Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[C:11]2[O:10][C:9]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[CH:8][C:7]=2[CH:6]=[C:5]([OH:19])[CH:4]=1.[OH-].[K+].[CH2:22]([OH:24])[CH3:23]>>[CH2:22]([O:24][CH2:2][C:3]1[C:11]2[O:10][C:9]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[CH:8][C:7]=2[CH:6]=[C:5]([OH:19])[CH:4]=1)[CH3:23]
Reactant: CCO
Reactant: Oc1ccc(-c2cc3cc(O)cc(CBr)c3o2)cc1
Agent: [K+]
Agent: [OH-]
Product: CCOCc1cc(O)cc2cc(-c3ccc(O)cc3)oc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
To a solution of benzyl bromide 4 (0.05 g, 0.159 mmole) in 5 mL ethanol was added potassium hydroxide (0.350 g, 0.627 mmole). After stirring at R.T. for 1 hour, the solvent was evaporated and the residue was poured into water and extracted with ethyl acetate. The combined organic phases were washed with saturated sodium bicarbonate, water, brine, and dried with magnesium sulfate. The organic phases were concentrated and the residue was loaded on to silica gel and chromatographed on silica gel (hexanes:ethyl acetate, 9:1) to afford 0.039 g (51%) of ethyl ether 7 as a tan solid: Mp=166-168° C.; 1H NMR (DMSO-d6) δ 9.82 (br s, 1 H), 9.12 (bs, 1 H), 7.70 (d, 2 H, J=8.6 Hz), 7.02 (s, 1 H), 6.86 (d, 2 H, J=8.6 Hz), 6.81 (d, 1 H, J=2.1 Hz), 6.69 (d, 1 H, J=2.2 Hz), 4.71 (s, 2 H), 3.56 (q, 2 H, J=7.2 Hz), 1.18 (t, 3 H, J=7.2 Hz); MS 283 (M−H)−
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]2[CH2:14][CH2:13][NH:12][C:11]2=[O:15])[CH2:3][CH2:2]1.Br[C:17]1[S:21][C:20]2[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:19]=2[CH:18]=1.CN[C@@H]1CCCC[C@H]1NC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]2[CH2:14][CH2:13][N:12]([C:17]3[S:21][C:20]4[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:19]=4[CH:18]=3)[C:11]2=[O:15])[CH2:3][CH2:2]1
Reactant: O=C1NCCN1c1cnccc1C1CC1
Reactant: Fc1ccc2sc(Br)cc2c1
Agent: I[Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: O=C1N(c2cc3cc(F)ccc3s2)CCN1c1cnccc1C1CC1
Yield: 48.8 %

Procedure:
Using analogous reagents and reaction conditions as described in Example 1 above, 1-(4-cyclopropylpyridin-3-yl)imidazolidin-2-one (I-1d: 100 mg, 0.4926 mmol) was reacted with 2-bromo-5-fluorobenzo[b]thiophene (125 mg, 0.5418 mmol), 1,4-dioxane (4 mL), copper iodide (9.3 mg, 0.0492 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (7.0 mg, 0.0492 mmol) and potassium phosphate (261 mg, 1.231 mmol) to afford the crude product. Purification by column chromatography on silica gel (0.5% methanol in CHCl3) afforded 85 mg of the product (49% yield).
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[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([CH:30]=O)=[CH:22][CH:21]=1>>[F:19][C:16]([F:17])([F:18])[C:13]1[N:11]2[N:12]=[C:7]([N:1]3[CH2:2][CH2:3][N:4]([CH2:30][C:23]4[C:24]5[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=5)[N:20]=[CH:21][CH:22]=4)[CH2:5][CH2:6]3)[CH:8]=[CH:9][C:10]2=[N:15][N:14]=1
Reactant: O=Cc1ccnc2ccccc12
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4ccnc5ccccc45)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with quinoline-4-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 4-[[4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl]methyl]quinoline.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:15])([CH3:14])[C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1)#[N:2].C(O)(=O)CC.[ClH:21]>>[ClH:21].[NH2:2][CH2:1][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:15])([CH3:14])[C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1
Reactant: CC(C)(C(=O)O)c1ccc(CC#N)cc1
Agent: Cl
Solvent: CCC(=O)O
Product: CC(C)(C(=O)O)c1ccc(CCN)cc1

Procedure:
The ethyl 2-[4-(2-aminoethyl)-phenyl]-2-methylpropionate hydrochloride (m.p. 150°-154° C.) used as starting material is obtained by the reaction of 2-(4-chloromethylphenyl)-2-methylpropionic acid (m.p. 121°-122° C.) with sodium cyanide. The 2-(4-cyanomethylphenyl)-2-methylpropionic acid obtained melts at 105°-106° C. This propionic acid derivative is catalytically hydrogenated in ethanolic hydrochloric acid solution to give 2-[4-(2-aminoethyl)-phenyl]-2-methylpropionic acid hydrochloride which, after recrystallization from isopropanol, melts at 247°-248° C. By esterification thereof with ethanol in hydrochloric acid solution, there is obtained the desired ethyl 2-[4-(2-aminoethyl)-phenyl]-2-methylpropionate hydrochloride.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:12](=O)([O-])[O-:13].[Na+].[Na+].O.C(Cl)(Cl)=O>C1(C)C=CC=CC=1>[I:1][C:2]1[CH:10]=[C:6]2[C:7]([O:9][C:12](=[O:13])[NH:11][C:5]2=[CH:4][CH:3]=1)=[O:8]
Reactant: O=C([O-])[O-]
Reactant: Nc1ccc(I)cc1C(=O)O
Agent: O=C(Cl)Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=c1[nH]c2ccc(I)cc2c(=O)o1
Reaction time: 2 h
Yield: 84.1 %

Procedure:
To a mechanically stirred solution of 26.3 grams of 5-iodo-2-amino benzoic acid (0.1 mol), 10.6 grams of sodium carbonate (0.1 mol), and 250 mL water, cooled to 0° C., was slowly added, via an addition funnel, 80 mL of a 1.93M solution of phosgene in toluene. After 2 hours, the precipitated product was isolated by filtration. The solids were washed with 200 mL water, 300 mL of a 1:1 mixture ethanol and ether, 200 mL of ether, and dried under vacuum to yield 24.3 grams (84%) of 5-iodoisatoic anhydride (264°-268° C., decomposition).
Reaction SMILES: [NH:1]([CH:3]1[C:7]2=[CH:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[N:6]2[CH2:5][CH2:4]1)[OH:2].C[Si]([N:19]=[C:20]=[O:21])(C)C.O>C1COCC1>[CH:3]1([N:1]([OH:2])[C:20]([NH2:19])=[O:21])[C:7]2=[CH:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[N:6]2[CH2:5][CH2:4]1
Reactant: ONC1CCn2c1cc1ccccc12
Reactant: C[Si](C)(C)N=C=O
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)N(O)C1CCn2c1cc1ccccc12
Reaction time: 0.5 h

Procedure:
To a solution of the product from Step 2 (652 mg, 3.47 mmol) in THF (20 mL) at r.t. there was added 85% trimethylsilyl isocyanate (850 mg, 6.28 mmol) and the mixture was stirred for 30 minutes. There was added H2O (5 mL) and after stirring for another 5 minutes the THF was evaporated. The residual aqueous suspension was diluted with H2O and filtered to afford the title compound as a white solid, m.p.: 194° C. (dec).
Reaction SMILES: [CH:1]([OH:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:15]1[CH2:20][CH2:19][CH:18]([CH2:21]O)[CH2:17][CH2:16]1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[OH-].[Na+]>C1(C)C=CC=CC=1>[C:2]1([CH:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[O:14][CH2:21][CH:18]2[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC(c1ccccc1)c1ccccc1
Reactant: OCC1CCNCC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: c1ccc(C(OCC2CCNCC2)c2ccccc2)cc1
Yield: 94.3 %

Procedure:
In a reactor fitted with a water trap, a mixture of benzhydrol (3.7 g), 4-piperidinemethanol (2.3 g), camphor-10-sulfonic acid (7.0 g), and toluene (30 mL) was refluxed for 2 hours. After cooling, 35 mL of 1N-aqueous sodium hydroxide was added and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous NaCl, dried over MgSO4, and concentrated under reduced pressure to provide 5.3 g of the title compound. Yield 94%. This product was not further purified but directly submitted to the next reaction.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[Li]CCCC.CON(C)[C:17]([CH:19]1[CH2:23][CH2:22][N:21]([C:24]2[N:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[CH2:20]1)=[O:18].CCOC(C)=O>C1COCC1.O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:17]([CH:19]2[CH2:23][CH2:22][N:21]([C:24]3[N:25]=[CH:26][CH:27]=[CH:28][N:29]=3)[CH2:20]2)=[O:18])=[CH:3][CH:4]=1
Reactant: Brc1ccc(Br)cc1
Reactant: CON(C)C(=O)C1CCN(c2ncccn2)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(c1ccc(Br)cc1)C1CCN(c2ncccn2)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 63.5 %

Procedure:
To a solution of 1,4-dibromobenzene (407.5 mg, 1.727 mmol) in THF (6 ml) was added n-BuLi (2.5 M in hexanes, 0.691 ml, 1.727 mmol) at −78° C. The mixture was stirred at the temperature for 30 minutes before the addition of a solution of the above amide (203.8 mg, 0.8636 mmol) in THF (4 ml). After stirring at −78° C. for 30 minutes, the mixture was warmed to room temperature for 1 hour. EtOAc (40 ml) and water (15 ml) was added to the reaction, followed by separation of the layers. The aqueous phase was extracted with EtOAc (15 ml). The combined organic layers were washed with brine (10 ml), dried (MgSO4), filtered, and concentrated under reduced pressure to furnish the crude product. This material was purified by column chromatography (40% acetone/hexanes) to furnish (4-bromo-phenyl)-(1-pyrimidin-2-yl-pyrrolidin-3-yl)-methanone (182.2 mg, 64%) as an off-white solid: 1H NMR (CDCl3, 400 MHz) δ 8.32 (d, J=6.4 Hz, 2H), 7.87 (d, J=12.0 Hz, 2H), 7.63 (d, J=12.0 Hz, 2H), 6.51 (t, J=6.4 Hz, 1H), 4.07 (m, 1H), 3.98 (m, 1H), 3.86 (m, 1H), 3.74 (m, 2H), 2.38 (m, 2H).
Reaction SMILES: [CH:1]1([O:7][CH2:8][C@H:9]2[CH2:14][C@H:13]([C:15](=[O:22])[CH2:16][C:17](OCC)=[O:18])[CH2:12][CH2:11][N:10]2[C:23]([O:25][CH3:26])=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[NH2:29]O.Cl>CO.O.C(Cl)Cl>[CH:1]1([O:7][CH2:8][C@H:9]2[CH2:14][C@H:13]([C:15]3[O:22][NH:29][C:17](=[O:18])[CH:16]=3)[CH2:12][CH2:11][N:10]2[C:23]([O:25][CH3:26])=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](COC2CCCCC2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1COC1CCCCC1
Temperature: -40 °C
Reaction time: 0.25 h
Yield: 62.7 %

Procedure:
Trans-methyl 2-(cyclohexyloxymethyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (210 mg, 0.57 mmol) (from example 84, step 1) was dissolved in MeOH (3 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (23.87 mg, 0.60 mmol) dissolved in water (0.300 mL) was added and the mixture was stirred at −40° C. for 15 min. Hydroxylamine (50% by weight in water, 0.037 mL, 0.60 mmol) was added. The resulting solution was stirred at −40° C. for 1 h. The mixture was transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (2.94 mL, 17.62 mmol) and the mixture was stirred at 80° C. for 20 min. Water and DCM were added and the phases separated. The aqueous phase was extracted with DCM and the combined organic layers were filtered through a phase separator and evaporated. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 15-55% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. Trans-methyl 2-(cyclohexyloxymethyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (121 mg, 63%) was isolated. MS m/z 339 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:6]=[CH:7][C:8]=1OS(C(F)(F)F)(=O)=O.[CH3:23][C:24]1[C:25](B(O)O)=[CH:26][S:27][CH:28]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:6]=[CH:7][C:8]=1[C:25]1[C:24]([CH3:23])=[CH:28][S:27][CH:26]=1
Reactant: Cc1cscc1B(O)O
Reactant: CCOC(=O)Cc1ccc(OS(=O)(=O)C(F)(F)F)c(OC)c1
Product: CCOC(=O)Cc1ccc(-c2cscc2C)c(OC)c1
Yield: 72 %

Procedure:
Prepared in a similar manner to example 1 from ethyl 2-(3-methoxy-4-(trifluoromethylsulfonyloxy)phenyl)acetate (example 27d) and 4-methylthiophen-3-ylboronic acid. Yield: 72%. 1H NMR (400 MHz, dMSO): δ 1.19-1.22 (m, 3H), 2.00 (s, 3H), 3.62 (s, 2H), 3.69-3.73 (m, 3H), 4.08-4.13 (m, 2H), 6.86-6.88 (d, 1H), 6.98-6.99 (d, 1H), 7.08-7.10 (d, 1H), 7.16-7.17 (t, 1H), 7.26-7.27 (d,1H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@@H:11]1[CH2:14][C@H:13]([NH:15][C:16](=[O:27])[C:17]([C:20]2[C:25](Cl)=[N:24][CH:23]=[CH:22][N:21]=2)([CH3:19])[CH3:18])[CH2:12]1.CC(C)([O-])C.[Na+]>CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C.CC(OC)(C)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].O1CCOCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@@H:11]1[CH2:14][C@H:13]([N:15]2[C:25]3=[N:24][CH:23]=[CH:22][N:21]=[C:20]3[C:17]([CH3:19])([CH3:18])[C:16]2=[O:27])[CH2:12]1
Reactant: CC(C)(C(=O)N[C@H]1C[C@@H](Nc2nc3ccccc3s2)C1)c1nccnc1Cl
Agent: Cl[Pd+]
Agent: CC(C)(C)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: COC(C)(C)C
Solvent: C1COCCO1
Product: CC1(C)C(=O)N([C@H]2C[C@@H](Nc3nc4ccccc4s3)C2)c2nccnc21
Temperature: 80 °C
Reaction time: 5 h
Yield: 48.2 %

Procedure:
To a glass microwave reaction vessel was added N-(cis-3-(benzo[d]thiazol-2-ylamino)cyclobutyl)-2-(3-chloropyrazin-2-yl)-2-methylpropanamide (0.3181 g, 0.791 mmol), RuPhos Precatalyst (0.035 g, 0.047 mmol, Strem Chemicals, Inc.), and sodium tert-butoxide (0.152 g, 1.583 mmol, Sigma-Aldrich Chemical Company, Inc.) in dry dioxane (0.791 ml) to stir at 80° C. for 5 h. The crude product was purified by reverse-phase preparative HPLC using 0.1% TFA in CH3CN/H2O, gradient 10% to 90% over 12 mins. The collected fractions were evaporated and the residue was taken up in DCM and filtered through a Silicycle Si-Carbonate cartridge to remove any salts to give the title compound (139.2 mg, 0.381 mmol, 48.1% yield). LCMS showed product peak at 1.607 min (m+1=366.0). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.35 (s, 6 H) 2.74 (qd, J=7.86, 2.64 Hz, 2 H) 3.00 (qd, J=9.13, 2.74 Hz, 2 H) 4.12-4.27 (m, 1 H) 4.55-4.69 (m, 1 H) 7.04 (td, J=7.58, 1.08 Hz, 1 H) 7.24 (td, J=7.68, 1.27 Hz, 1 H) 7.36-7.44 (m, 1 H) 7.69 (dd, J=7.83, 0.78 Hz, 1 H) 8.15-8.23 (m, 2 H) 8.49 (d, J=6.65 Hz, 1 H)
Reaction SMILES: [C:1]1([CH2:7][CH2:8][S:9]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][NH2:19])[CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:20][C:21]1[C:26](Cl)=[N:25][CH:24]=[CH:23][N:22]=1>>[Cl:20][C:21]1[C:26]([NH:19][CH2:18][CH:15]2[CH2:14][CH2:13][N:12]([S:9]([CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:10])=[O:11])[CH2:17][CH2:16]2)=[N:25][CH:24]=[CH:23][N:22]=1
Reactant: NCC1CCN(S(=O)(=O)CCc2ccccc2)CC1
Reactant: Clc1nccnc1Cl
Product: O=S(=O)(CCc1ccccc1)N1CCC(CNc2nccnc2Cl)CC1

Procedure:
EXAMPLE 89 was prepared from C-[1-(2-phenyl-ethanesulfonyl)-piperidin-4-yl]-methylamine and 2,3-dichloropyrazine (refluxing 2-butanol):
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[H-].[Na+].[Cl:12][C:13]1[CH:18]=[C:17]([N+]([O-])=O)[CH:16]=[CH:15][N:14]=1>>[Cl:12][C:13]1[CH:18]=[C:17]([O:9][C:3]2[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[CH:16]=[CH:15][N:14]=1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Reactant: Cc1cccc(C)c1O
Agent: [H-]
Agent: [Na+]
Product: Cc1cccc(C)c1Oc1ccnc(Cl)c1
Yield: 96.3 %

Procedure:
Using the method of Example 3, Step A, 2,6-dimethylphenol (0.771 g, 6.31 mmol), 60% sodium hydride in mineral oil (252 mg, 6.31 mmol), and 2-chloro-4-nitropyridine (1.00 g, 6.31 mmol) were reacted to provide 2-chloro-4-(2,6-dimethylphenoxy)pyridine (1.42 g, 96% yield) as a white solid. 1H NMR (CDCl3) δ 8.20 (d, 1H), 7.12 (s, 4H), 6.65-6.68 (m, 2H), 2.11 (s, 6H).
Reaction SMILES: [N:1]1([C:6](=[O:8])[CH3:7])[CH2:5][CH:4]=[CH:3][CH2:2]1.[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14](I)[CH:15]=1.C(N(CC)CC)C.C(O)=O>CN(C=O)C.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.O>[Br:9][C:10]1[CH:15]=[C:14]([CH:3]2[CH2:4][CH2:5][N:1]([C:6](=[O:8])[CH3:7])[CH2:2]2)[CH:13]=[N:12][CH:11]=1
Reactant: CC(=O)N1CC=CC1
Reactant: Brc1cncc(I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O=CO
Solvent: O
Product: CC(=O)N1CCC(c2cncc(Br)c2)C1
Temperature: 90 °C
Reaction time: 24 h
Yield: 14.7 %

Procedure:
A mixture of 1-(2,5-dihydro-pyrrol-1-yl)-ethanone (70 mg, 0.63 mmol), 3-bromo-5-iodo-pyridine (283 mg, 1 mmol), triethyl amine (130 mg, 1.26 mmol), formic acid (41 mg, 0.88 mmol) and tetrakis(triphenylphosphine)palladium(0) (72.8 mg, 0.063 mmol) in DMF (3 mL) was stirred for 24 hours at 90° C. under nitrogen. After cooling to room temperature, the mixture was treated with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate. After removal of solvents, the residue was purified by flash chromatography to afford the title compound as yellowish oil (25 mg, 15%). MS: 269.1 (M+H+).
Reaction SMILES: [C:1](=[O:26])([O:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[CH:23][C:22](=[O:25])[NH:21][N:20]=2)[CH2:15][CH2:14]1)OC1C=CC([N+]([O-])=O)=CC=1.[CH:27]1([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH2:30][CH2:29][CH2:28]1>C(Cl)Cl>[CH:27]1([N:31]2[CH2:36][CH2:35][N:34]([C:1]([O:12][CH:13]3[CH2:14][CH2:15][N:16]([C:19]4[CH:24]=[CH:23][C:22](=[O:25])[NH:21][N:20]=4)[CH2:17][CH2:18]3)=[O:26])[CH2:33][CH2:32]2)[CH2:30][CH2:29][CH2:28]1
Reactant: C1CC(N2CCNCC2)C1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1CCN(c2ccc(=O)[nH]n2)CC1
Solvent: ClCCl
Product: O=C(OC1CCN(c2ccc(=O)[nH]n2)CC1)N1CCN(C2CCC2)CC1
Temperature: 30 °C
Reaction time: 2 h

Procedure:
To a solution of 4-nitrophenyl 1-(6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl carbonate (440 mg, 1.22 mmol) in DCM (20 mL) was added TEA (616 mg, 6.1 mmol) and 1-cyclobutylpiperazine (388 mg, 1.83 mmol). The resulting mixture was stirred at 30° C. for 2 h before it was concentrated to dryness. The title compound was obtained as a white solid after silica gel chromatography (DCM/MeOH=50/1 to 5/1) (410 mg, 93%). [1H NMR (400 MHz, CDCl3) δ 11.20 (s, 1H), 7.20 (d, J=10 Hz, 1H), 6.87 (d, J=10 Hz, 1H), 4.87˜4.92 (m, 1H), 3.45˜3.50 (m, 6H), 3.16˜3.23 (m, 2H), 2.68˜2.76 (m, 1H), 2.29 (br, 4H), 1.72˜2.07 (m, 10H); LCMS: Rt=1.36 min, m/z 362.3 (M+H)+].
Reaction SMILES: C[O:2][C:3]([C:5]1[C:9]2=[N:10][C:11]([C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=4)[N:16]([CH3:27])[N:15]=3)=[CH:12][N:13]=[C:8]2[N:7](COC(=O)C(C)(C)C)[CH:6]=1)=[O:4].[OH-].[Na+]>O1CCOCC1.O>[CH3:26][S:23]([C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:27])[N:15]=[C:14]2[C:11]1[N:10]=[C:9]2[C:5]([C:3]([OH:4])=[O:2])=[CH:6][NH:7][C:8]2=[N:13][CH:12]=1)(=[O:25])=[O:24]
Reactant: COC(=O)c1cn(COC(=O)C(C)(C)C)c2ncc(-c3nn(C)c4ccc(S(C)(=O)=O)cc34)nc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2cc(S(C)(=O)=O)ccc21
Temperature: 85 °C
Reaction time: 4 h
Yield: 67.3 %

Procedure:
To a suspension of methyl2-(1-methyl-5-(methylsulfonyl)-1H-indazol-3-yl)-5-(pivaloyloxymethyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylate (80 mg, 0.16 mmol) in dioxane/water (6 mL/4 mL) was added NaOH (100 mg, 2.5 mmol), the reaction mixture was heated to 85° C. with stirring for 4 hours, the dioxane was removed under reduced pressure, the aqueous layer was adjusted to pH=4 with 2 N HCl. The formed precipitate was collected by filtration, washed with water (3 mL) and dried to afford 2-(5-methanesulfonyl-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (40 mg, 67.7%) as an orange solid. LCMS: (M+H)+=372; 1H NMR (300 MHz, DMSO): δ 12.89 (d, 1H, J=2.7 Hz), 12.49 (brs, 1H), 9.47 (s, 1H), 9.08 (s, 1H), 8.50 (d, 2H, J=3.3 Hz), 8.01-7.95 (m, 1H), 4.23 (s, 3H), 3.27 (s, 3H).
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[CH2:9][CH2:8][C:7]3[S:10][C:11]([NH:13][C:14]([CH:16]4[C:18]([CH3:20])([CH3:19])[C:17]4([CH3:22])[CH3:21])=[O:15])=[N:12][C:6]=3[C:5]=12.CC(C)([O-])C.[K+].[CH3:29][O:30][CH2:31][CH2:32]Br>CN(C=O)C.CCOC(C)=O>[CH3:29][O:30][CH2:31][CH2:32][N:12]1[C:6]2[C:5]3=[N:1][O:2][N:3]=[C:4]3[CH2:9][CH2:8][C:7]=2[S:10]/[C:11]/1=[N:13]\[C:14]([CH:16]1[C:18]([CH3:20])([CH3:19])[C:17]1([CH3:22])[CH3:21])=[O:15]
Reactant: CC1(C)C(C(=O)Nc2nc3c(s2)CCc2nonc2-3)C1(C)C
Reactant: COCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCn1c2c(s/c1=N\C(=O)C1C(C)(C)C1(C)C)CCc1nonc1-2
Temperature: 250 °C

Procedure:
The product of Example 123B (1 equiv), potassium tert-butoxide (1.1 equiv) and 2-bromoethyl methyl ether (1 equiv) were combined in DMF (0.1 M) and heated in a SmithSynthesizer™ microwave at 250° C. for 15 minutes. The mixture was diluted with EtOAc and washed with 1 M aqueous NaHCO3. The phases were separated and the aqueous phase was extracted with EtOAc (3×). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. Purification by silica gel chromatography afforded the title compound and the product of Example 124. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.20 (s, 6H), 1.26 (s, 6H), 1.57 (s, 1H), 3.10 (t, J=7.5 Hz, 2H), 3.23 (s, 3H), 3.26 (t, J=7.4 Hz, 2H), 3.71 (t, J=5.8 Hz, 2H), 4.67 (t, J=5.8 Hz, 2H); MS (ESI+) m/z 377 (M+H)+.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1)#[N:2].Cl.[C:11]1([NH:17]N)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)(=O)C>[C:1]([CH:3]1[CH2:8][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:17][C:6]=2[CH2:5][CH2:4]1)#[N:2]
Reactant: NNc1ccccc1
Reactant: N#CC1CCC(=O)CC1
Agent: Cl
Solvent: CC(=O)O
Product: N#CC1CCc2[nH]c3ccccc3c2C1
Yield: 50 %

Procedure:
A mixture of 4-cyano-cyclohexanone (0.48 g, 3.9 mmol) and phenylhydrazine hydrochloride (0.42 g, 3.9 mmol) in glacial acetic acid (5 ml) is stirred at reflux for 1 h. The solvent is evaporated and the residue chromatographed on silica gel (heptane/EtOAc 2:1) to deliver the title compound as a brownish solid (158 mg) in 50% yield. tR (LC-5) 0.91 min; ESI-MS (positive ion): m/z 197.10 [M+H]+ (calcd 196.25 for C13H12N2). 1H-NMR (CDCl3): 2.25 (m, 2H); 2.96 (m, 5H); 7.14 (m, 2H); 7.30 (d, J=7.7 Hz, 1H); 7.45 (d, J=7.1 Hz, 1H); 7.79 (br s, 1H).
Reaction SMILES: [F:1][C:2]([F:18])([C:9]([F:17])([F:16])[C:10]([F:15])([F:14])[CH:11]([F:13])[F:12])[CH2:3][CH:4]([C:7]#[N:8])[C:5]#[N:6].Br[CH2:20][CH2:21][CH:22]([Br:24])[CH3:23].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[Br:24][CH:22]([CH3:23])[CH2:21][CH2:20][C:4]([CH2:3][C:2]([F:18])([F:1])[C:9]([F:16])([F:17])[C:10]([F:14])([F:15])[CH:11]([F:13])[F:12])([C:7]#[N:8])[C:5]#[N:6]
Reactant: CC(Br)CCBr
Reactant: N#CC(C#N)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(Br)CCC(C#N)(C#N)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 57.8 %

Procedure:
1.4 g of 2-(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile and 2.2 g of 1,3-dibromobutane were dissolved in 10 ml of dimethyl sulfoxide, 0.83 g of potassium carbonate was added, and the mixture was stirred at room temperature for 4 hours. Thereafter, dilute hydrochloric acid was added to the reaction mixture, followed by extraction with methyl tert-butyl ether. The organic layer was washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.2 g of 2-(3-bromobutyl)-2-(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile (hereinafter, referred to as the present compound (62)).