Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[N:3]=1.C(NC(C)C)(C)C.[Li].[Cl:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]=[O:22]>C1COCC1>[Cl:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]([C:7]1[C:2]([F:1])=[N:3][C:4]([F:9])=[CH:5][C:6]=1[F:8])[OH:22]
Reactant: Fc1cc(F)nc(F)c1
Reactant: O=Cc1ccccc1Cl
Agent: [Li]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: OC(c1ccccc1Cl)c1c(F)cc(F)nc1F
Temperature: -78 °C

Procedure:
2,4,6-Trifluoropyridine (7.5 g, 56.36 mmol) was taken up in 9 mL of dry THF, and the reaction mixture was cooled to −78° C. under argon with stirring. Lithium diisopropylamine (42.3 mL of 2M solution in THF) was added dropwise, and the solution was stirred for 10 minutes. 2-Chlorobenzaldehyde (9.5 mL, 1.5 equiv) was added dropwise via syringe, and the reaction mixture was stirred for 15 minutes. The reaction was quenched by addition of saturated ammonium chloride and water, and the aqueous mixture was extracted once with EtOAc. The combined organic layers were washed with saturated brine and water, dried over MgSO4, filtered and evaporated. The residue was purified by FLASH column chromatography using 5%-10% EtOAc/Hexanes to yield 8.02 g of (2-Chloro-phenyl)-(2,4,6-trifluoro-pyridin-3-yl)-methanol. Mass spec., M+1=275.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]([F:25])([F:24])[F:23])=[CH:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14].[N+:28]([C:31]1[CH:36]=[CH:35][C:34](O)=[CH:33][CH:32]=1)([O-:30])=[O:29].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:28]([C:31]1[CH:36]=[CH:35][C:34]([O:14][C:13](=[O:15])/[CH:12]=[CH:11]/[CH:10]=[C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:24])([F:23])[F:25])[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:2]([F:26])([F:27])[F:1])=[CH:33][CH:32]=1)([O-:30])=[O:29]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: O=C(O)/C=C/C=C(c1ccccc1C(F)(F)F)c1ccccc1C(F)(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(/C=C/C=C(c1ccccc1C(F)(F)F)c1ccccc1C(F)(F)F)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 97.3 %

Procedure:
As in Example 115, (E)-5,5-bis[2-(trifluoromethyl) phenyl]-2,4-pentadienoic acid (1.135 g) and 4-nitrophenol (0.450 g) in dichloromethane (15 mL) was treated with 1,3-dicyclohexylcarbodiimide (0.607 g). The mixture was stirred at 0°-5° C. for 1 hour, then at room temperature for 30 minutes. The usual work up furnished 1.45 g of (E)-5,5-bis[2-(trifluoromethyl)phenyl]2,4-pentadienoic acid 4-nitrophenyl ester as an oil essentially homogeneous by tlc. This material was used without further purification in subsequent reactions.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([CH2:31]O)[CH:30]=1)[C:26]#[N:27]>C(#N)C>[Br:20][CH2:31][C:29]1[CH:28]=[C:25]([CH:24]=[C:23]([F:22])[CH:30]=1)[C:26]#[N:27]
Reactant: BrBr
Reactant: N#Cc1cc(F)cc(CO)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: N#Cc1cc(F)cc(CBr)c1
Reaction time: 0.5 h

Procedure:
(Step 3) Triphenylphosphine (1.91 g) was suspended in acetonitrile (50 ml), bromine (0.38 ml) was added, and the suspension was stirred for 30 min. 3-Fluoro-5-(hydroxymethyl)benzonitrile (1.1 g) synthesized by the method of Steps 1 and 2 was added to the reaction mixture, and the mixture was stirred at 85° C. for 2 hr. The reaction solution was quenched with water and extracted with ethyl acetate. The extract was washed with aqueous sodium hydrogen carbonate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was treated by basic silica gel chromatography (ethyl acetate:hexane=1:5) to give 3-(bromomethyl)-5-fluorobenzonitrile (0.69 g).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][N:5]=1.Br[CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.O>CN(C)C=O>[Br:3][C:4]1[C:9]([O:10][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: Oc1cccnc1Br
Reactant: BrC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ncccc1OC1CCCC1
Yield: 60 %

Procedure:
Sodium hydride (160 mg) was dissolved in dimethylformamide (5 ml) and 2-bromo-3-pyridinol (500 mg) dissolved in dimethylformamide is slowly added dropwise. Then, bromocyclopentane (0.63 ml) was added to the solution and reacted for 5 hours at room temperature. Water was added to the suspension to dilute and extracted with ethyl acetate to separate an organic layer. The separated organic layer was dried with anhydrous magnesium sulfate and distilled under reduced pressure. As a result, 2-bromo-3-cyclopentyloxy pyridine (480 mg, yield: 60%) was obtained as an oil phase.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH:24]1([O:28][C:29]2[CH:30]=[N:31][CH:32]=[C:33](B3OC(C)(C)C(C)(C)O3)[CH:34]=2)[CH2:27][CH2:26][CH2:25]1>>[CH:24]1([O:28][C:29]2[CH:34]=[C:33]([C:2]3[CH:11]=[CH:10][C:9]4[N:8]=[CH:7][C:6]5[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]6[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=6)[C:5]=5[C:4]=4[CH:3]=3)[CH:32]=[N:31][CH:30]=2)[CH2:25][CH2:26][CH2:27]1
Reactant: CC1(C)OB(c2cncc(OC3CCC3)c2)OC1(C)C
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cncc(OC5CCC5)c4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 3-cyclobutoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (Stage 60.1.1) to give the title compound as a white solid. (HPLC: tR 2.43 min (Method A); M+H=441 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 9.00 (s, 1H), 8.32-8.30 (m, 1H), 8.24-8.20 (m, 1H), 8.15 (s, 1H), 8.14-8.10 (m, 1H), 8.00-7.95 (m, 1H), 7.58-7.56 (m, 1H), 7.26-7.24 (m, 1H), 4.84 (qt, 1H), 3.91 (s, 3H), 3.58 (s, 3H), 2.53-2.45 (m, 2H), 2.15-2.00 (m, 2H), 1.96 (s, 3H), 1.88-1.66 (m, 2H))
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[O:13])[CH2:10][N:9]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCOCC>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([OH:13])[CH2:10][N:9]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(=O)CN1C(=O)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CC(O)CN1C(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 93 %

Procedure:
4-Oxo-pyrazolidine-1,2-dicarboxylic acid 1-benzyl ester 2-tert-butyl ester, 27, (5.0 g, 15.6 mmol) is dissolved in tetrahydrofuran (150 mL) and the solution cooled to −78° C. A 5.0 M solution of borane-dimethyl sulfide complex in ether (6.24 mL, 31.2 mmol) is added dropwise via syringe. After 40 minutes at −78° C., the reaction is quenched by slow addition of a saturated aqueous solution of ammonium chloride (20 mL). The cooling bath is removed, and the mixture allowed to warm to ambient temperature with vigorous stirring. The solvent is removed in vacuo and the residue diluted with dichloromethane (200 mL). The mixture is washed with water (150 mL) and saturated aqueous sodium bicarbonate solution (150 mL), water and brine. The combined aqueous layers are extracted with dichloromethane (200 mL), water (150 mL), NaCl (sat.) (200 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford 4.66 g (93% yield) of the desired product as a clear, viscous oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:3]=1[C:4](O)=O.[NH:13]([C:15](=[S:17])[NH2:16])[NH2:14].O=P(Cl)(Cl)Cl>O>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:3]=1[C:4]1[S:17][C:15]([NH2:16])=[N:13][N:14]=1
Reactant: COc1cccc(F)c1C(=O)O
Reactant: NNC(N)=S
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cccc(F)c1-c1nnc(N)s1
Temperature: 78 °C
Reaction time: 3 h
Yield: 93.6 %

Procedure:
A stirred mixture of 2-fluoro-6-methoxybenzoic acid (2 g, 11.7 6 mmol) and hydrazinecarbothioamide (1.607 g, 17.63 mmol) was cooled under nitrogen atmosphere in an ice bath and POCl3 (3.29 mL, 35.3 mmol) was added drop-wise. On completion of the addition, the reaction mixture was stirred at 78° C. for 3 hours. The reaction mixture was cooled in an ice bath and quenched by addition of ice water (˜50 mL) to give a solid/gum-like mass. This solid was sonicated for 1.5 hours and the resulting suspension was diluted with a further 50 mL of water then slurried at room temperature for ˜16 hours. The solid was collected by vacuum filtration, rinsed with water, re-suspended in saturated NaHCO3(aq) (˜100 mL) and slurried for ˜30 minutes. The resulting solid was collected by vacuum filtration, then rinsed with water to afford the crude product as an off-white solid. The crude material was pre-absorbed onto silica gel and purified by flash chromatography using a 120 g silica cartridge with a 0-10% MeOH/DCM gradient as the eluent to afford the title compound as a pale yellow solid (1.265 g, 45% yield). LC-MS: Rt 0.77 min; MS m/z 226.1 [M+H]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.48 (td, J=8.34, 6.57 Hz, 1H), 7.29 (s, 2H), 7.02 (d, J=8.08 Hz, 1H), 6.91-6.99 (m, 1H), 3.85 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[N+:12]([C:15]1[CH:16]=[C:17]([CH:19]=[C:20]([N+:22]([O-:24])=[O:23])[CH:21]=1)[NH2:18])([O-:14])=[O:13]>>[N+:12]([C:15]1[CH:16]=[C:17]([NH:18][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])[CH:19]=[C:20]([N+:22]([O-:24])=[O:23])[CH:21]=1)([O-:14])=[O:13]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: Nc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Product: O=C(O)Cc1ccccc1Nc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 3,5-dinitroaniline to yield 2-[(3,5-dinitrophenyl)amino]phenylacetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[C:11]([NH:14][NH2:15])(=[O:13])[CH3:12]>CN(C)C=O>[C:11]([NH:14][NH:15][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[N:3][CH:4]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)NN
Reactant: O=C(Cl)c1ccc(Cl)nc1
Solvent: CN(C)C=O
Product: CC(=O)NNC(=O)c1ccc(Cl)nc1
Temperature: 25 °C

Procedure:
6-Chloronicotinoyl chloride (500 mg, 2.84 mmol) and acetohydrazide (232 mg, 3.12 mmol) were added to dimethylformamide (14.2 mL) at 0° C. The mixture was allowed to warm to room temperature and maintained at room temperature overnight. The reaction was then slightly concentrated in vacuo and diluted in acetonitrile. This mixture was directly purified via reverse phase HPLC (10-100% acetonitrile/water+0.05% TFA modifier). Fractions containing the desired product were lyophilized and free based using bicarbonate resin to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=4)=[C:15]([NH:17]C(=O)C)[N:16]=3)[N:13]=2)=[CH:4][C:3]=1[NH:28][S:29]([CH3:32])(=[O:31])=[O:30].[OH-].[Na+].C([O-])(=O)C.[Na+]>CO>[NH2:17][C:15]1[N:16]=[C:11]2[CH:10]=[CH:9][C:8]([C:5]3[CH:4]=[C:3]([NH:28][S:29]([CH3:32])(=[O:30])=[O:31])[C:2]([Cl:1])=[N:7][CH:6]=3)=[N:13][N:12]2[C:14]=1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=1
Reactant: CC(=O)Nc1nc2ccc(-c3cnc(Cl)c(NS(C)(=O)=O)c3)nn2c1-c1cccc(F)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CS(=O)(=O)Nc1cc(-c2ccc3nc(N)c(-c4cccc(F)c4)n3n2)cnc1Cl
Temperature: 60 °C
Reaction time: 15 h
Yield: 88 %

Procedure:
To a 4-mL vial was added N-(6-(6-chloro-5-(methylsulfonamido)pyridin-3-yl)-3-(3-fluorophenyl)imidazo[1,2-b]pyridazin-2-yl)acetamide (TFA salt) (Example 22) (0.025 g, 0.042 mmol), methanol (2.5 mL) and sodium hydroxide (0.250 mL, 2.5 mmol, 10 M). The mixture was stirred at 60° C. for 15 h. After cooling to rt, the mixture was neutralized with pH 4.8 buffer (Teknova, 3 M sodium acetate solution pH adjusted to 4.8). The solution was partially concentrated to remove the MeOH. The solution was filtered and the filtercake was washed with water (2×) and then dried under vacuum to afford the title compound as a yellow solid (0.016 g, 86%). MS (ESI, positive ion) m/z: 433 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.68 (s, 3H), 5.90 (s, 2H), 7.08-7.13 (m, 1H), 7.51-7.58 (m, 2H), 7.76-7.81 (m, 1H), 7.84 (d, J=9.2 Hz, 1H), 8.00 (d, J=8.0 Hz, 1H), 8.06 (s, 1H), 8.15 (d, J=2.2 Hz, 1H), 11.93 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([O:17][CH2:18][CH:19]=[C:20]([Cl:22])[Cl:21])[CH:14]=[C:13]([Cl:23])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8]S(C)(=O)=O.O[C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:16]=[C:15]([O:17][CH2:18][CH:19]=[C:20]([Cl:22])[Cl:21])[CH:14]=[C:13]([Cl:23])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=1
Reactant: CS(=O)(=O)OCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: N#Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1

Procedure:
3 g of methanesulfonic acid 3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propyl ester, 0.93 g of 4-hydroxybenzonitrile and 2.9 g of potassium carbonate are stirred for 17 hours at 40° C. in 30 ml of dimethylformamide. The reaction mixture is poured onto water and extracted with ethyl acetate. Concentration of the organic phase yields 4-{3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propoxy}-benzonitrile. 1H-NMR (CDCl3) 300 MHz: 2.30 (m, 2H), 4.14 (t, 2H), 4.32 (t, 2H), 4.58 (d, 2H), 6.10 (t, 1H), 6.83 (s, 2H), 7.00 (d, 2H), 7.60 (d, 2H)
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=[O:7])=[CH:2]1.[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[O:1]1[CH:5]=[CH:4][CH:3]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH2:2]1
Reactant: O=C(O)c1ccoc1
Reactant: BrCc1ccccc1
Product: O=C(OCc1ccccc1)C1C=COC1

Procedure:
Synthesis takes place first of all by Birch reduction of 3-furancarboxylic acid followed by esterification with benzyl bromide to form benzyl 2,3-dihydrofuran-3-carboxylate (in accordance with G. Lowe, St. Swain; J. Chem. Soc. Perkin Trans I (1985), 391) ##STR29## b) The end product from a) is reduced with lithium aluminum hydride to give 3-hydroxymethyl-2,3-dihydrofuran
Reaction SMILES: [C:1]1([CH:7](O)[C:8]2[CH:9]=[C:10]([CH:14]([CH3:19])[C:15]([O:17][CH3:18])=[O:16])[CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:23])=O>C(Cl)Cl>[C:1]1([CH:7]([Cl:23])[C:8]2[CH:9]=[C:10]([CH:14]([CH3:19])[C:15]([O:17][CH3:18])=[O:16])[CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C(C)c1cccc(C(O)c2ccccc2)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COC(=O)C(C)c1cccc(C(Cl)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
Methyl 2-[3-(phenylhydroximethyl)phenyl]propionate (128 g) was dissolved in 100 mL of dry methylene chloride and the solution was cooled to 0° C. Then 41 mL of thionyl chloride in 50 mL methylene chloride were added along 1 hour, keeping the reaction temperature between 5 and 10° C. After staying for 1 hour at 5° C. and 1 hour at room temperature, solvents were removed and the residue (130.5 g, yellow oil) was vacuum distilled, yielding 103 g (75% yield) of the title compound as a yellow transparent liquid, b.p. 158-163° C./1 tor. In the 200 MHz 1H-NMR apparatus the signal of CH3 -- appears as two doublets of similar intensity, indicating the presence of the two possible diasteromers. By following analogous procedures, compounds IIc of Table 3 were obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([NH:8][CH3:9])=[C:4]([C:10]([OH:12])=[O:11])[CH:3]=1.[CH3:13][O-:14].[Na+]>CO>[CH3:13][O:14][C:2]1[N:7]=[N:6][C:5]([NH:8][CH3:9])=[C:4]([C:10]([OH:12])=[O:11])[CH:3]=1
Reactant: CNc1nnc(Cl)cc1C(=O)O
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: CNc1nnc(OC)cc1C(=O)O
Yield: 21.6 %

Procedure:
A solution of 6-chloro-3-methylamino-pyridazine-4-carboxylic acid (80 mg, 0.43 mmol), sodium methoxide solution (5.4 M in methanol, 1.0 mL, 5.4 mmol) in methanol (1 mL) was heated at 170° C. for 20 min. After cooling, the solution was evaporated, the residue dissolved in water (2 mL) and acidified to pH 3 by addition of 37% aq. hydrochloric acid solution. The precipitate was collected by filtration to afford the title compound (17 mg, 22%). White solid, MS (ISP): 182.1 (M−H)−.
Reaction SMILES: [C:1]([C:5]1[NH:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][N:21]=[C:20]([C:24]4[CH:25]=[N:26][N:27]([CH2:29][CH2:30][O:31]C5CCCCO5)[CH:28]=4)[CH:19]=3)=[C:13]([CH3:38])[N:12]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.C([O-])(O)=O.[Na+]>CC#N.O>[C:1]([C:5]1[NH:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][N:21]=[C:20]([C:24]4[CH:25]=[N:26][N:27]([CH2:29][CH2:30][OH:31])[CH:28]=4)[CH:19]=3)=[C:13]([CH3:38])[N:12]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nc(-n2nc(C(C)(C)C)[nH]c2=O)ccc1Oc1ccnc(-c2cnn(CCOC3CCCCO3)c2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cc1nc(-n2nc(C(C)(C)C)[nH]c2=O)ccc1Oc1ccnc(-c2cnn(CCO)c2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 87.8 %

Procedure:
3-(tert-Butyl)-1-(6-methyl-5-((2-(1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-1H-1,2,4-triazol-5(4H)-one (0.18 g, 0.34 mmol) was dissolved in MeCN and treated with a HCl (4 M in dioxane) (0.25 mL, 1.0 mmol). The mixture was stirred at RT for 20 min. Sat. NaHCO3 (aq) (15 mL) was added and the suspension was extracted with EtOAc (5×15 mL). The combined organics were dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel chromatography (MeOH/DCM). The product was triturated with MeCN (5 mL) and sonicated for 5 min. The solid was isolated by filtration, redissolved in MeCN and water, frozen to −78° C., and lyophilized to afford 3-(tert-butyl)-1-(5-((2-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyridin-4-yl)oxy)-6-methylpyridin-2-yl)-1H-1,2,4-triazol-5(4H)-one (0.13 g, 82%) as an off white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.97 (s, 1H), 8.37 (d, J=5.7 Hz, 1H), 8.27 (s, 1H), 7.99 (s, 1H), 7.85 (d, J=8.8 Hz, 1H), 7.68 (d, J=8.8 Hz, 1H), 7.21 (d, J=2.4 Hz, 1H), 6.64 (dd, J=5.7, 2.4 Hz, 1H), 4.89 (t, J=5.3 Hz, 1H), 4.13 (t, J=5.6 Hz, 2H), 3.73 (q, J=5.5 Hz, 2H), 2.33 (s, 3H), 1.27 (s, 9H); MS (ESI) m/z: 436.2 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:5]=1[OH:12])([O-:3])=[O:2].C(=O)(O)[O-].[Na+].[I:18]I>>[I:18][C:6]1[C:5]([OH:12])=[C:4]([N+:1]([O-:3])=[O:2])[C:9]([O:10][CH3:11])=[CH:8][CH:7]=1
Reactant: II
Reactant: COc1cccc(O)c1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1ccc(I)c(O)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A mixture of 1.36 g (8 mmol) of the product of Step 1 and 0.68 g (8 mmol) of sodium bicarbonate was sonicated at room temperature until it become homogenous. The resulting mixture was cooled to 0° C. and 2.04 g (8 mmol) of iodine was added. After stirring for 1 h at room temperature the precipitate formed was filtered off, dried and recrystallized from ethyl ether to give 2.28 g (96% yield of pure title compound as an orange crystals; 1H NMR (CDCl3) 3.92 (s, 3H, OMe); 6.41 (d, 1H, CH J=9 Hz); 7.82 (d, 1H, J=9 Hz); 10.37 (s, 1H, OH).
Reaction SMILES: C(O[C:9](=O)[N:10]([CH2:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([C:19]2[N:23]3[CH:24]=[CH:25][N:26]=[C:27]([CH3:28])[C:22]3=[C:21]([Br:29])[N:20]=2)[CH2:15][CH2:14]1)C)C1C=CC=CC=1.Cl>>[Br:29][C:21]1[N:20]=[C:19]([C@H:16]2[CH2:17][CH2:18][C@H:13]([CH2:12][NH:10][CH3:9])[CH2:14][CH2:15]2)[N:23]2[CH:24]=[CH:25][N:26]=[C:27]([CH3:28])[C:22]=12
Reactant: Cc1nccn2c1c(Br)nc2[C@H]1CC[C@H](CN(C)C(=O)OCc2ccccc2)CC1
Agent: Cl
Product: CNC[C@H]1CC[C@H](c2nc(Br)c3c(C)nccn32)CC1

Procedure:
The impure benzyl((trans)-4-(1-bromo-8-methylimidazo[1,5-a]pyrazin-3-yl)cyclohexyl)methyl(methyl)carbamate (0.299 mmol, 141 mg) in 37% hydrochloric acid (20.94 mmol, 1.745 ml) was stirred for 18 hours at room temperature and one hour at 40° C. The reaction mixture was concentrated in vacuo. The residue dissolved in water and washed with diethyl ether twice. The aqueous layer basified with 2 N aqueous sodium hydroxide and extracted with dichloromethane twice. The combined organic extracts were dried (Na2SO4) and concentrated in vacuo to give impure 1-((trans)-4-(1-bromo-8-methylimidazo[1,5-a]pyrazin-3-yl)cyclohexyl)-N-methylmethanamine (91 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:20]([O:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Oc1ccc(O)c([N+](=O)[O-])c1)c1ccccc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Oc1ccc(OCc2ccccc2)c([N+](=O)[O-])c1)c1ccccc1
Yield: 90 %

Procedure:
A mixture of benzoic acid 4-hydroxy-3-nitro-phenyl ester (Tapia, R.; Torres, G. and Valderrama, J. A. Synth. Commun. 1986, 16, 681) (20.7 g, 80 mmol), benzyl bromide (42.75 g, 250 mmol), potassium carbonate (48.3 g, 350 mmol) and DMF (300 mL) was stirred at room temperature for 2 days. After removing the solvent the residue was dissolved in water and extracted with CH2Cl2. The organic extracts were dried (MgSO4) and concentrated. The product was purified by flash silica gel chromatography eluting with CH2Cl2 to give the title compound as a pale yellowish solid (25.1 g, 90%); 1H NMR (300 MHz, CDCl3) δ 5.27(s, 2 H), 7.17(d, J=9.1 Hz, 1 H), 7.30–7.55(m, 8 H), 7.60–7.70(m, 1 H), 7.80(d, J=2.9 Hz, 1 H), 8.15–8.25(m, 2 H); MS (ES) m/z: 345.0 (MH+, 100%); HRMS Calcd. for C20H15NO5(M+): 349.0951. Found: 349.0952.
Reaction SMILES: N.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10]O)=[CH:6][CH:5]=1.[Li].[O:13]1CCC[CH2:14]1>>[CH3:2][O:3][C:4]1[CH2:5][CH:6]=[C:7]([CH2:10][CH2:14][OH:13])[CH2:8][CH:9]=1
Reactant: C1CCOC1
Reactant: COc1ccc(CO)cc1
Agent: N
Agent: [Li]
Product: COC1=CCC(CCO)=CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Liquid ammonia (520 mL) was condensed in a three-necked flask which was fitted with a cold finger and overhead stirrer and kept at -78° C. with a dry ice/isopropanol bath. A solution of 1-methoxy-4-hydroxymethyl-benzene (50 g, 329 mmol) in tetrahydrofuran (140 mL) was added to the reaction flask followed by the addition of small pieces of lithium wire (10.3 g, 1.48 mol) over a period of about 15 min. The reaction mixture was stirred an additional 30 min at -78° C. and then quenched by the slow addition of absolute ethanol (400 mL). After the reaction was completely quenched (white color), it was allowed to warm to room temperature overnight. This allowed most of the NH3 to evaporate. The residue was partitioned between water and diethyl ether, the organic layer collected, dried over anhydrous MgSO4, filtered and evaporated at reduced pressure. The residue, which still contained some water, was dissolved in methylene chloride, dried over anhydrous MgSO4, filtered and evaporated at reduced pressure to give crude 1-methoxy-4-(2-hydroxyethyl)-cyclohexa-1,4-diene (1) as an oil (40.3 g), which was used in the next step without further purification. This crude product was contaminated with the over-reduced product, 1-methoxy-4-(2-hydroxyethyl)-cyclohex-1-ene (2). Compound (1): 1H NMR δ (CDCl3) 2.12 (1H, br s), 2.28 (2H, t, J=7.5 Hz), 2.78 (4H, br s), 3.58 (3H, s), 3.73 (2H, t, J=7.5 Hz), 4.68 (1H, br s), 5.55 (1H, br s).