 mg, 0.253 mmol) in THF (2.53 mL) was treated with Pd(OH)2 (20 wt %, 53.3 mg, 0.076 mmol). Hydrogen gas (balloon) was bubbled through the reaction mixture for 5 min. The vent needle was removed and the reaction mixture was allowed to stir under hydrogen atmosphere at room temperature for 2 h. The reaction mixture was opened to air and filtered through a pad of Celite™, eluting with MeOH and EtOAc. The filtrate was collected and concentrated under reduced pressure to give (R)-2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-(1-methoxypropan-2-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine, as a TFA salt, as a yellow oil, which was carried forward without additional purification. ESI-MS m/z [M+H]+ 434.5.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=2)[CH:7]=1.[C:15]([C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)#[CH:16]>>[C:11]([C:9]1[CH:10]=[C:5]2[N:4]=[CH:3][C:2]([C:16]#[C:15][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[CH:7][N:6]2[N:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: C#Cc1ccncc1
Reactant: CC(C)(C)c1cc2ncc(Br)cn2n1
Product: CC(C)(C)c1cc2ncc(C#Cc3ccncc3)cn2n1

Procedure:
The title compound, white solid, MS: m/e=277.1 (M+H+), can be prepared in accordance with the general method of example 1 from 6-bromo-2-tert-butyl-pyrazolo[1,5-a]pyrimidine (example 9, step 1) and 4-ethynylpyridine.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:6](=[N:7][O:8][N:9]=2)[CH:5]=[CH:4][C:3]=1[OH:11].[O:12](S(C(F)(F)F)(=O)=O)[S:13]([C:16]([F:19])([F:18])[F:17])(=O)=[O:14].CCN(CC)CC>C(Cl)Cl>[F:17][C:16]([F:19])([F:18])[S:13]([O:11][C:3]1[CH:4]=[CH:5][C:6]2=[N:7][O:8][N:9]=[C:10]2[C:2]=1[CH3:1])(=[O:14])=[O:12]
Reactant: Cc1c(O)ccc2nonc12
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(OS(=O)(=O)C(F)(F)F)ccc2nonc12
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of 4-methyl-2,1,3-benzoxadiazol-5-ol (2.10 g, 17.9 mmol) in 40 mL of dry DCM was added Tf2O (7.61 g, 26.9 mmol) dropwise at −78° C. under Ar and stirred for 5 minutes, then Et3N (2.73 g, 26.9 mmol) was added dropwise to the mixture and the reaction was stirred at 0° C. for 4 hours. Then the reaction was poured into 200 mL of ice water and extracted with DCM (50 mL×3). The combined organic layers were washed with brine, dried and concentrated, the residue was purified by silica gel column to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:16]=[CH:17][C:18]([OH:22])=[N:19][C:20]=4[CH3:21])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([O:28][CH:29]([F:31])[F:30])[C:24]([F:27])([F:26])[F:25])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:38][C:39]([F:47])(S(F)(=O)=O)C(O)=O>C(#N)C>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:20]([CH3:21])=[N:19][C:18]([O:22][CH:39]([F:47])[F:38])=[CH:17][CH:16]=4)[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([O:28][CH:29]([F:30])[F:31])[C:24]([F:27])([F:26])[F:25])=[CH:4][CH:3]=1
Reactant: Cc1nc(O)ccc1N1CCCn2c1nc1c(Cl)ccc(C(OC(F)F)C(F)(F)F)c12
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1nc(OC(F)F)ccc1N1CCCn2c1nc1c(Cl)ccc(C(OC(F)F)C(F)(F)F)c12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 77.8 %

Procedure:
To a solution of 5-{9-chloro-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-3,4-dihydropyrimido[1,2-a]benzimidazol-1(2H)-yl}-6-methylpyridin-2-ol (90.0 mg, 0.194 mmol) in acetonitrile (2.0 mL) was added sodium carbonate (41.1 mg, 0.389 mmol) and 2,2-difluoro-2-fluorosulfonyl-aceticacid (40.2 μL, 0.389 mmol) 0° C. The reaction mixture was stirred at room temperature for 1.5 hrs. The mixture was concentrated. The precipitate was removed by filtration. The filtrate was concentrated and the residue was purified by silica gel column chromatography eluting with a 0-35% ethyl acetate/n-hexane gradient mixture. The resulting solid was recrystallized from ethyl acetate/n-hexane to give the title compound as a colorless powder (77.3 mg, 0.151 mmol, 78%).
Reaction SMILES: Cl.[Br:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12](=[NH:16])OCC)[CH:10]=2)[NH:5][N:4]=1.[NH:17]([C:19]([C@@H:21]1[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]1)=O)[NH2:18]>CO>[Br:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[N:16]=[C:19]([C@@H:21]4[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]4)[NH:17][N:18]=3)[CH:10]=2)[NH:5][N:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)NN)C1
Reactant: CCOC(=N)c1ccc2[nH]nc(Br)c2c1
Agent: Cl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@@H](c2nc(-c3ccc4[nH]nc(Br)c4c3)n[nH]2)C1
Temperature: 85 °C
Yield: 99.4 %

Procedure:
Mixture of ethyl 3-bromo-1H-indazole-5-carbimidate hydrochloride (4.1 g, 13.5 mmol) and (R)-tert-butyl 3-(hydrazinecarbonyl)piperidine-1-carboxylate (5.1 g, 20 mmol) in MeOH (25 ml) was heated in a sealed tube at 85° C. overnight. After solvent was evaporated, the residue was diluted with DCM (200 ml) and washed with H2O (50 ml), Dried over Na2SO4; filtered and evaporated solvent. Chromatographed residue eluting with 5% MeOH/DCM to yield (R)-tert-butyl 3-(3-(3-bromo-1H-indazol-5-yl)-1H-1,2,4-triazol-5-yl)piperidine-1-carboxylate as a white solid (6 g).
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[NH4+].FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH3:19][O:20][C:21]1[C:22]([O:31][CH2:32][C:33]([F:36])([F:35])[F:34])=[C:23]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[C:24]#[N:25]>ClCCl>[C:24]([C:23]1[C:22]([O:31][CH2:32][C:33]([F:34])([F:35])[F:36])=[C:21]([O:20][CH3:19])[C:28]([O:29][CH3:30])=[CH:27][C:26]=1[N+:1]([O-:4])=[O:2])#[N:25]
Reactant: O=[N+]([O-])[O-]
Reactant: COc1ccc(C#N)c(OCC(F)(F)F)c1OC
Agent: [NH4+]
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COc1cc([N+](=O)[O-])c(C#N)c(OCC(F)(F)F)c1OC
Yield: 73 %

Procedure:
Ammonium nitrate (2.82 g, 0.035 mol) and trifluoroacetic anhydride (12.4 ml, 0.088 mol) were added to a solution of 3,4-dimethoxy-2-(2,2,2,-trifluorethoxy)benzonitrile in dichloromethane. The temperature was maintained between 20° C. and 30° C. for 2 hours, after which time the reaction mixture was washed with saturated aqueous sodium bicarbonate solution. The organic layer was separated, dried (MgSO4) and evaporated under reduced pressure. Trituration with diethyl ether followed by filtration afforded a first crop of product. The filtrate was purified on silica gel, eluting with dichloromethane to afford the subtitle compound as a colourless solid (combined yield 6.56 g, 73%). Rf 0.31 (ethyl acetate:hexane 20:80, v/v). MS m/z 324 (MNH4)+
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]3[CH:12]=[N:13][N:14]=[C:7]3[C@@H:6]([CH2:15][CH3:16])[N:5]([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[C:4]=2[N:3]=1.[OH-].[NH4+:23]>>[CH:17]1([N:5]2[C:4]3[N:3]=[C:2]([NH2:23])[N:11]=[CH:10][C:9]=3[N:8]3[CH:12]=[N:13][N:14]=[C:7]3[C@H:6]2[CH2:15][CH3:16])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: [NH4+]
Reactant: CC[C@@H]1c2nncn2-c2cnc(Cl)nc2N1C1CCCC1
Agent: [OH-]
Product: CC[C@@H]1c2nncn2-c2cnc(N)nc2N1C1CCCC1
Yield: 36 %

Procedure:
A solution of (R)-7-chloro-5-cyclopentyl-4-ethyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridine (500 mg, 1.64 mmol) in ammonium hydroxide (10 ml) was heated under microwave irradiation at 140° C. for 30 minutes. The solvent was removed under reduced pressure and cold water (5 mL) was added. The resulting light brown solid was filtered under vacuum and washed with cold water to give the title compound (170 mg, 36% yield).
Reaction SMILES: [O:1]=[C:2]([CH2:9][CH3:10])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].S(Cl)([Cl:14])(=O)=O>>[Cl:14][CH:3]([C:2](=[O:1])[CH2:9][CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)CC(=O)CC
Product: CCOC(=O)C(Cl)C(=O)CC
Reaction time: 16 h

Procedure:
Ethyl 3-oxopentanoate, 20.0 grams (0.175 mole), was stirred at ambient temperature, and 23.6 grams (0.175 mole) of sulfuryl chloride was added dropwise during a 20 minute period. Upon completion of addition, the reaction mixture was stirred for about 16 hours. The reaction mixture was then distilled under reduced pressure, yielding 23.3 grams of ethyl 2-chloro-3-oxopentanoate; bp 100°-103° C. at 21mm.