Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[C:13]([F:22])=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)=[CH:9][N:10]=2)[N:7]=1.Cl.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][C:26]1=[O:31]>>[F:22][C:13]1[C:12]([CH2:11][C:8]2[N:6]3[N:7]=[C:2]([N:28]4[CH2:29][CH2:30][N:25]([CH3:24])[C:26](=[O:31])[CH2:27]4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][CH:17]=[N:18]2
Reactant: CN1CCNCC1=O
Reactant: Fc1c(Cc2cnc3ccc(Cl)nn23)ccc2ncccc12
Agent: Cl
Product: CN1CCN(c2ccc3ncc(Cc4ccc5ncccc5c4F)n3n2)CC1=O

Procedure:
The title compound was prepared in analogy to Example 38 using 6-(6-chloro-imidazo[1,2-b]pyridazin-3-ylmethyl)-5-fluoro-quinoline (Intermediate N, 70 mg, 0.224 mmol), 1-methylpiperazin-2-one hydrochloride (67.4 mg, 0.448 mmol) (tR 3.31 min (conditions 5), MH+=391, 1H-NMR in DMSO-d6: 8.91 (m, 1H); 8.47 (d, 1H); 7.85 (d, 1H); 7.78 (d, 1H); 7.69 (d, 1H); 7.66 (s, 1H); 7.61 (m, 1H); 7.50 (s, 1H); 4.42 (s, 2H); 4.03 (s, 2H); 3.74 (m, 2H); 3.35 (m, 2H); 2.84 (s, 3H)).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([NH:7][C:8]2[C:9]([C:20]([OH:22])=O)=[N:10][C:11]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:12][N:13]=2)[CH:4]=[N:3][CH:2]=1.[CH3:23][NH:24][C:25]([C:27]1[N:28]([CH3:33])[N:29]=[CH:30][C:31]=1[NH2:32])=[O:26]>>[CH3:33][N:28]1[C:27]([C:25](=[O:26])[NH:24][CH3:23])=[C:31]([NH:32][C:20]([C:9]2[C:8]([NH:7][C:5]3[CH:4]=[N:3][CH:2]=[N:1][CH:6]=3)=[N:13][CH:12]=[C:11]([O:14][CH2:15][C:16]([F:17])([F:18])[F:19])[N:10]=2)=[O:22])[CH:30]=[N:29]1
Reactant: CNC(=O)c1c(N)cnn1C
Reactant: O=C(O)c1nc(OCC(F)(F)F)cnc1Nc1cncnc1
Product: CNC(=O)c1c(NC(=O)c2nc(OCC(F)(F)F)cnc2Nc2cncnc2)cnn1C

Procedure:
The product was obtained starting from 3-(pyrimidin-5-ylamino)-6-(2,2,2-trifluoro-ethoxy)-pyrazine-2-carboxylic acid (114 mg, 0.36 mmol) and 4-amino-2-methyl-2H-pyrazole-3-carboxylic acid methylamide (67 mg, 0.43 mmol) according to the method described in example 64, step 6 as yellow solid (92 mg, 56%).
Reaction SMILES: O[C@@H:2]1[C@H:7]2[N:8]([CH:12]([O:19][CH3:20])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:9](=[O:11])[O:10][C@H:6]2[CH2:5][C@@H:4]2[CH2:21][O:22][CH:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:24][C@@H:3]12.COCCN(S(F)(F)[F:41])CCOC>C(Cl)Cl.C([O-])(O)=O.[Na+]>[F:41][C@H:2]1[C@H:7]2[N:8]([CH:12]([O:19][CH3:20])[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:9](=[O:11])[O:10][C@H:6]2[CH2:5][C@@H:4]2[CH2:21][O:22][CH:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:24][C@@H:3]12
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: COC(c1ccccc1)N1C(=O)O[C@H]2C[C@@H]3COC(c4ccccc4)O[C@H]3[C@H](O)[C@H]21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(c1ccccc1)N1C(=O)O[C@H]2C[C@@H]3COC(c4ccccc4)O[C@H]3[C@@H](F)[C@H]21
Temperature: 25 °C
Reaction time: 20 h
Yield: 50.5 %

Procedure:
To a solution of (3aR,4R,4aR,8aR,9aS)-4-hydroxy-3-(methoxy(phenyl)methyl)-6-phenyloctahydro-2H-[1,3]dioxino[5′,4′:4,5]benzo[1,2-d]oxazol-2-one (1.77 g, 4.31 mmol) in dry DCM (25 mL) at room temperature was added bis(2-methoxyethyl)aminosulfur trifluoride (3.81 g, 17.2 mmol). The mixture was stirred at room temperature under N2 for 20 h. The mixture was slowly diluted with saturated aqueous NaHCO3 (80 mL), extracted with EtOAc (2×50 mL). The extracts were washed with brine and dried with MgSO4. The solvents were evaporated to give the crude product. This was purified by SiO2 column, eluted with 25-35% EtOAc in hexanes to give (3aS,4S,4aR,8aR,9aS)-4-fluoro-3-(methoxy(phenyl)methyl)-6-phenyloctahydro-2H-[1,3]dioxino[5′,4′:4,5]benzo[1,2-d]oxazol-2-one (900 mg, 51%). MS m/z 436.6 (M+23, 100%); 1H NMR (400 MHz, CDCl3) δ 7.34-7.50 (m, 10H), 6.15 (s, 1H), 5.49 (s, 1H), 4.91 (dd, J=51.4 Hz, 3.0 Hz, 1H), 4.40 (d, J=5.0 Hz, 1H), 4.29 (dd, J=11.2 Hz, 4.8 Hz, 1H), 3.66 (s, 3H), 3.25-3.55 (m, 3H), 2.59-2.71 (m, 1H), 2.20-2.25 (m, 1H), 1.23-1.32 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:27])[C:5]([NH:18][C@H:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH3:20])=[N:6][C:7]=1[C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[N:13]2.BrC1N=C(N[C@H](C2C=CC=CC=2)C)C(N)=NC=1C.N1C2C=CC=C(B(O)O)C=2C=CC=1.[C:59](=O)([O-])[O-:60].[K+].[K+]>O.CN(C)C=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>[CH3:1][C:2]1[N:3]=[C:4]2[NH:27][C:59](=[O:60])[N:18]([C@H:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH3:20])[C:5]2=[N:6][C:7]=1[C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[N:13]2
Reactant: O=C([O-])[O-]
Reactant: Cc1nc(N)c(N[C@@H](C)c2ccccc2)nc1-c1cccc2ncccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1nc(N)c(N[C@@H](C)c2ccccc2)nc1Br
Agent: OB(O)c1cccc2ncccc12
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2[nH]c(=O)n([C@@H](C)c3ccccc3)c2nc1-c1cccc2ncccc12
Yield: 18 %

Procedure:
5-Methyl-N2-((S)-1-phenylethyl)-6-(quinolin-5-yl)pyrazine-2,3-diamine. A solution of (S)-6-bromo-5-methyl-N2-(1-phenylethyl)pyrazine-2,3-diamine (0.975 g, 3.19 mmol), quinoline-5-boronic acid (0.606 g, 3.50 mmol), tetrakis(triphenylphosphine)palladium (0.368 g, 0.319 mmol), and potassium carbonate (1.76 g, 12.76 mmol) in water (8 mL) and dimethylformamide (30 mL) was reacted according to General Procedure B and purified via Biotage silica gel chromatography (0-10% methanol in dichloromethane, 40M column). The resultant solid was triturated with water/methanol to afford the title compound (0.200 g, 18% yield). MS (ESI) m/z 356.5 [M+1]+.
Reaction SMILES: [C:1]([CH:3]([OH:17])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=1)#[N:2].[CH3:18][S:19](Cl)(=[O:21])=[O:20].C(N(CC)CC)C.O>CCOCC>[S:19]([O:17][CH:3]([C:1]#[N:2])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=1)(=[O:21])(=[O:20])[CH3:18]
Reactant: CS(=O)(=O)Cl
Reactant: N#CC(O)c1cccc(Oc2ccccc2)c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CS(=O)(=O)OC(C#N)c1cccc(Oc2ccccc2)c1
Reaction time: 0.33 h

Procedure:
α-Cyano-m-phenoxybenzyl alcohol (8.5 g, 38 mmol) is dissolved in 150 ml ether and cooled in an ice-bath. To the solution is slowly added methanesulfonyl chloride (5.4 g, 47 mmol) in 20 ml ether. After the mixture is stirred about 20 minutes, triethylamine (4.76 g, 47 mmol) in 20 ml ether is added slowly and the mixture kept at 0° for 24 hours. Water is then added and the organic layer is separated, washed with 30% aqueous sodium bisulfite and water, dried and solvent removed under vacuum to yield α-cyano-m-phenoxybenzyl mesylate.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1.[CH:11]([C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)=[O:12].F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>CN(C=O)C.C(N(C(C)C)CC)(C)C>[CH:1]1([CH2:4][N:5]([C:17](=[O:18])[C:16]2[CH:20]=[CH:21][C:13]([CH:11]=[O:12])=[CH:14][CH:15]=2)[CH2:6][CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: O=C(O)CCNCC1CC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=Cc1ccc(C(=O)N(CCC(=O)O)CC2CC2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To the above resin bound N-(cyclopropylmethyl) 3-aminopropionic acid (50 mg) was added 200 μmol 4-formylbenzoic acid (30 mg) dissolved in a mixture of 430 μL DMF and 70 μL diisopropylethylamine followed by 200 μmol bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrOP, 93 mg) dissolved in 500 μL DMF. The mixture was shaken at 25° C. for 4 hours followed by filtration and washing of the resin with 3×1 mL DMF and 1 mL trimethylorthoformate.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=3[CH:25]=O)[CH:8]=2)[N:3]=1.[NH:31]1[CH2:36][CH2:35][CH:34]([OH:37])[CH2:33][CH2:32]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O1CCCC1.O>[NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=3[CH2:25][N:31]3[CH2:36][CH2:35][CH:34]([OH:37])[CH2:33][CH2:32]3)[CH:8]=2)[N:3]=1
Reactant: OC1CCNCC1
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3ccccc3C=O)ccc2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Solvent: CC(=O)O
Product: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3ccccc3CN3CCC(O)CC3)ccc2n1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
200 mg of 2-[2-amino-4-(1,3-dihydroisoindole-2-carbonyl)quinazolin-6-yl]benzaldehyde are dissolved in 10 ml of 1,2-dichloroethane and 10 ml of tetrahydrofuran. 103 mg of 4-piperidinol and 29 μl of glacial acetic acid are added, and the mixture is stirred at 60° C. for 6 h. After cooling to 25° C., 226 mg of sodium triacetoxyborohydride are added and stirred at 25° C. for a further 12 h. The mixture is poured into water, extracted three times with dichloromethane, and the combined organic phases are dried over sodium sulfate. After filtration, the filtrate is evaporated to dryness and purified by chromatography (reversed phase HPLC).
Reaction SMILES: [C:1]([OH:12])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:13](O)(=O)C>>[CH3:13][C:1](=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CC(=O)O
Reactant: CCCCCCCCCC(=O)O
Product: CCCCCCCCCC(C)=O

Procedure:
The cross ketonization reaction with the triacylglycerol from Cuphea sp. and acetic acid is demonstrated. The seed oil from Cuphea sp. contains up to 71% decanoic acid and the reaction of this with acetic acid yields the fragrance compound 2-undecanone. Several ketonization catalysts from the literature including CeO2, CeO/Al2O3, CeO/ZrO2, MnOx/Al2O3 were screened and compared with a coprecipitated mixed metal oxide of empirical formula Fe0.5Ce0.2Al0.3Ox (also represented as 50Fe20Ce30AlOx). Each of these catalysts effected the conversion but the highest yield was found with Fe0.5Ce0.2Al0.3Ox. In a flow reactor, Fe0.5Ce0.2Al0.3Ox gave 2-undecanone at 91% theoretical yield with reaction conditions of 400° C., weight hourly space velocity of 2, molar ratio of acetic acid to Cuphea oil of 23, and N2 carrier gas flow of 125 ml/min at 2.4 bar. In the absence of acetic acid, coupling of the decanoic acid residues gives 10-ketononadecane.
Reaction SMILES: [CH:1]([C:3]1[CH:23]=[CH:22][C:6]([C:7]([N:9]2[CH2:14][CH2:13][N:12]([C:15](OC(C)(C)C)=O)[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1)=[O:2].[C:24](O)([C:26](F)(F)F)=[O:25]>C(Cl)Cl>[OH:25][CH:24]([CH3:26])[CH2:15][N:12]1[CH2:11][CH2:10][N:9]([C:7]([C:6]2[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:23][CH:22]=2)=[O:8])[CH2:14][CH2:13]1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(C=O)cc2)CC1
Solvent: ClCCl
Product: CC(O)CN1CCN(C(=O)c2ccc(C=O)cc2)CC1
Yield: 31.4 %

Procedure:
In an analagous manner to 23, tert-butyl 4-(4-formylbenzoyl)piperazine-1-carboxylate 26 (500 mg, 1.57 mmol) in DCM (10 mL) was reacted with TFA (1.17 mL, 15.72 mmol) to afford product as white sticky solid. Yield: 31.4%.
Reaction SMILES: Cl[S:2]([N:5]=C=O)(=[O:4])=[O:3].C(O)=O.[NH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]2[S:21][C:20]3[N:22]=[CH:23][CH:24]=[N:25][C:19]=3[NH:18][C:17]=2[CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C(OCC)(=O)C>[N:25]1[C:19]2[NH:18][C:17]3[CH:26]=[C:13]([CH2:12][NH:11][S:2]([NH2:5])(=[O:4])=[O:3])[CH:14]=[CH:15][C:16]=3[S:21][C:20]=2[N:22]=[CH:23][CH:24]=1
Reactant: NCc1ccc2c(c1)Nc1nccnc1S2
Reactant: O=C=NS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NS(=O)(=O)NCc1ccc2c(c1)Nc1nccnc1S2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 12.1 %

Procedure:
5 ml of a solution of 283 mg of chlorosulfonyl isocyanate in tetrahydrofuran was ice-cooled and 92 mg of formic acid was added thereto. After stirring at room temperature for 30 minutes, the mixture was added to a solution of 276 mg of 8-aminomethyl-10H-pyrazino[2,3-b][1,4]benzothiazine in tetrahydrofuran (5 ml) and the resulting mixture was stirred at room temperature for 20 minutes. Next, it was distributed into an aqueous solution of potassium carbonate and ethyl acetate and the aqueous layer was extracted. The aqueous layer was well washed with ethyl acetate and the organic solvent contained therein was distilled off under reduced pressure. The residual aqueous solution was purified by High-porous gel chromatography (CHP20P mfd. by Mitsubishi Chemical Industries, Ltd., 75-150 μ) (eluted with water/methanol) to thereby give 45 mg of the title compound as yellow crystals.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:21])[CH:16](OCC)O)=[CH:11][C:10]=1[NH:22][S:23]([CH3:26])(=[O:25])=[O:24])C1C=CC=CC=1.Cl.[CH3:28][O:29][C:30]1[CH:42]=[CH:41][C:33]([CH2:34][C:35]2([NH2:40])[CH2:39][CH2:38][CH2:37][CH2:36]2)=[CH:32][CH:31]=1.Cl>>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:21])[CH2:16][NH:40][C:35]2([CH2:34][C:33]3[CH:41]=[CH:42][C:30]([O:29][CH3:28])=[CH:31][CH:32]=3)[CH2:36][CH2:37][CH2:38][CH2:39]2)=[CH:11][C:10]=1[NH:22][S:23]([CH3:26])(=[O:24])=[O:25]
Reactant: CCOC(O)C(=O)c1ccc(OCc2ccccc2)c(NS(C)(=O)=O)c1
Reactant: COc1ccc(CC2(N)CCCC2)cc1
Agent: Cl
Product: COc1ccc(CC2(NCC(O)c3ccc(O)c(NS(C)(=O)=O)c3)CCCC2)cc1

Procedure:
Prepared from 645 mg (1.70 mmol) N-[2-benzyloxy-5-(2-ethoxy-2-hydroxy-acetyl)-phenyl]-methanesulphonamide and 411 mg (1.70 mmol) 1-(4-methoxy-benzyl)-cyclopentylamine hydrochloride according to general method 6. Yield: 369 mg (46%, hydrochloride). Mass spectroscopy: [M+H]+=435.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH:9]([OH:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].[N+](=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N-]>ClC(Cl)C.C([O-])(=O)C.[Rh+3].C([O-])(=O)C.C([O-])(=O)C>[CH2:19]([O:18][C:16](=[O:17])[CH2:15][O:11][CH:9]([CH3:10])[CH2:8][NH:7][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:12])[CH3:20]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: CC(O)CNC(=O)OC(C)(C)C
Agent: [Rh+3]
Agent: CC(=O)[O-]
Solvent: CC(Cl)Cl
Product: CCOC(=O)COC(C)CNC(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 50.9 %

Procedure:
500 mg (2.85 mmol) of (2-hydroxy-propyl)-carbamic acid t-butyl ester was dissolved in 10 mL of dichloroethane, then 0.44 mL (4.24 mmol) of ethyl diazoacetate was added thereto. 38 mg (0.085 mmol) of rhodium acetate was added to the reaction and then heated to 80° C. for 2 hours. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography to give 381 mg (1.45 mmol) of the title compound in a yield of 50%.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.C([Sn](CCCC)(CCCC)[C:29]([O:31]CC)=[CH2:30])CCC.Cl.O>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:23][C:22]1[CH:21]=[C:20]2[C:15]([CH:16]=[CH:17][CH:18]=[N:19]2)=[CH:14][C:13]=1[CH:11]([C:8]1[N:6]2[N:7]=[C:2]([C:29](=[O:31])[CH3:30])[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1)[CH3:12]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CC(c1cc2cccnc2cc1F)c1cnc2ccc(Cl)nn12
Agent: [Pd]
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1ccc2ncc(C(C)c3cc4cccnc4cc3F)n2n1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
In a flask was charged with tetrakis-(triphenylphosphine)-palladium (46 mg, 0.040 mmol) under nitrogen. A solution of 6-(1-(6-chloroimidazo[1,2-b]pyridazin-3-yl)ethyl)-7-fluoroquinoline (130 mg, 0.40 mmol) in DMF (5 mL) was added. The system was purged with nitrogen gas three times and tributyl-(1-ethoxy-vinyl)-stannane (0.14 mL, 0.42 mmol) was added. The temperature was increased to 100° C. and stirred for 2 hrs. Then the reaction mixture was cooled to room temperature, 3N HCl was added and the mixture was stirred for additional 4 hrs. Water was added and the mixture was then extracted with EtOAc, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (3% to 10% MeOH in CH2Cl2) to afford 120 mg (yield: 90) of title compound. LCMS (method B): [MH]+=335, tR=2.41 min.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](C)=[N:9]2)=[CH:4][N:3]=1.[Se](=O)=O.[CH:16]([OH:18])=[O:17].OO>O1CCOCC1.C(Cl)Cl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:16]([OH:18])=[O:17])=[N:9]2)=[CH:4][N:3]=1
Reactant: Cc1ccc2cnc(Br)cc2n1
Reactant: O=CO
Agent: O=[Se]=O
Agent: OO
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(O)c1ccc2cnc(Br)cc2n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
7-Bromo-2-methyl-1,6-napthyridine (Preparation 65, 206 mg, 0.92 mmol) and selenium dioxide (102.5 mg, 0.92 mmol) were heated in dioxane (3 mL) at 80° C. for 2 hours. The reaction was diluted with DCM (6 mL) and filtered through celite. The filter cake was washed with DCM (3×9 mL) and the combined filtrates concentrated in vacuo. The residue was stirred with formic acid (1 mL) and hydrogen peroxide (35% aqueous solution, 50 uL, 0.67 mmol) was added. The reaction was stirred at 0° C. for 1 hour before the reaction was quenched by the addition of palladium on charcoal (3 mg) and stirred for a further 20 minutes. The reaction was concentrated in vacuo to afford the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][C:6]=1[CH3:12])[CH3:2].[C:14]1([OH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[Cs+].[Cs+].C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([O:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:7][C:6]=1[CH3:12])[CH3:2]
Reactant: Oc1ccccc1
Reactant: CCOC(=O)c1ccc(Br)cc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(Oc2ccccc2)cc1C

Procedure:
27.5 g of 4-bromo-2-methyl-benzoic acid ethyl ester was dissolved in 120 mL of anhydrous toluene. To the solution was added 21.3 g of phenol, 73.6 g of Cs2CO3, 551 μL of ethyl acetate, 22 g of activated 4 A molecular sieves, and 5.68 g of 90% copper(I) trifluoromethanesulfonate benzene complex. The reaction was placed under a nitrogen atmosphere and heated at reflux temperature for 48 h. The resultant mixture was partitioned between water and ethyl acetate, and the mixture filtered through a fine sintered glass filter to remove insoluble material. The organic fraction was washed three times with 1.0 N NaOH, once with brine, dried over anhydrous sodium sulfate, and concentrated to 18.2 g of a pale tan liquid: 1H NMR (200 MHz, CDCl3) δ 7.93-7.88 (dd, J=1.3, 7.8 Hz, 1H) 7.39-7.30 (m, 2H), 7.19-7.10 (tt, J=1.2, 7.4 Hz, 1H), 7.06-7.7.0 (m, 2H), 6.80-6.75 (m, 2H), 4.37-4.26 (q, J=7.0 Hz, 2H), 2.56 (s, 3H), 1.40-1.33 (t, J=7.0 Hz, 3H).
Reaction SMILES: [O:1]=[C:2]1[C:11](/[CH:12]=[CH:13]/[C:14](Cl)=[O:15])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[O:3]1.[C:17]([OH:26])(=[O:25])[C:18]1[C:19](=[CH:21][CH:22]=[CH:23][CH:24]=1)[NH2:20].C(N(CC)CC)C>O1CCCC1>[C:17]([C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH:20][C:14](=[O:15])/[CH:13]=[CH:12]/[C:11]1[C:2](=[O:1])[O:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2)([OH:26])=[O:25]
Reactant: Nc1ccccc1C(=O)O
Reactant: O=C(Cl)/C=C/c1cc2ccccc2oc1=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(/C=C/c1cc2ccccc2oc1=O)Nc1ccccc1C(=O)O

Procedure:
Prepared analogously to Example 31 from trans-3-(2-oxo-2H-chromen-3-yl)-acrylic acid chloride and anthranilic acid in tetrahydrofuran with the addition of triethylamine.
Reaction SMILES: [NH2:1][C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:3]=1[CH:4]=O.[N+:12]([CH2:15][C:16](OCC)=[O:17])([O-:14])=[O:13].N1CCCCC1>C(O)C>[N+:12]([C:15]1[C:16](=[O:17])[NH:1][C:2]2[C:3]([CH:4]=1)=[C:6]([CH3:11])[CH:7]=[C:8]([CH3:10])[N:9]=2)([O-:14])=[O:13]
Reactant: Cc1cc(C)c(C=O)c(N)n1
Reactant: CCOC(=O)C[N+](=O)[O-]
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C)c2cc([N+](=O)[O-])c(=O)[nH]c2n1

Procedure:
A mixture of 2-amino-4,6-dimethylnicotinaldehyde (2.40 g., 16 mmole), ethyl nitroacetate (5.12 g., 32 mmole), piperidine (336 mg., 4 mmole) and ethanol (4 ml.) is heated under reflux with stirring for an hour. The mixture then is cooled, treated with petroleum ether, the solid removed by filtration and recrystallized from methanol yielding 1.55 g. (44%) of product, m.p. 270°-272° C. (dec.). Following recrystallization from the same solvent the product melts at 272°- 274° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=3)[C:15]([O:17][CH3:18])=[O:16])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:22]1([C:25](Cl)=[O:26])[CH2:24][CH2:23]1>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH:22]1([C:25]([NH:1][C:2]2[O:3][C:4]3[CH:10]=[C:9]([O:11][C:12]4[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=4)[C:15]([O:17][CH3:18])=[O:16])[CH:8]=[CH:7][C:5]=3[N:6]=2)=[O:26])[CH2:24][CH2:23]1
Reactant: O=C(Cl)C1CC1
Reactant: COC(=O)c1cccc(Oc2ccc3nc(N)oc3c2)c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: COC(=O)c1cccc(Oc2ccc3nc(NC(=O)C4CC4)oc3c2)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution (100 mL) of methyl 3-[(2-amino-1,3-benzooxazol-6-yl)oxy]benzoate (6.84 g, 24.1 mmol) in pyridine were added N,N-dimethylpyridine-4-amine (129 mg, 1.05 mmol) and cyclopropanecarbonyl chloride (2.5 mL, 27.5 mmol), and the mixture was stirred at room temperature for 1.5 hr. To the reaction mixture was added cyclopropanecarbonyl chloride (2.5 mL, 27.5 mmol), and the mixture was further stirred at room temperature for 1.5 hr. Cyclopropanecarbonyl chloride (1.5 mL, 16.5 mmol) was further added to the reaction mixture, and the mixture was continuously stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in ethyl acetate (200 mL). This suspension was washed with 0.1N hydrochloric acid (150 mL) and saturated aqueous sodium hydrogencarbonate solution (150 mL), successively. The diluted hydrochloric acid layer was extracted with ethyl acetate (100 mL×2), and the combined organic layers were washed with saturated aqueous sodium hydrogencarbonate solution (150 mL) and saturated brine (150 mL), successively, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated to give a brown amorphous substance (8.2 g).