Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]([CH:8]([CH3:16])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:4](=[O:17])[CH:3]=1.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1B(O)O>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>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[C:2]1[CH:7]=[CH:6][N:5]([CH:8]([CH3:16])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:4](=[O:17])[CH:3]=1
Reactant: OB(O)c1cc(Cl)ccc1Br
Reactant: CC(C(=O)OC(C)(C)C)n1ccc(Br)cc1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CC(C(=O)OC(C)(C)C)n1ccc(-c2cc(Cl)ccc2Br)cc1=O

Procedure:
856 mg (2.75 mmol) of tert-butyl 2-(4-bromo-2-oxopyridin-1(2H)-yl)propanoate (racemate) and 776 mg (3.3 mmol) of 2-bromo-5-chlorophenylboronic acid in the presence of tetrakis(triphenylphosphine)palladium(0) were reacted according to General Method 2A. Yield: 921 mg (80% of theory)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8](Br)[N:7]=1)=[O:5])[CH3:2].[CH:13]1(B(O)O)[CH2:15][CH2:14]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:13]2[CH2:15][CH2:14]2)[N:7]=1)=[O:5])[CH3:2]
Reactant: OB(O)C1CC1
Reactant: CCOC(=O)c1cccc(Br)n1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cccc(C2CC2)n1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a mixture of 2.90 g (12.6 mmol) 6-bromo-pyridine-2-carboxylic acid ethyl ester in 25 mL toluene was added 3.00 g (29.7 mmol) cyclopropylboronic acid and 5.50 g (25.9 mmol) potassium phosphate followed by 700 mg (0.957 mmol) 1,1′-bis(diphenylphosphino)-ferrocenedichloropalladium(II). The reaction mixture was stirred at 100° C. for 8 h. 1.00 g (9.90 mmol) of cyclopropylboronic acid and 1.50 g (7.07 mmol) of potassium phosphate were added and the mixture was stirred at 100° C. for 5 h. The reaction mixture was filtered through Celite, and washed with DCM and the solvent was evaporated in vacuo. The crude material was purified by flash chromatography (PE/EtOAc=4/1→2/1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.Cl.C(N=C=NCCCN(C)C)C.[NH2:22][C:23]1[CH:34]=[CH:33][C:26]([C:27]([N:29]([O:31][CH3:32])[CH3:30])=[O:28])=[C:25]([F:35])[CH:24]=1>N1C=CC=CC=1>[F:35][C:25]1[CH:24]=[C:23]([NH:22][C:7]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)=[O:9])[CH:34]=[CH:33][C:26]=1[C:27]([N:29]([O:31][CH3:32])[CH3:30])=[O:28]
Reactant: O=C(O)c1cnccn1
Reactant: CON(C)C(=O)c1ccc(N)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Product: CON(C)C(=O)c1ccc(NC(=O)c2cnccn2)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.56 g of pyrazine-2-carboxylic acid and 4.66 g of 1-ethyl-3-(3′-dimethylaminopropyl)-carbodiimide hydrochloride were added to a pyridine (20 ml) solution of 3.7 g of 4-amino-2-fluoro-N-methoxy-N-methylbenzamide, and the reaction liquid was stirred at room temperature for 1 hour. Pyridine was evaporated away under reduced pressure, and the residue was diluted with ethyl acetate, washed with water, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the resulting solid was washed with a mixed solvent of ethyl acetate and hexane to obtain the entitled compound as a pale yellow solid.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]([OH:8])=O)(=[O:3])[CH3:2].[C:9]([CH:11]1[CH2:13][NH:12]1)#[N:10].C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[C:1]([NH:4][CH2:5][C:6]([N:12]1[CH2:13][CH:11]1[C:9]#[N:10])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)NCC(=O)O
Reactant: N#CC1CN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CC(=O)NCC(=O)N1CC1C#N

Procedure:
5.85 g. N-Acetylglycine, 3.4 g. 2-cyanoaziridine and 10.8 g. dicyclohexylcarbodiimide are stirred in 60 ml. tetrahydrofuran for 2 hours at ambient temperature. The precipitated dicyclohexylurea is filtered off, the filtrate is evaporated and the residue is stirred with diethyl ether, 5.2 g. of crude product thus being obtained. This water-soluble product is recrystallized from methanolic diethyl ether to give 1-(N-acetylglycyl)-2-cyanoaziridine, which melts at 102°-104° C.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12]([OH:14])=O)[CH:10]=[CH:11][C:5]=2[O:4][CH2:3]1.[CH3:15][O:16][C:17]1[CH:26]=[C:25]2[C:20]([N:21]=[CH:22][C:23]([S:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]3)=[N:24]2)=[CH:19][CH:18]=1>>[CH3:15][O:16][C:17]1[CH:26]=[C:25]2[C:20]([N:21]=[CH:22][C:23]([S:27][CH2:28][CH2:29][N:30]3[CH2:31][CH2:32][CH:33]([NH:36][C:12]([C:9]4[CH:10]=[CH:11][C:5]5[O:4][CH2:3][C:2](=[O:1])[NH:7][C:6]=5[CH:8]=4)=[O:14])[CH2:34][CH2:35]3)=[N:24]2)=[CH:19][CH:18]=1
Reactant: COc1ccc2ncc(SCCN3CCC(N)CC3)nc2c1
Reactant: O=C1COc2ccc(C(=O)O)cc2N1
Product: COc1ccc2ncc(SCCN3CCC(NC(=O)c4ccc5c(c4)NC(=O)CO5)CC3)nc2c1

Procedure:
The title compound is prepared as an off-white solid (42 mg, 38% yield) following Scheme 3 and in analogy to Example 35 using 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid (42 mg, 0.22 mmol 1.0 eq) and 1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-ylamine (70 mg, 0.22 mmol, 1.0 eq) as starting materials.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:6](=[N:8][NH2:9])[CH3:7])[CH3:5].[O:10]1[CH2:15][CH2:14][O:13][C:12]([C:16](=[N:25][O:26][CH3:27])[C:17]2[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=2[CH:19]=O)=[N:11]1>C(O)C>[CH3:1][O:2][N:3]=[C:4]([C:6](=[N:8][N:9]=[CH:19][C:18]1[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=1[C:16]([C:12]1[O:13][CH2:14][CH2:15][O:10][N:11]=1)=[N:25][O:26][CH3:27])[CH3:7])[CH3:5]
Reactant: CON=C(C1=NOCCO1)c1ccccc1C=O
Reactant: CON=C(C)C(C)=NN
Solvent: CCO
Product: CON=C(C)C(C)=NN=Cc1ccccc1C(=NOC)C1=NOCCO1
Temperature: 20 °C
Yield: 64.2 %

Procedure:
0.5 g (0.0039 mol) of 3-hydrazono-butan-2-one O-methyl oxime is boiled under reflux in 5 ml of ethanol with 0.96 g (0.0039 mol) of 2-[(5,6-dihydro-[1,4,2]dioxazin-3-yl)-methoxyimino-methyl]-benzaldehyde for 2 hours. The reaction mixture is allowed to cool slowly to 20° C. and the crystals are filtered off to give 0.9 g (64.7% of theory) of 3-({2-[(5,6-dihydro-[1,4,2]dioxazin-3-yl)-methoxyimino-methyl]-benzylidene}-hydrazono)-butan-2-one O-methyl oxime.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4]/[N:5]=[C:6](/[C:8]1[N:13]=[C:12]2[N:14]([CH2:17][C:18]3[CH:19]=[C:20]4[C:25](=[CH:26][CH:27]=3)[N:24]=[CH:23][CH:22]=[CH:21]4)[N:15]=[N:16][C:11]2=[N:10][CH:9]=1)\[CH3:7].Cl[C:29]([O:31][CH3:32])=[O:30].C(N(CC)CC)C>C(Cl)Cl>[N:24]1[C:25]2[C:20](=[CH:19][C:18]([CH2:17][N:14]3[C:12]4=[N:13][C:8](/[C:6](=[N:5]/[O:4][CH2:3][CH2:2][NH:1][C:29](=[O:30])[O:31][CH3:32])/[CH3:7])=[CH:9][N:10]=[C:11]4[N:16]=[N:15]3)=[CH:27][CH:26]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)Cl
Reactant: C/C(=N\OCCN)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)NCCO/N=C(\C)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Temperature: 25 °C
Reaction time: 10 h
Yield: 47.6 %

Procedure:
To a solution of (E)-1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone O-2-aminoethyl oxime (example 34) (6 mg, 0.017 mmol) in DCM (5 mL) were added methyl chloroformate (2.66 mg, 0.028 mmol) and triethyl amine (3.35 mg, 0.033 mmol). The mixture was stirred at rt for 10 h. After concentration, the crude was purified by chromatography on silica gel to afford 3.4 mg (46%) of the title compound. 1H-NMR (400 MHz, CDCl3) δ ppm 9.41 (s, 1H), 8.93 (s, 1H), 8.14 (dd, 2H), 7.92 (s, 1H), 7.84 (dd, 1H), 7.44 (m, 1H), 6.12 (s, 2H), 4.42 (t, 2H), 3.69 (s, 3H), 3.60 (m, 2H), 2.39 (s, 3H). LCMS (method B): [MH]+=421, tR=1.95 min.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](=[O:11])[NH:9][N:10]=2)[N:7]=1.[CH2:12]([NH2:16])[CH2:13][CH2:14][CH3:15]>>[CH2:12]([NH:16][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](=[O:11])[NH:9][N:10]=2)[N:7]=1)[CH2:13][CH2:14][CH3:15]
Reactant: O=c1[nH]nc2ccc(Cl)nn12
Reactant: CCCCN
Product: CCCCNc1ccc2n[nH]c(=O)n2n1

Procedure:
17 g. of 6-chloro-1,2,4-triazolo[4,3-b]pyridazin-3(2H)-one (0.1 mol.) and 150 ml. of n-butylamine are refluxed for 5 hours. The clear solution is evaporated in vacuo and the oily residue is dissolved in 250 ml. of water. After treating with charcoal, the aqueous solution is acidified with dilute hydrochloric acid to give 18.6 g. (90%) of 6-butylamino-1,2,4-triazolo[4,3-b]pyridazin-3(2H)-one, which, after recrystallization from a mixture of acetonitrile and methanol (1:1), melts at 259°-261° .
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:7][N:6]1[S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[O:4].[I-].[Na+].[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]=[C:24]=[O:25]>>[CH3:1][O:2][C:3]([CH:5]1[CH2:7][N:6]([S:8]([CH:11]([CH3:12])[CH3:13])(=[O:9])=[O:10])[C:24](=[O:25])[N:23]1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[Cl:16])=[O:4]
Reactant: O=C=Nc1ccccc1Cl
Reactant: COC(=O)C1CN1S(=O)(=O)C(C)C
Agent: [I-]
Agent: [Na+]
Product: COC(=O)C1CN(S(=O)(=O)C(C)C)C(=O)N1c1ccccc1Cl

Procedure:
In analogy to example 1, the crude 1-(propane-2-sulfonyl)-aziridine-2-carboxylic acid methyl ester from example 82, step 1 was reacted with sodium iodide and 2-chlorophenyl isocyanate to give (RS)-3-(2-chloro-phenyl)-2-oxo-1-(propane-2-sulfonyl)-imidazolidine-4-carboxylic acid methyl ester as a light yellow oil. MS: 361.1 ([M+H]+)
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][S:7][C:8]2[C:9](=[O:17])[CH2:10][C:11]([CH3:16])([CH3:15])[CH2:12][C:13]=2[OH:14])=[CH:4][CH:3]=1.[OH:20]O>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][S:7]([C:8]2[C:13](=[O:14])[CH2:12][C:11]([CH3:16])([CH3:15])[CH2:10][C:9]=2[OH:17])=[O:20])=[CH:18][CH:19]=1
Reactant: OO
Reactant: CC1(C)CC(=O)C(SCc2ccc(Cl)cc2)=C(O)C1
Solvent: CC(=O)O
Product: CC1(C)CC(=O)C(S(=O)Cc2ccc(Cl)cc2)=C(O)C1
Temperature: 0 °C
Reaction time: 23 h

Procedure:
A mixture of 2-(p-chlorobenzylthio)-3-hydroxy-5,5-dimethyl-2-cyclohexen-1-one (10.0 g., 0.0338 mole), 30 percent hydrogen peroxide (3.83 g., 0.0338 mole), and 350 ml. of glacial acetic acid was allowed to stand at room temperature for 23 hours. The solution was poured into ice water, and the precipitated pink solid was filtered and dried (10 g., m.p. 143.5°-145°C.).
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.[F:17][C:18]([F:27])([F:26])[C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22]>>[F:17][C:18]([F:26])([F:27])[C:19]1[CH:20]=[C:21]([NH:22][C:2]2[CH:16]=[CH:15][C:5]3[C:6](=[O:14])[NH:7][C:8]4[C:13]([C:4]=3[CH:3]=2)=[CH:12][CH:11]=[CH:10][N:9]=4)[CH:23]=[CH:24][CH:25]=1
Reactant: O=c1[nH]c2ncccc2c2cc(Cl)ccc12
Reactant: Nc1cccc(C(F)(F)F)c1
Product: O=c1[nH]c2ncccc2c2cc(Nc3cccc(C(F)(F)F)c3)ccc12
Yield: 2.6 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 231 using 6 (50 mg, 0.22 mmol) and 3-(trifluoromethyl)aniline (0.04 mL, 0.33 mmol) to provide 239 (2 mg, 3% yield) as a brown solid. LC-MS (M+H=356, obsd.=356).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]([C:13]([O:15]CC)=O)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:18][NH2:19]>CCO>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]([C:13]([NH:18][NH2:19])=[O:15])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NN
Reactant: CCOC(=O)c1cc(-c2cccc(F)c2)on1
Solvent: CCO
Product: NNC(=O)c1cc(-c2cccc(F)c2)on1
Temperature: 80 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
To a solution of ethyl 5-(3-fluorophenyl)isoxazole-3-carboxylate (25.8 g, 110 mmol, 1.0 equiv.) in EtOH (300 mL), was added hydrazine (10.5 mL, 330 mmol, 3.0 equiv.). The mixture was stirred at 80° C. for 1 h and then cooled to RT The precipitate was filtered, washed with H2O, and dried in vacuum to give 5-(3-fluorophenyl)isoxazole-3-carbohydrazide (20 g). The filtrate was concentrated and the resulting residue was purified on RP-HPLC using a mixture of acetonitrile and H2O to give desired product (2.5 g). LRMS (M+H+) m/z 222.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]23[CH2:18][CH2:17][CH2:16][CH:15]=[C:14]2[C:13](=[O:19])[NH:12][C:11](=[O:20])[CH2:10]3)[CH:6]=[CH:7][CH:8]=1.[H][H]>C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@@:9]23[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]2[C:13](=[O:19])[NH:12][C:11](=[O:20])[CH2:10]3)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C23CCCC=C2C(=O)NC(=O)C3)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1cccc([C@@]23CCCC[C@H]2C(=O)NC(=O)C3)c1

Procedure:
A solution of 4a-(m-methoxyphenyl)-1,3-diketo-1,2,3,4,4a,5,6,7-octahydroisoquinoline (6.0 g) in 250 ml of glacial acetic acid was treated with 1 g of 5% palladium on carbon and the mixture hydrogenated under 40 psi of hydrogen for 24 hours in a Parr shaker. The catalyst was then filtered off and the filtrate evaporated. The residual 4a-(m-methoxyphenyl)-1,3-diketo-trans-decahydroisoquinoline was recrystallized from ethanol, m.p. 189-190.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:23]2[N:27]=[CH:26][NH:25][N:24]=2)=[C:5]([NH:8][C:9](=[O:22])[CH2:10][N:11]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH2:13][C:12]2=[O:21])[S:6][CH:7]=1)#[N:2].[Si](C=[N+]=[N-])(C)(C)[CH3:29]>CO.C(Cl)Cl>[C:1]([C:3]1[C:4]([C:23]2[N:27]=[CH:26][N:25]([CH3:29])[N:24]=2)=[C:5]([NH:8][C:9](=[O:22])[CH2:10][N:11]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH2:13][C:12]2=[O:21])[S:6][CH:7]=1)#[N:2]
Reactant: N#Cc1csc(NC(=O)CN2C(=O)CCc3ncccc32)c1-c1nc[nH]n1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Solvent: CO
Product: Cn1cnc(-c2c(C#N)csc2NC(=O)CN2C(=O)CCc3ncccc32)n1
Reaction time: 4 h

Procedure:
N-(4-cyano-3-(1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetamide (180 mg, 0.475 mmol) was dissolved in MeOH/CH2Cl2 (1:1, 4 mL total), and TMSCHN2 (Aldrich, 2.0 M in diethyl ether, 8 mL, 16 mmol) was added at rt. This was stirred for 4 h, whereupon the reaction mixture was concentrated under reduced pressure. The crude residue was purified by HPLC to give a white solid as a trifluoroacetic acid salt: method [11], retention time=7.56 min; MS (ESI) 394.2 (MH+); 1H NMR (300 MHz, CD3OD) 8.41 (s, 1H), 8.25 (d, J=5.0 Hz, 1H), 7.87 (s, 1H), 7.72 (d, J=8.7 Hz, 1H), 7.52-7.42 (m, 1H), 4.98 (s, 2H), 3.97 (s, 3H), 3.40-3.20 (m, 2H), 2.96 (t, J=8.3 Hz, 2H).
Reaction SMILES: [F:1][CH2:2][C:3]([CH3:12])([C:8]([F:11])([F:10])[F:9])[C:4]([OH:7])([F:6])[F:5].C(N(CC)CC)C.F[C:21](=[CH2:25])[C:22](F)=[O:23]>C(Cl)(Cl)Cl>[C:22]([O:7][C:4]([F:5])([F:6])[C:3]([CH3:12])([CH2:2][F:1])[C:8]([F:9])([F:10])[F:11])(=[O:23])[CH:21]=[CH2:25]
Reactant: CC(CF)(C(O)(F)F)C(F)(F)F
Reactant: C=C(F)C(=O)F
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C=CC(=O)OC(F)(F)C(C)(CF)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.7 %

Procedure:
Into a 200-ml, four-necked glass flask provided with a thermometer, a dropping funnel, a stirrer and a reflux condenser were placed 58.83 g (0.3 mol) of hexafluoroneopentyl alcohol, 30.36 g (0.3 mol) of triethylamine and 50 g of chloroform. Subsequently, to the mixture was added dropwise 30.37 g (0.33 mol) of 2-fluoroacrylic fluoride at a temperature of up to 10° C. with ice-cooling. After addition, the mixture was stirred at room temperature for 30 minutes. The mixture was washed with an aqueous solution of sodium bicarbonate (5%) and then with pure water, followed by evaporation to remove chloroform, producing hexafluoroneopentyl acrylate. The amount of the obtained product was 67.17 g and the yield was 76.7%. To the product was further added 0.1 g of t-butyl catechol as a polymerization inhibitor and the mixture was distilled under reduced pressure for purification. The boiling point was 55° to 56° C./20 mm.Hg. The identification was performed with 1H-NMR spectrum, 19F-NMR spectrum and 13C-NMR spectrum (in every case, sovent: acetone-d6).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C@@H:15]([N:17]3[CH2:22][CH2:21][C@:20]([CH2:29][C:30]([OH:33])([CH3:32])[CH3:31])([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[O:19][C:18]3=[O:34])[CH3:16])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[NH2:8].[C:35](O)(=O)[CH3:36]>>[OH:33][C:30]([CH3:31])([CH3:32])[CH2:29][C@@:20]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[O:19][C:18](=[O:34])[N:17]([C@H:15]([C:12]2[CH:11]=[CH:10][C:9]([C:4]3[CH:5]=[CH:6][C:7]4[N:8]=[C:35]([CH3:36])[NH:1][C:2]=4[CH:3]=3)=[CH:14][CH:13]=2)[CH3:16])[CH2:22][CH2:21]1
Reactant: C[C@@H](c1ccc(-c2ccc(N)c(N)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: CC(=O)O
Product: Cc1nc2ccc(-c3ccc([C@H](C)N4CC[C@](CC(C)(C)O)(c5ccccc5)OC4=O)cc3)cc2[nH]1
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
3-[(S)-1-(3′,4′-Diamino-biphenyl-4-yl)-ethyl]-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one (120 mg) taken up in acetic acid (2 mL) was stirred under microwave irradiation at 150° C. for 30 min. After cooling to ambient temperature, the mixture was concentrated under reduced pressure and the residue was purified by HPLC on reversed phase (MeCN/H2O) to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18](=[O:23])[CH:17]=[C:16]4[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=3)OCC[O:9]2)=[CH:4][CH:3]=1>Cl.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[NH:19][C:18](=[O:23])[CH:17]=[C:16]3[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: COc1cccc(-c2cc(=O)[nH]c3ccc(C4(c5ccc(Cl)cc5)OCCO4)cc23)c1
Agent: Cl
Solvent: CO
Product: COc1cccc(-c2cc(=O)[nH]c3ccc(C(=O)c4ccc(Cl)cc4)cc23)c1
Yield: 69.9 %

Procedure:
A mixture of interm. (5-e) (43 g) in HCl (3N, 400 ml) and methanol (150 ml) was stirred and refluxed overnight. The mixture was cooled and filtered off. The precipitate was washed with water and diethyl ether and dried. The product was used without further purification, yielding 27 g (94%) of 6-(4-chlorobenzoyl)-4-(3-methoxyphenyl)-2(1H)-quinolinone (interm. 5-f).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:13]2[N:14]=[C:15]([C:18]3[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=3[F:25])[CH:16]=[CH:17][C:12]2=[CH:11][N:10]=1.[OH:26][C:27]1[N:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1.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>[F:25][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]([F:24])[C:18]=1[C:15]1[CH:16]=[CH:17][C:12]2[N:13]([C:9]([NH:8][C:3]3[CH:4]=[N:5][CH:6]=[CH:7][C:2]=3[C:30]3[CH:29]=[CH:28][C:27](=[O:26])[NH:32][CH:31]=3)=[N:10][CH:11]=2)[N:14]=1
Reactant: OB(O)c1ccc(O)nc1
Reactant: Fc1cccc(F)c1-c1ccc2cnc(Nc3cnccc3Cl)n2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=c1ccc(-c2ccncc2Nc2ncc3ccc(-c4c(F)cccc4F)nn23)c[nH]1
Temperature: 120 °C
Yield: 2.2 %

Procedure:
A glass microwave reaction vessel was charged with N-(4-chloro-3-pyridinyl)-2-(2,6-difluorophenyl)imidazo[1,5-b]pyridazin-7-amine (Example 27, Step 1, 40 mg, 0.11 mmol), 6-hydroxypyridin-3-ylboronic acid (19 mg, 0.13 mmol, Combi-Blocks, Inc.), Pd(PPh3)4 (13 mg, 0.01 mmol) and 2 M Na2CO3 (aq., 0.17 mL, 0.34 mmol) in dioxane (1.00 mL). The reaction was stirred and heated in a microwave at 120° C. for 20 min. H2O was added and the mixture was extracted with EtOAc (3×). The combined organic layers were dried over anh. Na2SO4, filtered and concentrated. The crude material was purified by silica gel chromatography (0-5% MeOH in CH2Cl2) to provide 3′-((2-(2,6-difluorophenyl)imidazo[1,5-b]pyridazin-7-yl)amino)-3,4′-bipyridin-6(1 H)-one (1 mg, 2.40 μmol, 2% yield) as a yellow solid. MS (ESI, pos. ion) m/z: 416.9 (M+1). 1H NMR (400 MHz, MeOH-d4) δ ppm 8.82 (s, 1 H), 8.30 (d, J=5.09 Hz, 1 H), 7.96 (d, J=9.39 Hz, 1 H), 7.74 (dd, J=9.59, 2.54 Hz, 1 H), 7.55-7.64 (m, 2 H), 7.37 (d, J=5.09 Hz, 1 H), 7.24 (s, 1 H), 6.69 (d, J=9.39 Hz, 1 H), 6.44 (d, J=9.39 Hz, 1 H).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH:19]([CH2:23][C:24]4[CH:25]=[C:26]([CH:34]=[CH:35][CH:36]=4)[O:27][CH2:28][C:29]([O:31]CC)=[O:30])[CH2:20][CH2:21][CH:22]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+:38]>C(O)C>[C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH:19]([CH2:23][C:24]4[CH:25]=[C:26]([CH:34]=[CH:35][CH:36]=4)[O:27][CH2:28][C:29]([O-:31])=[O:30])[CH2:20][CH2:21][CH:22]=3)[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[Na+:38]
Reactant: CCOC(=O)COc1cccc(CC2CCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C([O-])COc1cccc(CC2CCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reaction time: 8 h

Procedure:
To a solution of ethyl [3-[[2-(4,5-diphenyloxazol-2-yl)-2-cyclopenten-1-yl]methyl]phenoxy]acetate (400 mg) in ethanol (20 ml) was added 1N-sodium hydroxide solution (0.83 ml). After being stirred for 8 hours, the solvent was evaporated in vacuo. The residue was triturated in ether to give sodium [3-[[2-(4,5-diphenyloxazol-2-yl)-2-cyclopenten-1-yl]methyl]phenoxy]acetate (350 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([CH2:24][CH3:25])[C:13]3[C:18]([C:19]=2[C:20]#[N:21])=[CH:17][CH:16]=[C:15]([O:22][CH3:23])[CH:14]=3)=[CH:7][CH:6]=1.[CH2:26]([N:28]=[C:29]=[O:30])[CH3:27]>N1C=CC=CC=1>[C:20]([C:19]1[C:18]2[C:13](=[CH:14][C:15]([O:22][CH3:23])=[CH:16][CH:17]=2)[N:12]([CH2:24][CH3:25])[C:11]=1[C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][NH:1][C:29]([NH:28][CH2:26][CH3:27])=[O:30])=[CH:6][CH:7]=1)#[N:21]
Reactant: CCn1c(-c2ccc(OCCN)cc2)c(C#N)c2ccc(OC)cc21
Reactant: CCN=C=O
Solvent: c1ccncc1
Product: CCNC(=O)NCCOc1ccc(-c2c(C#N)c3ccc(OC)cc3n2CC)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.9 %

Procedure:
2-[4-(2-Aminoethoxy)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (30 mg, 0.09 mmol), prepared as in example 1BB, was combined with ethyl isocyanate (18 μL, 0.21 mmol) and pyridine (300 μL). This mixture was stirred at room temperature for 90 minutes, and was then partitioned between EtOAc and aqueous HCl. The organic layer was dried and concentrated. Purification by silica gel chromatography (EtOAc) yielded 1-{2-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenoxy]-ethyl}-3-ethyl-urea (34 mg, 93%) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]([CH2:14][CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)C(=O)OCC)[N:5]=[C:4]2[NH:22][CH:23]=[N:24][C:3]=12.O.[NH2:26]N>>[NH2:26][C:2]1[CH:7]=[C:6]([NH:8][CH2:14][CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[N:5]=[C:4]2[NH:22][CH:23]=[N:24][C:3]=12
Reactant: NN
Reactant: CCOC(=O)N(CCC1CCCCC1)c1cc(Cl)c2nc[nH]c2n1
Solvent: O
Product: Nc1cc(NCCC2CCCCC2)nc2[nH]cnc12

Procedure:
A mixture of 100 mg ethyl N-(7-chloro-3H-imidazo[4,5-b]pyridin-5-yl)-N-(2-cyclohexylethyl)-carbamate in 1 ml of hydrazine monohydrate is heated at 120° in a sealed tube for 24 hours. The solvent is evaporated in vacuo and 5 ml of methanol saturated with ammonia is added to the residue. This is followed by 0.1 ml of a suspension of Raney nickel in methanol saturated with ammonia. The mixture is heated in a sealed tube at 130° for 24 hours. The catalyst is filtered and washed with methanol, and the solvents are evaporated in vacuo to give a residue which is purified by flash chromatography (10% methanol saturated with ammonia/methylene chloride) to give 7-amino-N-(2-cyclohexylethyl)-3H-imidazo[4,5-b]pyridin-5-amine.