Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[N:5]2[CH:6]=[CH:7][CH:8]=[N:9][C:4]2=[C:3]([C:10]#[N:11])[CH:2]=1.S(=O)(=O)(O)[OH:13]>>[N:1]1[N:5]2[CH:6]=[CH:7][CH:8]=[N:9][C:4]2=[C:3]([C:10]([NH2:11])=[O:13])[CH:2]=1
Reactant: N#Cc1cnn2cccnc12
Reactant: O=S(=O)(O)O
Product: NC(=O)c1cnn2cccnc12

Procedure:
As shown hereinabove a pyrazolo(1,5-a)pyrimidine-3-carbonitrile (4) (prepared in the manner described in U.S. Pat. Nos. 4,281,000; 4,236,005 and 4,178,499) is stirred with concentrated sulfuric acid at room temperature for from 2-20 hours. The mixture is carefully poured onto ice and the precipitate is collected, neutralized with sodium hydroxide, ammonium hydroxide or saturated sodium bicarbonate and the like and washed with water to obtain the corresponding pyrazolo(1,5-a)pyrimidine-3-carboxamide compound (3).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12].[C:16]([NH2:19])(=[S:18])[CH3:17]>>[CH3:1][O:2][C:3]([C:4]1[N:19]=[C:16]([CH3:17])[S:18][C:5]=1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])=[O:15]
Reactant: COC(=O)C(=O)C(Cl)c1ccccc1Cl
Reactant: CC(N)=S
Product: COC(=O)c1nc(C)sc1-c1ccccc1Cl

Procedure:
prepared by reaction of 3-chloro-3-(2-chloro-phenyl)-2-oxo-propionic acid methyl ester with thioacetamide. LC-MS: tR=0.92 min; [M+H]+=268.0.
Reaction SMILES: C(OC([N:8]1[C@@H:13]([CH3:14])[CH2:12][N:11]([C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[N:24][C:25]([NH2:29])=[C:26]([OH:28])[CH:27]=3)=[CH:18][CH:17]=2)[CH2:10][C@H:9]1[CH3:31])=O)(C)(C)C.Br[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH3:40].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[NH2:29][C:25]1[N:24]=[CH:23][C:22]([C:19]2[CH:20]=[CH:21][C:16]([C:15]([N:11]3[CH2:10][CH:9]([CH3:31])[NH:8][CH:13]([CH3:14])[CH2:12]3)=[O:30])=[CH:17][CH:18]=2)=[CH:27][C:26]=1[O:28][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH3:40]
Reactant: Cc1ccccc1CBr
Reactant: C[C@@H]1CN(C(=O)c2ccc(-c3cnc(N)c(O)c3)cc2)C[C@H](C)N1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccccc1COc1cc(-c2ccc(C(=O)N3CC(C)NC(C)C3)cc2)cnc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.5 %

Procedure:
To a mixture of (2R,6S)-4-[4-(6-Amino-5-hydroxy-pyridin-3-yl)-benzoyl]-2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (100 mg, 0.23 mmol) and 1-bromomethyl-2-methyl-benzene (47 mg, 0.25 mmol) in DMF (2 mL) was added 2 M Cs2CO3 (0.35 mL, 0.7 mmol) followed by water (0.5 mL). The mixture was stirred at room temperature overnight. LCMS showed the reaction was completed, DMF was removed, followed by addition of 4 N HCl in dioxane (2 mL) and the reaction was stirred at room temperature for 3 hr. The volatiles were removed followed by addition of methanol. This solution was purified by prep-HPLC to afford {4-[6-Amino-5-(2-methyl-benzyloxy)-pyridin-3-yl]-phenyl}-(3,5-dimethyl-piperazin-1-yl)-methanone (47 mg, yield 46.6%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[N:6][CH:7]=1.[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.C(O)C>[C:11]1([C:2]2[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[N:6][CH:7]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(=O)c1cncc(Br)c1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)c1cncc(-c2ccccc2)c1

Procedure:
A mixture of 5-Bromo-3-acetylpyridine (2 g, 10 mmol), phenylboronic acid (1.5 g, 12 mmol), trans-dibromobis(triphenylphosphine) palladium (II) (0.4 g, 0.5 mmol), toluene (60 ml), ethanol (20 ml) and 2M aqueous sodium carbonate (40 ml) was refluxed for 1 hour under a nitrogen atmosphere. The mixture was diluted with ethyl acetate and the organic phase was washed with water and brine, dried and evaporated. The crude product was chromatographed on silica gel eluting with a gradient of 0-100% EtoAc in hexane to afford the: 5-(Phenyl)-3-acetylpyridine as a solid. 2 g (10 mmol, 100%). TLC Rf 0.3 (1:1 hexane/EtOAc); MS: 198.5 (M+H); 1H NMR (DMSO) δ 9.12 (dd, J=2.2 Hz, 2H), 8.50 (t, J=2.1 Hz, 1H), 7.83 (d, J=8.1 Hz, 2H), 7.54 (t, J=7.7 Hz, 2H), 7.49 (t, J=7.7 Hz, 1H), 3.02 (s, 3H); 13C NMR δ 197.51, 151.30, 148.12, 136.14, 135.51, 134.05, 133.34, 132.00, 129.91, 129.78, 129.19, 127.64, 27.14.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([F:9])[CH:3]=1.C([Li])CCC.[C:15]([O:19][C:20](=[O:37])[NH:21][CH:22]([C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=1)[C:23](=[O:28])N(OC)C)([CH3:18])([CH3:17])[CH3:16]>O1CCCC1>[C:15]([O:19][C:20](=[O:37])[NH:21][CH:22]([C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=1)[C:23]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[F:9])=[O:28])([CH3:18])([CH3:16])[CH3:17]
Reactant: Fc1cc(Br)ccc1I
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(Br)cc1F)c1ccc(Cl)c(Cl)c1
Temperature: -78 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 1.75 g (5.78 mmol) 1-bromo-3-fluoro-4-iodo-benzene in 12 ml dry tetrahydrofuran were added at −78° C. 3.61 ml (5.78 mmol) of a 1.6M butyl lithium solution in hexanes. After 1 h 0.600 g (1.65 mmol) rac-[(3,4-dichloro-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 9) were added and stirred at −78° C. fur further 4 h. Then the reaction mixture was quenched by addition of saturated aqueous ammonium chloride solution, warmed to ambient temperature and extracted with ethyl acetate. The combined extracts were washed with brine, dried over Na2SO4, filtered and evaporated. The crude product was purified by flash-chromatography over silica gel with a heptane/AcOEt gradient starting with pure heptane: rac-[2-(4-bromo-2-fluoro-phenyl)-1-(3,4-dichloro-phenyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester was obtained as a colorless viscous oil: MS (ISP): 476.0 and 477.9 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[CH2:3][CH2:4][Si:5]1(C2C=CC=CC=2)[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1.Br[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])=[CH:27][F:28])=[CH:22][CH:21]=1>>[CH3:18][CH:2]([CH3:1])[CH2:3][CH2:4][Si@H:5]1[CH2:6][CH2:7][C@H:8]([C:20]2[CH:25]=[CH:24][C:23]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])=[CH:27][F:28])=[CH:22][CH:21]=3)=[CH:22][CH:21]=2)[CH2:9][CH2:10]1
Reactant: CC(C)CC[Si]1(c2ccccc2)CCC(=O)CC1
Reactant: FC=C(F)c1ccc(Br)cc1
Product: CC(C)CC[Si@H]1CC[C@H](c2ccc(-c3ccc(C(F)=CF)cc3)cc2)CC1

Procedure:
The general procedure of Example 35 was repeated using 4-(3-methylbutyl)-4-phenyl-4-silacyclohexanone instead of 4-pentyl-4-phenyl-4-silacyclohexanone and 4-bromo-1-(1,2-difluorovinyl)benzene instead of 4-bromo-2,6-difluoro-1-(2,2-difluorovinyloxy)benzene, thereby obtaining the intended compound.
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:4]=2[CH:3]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:16]1[CH2:17][CH2:18][N:13]([C:2]2[CH:12]=[CH:11][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][NH:10][C:4]=3[CH:3]=2)[CH2:14][CH2:15]1
Reactant: C1COCCN1
Reactant: Brc1ccc2c(c1)NCCCC2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: C1=CNc2cc(N3CCOCC3)ccc2C=C1
Temperature: 25 °C
Yield: 94.2 %

Procedure:
To a solution of the 8-bromotetrahydrobenzazepine (72 mg, 0.186 mmol) from step G above in toluene (2 mL) was added morpholine (33 mg, 0.372 mmol), cesium carbonate (182 mg, 0.558 mmol), and 2-(dicyclohexylphosphino)-2′,4′,6′-tri-i-propyl-1,1′-biphenyl (18 mg, 0.037 mmol). The resultant mixture was degassed with argon for 5 minutes, and then added palladium(II) acetate (5 mg, 0.019 mmol). The reaction solution was heated at reflux under argon for 2 hours, and then cooled to room temperature. The resultant mixture was partitioned between ethyl acetate and water. The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product obtained was purified by flash column chromatography [3% to 5% methanol (containing 10% concentrated ammonium hydroxide)/dichloromethane] to give the 8-morpholinobenzazepine (40 mg, 55%): 1H NMR (CDCl3, 500 MHz) δ 6.72 (d, J=2.5 Hz, 1H), 6.65-6.59 (m, 5H), 4.31 (t, J=4.4 Hz, 2H), 4.11 (d, J=8.8 Hz, 1H), 3.85-3.83 (m, 5H), 3.69 (d, J=13.8 Hz, 1H), 3.25 (t, J=4.4 Hz, 2H), 3.12-3.08 (m, 5H), 2.93-2.90 (m, 1H), 2.88 (s, 3H), 2.33 (s, 3H), 2.24-2.17 (m, 1H), 2.07 (br, 1H); ESI MS m/z 394 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@H:15]3[C:19]([CH3:21])([CH3:20])[C@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.C(O)C>[CH2:23]([N:10]1[C:11]2[C@:12]3([CH3:22])[C:19]([CH3:21])([CH3:20])[C@@H:15]([CH2:14][CH2:13]3)[C:16]=2[C:17](=[O:18])[N:9]1[C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC1(C)[C@H]2CC[C@]1(C)c1[nH]n(-c3ccc(F)cc3F)c(=O)c12
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCO
Product: CC1(C)[C@H]2CC[C@]1(C)c1c2c(=O)n(-c2ccc(F)cc2F)n1Cc1ccccc1
Temperature: 50 °C
Reaction time: 24 h
Yield: 79.7 %

Procedure:
A solution of (4R,7S)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 42; 213 mg, 0.7 mmol), tetrabutylammonium iodide (271 mg, 0.7 mmol) and benzyl bromide (0.45 mL, 3.7 mmol) in dimethylformamide (1.4 mL) was heated at 100° C. in a sealed tube for 24 h and then left at room temperature for a further 24 h. The solvent was evaporated and ethyl acetate was added. The solution was washed with 10% aqueous sodium thiosulfate and brine, dried (sodium sulfate), filtered, evaporated, and purified using an Analogix Intelliflash 280 system (Analogix, Inc. Burlington, Wis.) with a RS-12G silica gel column, eluting with 10-100% ethyl acetate/hexanes, to give a light brown foam. This was dissolved in ethanol and the solution was treated with activated carbon (15 mg) and heated at 50° C. for 1 h. The mixture was filtered through Celite and the Celite was washed with ethanol. The combined filtrates were evaporated and the resulting foam was dried under high vacuum to give (4R,7S)-1-benzyl-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (220 mg, 80%) as an off-white solid. ES(+)-MS (M+H) 395.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH:10]=O)=[C:2]1[CH:12]=O.C([NH:17][CH:18](P(OC)(OC)=O)[C:19]([O:21][CH3:22])=[O:20])(=O)C.N12CCCN=C1CCCCC2>C(Cl)Cl>[CH:10]1[C:3]2[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[S:1][C:2]=2[CH:12]=[C:18]([C:19]([O:21][CH3:22])=[O:20])[N:17]=1
Reactant: O=Cc1sc2ccccc2c1C=O
Reactant: COC(=O)C(NC(C)=O)P(=O)(OC)OC
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COC(=O)c1cc2sc3ccccc3c2cn1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 73 %

Procedure:
1-Benzothiophene-2,3-dicarbaldehyde (C180) (1.91 g, 10.0 mmol) is dissolved in CH2Cl2 (100 ml) and chilled in an ice bath. Methyl (acetylamino)(dimethoxyphosphoryl)acetate (C152) (2.63 g, 11.0 mmol) is dissolved in CH2Cl2 (50 ml) and added to 1,8-diazabicyclo[5.4.0]undec-7-ene (1.65 ml, 11.0 mmol), stirring for 5 minutes. This solution is added dropwise to the chilled thiophene solution. The reaction mixture is stirred in the ice bath for 1 h and then over night at rt. The reaction is concentrated in vacuo and the crude material is chromatographed over 500 g slurry-packed silica eluting with 50% ethyl acetate/hexane to afford methyl benzothieno[3,2-c]pyridine-3-carboxylate (C 181) as a white solid (73% yield). MS for C13H9NO2S, (EI) m/z: 243 (M)+.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[F:12][CH:13]([F:38])[O:14][C:15]1[C:35]([CH3:36])=[CH:34][C:18]2[NH:19][C:20]([S:22][CH2:23][C:24]3[C:29]([O:30][CH3:31])=[C:28]([O:32][CH3:33])[CH:27]=[CH:26][N:25]=3)=[N:21][C:17]=2[C:16]=1[CH3:37].C(=O)([O-])[O-].[Na+].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.C(N(CC)CC)C>[F:38][CH:13]([F:12])[O:14][C:15]1[C:35]([CH3:36])=[CH:34][C:18]2[NH:19][C:20]([S:22]([CH2:23][C:24]3[C:29]([O:30][CH3:31])=[C:28]([O:32][CH3:33])[CH:27]=[CH:26][N:25]=3)=[O:6])=[N:21][C:17]=2[C:16]=1[CH3:37]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccnc(CSc2nc3c(C)c(OC(F)F)c(C)cc3[nH]2)c1OC
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccnc(CS(=O)c2nc3c(C)c(OC(F)F)c(C)cc3[nH]2)c1OC
Reaction time: 0.25 h

Procedure:
5 ml of a 0.2N solution of m-chloroperoxybenzoic acid in methylene chloride are added dropwise at -40° C. to a solution of 0.39 g (1 mmol) of 5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)methylthio]-4,6-dimethyl-1H-benzimidazole in 20 ml of methylene chloride, and the mixture is stirred for 15 minutes. 0.5 ml of triethylamine are then added and the reaction mixture is poured into 20 ml of a 1:1 mixture of 5% sodium carbonate solution and 5% sodium thiosulphate solution. After phase separation, the aqueous phase is extracted twice more with 30 ml of methylene chloride each time, and the combined organic phases are washed with sodium carbonate solution, dried over magnesium sulphate, filtered and concentrated to 2 ml. After crystallisation from diisopropyl ether, the crystals are filtered off and dried to constant weight. This gives 0.3 g (74% of theory) of the title compound as a colourless solid of m.p. 163°-164° C. (decomposition).
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][CH:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.CCN(C(C)C)C(C)C.[Si]([N:40]=[C:41]=[O:42])(C)(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][CH:21]4[CH2:26][CH2:25][N:24]([C:41]([NH2:40])=[O:42])[CH2:23][CH2:22]4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: C[Si](C)(C)N=C=O
Reactant: c1cc(OC2CCNCC2)c2nc(-c3nnc4ccccn34)ccc2c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)N1CCC(Oc2cccc3ccc(-c4nnc5ccccn45)nc23)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.9 %

Procedure:
To a solution of 2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-(piperidin-4-yloxy)quinoline (prepared as described in Example 9, 46 mg, 0.133 mmol) in CH2Cl2 (5 mL) were added DIEA (116 μL, 0.67 mmol), DMAP (2 mg, 0.01 mmol), and TMS-isocyanate (104 μL, 0.67 mmol). The reaction mixture was stirred at ambient temperature for 16 hours then partitioned between saturated NaHCO3 and CH2Cl2. The aqueous layer was extracted with CH2Cl2 and the combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography with gradient elution (CH2Cl2 to 1% MeOH/CH2Cl2 to 3% MeOH/CH2Cl2) to afford desired product (33 mg, 64%) as a colorless glass. MS ESI (+) m/z 411.2 (M+Na+) detected.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:28]=1B(O)O>>[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:28]=1[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1
Reactant: OB(O)c1c(F)cccc1F
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1Br
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1c(F)cccc1F

Procedure:
The title compound was prepared in analogy to example 58, from N-(4-bromo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 25, intermediate a) and 2,6-difluorophenyl-boronic acid (CAS RN 162101-25-9) and using preparative HPLC for the chromatographic purification. Off-white solid (16%). MS (ESI): m/z=461.2 [M+H]+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[P:10]([O:17]CC)([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13]>>[C:1]1([CH2:7][CH2:8][P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOP(OCC)OCC
Reactant: BrCCc1ccccc1
Product: CCOP(=O)(CCc1ccccc1)OCC

Procedure:
In a manner according to Preparation 2 combine 2-phenylethyl bromide and triethyl phosphite. Distill the mixture at reduced pressure (0.15 mm Hg) and collect the fraction distilling at 115°-130° C. to obtain the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1.[N+:20]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)([O-:22])=[O:21].C(OCC)(=O)C>O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Cl-].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.[Pd+2]>[CH3:19][O:18][C:17]1[C:2]([C:27]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:20]([O-:22])=[O:21])[CH:28]=2)=[CH:3][C:4]([CH2:5][N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7]2)=[CH:15][CH:16]=1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: COc1ccc(Cn2ccc3ccccc32)cc1Br
Agent: [Pd+2]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2ccc3ccccc32)cc1-c1cccc([N+](=O)[O-])c1
Temperature: 85 °C
Reaction time: 22 h
Yield: 17 %

Procedure:
A suspension of 1-(3-Bromo-4-methoxy-benzyl)-1H-indole (150 mg, 0.474 mmol), palladium bis(triphenylphosphine)dichloride (13.3 mg, 0.0190 mmol), and 3-nitrophenylboronic acid (94.9 mg, 0.569 mmol) in dioxane (10 mL) and 1 M aqueous sodium carbonate (1.1 mL) was stirred at 85° C. for 22 h. To the reaction was added ethyl acetate (30 mL). The organic suspension was washed with water (4×30 mL), brine (2×30 mL), dried over sodium sulfate, and the solvent removed under vacuum. The residue was purified by flash silica gel column chromatography (10% ethyl acetate in hexanes as the elutant) to yield 1-(6-Methoxy-3′-nitro-biphenyl-3-ylmethyl)-1H-indole P-010 (23.6 mg, 17% yield).
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][N:9]2[C:22]=1[CH2:23][CH:24]([CH3:26])[CH3:25])=O>CC(=O)OCC>[NH2:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][N:9]2[C:22]=1[CH2:23][CH:24]([CH3:26])[CH3:25]
Reactant: CC(C)Cc1c(NC(=O)C(F)(F)F)nc2ccc(C(=O)c3ccccc3)cn12
Solvent: CCOC(C)=O
Product: CC(C)Cc1c(N)nc2ccc(C(=O)c3ccccc3)cn12

Procedure:
The 2-trifluoroacetamido-3-isobutyl-6-benzoyl-imidazo[1,2-a]pyridine (2.37 g, 6.09 mmol) was converted to product in a manner substantially analogous to Example 67 to yield 1.49 g. (83.5%). EA, MS(FD).
Reaction SMILES: CS([O:5][CH2:6][C:7]1[CH:8]=[C:9]([CH:17]=[CH:18][CH:19]=1)[O:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(=O)=O.[F:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[C:29]1[CH:34]=[CH:33][C:32](O)=[CH:31][C:30]=1[CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[C:29]1[CH:34]=[CH:33][C:32]([O:5][CH2:6][C:7]2[CH:8]=[C:9]([CH:17]=[CH:18][CH:19]=2)[O:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:31][C:30]=1[CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38]
Reactant: CCOC(=O)COc1cccc(COS(C)(=O)=O)c1
Reactant: COc1ccc(F)c(-c2ccc(O)cc2CC(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1cccc(COc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 65.1 %

Procedure:
To a solution of ethyl 2-(3-(((methylsulfonyl)oxy)methyl)phenoxy)acetate (94 mg) and 2′-fluoro-5′-methoxy-2-neopentyl-[1,1′-biphenyl]-4-ol (120 mg) in DMF (3.0 mL) was added potassium carbonate (67 mg), and the mixture was stirred at 80° C. for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (102 mg) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:4]([F:13])[C:3]=1[OH:14].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([CH3:25])=[C:20]([N:22]=[C:23]=S)[CH:21]=1>CO>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([CH3:25])=[C:20]([NH:22][C:23]2[O:14][C:3]3[C:4]([F:13])=[C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:7][C:2]=3[N:1]=2)[CH:21]=1
Reactant: COC(=O)Cc1ccc(N)c(O)c1F
Reactant: Cc1ccc(Cl)cc1N=C=S
Solvent: CO
Product: COC(=O)Cc1ccc2nc(Nc3cc(Cl)ccc3C)oc2c1F
Temperature: 25 °C
Reaction time: 120 h
Yield: 104.6 %

Procedure:
In methanol (30 ml) was dissolved methyl (4-amino-2-fluoro-3-hydroxyphenyl)acetate (1.0 g, 5.02 mmol). To the resulting solution was added 5-chloro-2-methylphenyl isothiocyanate (0.674 ml, 4.58 mmol). After the mixture was stirred at room temperature for 5 days, mercuric oxide (yellow) (1.14 g, 4.36 mmol) was added thereto. The resulting mixture was stirred at 70° C. for 6 hours. After cooling to room temperature, the reaction mixture was filtered through Celite and washed with methanol. The filtrate was distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from chloroform/ethyl acetate (30/1, v/v) eluate fractions, methyl (2-(5-chloro-2-methylphenylamino)-7-fluoro-6-benzoxazolyl)acetate (1.67 g, 100%) was obtained as a brown solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]([CH2:13][OH:14])[CH2:5]2.CCN(C(C)C)C(C)C.[C:24]([N:28]1[CH2:33][CH2:32][CH:31]([CH2:34][O:35][C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)[CH2:30][CH2:29]1)(=[O:27])[CH:25]=[CH2:26].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.C(#N)CC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[OH:14][CH2:13][CH:6]1[CH2:5][C:4]2[C:9](=[N:10][CH:11]=[C:2](/[CH:26]=[CH:25]/[C:24]([N:28]3[CH2:33][CH2:32][CH:31]([CH2:34][O:35][C:36]4[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=4)[CH2:30][CH2:29]3)=[O:27])[CH:3]=2)[NH:8][C:7]1=[O:12]
Reactant: C=CC(=O)N1CCC(COc2ccc(F)cc2)CC1
Reactant: O=C1Nc2ncc(Br)cc2CC1CO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: O=C1Nc2ncc(/C=C/C(=O)N3CCC(COc4ccc(F)cc4)CC3)cc2CC1CO
Temperature: 100 °C
Reaction time: 48 h
Yield: 5.8 %

Procedure:
To a suspension of 6-bromo-3-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one (10 mg, 0.039 mmol; which may be prepared as described in Step 2) in DMF (200 μL) and proprionitrile (200 μL) under Argon were added DIPEA (8 μL, 0.047 mmol), 1-acryloyl-4-[(4-fluorophenoxy)methyl]piperidine (14 mg, 0.053 mmol; which may be prepared as described in Step 1), tri(o-tolyl)phosphine (2 mg, 0.008 mmol) and palladium acetate (1 mg, 0.004 mmol). The mixture was stirred at 100° C. for 2 days, then was allowed to come back to room temperature, filtered through Celite pad. The residue obtained after concentration of the filtrate was purified by preparative TLC (eluent: DCM/MeOH 9/1) to give the title compound as a white solid (1 mg, 6%).