Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]([NH2:10])[CH3:9])[CH:3]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]([NH:10][C:11](=[O:13])[CH3:12])[CH3:9])[CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC(N)c1cc(Br)ccn1
Solvent: ClC(Cl)Cl
Product: CC(=O)NC(C)c1cc(Br)ccn1

Procedure:
To a solution of 1-(4-bromopyridin-2-yl)ethanamine (2.3 g, 11.44 mmol) in chloroform (30 mL) was added acetic anhydride (2.16 mL, 22.88 mmol) dropwise at 0° C. The reaction was then quenched with ice water (40 mL) and extracted with chloroform (2×50 mL). The organic extracts were combined, then washed with 1M NaOH (50 mL), dried over Na2SO4, concentrated, and purified by column chromatography (gradient 0 to 5% MeOH/DCM) to afford the product. 1H NMR (400 MHz, CDCl3) δ 8.35 (d, J=5.3 Hz, 1H), 7.42 (s, 1H), 7.36 (dd, J=5.3, 1.7 Hz, 1H), 6.71 (br s, 1H), 5.10 (p, J=7.0 Hz, 1H), 2.02 (s, 3H), 1.45 (d, J=6.8 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:18]=[CH:17][C:9]2[N:10]=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[S:12][C:8]=2[C:7]=1[C:19]#[N:20].[N:24]([C:27]1[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=1)=[C:25]=[O:26]>CN(C)C=O.C(OCC)(=O)C>[C:19]([C:7]1[C:8]2[S:12][C:11]([NH:13][C:14](=[O:16])[CH3:15])=[N:10][C:9]=2[CH:17]=[CH:18][C:6]=1[O:5][C:4]1[CH:21]=[CH:22][CH:23]=[C:2]([NH:1][C:25](=[O:26])[NH:24][C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]([F:35])([F:37])[F:36])=[CH:29][CH:28]=2)[CH:3]=1)#[N:20]
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Reactant: CC(=O)Nc1nc2ccc(Oc3cccc(N)c3)c(C#N)c2s1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1nc2ccc(Oc3cccc(NC(=O)Nc4ccc(OC(F)(F)F)cc4)c3)c(C#N)c2s1
Temperature: 25 °C
Reaction time: 12 h
Yield: 60.3 %

Procedure:
N-[6-(3-Aminophenoxy)-7-cyano-1,3-benzothiazol-2-yl]acetamide (150 mg, 0.462 mmol) produced in Example 12(ii) was dissolved in N,N-dimethylformamide (2 mL), 1-isocyanato-4-(trifluoromethoxy)benzene (91 μL, 0.60 mmol) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was diluted with ethyl acetate (10 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (5 mL) and saturated brine (5 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=80/20→100/0), and the obtained solution was concentrated under reduced pressure. The residue was crystallized from diisopropyl ether to give the title compound (147 mg, 60%) as a white powder.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[O:8])([O-:3])=[O:2].[CH:12](O)([OH:14])[CH3:13]>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]2[O:14][CH2:12][CH2:13][O:8]2)[CH:9]=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CC(O)O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cccc(C2OCCO2)c1

Procedure:
Protection of the aldehyde was performed following reported procedures. (Borchardt, R. T.; Huber, J. A.; Houston, M. J. Med. Chem. 1982, 25, 258.; Brasili, L.; Sorbi, C.; Franchini, S.; Manicardi, M.; Angeli, P.; Marucci, G.; Leonarke, A.; Poggesi, E. J. Med. Chem. 2003, 46, 1504) 3-Nitrobenzaldehyde (4.0 g, 26.4 mmol) was dissolved in toluene (200 mL). Following this, ethanediol (3.0 mL, 53 mmol, 2.0 eq) was added to the solution and the resulting mixture was refluxed overnight with a Dean-Stark trap. The reflux mixture was then extracted with saturated NaHCO3 (2×75 mL). The organic layer was dried with Na2SO4 and concentrated under reduced pressure. The residue was then purified by flash column chromatography (30% EtOAc/hexanes) to afford 3-nitrophenyl-1,3-dioxolane as a clear yellow oil that solidified upon standing. (5.09 g, 98%, Rf=0.7 40% EtOAc/hexanes). 1H-NMR (400 MHz, CDCl3, δ): 4.0-4.2 (m, 4H), 5.87 (s, 1H), 7.55 (t, 1H, J=7.93 Hz), 7.79 (d, 1H, J=7.7 Hz), 8.21 (dd, 1H, J1=1.2 Hz, J2=8.2 Hz), 8.34 (s, 1H). 13C-NMR (100 MHz, CDCl3, δ): 148.4, 140.5, 132.8, 129.6, 124.1, 121.8, 102.3, 65.6.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][OH:5].[Br:6][C:7]1[CH:8]=[C:9]([CH:22]=[CH:23][C:24]=1[Cl:25])[C:10]([N:12]([C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=1[OH:21])[CH3:13])=[O:11].C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C>[Br:6][C:7]1[CH:8]=[C:9]([CH:22]=[CH:23][C:24]=1[Cl:25])[C:10]([N:12]([C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=1[O:21][CH2:2][CH2:3][CH2:4][OH:5])[CH3:13])=[O:11]
Reactant: OCCCBr
Reactant: Cc1cccc(O)c1N(C)C(=O)c1ccc(Cl)c(Br)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc(OCCCO)c1N(C)C(=O)c1ccc(Cl)c(Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.5 %

Procedure:
3-Bromo-1-propanol (2.48 mL, 27.3 mmol) was added to a solution of 3-bromo-4-chloro-N-(2-hydroxy-6-methyl-phenyl)-N-methyl-benzamide (6.47 g, 18.3 mmol, Step 3B) in DMF (80 mL). To this was added K2CO3 (3.3 g, 24 mmol) and the mixture was stirred at room temperature for approximately 16 hrs. At this time the reaction was neutralized with 1N hydrochloric acid and the mixture was extracted with ethyl acetate. The organic layer was washed with first water and then brine solution. The organic filtrate was evaporated and the residue purified using column chromatography in a gradient of 50% ethyl acetate to 60% ethyl acetate in hexanes giving 3-bromo-4-chloro-N-[2-(3-hydroxy-propoxy)-6-methyl-phenyl]-N-methyl-benzamide (5.7 g, 76%). MS [M+H]+: 413.9; tR=2.29 min. (method 1)
Reaction SMILES: FC1C=C(C2N=C(SC)N=C(N3CCOC[C@@H]3C)C=2)C=NC=1.Cl[C:24]1[CH:29]=[C:28]([C:30]2[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=2[S:37]([CH3:40])(=[O:39])=[O:38])[N:27]=[C:26]([N:41]2[CH2:46][CH2:45][O:44][CH2:43][C@@H:42]2[CH3:47])[N:25]=1.[F:48][CH2:49][CH2:50][NH:51][C:52]([NH:54][C:55]1[CH:60]=[CH:59][C:58](B2OC(C)(C)C(C)(C)O2)=[CH:57][CH:56]=1)=[O:53]>>[F:36][C:34]1[CH:33]=[CH:32][C:31]([S:37]([CH3:40])(=[O:39])=[O:38])=[C:30]([C:28]2[N:27]=[C:26]([N:41]3[CH2:46][CH2:45][O:44][CH2:43][C@@H:42]3[CH3:47])[N:25]=[C:24]([C:58]3[CH:57]=[CH:56][C:55]([NH:54][C:52]([NH:51][CH2:50][CH2:49][F:48])=[O:53])=[CH:60][CH:59]=3)[CH:29]=2)[CH:35]=1
Reactant: C[C@H]1COCCN1c1nc(Cl)cc(-c2cc(F)ccc2S(C)(=O)=O)n1
Reactant: CC1(C)OB(c2ccc(NC(=O)NCCF)cc2)OC1(C)C
Agent: CSc1nc(-c2cncc(F)c2)cc(N2CCOC[C@@H]2C)n1
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NCCF)cc2)cc(-c2cc(F)ccc2S(C)(=O)=O)n1
Yield: 22 %

Procedure:
Method as described for intermediate 5 using (S)-4-(4-chloro-6-(5-fluoro-2-(methylsulfonyl)phenyl)pyrimidin-2-yl)-3-methylmorpholine (intermediate 16) and 1-(2-fluoroethyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (intermediate 19). Material was purified by prep HPLC (low pH) to afford a brown solid. Further purification was achieved using an SCX-2 cartridge to afford a brown solid (50 mg, 22%).
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(O)C>Cl.O>[CH:1](=[N:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4]
Reactant: O=Cc1ccccc1O
Reactant: Nc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: Oc1ccccc1C=Nc1ccccc1
Temperature: 25 °C
Yield: 42.7 %

Procedure:
To a mixture of salicylaldehyde (40 mL, 45.84 g, 375.37 mmol)) and aniline (22 mL, 31.72 g, 374.66 mmol), was added ethanol (90 mL), 8 drops of concentrated hydrochloric acid and water (10 mL). This reaction mixture was refluxed for one hour, allowed to cool to room temperature and left in the refrigerator over the weekend. A large quantity of orange solid was formed after 2 hours in the refrigerator. It was filtered off and washed with ethanol. Recrystallisation from ethanol afforded 31.53 g of product.
Reaction SMILES: [CH3:1]N(C=O)C.[NH2:6][C:7]1[N:8]=[C:9]([NH2:27])[C:10]2[C:15]([CH2:16][CH2:17][C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)=[CH:14][NH:13][C:11]=2[N:12]=1.[C:28]([O:32][C:33]([NH:35][CH2:36][CH2:37][CH2:38][C@@H:39]([C:41]([OH:43])=[O:42])[NH2:40])=[O:34])([CH3:31])([CH3:30])[CH3:29].P(C#N)(OCC)(OCC)=O>C(N(CC)CC)C>[NH2:6][C:7]1[N:8]=[C:9]([NH2:27])[C:10]2[C:15]([CH2:16][CH2:17][C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH:40][C@H:39]([C:41]([O:43][CH3:1])=[O:42])[CH2:38][CH2:37][CH2:36][NH:35][C:33]([O:32][C:28]([CH3:31])([CH3:29])[CH3:30])=[O:34])=[O:23])=[CH:20][CH:19]=3)=[CH:14][NH:13][C:11]=2[N:12]=1
Reactant: Nc1nc(N)c2c(CCc3ccc(C(=O)O)cc3)c[nH]c2n1
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)NCCC[C@H](N)C(=O)O
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CCCNC(=O)OC(C)(C)C)NC(=O)c1ccc(CCc2c[nH]c3nc(N)nc(N)c23)cc1
Yield: 85 %

Procedure:
To a DMF solution of 4-[2-(2,4-diamino-7H-pyrrolo [2,3-d]pyrimidin-5-yl)ethyl]benzoic acid (1.52 g) and methyl ester of N(δ)-t-butyloxycarbonyl-L-ornithine (1.3 g) was added diethyl cyanophosphate (1.4 g). The mixture was stirred for one hour at room temperature in the presence of triethylamine (3.0 g). The reaction mixture was concentrated under reduced pressure. The concentrate was purified by column chromatography on silica gel (carrier: 30 g; chloroform:ethanol containing 1% ammonium=20:1-15:1) to afford methyl N(α)-[4-[2-(2,4-diamino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-N-(δ)-(t-butyloxycarbonyl)-L-ornithinate (2.30 g; yield 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:28]([NH2:29])=[N:27][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[N:15]=[CH:16][C:11]=2[CH:10]=1.[H-].[Na+].[C:32]1([N:38]=[C:39]=[O:40])[CH:37]=CC=C[CH:33]=1.[CH3:41]N(C=O)C>>[C:32]([NH:38][C:39]([NH:29][C:28]1[C:9]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])=[CH:10][C:11]2[CH:16]=[N:15][C:14]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[N:13][C:12]=2[N:27]=1)=[O:40])([CH3:41])([CH3:37])[CH3:33]
Reactant: CCN(CC)CCCCNc1ncc2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1
Reactant: O=C=Nc1ccccc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: CCN(CC)CCCCNc1ncc2cc(-c3c(Cl)cccc3Cl)c(NC(=O)NC(C)(C)C)nc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-(2,6-dichlorophenyl)-N2 -(4-diethylamino-butyl)-pyrido[2,3-d]pyrimidine-2,7-diamine (25.0 g) from Example 53 in DMF (300 mL) was added 1 equivalent of 60% sodium hydride suspension (2.31 g). After stirring for approximately 2 hours at room temperature, one equivalent of phenyl isocyanate (5.72 g) was added and the reaction monitored by thin layer chromatography After approximately 24 hours, the solvent was removed in vacuo. The residue was dissolved in dichloromethane and this solution was washed several times, first with water and then a saturated solution of sodium chloride. The dichloromethane layer was dried with magnesium sulfate and concentrated in vacuo. Chromatography of the residue on silica gel eluting with ethyl acetate:ethanol:triethylamine (9:2:1), followed by crystallization from tert-butyl methyl ester gave 21.58 g of the title compound 1-tert-butyl-3-[6-(2,6-dichlorophenyl)-2-(4-diethylamino-butylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea, ESMS (20/80 MeOH/CH3CN+0.1% AcOH): M+ +H=532; mp dec 157° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH2:13][CH3:14])[C:9](=[O:15])CCC2)[CH3:2].C[C:17]([CH3:20])([O-:19])[CH3:18].[K+].C([OH:26])(C)(C)C>>[CH2:13]([C:12]1[CH:11]=[C:18]2[C:5](=[CH:4][C:3]=1[CH2:1][CH3:2])[C:10](=[O:26])[C:9]([OH:15])=[CH:20][C:17]2=[O:19])[CH3:14]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)O
Reactant: CCc1cc2c(cc1CC)C(=O)CCC2
Agent: [K+]
Product: CCc1cc2c(cc1CC)C(=O)C(O)=CC2=O
Yield: 63 %

Procedure:
Autoxidation of 6,7-diethyl-1-tetralone (48g; 0.24 mole ) with potassium t-butoxide in t-butanol as described in example 8(b) afforded 34.60g (63%) of the title compound. Recrystallisation from aqueous ethanol in the presence of charcoal gave a yellow crystalline solid of m.p. 105°-109° C. (Found; C, 70.45; H, 6.10; C14H14O3 1/2H2O requires; C, 70.28; H, 6.32%).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10](=[O:27])[O:11][CH:12]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:26])[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[CH2:2]2.Cl[CH2:29][C:30]([C:32]1[S:33][CH:34]=[CH:35][CH:36]=1)=[O:31]>C(OCC)(=O)C>[Cl-:19].[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH:12]([C:13]1[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=1)[O:11][C:10]([NH:9][C@@H:3]1[CH:4]2[CH2:7][CH2:8][N+:1]([CH2:29][C:30](=[O:31])[C:32]3[S:33][CH:34]=[CH:35][CH:36]=3)([CH2:6][CH2:5]2)[CH2:2]1)=[O:27]
Reactant: O=C(CCl)c1cccs1
Reactant: O=C(N[C@H]1CN2CCC1CC2)OC(c1ccc(Cl)cc1)c1ccccc1Cl
Solvent: CCOC(C)=O
Product: O=C(N[C@H]1C[N+]2(CC(=O)c3cccs3)CCC1CC2)OC(c1ccc(Cl)cc1)c1ccccc1Cl
Product: [Cl-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.1 %

Procedure:
To a solution of (2-chlorophenyl)(4-chlorophenyl)methyl(R)-quinuclidin-3-ylcarbamate (95.0 mg, 0.23 mmol) in ethyl acetate (3 ml), 2-chloro-1-(thiophen-2-yl)ethanone (37.6 mg, 0.23 mmol) was added, and the mixture was stirred at room temperature overnight. The solvent was removed under vacuum, and the residue was taken up in diethyl ether and filtered. The product was purified by flash chromatography (DCM/MeOH=95/5) to obtain (3R)-3-(((2-chlorophenyl)(4-chlorophenyl)methoxy)carbonylamino)-1-(2-oxo-2-(thiophen-2-yl)ethyl)-1-azoniabicyclo[2.2.2]octane chloride (45.0 mg, mixture of diastereoisomers).
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].CN(C)C=O.C(Cl)(=O)C([Cl:20])=O>C1(C)C=CC=CC=1.C(Cl)(=O)C(Cl)=O>[CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:20])=[O:5]
Reactant: Cc1cccc(C(=O)O)c1C
Reactant: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1cccc(C(=O)Cl)c1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.9 %

Procedure:
To a solution of 2,3-dimethylbenzoic acid (2.0 kg, 13.2 mol) in toluene (20 L) was added N,N-dimethylformamide (20 ml), followed by oxalyl chloride (2.0 kg, 15.6 mol) at room temperature. The reaction mixture was stirred at room temperature for 4 h and monitored by thin layer chromatography. If necessary, excess oxalyl chloride (25 g) was added until no starting material was observed. Excess toluene and oxalyl chloride were removed by distillation under vacuum at temperatures below 70° C. To the residue was added toluene (150 ml) and the mixture was again concentrated in vacuo to give 2,3-dimethylbenzoyl chloride (2.0 kg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16]S(C3C=CC(C)=CC=3)(=O)=O)=[C:12]([C:27]3[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].N>>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:11][CH:12]([CH3:27])[CH3:13])=[C:12]([C:27]3[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1ccc(S(=O)(=O)Oc2c(-c3ccc(S(C)(=O)=O)cc3)cnn(-c3ccc(F)c(F)c3)c2=O)cc1
Agent: N
Product: CC(C)COc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O

Procedure:
The title compound was prepared according to the method of Example 335, substituting 2-(3,4-difluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-(3-chlorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 150 mg, 61%). mp 116–117° C. 1H NMR (300 MHz, DMSO-d6) δ 0.78 (d, 6H), 1.84, (m, 1H), 3.3 (s, 3H), 4.2 (d, 2H), 7.54 (m, 1H), 7.6 (m, 1H), 7.82 (m, 1H), 7.91 (d, 2H), 8.07 (d, 2H), 8.21 (s, 1H). MS (DCI/NH3) m/z 435 (M+H)+, 452 (M+NH4)+. Anal. calc. for C21F2H20N2O4S: C, 58.06; H, 4.64; N, 6.45.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[N+:18]([O-])=O.Br[C:22]1[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=1[F:29]>>[F:28][C:27]1[CH:26]=[CH:25][CH:24]=[C:23]([F:29])[C:22]=1[C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([NH2:1])=[C:3]([NH2:18])[CH:4]=1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc([N+](=O)[O-])c1N
Reactant: Fc1cccc(F)c1Br
Product: Cc1cc(-c2c(F)cccc2F)cc(N)c1N

Procedure:
The title compound was prepared from 2-methyl-6-nitro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (as prepared in Example 8, step A) and 2-bromo-1,3-difluoro-benzene according to the procedures described in Example 4, step A and Example 1, step E. 1H-NMR (400 MHz, CDCl3) δ: 7.17 (tt, J=8.3, 6.3 Hz, 1H), 6.87-6.97 (m, 2H), 6.76 (s, 1H), 6.72 (s, 1H), 3.44 (br. s., 4H), 2.21 (s, 3H).
Reaction SMILES: [CH2:1]([C@H:4]1[N:7]([C:8](=[C:13]([CH3:15])[CH3:14])[C:9]([O:11][CH3:12])=[O:10])[C:6](=[O:16])[CH2:5]1)[CH:2]=[CH2:3].CN(C)C=[O:20]>O.C(OCC)(=O)C.[Pd](Cl)Cl>[O:20]=[C:2]([CH3:3])[CH2:1][C@H:4]1[N:7]([C:8](=[C:13]([CH3:15])[CH3:14])[C:9]([O:11][CH3:12])=[O:10])[C:6](=[O:16])[CH2:5]1
Reactant: C=CC[C@@H]1CC(=O)N1C(C(=O)OC)=C(C)C
Reactant: CN(C)C=O
Agent: Cl[Pd]Cl
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)C(=C(C)C)N1C(=O)C[C@H]1CC(C)=O
Reaction time: 3.5 h

Procedure:
A mixture of methyl 2-[(4R)-4-allyl-2-oxoazetidin-1-yl]-3-methylbut-2-enoate (100 mg), palladium chloride (16 mg) and cuprous chloride (44 mg) in a mixture of dimethylformamide (1 ml) and water (0.12 ml) was stirred under an oxygen atmosphere for 3.5 hours. The reaction mixture was diluted with ethyl acetate (20 ml), and filtered. The filtrate was washed with water and brine. The combined aqueous layer was extracted with ethyl acetate (10 ml×2) and the extract was washed with brine. The organic layers were combined, and dried over magnesium sulfate, and evaporated in vacuo. The oily residue was chromatographed on silica gel (1 g) eluting with methylene chloride and acetone (100:2-100:5) to give methyl 2-[(4R)-4-(2-oxopropyl)-2-oxoazetidin-1-yl]-3-methylbut-2-enoate (89 mg as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][NH:6][C:7]1[CH:12]=[N:11][CH:10]=[C:9](Cl)[N:8]=1.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].N12CCCN=C1CCCCC2.O>C(O)C>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:9]2[CH:10]=[N:11][CH:12]=[C:7]([NH:6][CH2:5][C:4]3[CH:14]=[CH:15][CH:16]=[C:2]([Cl:1])[CH:3]=3)[N:8]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: Clc1cccc(CNc2cncc(Cl)n2)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2cncc(NCc3cccc(Cl)c3)n2)CC1
Temperature: 25 °C

Procedure:
A mixture of (3-chloro-benzyl)-(6-chloro-pyrazin-2-yl)-amine (I-2a) (71.0 mg, 0.28 mmol), piperazine-1-carboxylic acid tert-butyl ester (260.2 mg, 1.40 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (208.9 μL, 1.40 mmol) in 1.0 mL of ethanol was refluxed for 18 h under nitrogen. The reaction was then cooled to ambient temperature and poured into 20 mL of water. This was extracted 2×30 mL of ethyl acetate and the combined organic extracts were washed with 3×15 mL water followed by 15 mL of brine. The organic layer was then dried over sodium sulfate, filtered and concentrated in vacuo to a yellow residue that was chromatographed (prep. TLC, 1:1 hexane:ethyl acetate) to give the title compound (I-2b) as a white solid, 13.5 mg.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH:14]=[C:13]([C:18](=[O:20])[CH3:19])[CH:12]=[CH:11]2.[C:21]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)(=[O:23])[CH3:22]>O.C1(C)C=CC=CC=1.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>[C:18]([C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:27]1[CH:28]=[CH:29][C:24]([C:21](=[O:23])[CH3:22])=[CH:25][CH:26]=1)[CH:17]=[CH:16]2)(=[O:20])[CH3:19]
Reactant: CC(=O)c1ccc2cc(Br)ccc2c1
Reactant: CC(=O)c1ccc(B(O)O)cc1
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: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CC(=O)c1ccc(-c2ccc3cc(C(C)=O)ccc3c2)cc1
Temperature: 95 °C
Reaction time: 8 h
Yield: 62.3 %

Procedure:
A solution of sodium carbonate (5.43 g, 51.3 mmol) in water (35 mL) was added to a stirred solution of 1-(6-bromonaphthalen-2-yl)ethanone (2.554 g, 10.25 mmol) and 4-acetylphenylboronic acid (2.017 g, 12.30 mmol) in toluene (35.0 mL) and ethanol (35.0 mL) and nitrogen was bubbled through the reaction mixture for 15 min. Then Pd(PPh3)4 (0.237 g, 0.205 mmol) was added, and the reaction was flushed with nitrogen and heated at 95° C. under nitrogen for 8 h and then stirred overnight at rt. The reaction was concentrated to dryness under high vacuum and then partitioned between DCM (˜200 mL) and water (˜150 mL). The organic layer was then washed with brine (˜100 mL), dried (MsSO4), filtered and concentrated. The residue was triturated with MeOH (˜120 mL) and the remaining solids were redissolved into DCM and concentrated to dryness (˜2.7 g of orange solid). This material was dissolved into hot EtOAc (80 mL) and allowed to cool. The resulting solids were collected by filtration and rinsed with Et2O to yield 1-(4-(6-acetylnaphthalen-2-yl)phenyl)ethanone (1.84 g). LC-MS retention time 2.443 min; m/z 288.98 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where Solvent A was 5% MeOH/95% H2O/10 mM ammonium acetate and Solvent B was 5% H2O/95% MeOH/10 mM ammonium acetate. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (400 MHz, chloroform-d) δ ppm 8.51 (s, 1 H), 8.05-8.16 (m, 5 H), 7.98 (d, J=8.8 Hz, 1 H), 7.81-7.88 (m, 3 H), 2.76 (s, 3 H), 2.68 (s, 3 H).
Reaction SMILES: [CH3:1][C:2](C)=[CH:3][CH2:4][OH:5].[CH3:7][C:8](C)=[CH:9]CC=O.[C:14]1(P(=CC(=O)C)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[CH3:7][C:8]([CH3:9])=[CH:1][CH:2]=[CH:3][C:4](=[O:5])[CH3:14]
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)=CCO
Reactant: CC(C)=CCC=O
Product: CC(=O)C=CC=C(C)C

Procedure:
3-methyl-2-butenol is converted to 3-methyl-2-butene carboxaldehyde which in turn is reacted with triphenylphosphoranyliden-2-propanone to provide 6-methyl-hept-3,5-diene-2-one.