Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14].[CH3:15][C:16]1[CH:26]=[CH:25][C:19](/[CH:20]=[CH:21]/[C:22]([Cl:24])=O)=[CH:18][CH:17]=1.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.Cl>CO>[ClH:24].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]=[C:22]1/[CH:21]=[CH:20]/[C:19]1[CH:25]=[CH:26][C:16]([CH3:15])=[CH:17][CH:18]=1
Reactant: Nc1ccccc1Nc1ccccn1
Reactant: Cc1ccc(/C=C/C(=O)Cl)cc1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: Cl
Solvent: CO
Product: Cc1ccc(/C=C/c2nc3ccccc3n2-c2ccccn2)cc1

Procedure:
Free base of the titled compound was prepared from N-(2-pyridyl)-o-phenylenediamine and (E)-4-methylcinnamoyl chloride (Aitken, R. A.; Boeters, C.; Morrison, J. J. J. Chem. Soc. Perkin Trans.I; 1994, 17, 2473) according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). The free base was dissolved with a 10% methanol solution of hydrogen chloride (5 ml). Concentration and recrystallization from ethyl acetate/ethanol yielded the titled compound.
Reaction SMILES: C(O[C:4]([C:6]1[C:11](=[O:12])[N:10]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[N:9]2[CH:18]=[CH:19][CH:20]=[C:8]2[C:7]=1[OH:21])=O)C.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=1[S:30]([NH2:33])(=[O:32])=[O:31].N12CCCN=C1CCCCC2>N1C=CC=CC=1>[OH:21][C:7]1[C:8]2[N:9]([CH:18]=[CH:19][CH:20]=2)[N:10]([CH2:13][CH2:14][CH:15]([CH3:16])[CH3:17])[C:11](=[O:12])[C:6]=1[C:4]1[NH:22][C:23]2[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=2[S:30](=[O:32])(=[O:31])[N:33]=1
Reactant: CCOC(=O)c1c(O)c2cccn2n(CCC(C)C)c1=O
Reactant: Nc1ccc(I)cc1S(N)(=O)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccncc1
Product: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(I)ccc3N2)c(O)c2cccn21
Temperature: 120 °C
Yield: 27.9 %

Procedure:
4-Hydroxy-1-(3-methyl-butyl)-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid ethyl ester (Example 1f, 0.218 g, 0.75 mmol) was dissolved in pyridine (1.5 mL) and 2-amino-5-iodo-benzenesulfonamide (Example 4a, 0.222 g, 0.75 mmol) was added. The reaction mixture was heated at 120° C. for 16 h, and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.12 mL, 0.78 mmol) was added an heated for another 4 h. The pyridine was removed in vacuo to afford the crude desired product. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm, 5%-10% methanol in dichloromethane) afforded the desired product, 4-hydroxy-3-(7-iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-1-(3-methyl-butyl)-pyrrolo[1,2-b]pyridazin-2-one (0.110 g, 0.209 mmol, 28% yield) as a white solid. LC-MS (ESI) calcd for C19H19IN4O4S. found 526.02. found 527.20 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:12])[CH2:9][CH2:10][S:11][C:6]=2[C:5]([Cl:13])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Br:18]Br.Cl>C(Cl)Cl>[Br:18][C:3]1[CH:4]=[C:5]([Cl:13])[C:6]2[S:11][CH2:10][CH2:9][C:8](=[O:12])[C:7]=2[C:2]=1[Cl:1]
Reactant: O=C1CCSc2c(Cl)ccc(Cl)c21
Reactant: BrBr
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C1CCSc2c(Cl)cc(Br)c(Cl)c21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 96.8 %

Procedure:
A solution of 45.18 g (0.19 mol) of the title compound of Step B in 400 mL of methylene chloride was added dropwise at room temperature under nitrogen to a mixture of 64.6 g (0.48 mol) of aluminum chloride in 400 mL of methylene chloride. After stirring for 15 min, 10.5 mL (0.20 mol) of bromine was added dropwise and the mixture was refluxed for 10 min. The mixture, while still warm, was poured into 550 g of ice containing 110 mL of concentrated hydrochloric acid, and the resulting mixture was extracted with diethyl ether (2×500 mL). The combined organic layers were dried (Na2SO4), filtered, and evaporated to dryness to yield 57.37 g of the title compound of Step C as a solid melting at 89-90° C. 1H NMR (CDCl3): δ3.0 (m,2H), 3.3 (m,2H), 7.7 (s,1H).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11](=[O:26])[C:12]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][CH:19]=2)(=[O:17])=[O:16])([CH3:14])[CH3:13])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11](=[O:26])[C:12]([S:15]([C:18]2[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=2)(=[O:17])=[O:16])([CH3:14])[CH3:13])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc(S(=O)(=O)C(C)(C)C(=O)Nc2cc(C(C)(C)C)on2)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)c1cc(NC(=O)C(C)(C)S(=O)(=O)c2ccc(O)cc2)no1
Temperature: 25 °C
Reaction time: 18 h
Yield: 33 %

Procedure:
To a solution of 203 mg (0.53 mmol) of N-(5-tert-butyl-isoxazol-3-yl)-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionamide (Example 43, Table 19, prepared according to method A) in DCM (5 mL) were added 0.3 mL (3.18 mmol) of BBr3 at 0° C. under nitrogen atmosphere. The reaction was allowed to warm to room temperature and stirred for 18 h. The reaction was poured onto a saturated aqueous NaHCO3 solution-ice mixture (20 mL). The aqueous mixture was acidified to pH 5 and extracted with DCM (3×15 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was further purified by column chromatography (silica, eluent DCM, 0-20% ethyl acetate) to afford 64 mg of N-(5-tert-butyl-isoxazol-3-yl)-2-(4-hydroxy-benzenesulfonyl)-2-methyl-propionamide.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[CH:12][CH:13]=2)[CH:8]=1)(=O)=O.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.[OH-].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[CH3:18][O:17][C:11]1[CH:12]=[CH:13][C:14]2[C:9](=[CH:8][C:7]([C:26]3[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=3)=[CH:16][CH:15]=2)[CH:10]=1
Reactant: COc1ccc2ccc(OS(=O)(=O)C(F)(F)F)cc2c1
Reactant: COc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: COc1ccc(-c2ccc3ccc(OC)cc3c2)cc1
Temperature: 25 °C
Yield: 79.7 %

Procedure:
A mixture of 7-methoxy-2-naphthyl trifluoromethanesulfonate (3.15 g, 10.3 mmol), 4-methoxy-phenylboronic acid (2.2 g, 14 mmol) sodium carbonate (10 mL of 2N aqueous solution), tetrakis(triphenylphosphine)palladium (0.59 g, 0.05 mmol), and 100 mL ethylene glycol dimethyl ether were heated to reflux for 8 hr. The mixture was cooled to room temperature and poured into 100 mL of 1N NaOH, The mixture was extracted with ethyl acetate (3×250 mL), washed with brine (2×100 mL), dried over magnesium sulfate, filtered, evaporation of the solvent and purification by silica chromatography (5%–10% ethyl adetate-hexanes) yielded 2.17 g (79%) of the title compound as a white solid: mp 154° C.; 1H NMR (CDCl3): δ 3.87 (3H, s), 3.94 (3H, s), 7.02 (2H, d, J=8.72 Hz), 7.13 (1H, dd, J=2.54 Hz, J=9.09 Hz), 7.18 (1H, J=2.55 Hz), 7.56 (1H, dd, J=1.82 Hz, J=8.36 Hz), 7.65 (2H, d, J=8.72 Hz), 7.74 (1H, d, J=9.09 Hz), 7.81 (1H, d, J=8.36 Hz), 7.89 (1H, d, J=1.09 Hz); MS (EI) m/z 264 (M).
Reaction SMILES: CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].I[CH2:13][CH2:14][CH3:15].[F:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([N+:24]([O-:26])=[O:25])[CH:18]=1>O>[F:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:13][CH2:14][CH3:15])=[C:19]([N+:24]([O-:26])=[O:25])[CH:18]=1
Reactant: CCCI
Reactant: O=[N+]([O-])c1cc(F)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1ccc(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 96.3 %

Procedure:
A N,N-dimethylformamide (DMF) solution (3 ml) of potassium carbonate (3.48 g, 25.2 mmol) and 1-iodopropane (3.95 g, 23.2 mmol) was added to a DMF solution (7 ml) of 4-fluoro-2-nitrophenol (3.3 g, 21.0 mmol). The mixture was stirred at room temperature for 48 hours. Water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution twice, and concentrated under reduced pressure. The residue was purified using silica gel column chromatography (n-hexane:ethyl acetate=9:1). The purified product was concentrated under reduced pressure to thereby obtain 4.03 g of oily yellow 4-fluoro-2-nitro-1-propoxybenzene (yield: 96%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12](=[O:25])(=[O:24])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:6]([CH2:8][C:9](O)=[O:10])[CH:7]=1.O/[N:27]=[C:28](/[NH2:31])\[CH2:29][CH3:30].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12]([NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)(=[O:25])=[O:24])=[C:6]([CH2:8][C:9]2[O:10][N:31]=[C:28]([CH2:29][CH3:30])[N:27]=2)[CH:7]=1
Reactant: CC/C(N)=N\O
Reactant: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(CC(=O)O)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O
Solvent: CN(C)C=O
Product: CCc1noc(Cc2cc(N)ccc2S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)n1
Reaction time: 24 h
Yield: 1 %

Procedure:
To a stirred solution of 2-(5-amino-2-(N-(1-hydroxy-1,3-dihydrobenzo [c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)acetic acid (0.5 g, 1.4 mmol) and (E)-N′-hydroxypropionimidamide (0.19 mL, 2.1 mmol) in 10 mL of DMF was added EDC (0.5 g, 3.6 mmol) and HOBt (700 mg, 3.6 mmol). The reaction mixture was stirred for 24 hours. After water was added, the reaction mixture was extracted with ethyl acetate and washed with water, 1N HCl and brine. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column) to give the title compound as a yellow solid (6 mg, yield 13%), and cyclized product (7 mg, yield 1%). 4-Amino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-((3-ethyl-1,2,4-oxadiazol-5-yl)methyl)benzenesulfonamide: MS calcd for (C18H19BN4O5S): 414.24. MS found (ESI negative): (M−H)−=413.1. 1H NMR (DMSO-d6) δ (ppm): 10.0 (s, 1H), 9.18 (bs, 1H), 7.55 (d, J=8.8 Hz, 1H), 7.41 (s, 1H), 7.22 (d, J=8 Hz, 1H), 7.08 (dd, J=8, 2 Hz, 1H), 6.45 (dd, J=8.8, 2 Hz, 1H, 6.39 (d, J=3 Hz, 1H), 4.86 (s, 2H), 4.48 (s, 2H), 2.63 (q, J=7.6 Hz 2H), 1.17 (t, J=7.6 Hz, 3H).
Reaction SMILES: [OH:1][CH2:2][C:3](=[CH2:6])[C:4]#[N:5].[CH3:7][NH:8][CH3:9]>C1COCC1>[OH:1][CH2:2][CH:3]([CH2:6][N:8]([CH3:9])[CH3:7])[C:4]#[N:5]
Reactant: C=C(C#N)CO
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)CC(C#N)CO
Temperature: 45 °C

Procedure:
2-hydroxymethyl-acrylonitrile (37 mmol, 3.1 g, prepared as per procedure described by Csuk et al. in Tetrahedron, 1996, 52, 9759-9776) was treated with dimethylamine (25 mL of a 2M solution in THF) and the reaction was heated in a sealed vessel at 45° C. for 14 h. The reaction was cooled to room temperature and all the volatiles were removed by concentration under vacuum. The crude 2-hydroxymethyl-3-dimethylaminopropionitrile thus obtained was dissolved in dry THF (50-60 mL) and this solution was added dropwise to a cold (−78° C.) suspension of LAH (6 g) in THF (300 ML). The reaction was gradually warmed to room temperature and stirred for an additional 12 h at room temperature. The reaction was then cooled in an ice bath and very carefully quenched by the sequential addition of H2O (6 mL), 4M NaOH (6 mL) and H2O (18 mL). The white slurry thus obtained was filtered through celite and the filter bed was washed with additional CH2Cl2. The entire filtrate was then concentrated under vacuum to provide crude amine 23.
Reaction SMILES: [O:1]=[S:2]1(=[O:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[Cl:30][C:31]1[CH:36]=[C:35](B(O)O)[CH:34]=[CH:33][N:32]=1>>[Cl:30][C:31]1[CH:36]=[C:35]([N:11]2[C:12]3[C:17](=[CH:16][C:15]([O:19][CH:20]4[CH2:25][CH2:24][N:23]([CH:26]([CH3:27])[CH3:28])[CH2:22][CH2:21]4)=[CH:14][CH:13]=3)[CH:18]=[C:10]2[C:8]([N:5]2[CH2:6][CH2:7][S:2](=[O:1])(=[O:29])[CH2:3][CH2:4]2)=[O:9])[CH:34]=[CH:33][N:32]=1
Reactant: OB(O)c1ccnc(Cl)c1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCS(=O)(=O)CC4)cc3c2)CC1
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCS(=O)(=O)CC2)n3-c2ccnc(Cl)c2)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 5, the title compound was synthesized from (1,1-dioxo-thiomorpholin-4-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone (Example 2) and 2-chloropyridine-4-boronic acid. The desired product was obtained in a yield of 8% as an off-white solid. MS (m/e): 531.5 (M+, 100%).
Reaction SMILES: C[N:2]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C@:3]([CH3:17])([C:14]([OH:16])=[O:15])[CH2:4][C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1.O.[OH-].[Li+].O1CCOCC1>O>[C:18]([NH:2][C@:3]([CH3:17])([C:14]([OH:16])=[O:15])[CH2:4][C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1)([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]
Reactant: CN(C(=O)OCc1ccccc1)[C@@](C)(Cc1cc2ccccc2s1)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: C[C@@](Cc1cc2ccccc2s1)(NC(=O)OCc1ccccc1)C(=O)O
Yield: 82.8 %

Procedure:
A solution of methyl N-CBZ-α-methyl-3-benzothiophenylalanine (0.6 g, 1.57 mmol), lithium hydroxide hydrate (0.14 g, 3.33 mmol) in water (20 mL), and dioxan (20 mL) was stirred at room temperature overnight. The reaction mixture was diluted with water, washed with ether, acidified with 1N hydrochloric acid, and extracted with ethyl acetate three times. The combined extracts were washed with water, dried over magnesium sulphate, filtered, and evaporated to dryness. Crystallization from ether/hexane gave colorless crystals 0.48 g (83%);
Reaction SMILES: [S:1]([O-])([O-:3])=[O:2].[Ca+2:5].[S:6](=[O:9])([OH:8])[O-:7].[Ca+2].S(=O)(O)[O-:12]>>[S:1](=[O:3])=[O:2].[S:6]([O-:12])([O-:8])(=[O:7])=[O:9].[Ca+2:5]
Reactant: O=S([O-])[O-]
Reactant: O=S([O-])O
Agent: [Ca+2]
Product: O=S(=O)([O-])[O-]
Product: O=S=O

Procedure:
An oxidation zone can be provided in the sump to convert calcium sulfite and calcium bisulfite, formed by the absorption of sulfur dioxide, into calcium sulfate so that the solids which tend to come out of solution in the sump to form the sludge, predominantly consist of calcium sulfate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.[CH2:31]([O:33][CH2:34][CH2:35]O)[CH3:32].B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:26]([O:28][CH2:32][CH2:31][O:33][CH2:34][CH3:35])=[O:27])=[CH:29][CH:30]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(NCCCCCCCCCCCC#Cc2ccc(Cl)cc2)cc1
Reactant: CCOCCO
Agent: FB(F)F
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCOCCOC(=O)c1ccc(NCCCCCCCCCCCC#Cc2ccc(Cl)cc2)cc1
Reaction time: 120 h

Procedure:
A solution of 11.8 g. of 4-[13-(4-chlorophenyl)tridec-12-ynylamino]benzoic acid, 1.00 g. of 2-ethoxyethanol and 5.35 ml. of boron trifluoride etherate in 200 ml. toluene is stirred under reflux for 48 hours. The solution is treated with an additional 5.35 ml. of boron trifluoride etherate and refluxing is continued for 120 hours. Dilution with water and methylene chloride followed by filtration affords 2-ethoxyethyl 4-[13-(4-chlorophenyl)tridec-12-ynylamino]benzoate as a white solid.
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[N:21]=[CH:22][N:23]4[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=34)[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[N:21]=[CH:22][N:23]4[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=34)[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(-c3ncn4cc(F)ccc34)nc12)c1ncco1
Solvent: NCCN
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](NC(=O)c1c[nH]c2ncc(-c3ncn4cc(F)ccc34)nc12)c1ncco1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
In a round-bottomed flask, 2-(6-fluoro-imidazo[1,5-a]pyridin-1-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-oxazol-2-yl-ethyl)-amide (107 mg, 0.205 mmol) was dissolved in dichloromethane (1.1 ml) and trifluoroacetic acid (0.64 ml, 8.3 mmol) was added. The reaction mixture was stirred at room temperature for 2 h then concentrated. The residue was dissolved in dichloromethane (1.1 ml) and ethylenediamine (0.84 ml, 12.4 mmol) was added. The yellow reaction mixture was stirred at room temperature for 1 h then quenched with water and diluted with ethyl acetate. The resultant suspension was filtered, washed with hot water and ethyl acetate and dried under high vacuum to provide 76 mg (90%) of 2-(6-fluoro-imidazo[1,5-a]pyridin-1-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-oxazol-2-yl-ethyl)-amide as a yellow powder. MS: (M+Na)+=414; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.76 (br. s., 1H), 9.12 (s, 1H), 8.70 (dd, J=4.7, 2.1 Hz, 1H), 8.60 (d, J=8.7 Hz, 1H), 8.54 (s, 1H), 8.36-8.46 (m, 2H), 8.11 (s, 1H), 7.25 (s, 1H), 7.04 (ddd, J=9.9, 7.8, 1.9 Hz, 1H), 5.45-5.60 (m, 1H), 1.65 (d, J=6.8 Hz, 3H).
Reaction SMILES: [Si]([N:8]1[C@H:11]([C:12]2[CH:16]=[N:15][NH:14][N:13]=2)[CH2:10][C:9]1=[O:17])(C(C)(C)C)(C)C.[ClH:18].[CH3:19][CH2:20][OH:21]>>[ClH:18].[CH2:20]([O:21][C:9](=[O:17])[CH2:10][C@@H:11]([C:12]1[CH:16]=[N:15][NH:14][N:13]=1)[NH2:8])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)C[C@H]1c1cn[nH]n1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)C[C@H](N)c1cn[nH]n1
Reaction time: 1 h
Yield: 94.4 %

Procedure:
1-tert-Butyldimethylsilyl-4(S)-(2H-1,2,3-triazol-4-yl)-2-azetidinone (0.3 g) was added to 6N HCl/EtOH (10 ml). The mixture was stirred for 1 hour, and then evaporated in vacuo. The crystalline solid was washed with diethyl ether to give 3(S)-(2H-1,2,3-triazol-4-yl)-β-alanine ethyl ester hydrochloride (0.25 g, 94.4%) as a white solid.
Reaction SMILES: [CH2:1]([N:3]1C=NN=C1C1C=CN=CC=1)C.[CH2:14]([N:16]1[C:20]([C:21]2[CH:26]=[CH:25]N=C[CH:22]=2)=[N:19][N:18]=[C:17]1[CH2:27][OH:28])C.C(N1C(C2C=CN=CC=2)=NN=C1C=O)C.CN1C(C2C=NC=CC=2)=NNC1=S>>[CH3:14][N:16]1[C:20]([C:21]2[CH:22]=[N:3][CH:1]=[CH:25][CH:26]=2)=[N:19][N:18]=[C:17]1[CH:27]=[O:28]
Reactant: CCn1c(CO)nnc1-c1ccncc1
Reactant: CCn1cnnc1-c1ccncc1
Agent: CCn1c(C=O)nnc1-c1ccncc1
Agent: Cn1c(-c2cccnc2)n[nH]c1=S
Product: Cn1c(C=O)nnc1-c1cccnc1

Procedure:
The title compound is prepared analogously to the sequence described for 4-(4-ethyl-4H-[1,2,4]triazol-3-yl)-pyridine (example 21), (4-ethyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-methanol (example 22), and 4-ethyl-5-pyridin-4-yl-4H-[1,2,4]triazole-3-carbaldehyde (example 23a) by using 4-methyl-5-pyridin-3-yl-2,4-dihydro-[1,2,4]triazole-3-thione as starting material.
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]([CH2:6][NH:7][C:8](=[O:17])[C:9]2[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:16])=[CH:4][C:3]=1[CH3:20].[O:21]=[C:22]1[CH:27]=[C:26](B(O)O)[CH:25]=[CH:24][NH:23]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[Cl:16][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([Cl:15])[C:9]=1[C:8]([NH:7][CH2:6][C:5]1[CH:18]=[CH:19][C:2]([C:26]2[CH:25]=[CH:24][NH:23][C:22](=[O:21])[CH:27]=2)=[C:3]([CH3:20])[CH:4]=1)=[O:17]
Reactant: O=c1cc(B(O)O)cc[nH]1
Reactant: Cc1cc(CNC(=O)c2c(Cl)cccc2Cl)ccc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(CNC(=O)c2c(Cl)cccc2Cl)ccc1-c1cc[nH]c(=O)c1
Temperature: 85 °C

Procedure:
N-(4-Bromo-3-methylbenzyl)-2,6-dichlorobenzamide (0.13 g, 0.35 mmol), 2-oxo-1,2-dihydropyridin-4-ylboronic acid (0.053 g, 0.39 mmol), cesium carbonate (0.34 g, 1.05 mmol), [1,1′Bis(diphenylphosphino(ferrocene]dichloropalladium(II) (25 mg, 0.035 mmol) were dissolved in degassed DMF (3 mL) and H2O (1.5 mL). The reaction mixture was degassed again by bubbling nitrogen through for 15 min then heated in the microwave at 85° C. for 20 min. The reaction mixture was diluted with EtOAc and extracted three times with water. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuum. The resulting solid was purified by reverse phase chromatography to afford 2,6-dichloro-N-(3-methyl-4-(2-oxo-1,2-dihydropyridin-4-yl)benzyl)benzamide.
Reaction SMILES: [C:1](=[O:13])([O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[O:2][CH:3](Cl)[CH3:4].[OH:14][C@H:15]([CH2:35][NH:36][C:37]([CH3:50])([CH3:49])[CH2:38][C:39]1[CH:48]=[CH:47][C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=1)[CH2:16][O:17][CH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29]([C:32]([OH:34])=[O:33])=[CH:28][CH:27]=1)[CH3:19].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.O>[OH:14][C@H:15]([CH2:35][NH:36][C:37]([CH3:49])([CH3:50])[CH2:38][C:39]1[CH:48]=[CH:47][C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=1)[CH2:16][O:17][CH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:27]=[CH:28][C:29]([C:32]([O:34][CH:3]([O:2][C:1]([O:6][CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)=[O:13])[CH3:4])=[O:33])=[CH:30][CH:31]=1)[CH3:19]
Reactant: CC(Cl)OC(=O)OC1CCCCC1
Reactant: CC(OC[C@H](O)CNC(C)(C)Cc1ccc2ccccc2c1)c1ccccc1-c1ccc(C(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(OC(=O)OC1CCCCC1)OC(=O)c1ccc(-c2ccccc2C(C)OC[C@H](O)CNC(C)(C)Cc2ccc3ccccc3c2)cc1
Temperature: 60 °C
Reaction time: 24 h
Yield: 94.6 %

Procedure:
1-Chloroethyl cyclohexyl carbonate (149 mg) obtained in Step 1 was dissolved in N,N-dimethylformamide (5.0 ml), 2′-[1-[(2R)-2-hydroxy-3-[[2-methyl-1-(naphthalen-2-yl)propan-2-yl]amino]propoxy]ethyl]biphenyl-4-carboxylic acid (300 mg) obtained in Step 2, potassium carbonate (99 mg) and potassium iodide (50 mg) were successively added and the mixture was stirred at 60° C. for 1 day. Water was added to the reaction mixture and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed successively with water (3 times) and brine, and dried over sodium sulfate. The organic layer was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (chloroform:methanol=15:1) to give the title compound (381 mg).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[NH2:5].C(OC(=O)C)(=O)C.C([O-])(=O)C.[K+].[N:24](OCCCCC)=O>C(#N)C>[Br:1][C:2]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[C:4]2[C:3]=1[CH:11]=[N:24][NH:5]2
Reactant: COc1ccc(N)c(C)c1Br
Reactant: CCCCCON=O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: CC#N
Product: COc1ccc2[nH]ncc2c1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
To a solution of 3-bromo-4-methoxy-2-methylaniline (19.06 g) in acetonitrile (250 mL) was slowly added acetic anhydride (18.9 mL), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture were added potassium acetate (2.60 g) and pentyl nitrite (22.3 g), and the mixture was heated under reflux for 8 hr. The reaction mixture was concentrated, and to the residue was added 6M hydrochloric acid (200 mL), and the mixture was heated under reflux overnight. The reaction mixture was neutralized with 8M sodium hydroxide, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was dissolved in tetrahydrofuran, and the solution was treated with activated carbon. The activated carbon was filtered off, the filtrate was concentrated, and the obtained residue was crystallized from diisopropyl ether. The crystals were collected by filtration, washed with diisopropyl ether, and dried to give the title compound (10.42 g, yield 52%) as yellow crystals. melting point 178-180° C. MS: 229 (MH+).