Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:33][NH:34][CH2:35][CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]([CH2:17][C:18]([N:34]([CH3:33])[CH2:35][CH2:36][CH2:37][N:38]3[CH2:39][CH2:40][N:41]([CH3:44])[CH2:42][CH2:43]3)=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1c(-c2cccc(Cl)c2)nc2cccnc21
Reactant: CNCCCN1CCN(C)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Product: CN1CCN(CCCN(C)C(=O)Cn2c(-c3cccc(Cl)c3)nc3cccnc32)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 19.8 %

Procedure:
Under nitrogen bubbling, a mixture of 2-(3-chlorophenyl)-3H -imidazo[4,5-b]pyridine-3-acetic acid (2.38 g, 0.008 mole) and 1,1'-carbonyldiimidazole (1.34 g, 0.008 mole) was stirred at room temperature for 3 hours. The N,4-dimethyl-1-piperazinepropanamine (1.42 g, 0.008 mole) was added and the reaction mixture was allowed to stir at room temperature for 2 hours. The reaction mixture was evaporated to dryness. The residue was partitioned between methylene chloride and aqueous potassium bicarbonate. The aqueous layer was separated and extracted with methylene chloride. The methylene chloride layers were combined, extracted with aqueous potassium bicarbonate and water and dried over sodium sulfate. The filtrate was evaporated and the solid residue was recrystallized as a fumarate salt from ethyl alcohol-isopropyl ether. Recrystallization from isopropyl alcohol-acetonitrile-isopropyl ether did not improve the analysis. The solid was converted to the free base. The free base was treated with boiling hexanes and allowed to cool to room temperature. The solid was collected by filtration, washed with hexane, and dried under high vacuum overnight to give 0.7 g of title compound, mp 114°-17° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.CC1(C)C(C)(C)[O:33][B:32](B2OC(C)(C)C(C)(C)O2)[O:31]1.C([O-])(=O)C.[K+].Cl>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:8][N:6]1[C:5](=[O:9])[CH:4]=[CH:3][C:2]([B:32]([OH:33])[OH:31])=[CH:7]1
Reactant: Cn1cc(Br)ccc1=O
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Product: Cn1cc(B(O)O)ccc1=O
Temperature: 90 °C
Reaction time: 8 h

Procedure:
5-Bromo-1-methylpyridin-2(1H)-one (400 mg, 2.17 mmol), tricyclohexylphosphine (72 mg, 0.26 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (540 mg, 2.17 mmol), potassium acetate (522 mg, 5.32 mmol) and Pd2(dba)3 (97 mg, 0.11 mmol) were added to a flask. The flask was evacuated and purged with argon three times. Fully degassed dioxane (9.5 mL) was added and the reaction was sealed and heated at 90° C. overnight. The mixture was then cooled to room temperature, filtered over a thin layer of celite, eluting with dichloromethane. The majority of the dichloromethane was evaporated under reduced pressure and hexane was added until a precipitate formed. The slurry was filtered and the filtrate was concentrated. The resulting residue was dissolved in dioxane, 10 equivalents of 1 N hydrochloric acid were added, and the mixture was stirred overnight. Removal of the solvent under reduced pressure and purification of the resulting residue via reverse phase HPLC (10-100% acetonitrile/water+0.05% TFA modifier) afforded the title compound.
Reaction SMILES: C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[C:47]([O:51][C:52]([N:54]1[CH2:59][CH2:58][N:57]([C:60]2[C:65]([CH:66]3[CH2:68][CH2:67]3)=[C:64](Cl)[N:63]=[CH:62][N:61]=2)[CH2:56][CH2:55]1)=[O:53])([CH3:50])([CH3:49])[CH3:48].[C:70](=[NH:83])([C:77]1[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=1)[C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1.C1(C)C=CC=CC=1>CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:47]([O:51][C:52]([N:54]1[CH2:59][CH2:58][N:57]([C:60]2[C:65]([CH:66]3[CH2:68][CH2:67]3)=[C:64]([N:83]=[C:70]([C:71]3[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=3)[C:77]3[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=3)[N:63]=[CH:62][N:61]=2)[CH2:56][CH2:55]1)=[O:53])([CH3:50])([CH3:49])[CH3:48]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc(Cl)c2C2CC2)CC1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ncnc(N=C(c3ccccc3)c3ccccc3)c2C2CC2)CC1
Temperature: 95 °C
Yield: 89.3 %

Procedure:
A round bottom flask was charged with Pd(OAc)2 (84 mg, 0.37 mmol) and rac-BINAP (234 mg, 0.37 mmol) and purged with N2. To the flask was added 4-(5-cyclopropyl-6-chloro-pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (1.27 g, 3.75 mmol), benzophenone imine (815 mg, 4.50 mmol), NaOBut (793 mg, 8.25 mmol) and toluene (24 mL). The mixture was heated to 95° C. for 1 hour. After cooling to room temperature, the reaction was diluted with EtOAc, filtered through Celite, and concentrated. The crude product was purified by column chromatography (hexanes:EtOAc, 2:1) to give 4-[6-(Benzhydrylidene-amino)-5-cyclopropyl-pyrimidin-4-yl]-piperazine-1-carboxylic acid tert-butyl ester (1.62 g, 89%) as a colorless oil. 1H NMR (CDCl3, 400 MHz) δ 8.38 (s, 1H), 7.41 (m, 10H), 3.40 (m, 4H), 3.32 (m, 4H), 1.46 (s, 9H), 0.93 (m, 1H), 0.86 (m, 2H), 0.59 (m, 2H). LCMS (APCI+) m/z 484 [M+H]+; Rt=3.94 min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]#[N:8])=[CH:3][CH:2]=1.[CH:9](=[O:11])[CH3:10].S(=O)(=O)(O)O>O.C(OO)(C)(C)C>[C:9]([C:2]1[CH:3]=[C:4]([C:7]#[N:8])[CH:5]=[CH:6][N:1]=1)(=[O:11])[CH3:10]
Reactant: CC=O
Reactant: N#Cc1ccncc1
Agent: CC(C)(C)OO
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)c1cc(C#N)ccn1

Procedure:
A solution of ferrous sulfate heptahydrate (496 g) in water (1080 ml) and tert-butylhydroperoxide (173 ml) were simultaneously added to a solution of 4-pyridinecarbonitrile (30 g), acetaldehyde (97.6 ml) and sulfuric acid (15.4 ml) in water (90 ml) at 0° C. with stirring. After stirring at the same temperature for one hour, the resulting precipitate was collected by filtration and washed with water to give 2-acetyl-4-pyridinecarbonitrile (22.5 g).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([SH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([F:33])=[C:29]([F:32])[CH:30]=2)[N:25]=[CH:24][N:23]=1>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:22]3[C:31]4[C:26](=[CH:27][C:28]([F:33])=[C:29]([F:32])[CH:30]=4)[N:25]=[CH:24][N:23]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(S)c2)no1
Reactant: Fc1cc2ncnc(Cl)c2cc1F
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc(Sc3ncnc4cc(F)c(F)cc34)c2)no1
Yield: 37 %

Procedure:
The title compound was prepared from 1-(5-tert-butylisoxazol-3-yl)-3-(3-mercaptophenyl)urea described in Example 44A (87 mg, 0.3 mmol) and 4-chloro-6,7-difluoroquinazoline (60 mg, 0.3 mmol) from Example 4A Step 2 as described in Example 46 to give 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6,7-difluoro quinazolin-4-ylthio)phenyl)urea (50 mg, 0.11 mmol, 37%). 1H NMR (300 MHz, DMSO-d6) δ 9.61 (s, 1H), 9.05 (s, 1H), 8.88 (s, 1H), 8.34 (dd, 1H), 8.09 (dd, 1H), 7.88 (s, 1H), 7.53 (d, 1H), 7.47 (t, 1H), 7.30 (d, 1H), 6.49 (s, 1H), 1.28 (s, 9H); LC-MS (ESI) m/z 478 (M+Na)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[C:9]([N+:14]([O-:16])=[O:15])[CH:8]=2)[CH:2]=1.[Br:17]Br>CC(O)=O>[Br:17][C:12]1[CH:13]=[C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:8]=[C:9]([N+:14]([O-:16])=[O:15])[C:10]=1[NH2:11]
Reactant: BrBr
Reactant: Nc1ccc(-c2cccnc2)cc1[N+](=O)[O-]
Solvent: CC(=O)O
Product: Nc1c(Br)cc(-c2cccnc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.2 %

Procedure:
To a solution of 4-(pyridin-3-yl)-2-nitroaniline (1.3 g, 9 mmol) in HOAc (25 mL) was added bromine (1.58 g, 9.9 mmol) in HOAc (5 mL). The resulting mixture was stirred at room temperature for one hour and then quenched with ice-water. The solids were collected, washed with water and dried. The solids in EtOAc was then washed with NaOH (2N; 20 mL), water, brine and concentrated in vacuo. The concentrate was purified by chromatography [Silica Gel, ethyl acetate: hexanes (1:1)] to afford the title compound (0.8 g). 1H NMR (CDCl3) δ 8.83 (d, 1H), 8.55 (m, 1H), 8.41 (d, 1H), 8.15 (d, 1H), 7.96 (m, 1H), 7.41 (m, 1H), 6.80 (br s, 2H). (M+1) 294.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:19]([O:25][C:26](=[O:28])[CH3:27])[C@@H:18]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[O:17][C@@H:6]1[O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15]Cl)(=[O:3])[CH3:2].[N-:34]=[N+:35]=[N-:36].[Na+]>[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].CN(C=O)C.CCOC(C)=O>[C:1]([O:4][C@H:5]1[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:19]([O:25][C:26](=[O:28])[CH3:27])[C@@H:18]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[O:17][C@@H:6]1[O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][N:34]=[N+:35]=[N-:36])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@H](OCCOCCOCCCl)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: [N-]=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)OC[C@H]1O[C@H](OCCOCCOCCN=[N+]=[N-])[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Yield: 86.6 %

Procedure:
A solution of 36 (2.9 g, 5.8 mmol), sodium azide (1.89 g, 29.1 mmol) and nBu4NI (4.3 g, 11.6 mmol) in anhydrous DMF (20 mL) was stirred at 90° C. for 24 h. The solution was cooled to rt then diluted with EtOAc (300 mL). The organic layer was washed with water (3×200 mL), dried (Na2SO4), filtered and evaporated. The oily residue was purified by flash silica gel column chromatography (PE then PE/EtOAc 1:1) to afford 37 (2.54 g, 86%) as a pale yellow oil. 1H NMR (CDCl3, 300 MHz): δ 1.96, 2.02, 2.08, 2.13 (4s, 4×3H, 4×CH3CO), 3.37 (t, 2H, J=5.0 Hz, CH2N3), 3.60-3.72 (m, 9H, OCH2CH2O), 3.74-3.84 (m, 1H, OCH2), 4.00-4.15 (m, 2H, H-5, H-6), 4.27 (dd, 1H, J6′,5=5.1 Hz, J6′,6=12.4 Hz, H-6′), 4.85 (d, 1H, J1,2=1.5 Hz, H-1), 5.20-5.37 (m, 3H, H-2, H-3, H-4). 13C NMR (CDCl3, 75 MHz): δ 20.62, 20.63, 20.7, 20.8 (4s, 4×CH3CO), 50.6 (CH2N3), 62.3 (C-6), 66.0, 68.3, 69.0, 69.5 (4s, C-2 to C-5), 67.2, 69.97, 70.02, 70.6, 70.7 (5s, 5×CH2O), 97.6 (C-1), 169.6, 169.8, 170.0, 170.6 (4s, 4×CH3CO). [α]D=+34 (c=1/CH2Cl2). ESIMS (positive mode) m/z: 528 [M+Na]+. HRESIMS (positive mode) m/z: calcd for C20H31N3O12Na1 [M+Na]+528.1805, found 528.1801.
Reaction SMILES: N.C1(S([N:11]2[C:19]3[CH:18]=[CH:17][N:16]=[C:15]([Cl:20])[C:14]=3[CH:13]=[C:12]2[CH2:21][N:22]2[CH2:26][CH2:25][C@H:24]([NH:27][S:28]([C:31]3[S:35][C:34]4[CH:36]=[C:37]([Cl:40])[CH:38]=[CH:39][C:33]=4[CH:32]=3)(=[O:30])=[O:29])[C:23]2=[O:41])(=O)=O)C=CC=CC=1>CO>[Cl:20][C:15]1[C:14]2[CH:13]=[C:12]([CH2:21][N:22]3[CH2:26][CH2:25][C@H:24]([NH:27][S:28]([C:31]4[S:35][C:34]5[CH:36]=[C:37]([Cl:40])[CH:38]=[CH:39][C:33]=5[CH:32]=4)(=[O:29])=[O:30])[C:23]3=[O:41])[NH:11][C:19]=2[CH:18]=[CH:17][N:16]=1
Reactant: O=C1[C@@H](NS(=O)(=O)c2cc3ccc(Cl)cc3s2)CCN1Cc1cc2c(Cl)nccc2n1S(=O)(=O)c1ccccc1
Agent: N
Solvent: CO
Product: O=C1[C@@H](NS(=O)(=O)c2cc3ccc(Cl)cc3s2)CCN1Cc1cc2c(Cl)nccc2[nH]1
Yield: 59.1 %

Procedure:
Ammonia gas is bubbled for 5 minutes into a solution of 6-chloro-benzo[b]thiophene-2-sulfonic acid [1-(1-benzenesulfonyl-4-chloro-1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide (0.4 g, 0.22 mmol) in MeOH (10 mL). The solution is refluxed overnight then concentrated to dryness. The crude product is purified by column chromatography eluting with 5% MeOH/CH2Cl2 to give the product (0.065 g, 0.13 mmol) as a white solid.
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.[F:23][C:24]([F:34])([F:33])[C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1.ClCCl.O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.[Cl-].[Na+].O>[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[N:10]1[CH2:29][C:28]1[CH:27]=[CH:26][C:25]([C:24]([F:23])([F:33])[F:34])=[CH:32][CH:31]=1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccc(F)cc3F)c(=O)c12
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [I-]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1c2c(=O)n(-c2ccc(F)cc2F)n1Cc1ccc(C(F)(F)F)cc1
Temperature: 100 °C
Yield: 38 %

Procedure:
A mixture of (4S,7R)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 14; 100 mg, 0.33 mmol), tetrabutylammonium iodide (85 mg, 0.23 mmol) and 4-(trifluoromethyl)benzyl bromide (315 mg, 1.3 mmol) in dimethylformamide (2 mL) was heated at 100° C. overnight. Dichloromethane (50 mL) and a mixture of water (13 mL) and brine (6 mL) were added. The organic layer was washed with 10% aqueous sodium thiosulfate (20 mL), and brine (20 mL). The solution was dried (magnesium sulfate), filtered, evaporated, and purified by column chromatography, eluting with 50% ethyl acetate/petroleum ether, to give (4S,7R)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1-(4-trifluoromethyl-benzyl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (58 mg, 38%) as a white solid. ES(+)-MS (M+H) 463.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:6][CH:5]=1.[H-].[Na+].[Cl:24][C:25]1[CH:30]=[C:29](F)[CH:28]=[CH:27][N:26]=1.O>CN(C=O)C>[Cl:24][C:25]1[CH:30]=[C:29]([O:1][CH2:2][CH2:3][C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[CH:6][CH:5]=2)[CH:28]=[CH:27][N:26]=1
Reactant: Fc1ccnc(Cl)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CCO)c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(CCOc2ccnc(Cl)c2)c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
To a degassed solution of tert-butyl 4-(2-hydroxyethyl)naphthalen-1-ylcarbamate (32) (0.64 g, 2.23 mmol) in DMF (10 mL) was added sodium hydride (0.267 g, 60% dispersion in mineral oil, 6.68 mmol) under nitrogen at 0° C. The solution was warmed to RT and was stirred for 30 min and then cooled to 0° C. To this mixture was added a solution of 2-chloro-4-fluoro-pyridine (0.381 g, 2.90 mmol) in DMF (5.0 mL) and the reaction mixture was warmed to RT and stirred for 16 hr. Water was added and the mixture was extracted with ethyl acetate. The ethyl acetate extract was washed with brine (3×), dried (MgSO4) and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, 0-40% ethyl acetate in isohexane, gradient elution) to afford the title compound (33) (0.67 g, 75%); m/z 399 (M+H)+, (ES+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Li]CCCC.[CH3:11][O:12][C:13](=[O:34])[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=2)[NH:17][C:16]=1[C:25](=[O:33])[C:26]1[CH:31]=[CH:30][C:29](Br)=[CH:28][CH:27]=1.O>C(OCC)C.[Pd].C1COCC1.[Cl-].[Zn+2].[Cl-].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:11][O:12][C:13](=[O:34])[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=2)[NH:17][C:16]=1[C:25](=[O:33])[C:26]1[CH:31]=[CH:30][C:29]([C:2]2[S:1][CH:5]=[CH:4][N:3]=2)=[CH:28][CH:27]=1
Reactant: COC(=O)Cc1c(C(=O)c2ccc(Br)cc2)[nH]c2cc(Cl)ccc12
Reactant: c1cscn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: [Cl-]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)Cc1c(C(=O)c2ccc(-c3nccs3)cc2)[nH]c2cc(Cl)ccc12
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
To a stirred solution of thiazole (0.11 g, 1.23 mmol) in diethyl ether (4 ml) was added n-BuLi (1.55M in hexane, 0.79ml) at −78° C. under nitrogen atmosphere. After stirring for 30 min., zinc chloride (1.0M in diethyl ether, 3.7 ml, 3.7 mmol) was added, and the mixture stirred at 0° C. for 30 min. To the resulting mixture was added palladium catalyst prepared in THF (5 ml) by the treatment of a suspension of dichlorobis(triphenylphosphine)palladium(II) (0.22 g, 0.31 mmol) with n-BuLi (1.55M in hexane, 0.39 ml). Methyl[6-chloro-2-(4-bromobenzoyl)-1H-indol-3-yl]acetate (Example 206, 0.25 g, 0.61 mmol) was added to the mixture. The reaction mixture was heated at reflux temperature for 4 h., poured into water (50 ml), and extracted with ethyl acetate (50 ml). The combined extracts were washed with brine (50 ml), dried (MgSO4), and concentrated. This crude product was purified by flash column chromatography eluting with ethyl acetate-hexane (1:3) to afford 0.18 g (72%) of the title compound as yellow solids.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]([C@@H:13]([CH2:17][CH3:18])[C:14]([OH:16])=[O:15])[C:9]2=[O:12])=[CH:4][CH:3]=1.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[F-].[K+]>C1COCC1.Cl.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>[C:19]1([C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][N:8]([C@@H:13]([CH2:17][CH3:18])[C:14]([OH:16])=[O:15])[C:9]3=[O:12])=[CH:4][CH:3]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OB(O)c1ccccc1
Reactant: CC[C@@H](C(=O)O)n1ccc2ccc(Cl)cc2c1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC[C@@H](C(=O)O)n1ccc2ccc(-c3ccccc3)cc2c1=O
Yield: 66.1 %

Procedure:
To a solution of (S)-2-(7-chloro-1-oxo-1H-isoquinolin-2-yl)-butyric acid (prepared as described in methods A-E) (200 mg) and phenyl boronic acid (276 mg) in THF (2 ml) was added palladium (II) acetate (1.7 mg), 2-(di-tert-butylphosphino)biphenyl (4.5 mg) and potassium fluoride (262 mg). The resulting mixture was heated at reflux for 18 hours, then cooled and diluted with 1M HCl (5 ml) and ethyl acetate (15 ml). The organic phase was separated and the aqueous extracted with ethyl acetate (2×15 ml). The combined organics were dried (magnesium sulfate), filtered and concentrated. The residue was purified through a plug of silica gel, then further purified by radial chromatography eluting with 1% acetic acid in ethyl acetate. This gave the subtitled product as a brown solid (153 mg, 66%). 1H NMR (400 MHz, CDCl3) δ 1.00 (3H, t), 2.15 (1H, m), 2.40 (1H, m), 5.37 (1H, m), 6.70 (1H, d), 7.15 (1H, d), 7.45 (1H, m), 7.55 (2H, m), 7.68 (1H, m), 7.75 (2H, m), 7.99 (1H, d), 8.70 (1H, s) ppm.
Reaction SMILES: [O:1]([C:3]1[CH:4]=[C:5]([C:9]2[N:18]=[C:17]([C:19](O)=[O:20])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:6]=[CH:7][CH:8]=1)[CH3:2].Cl.[OH:23][C:24]1[C:33]([N:34]([CH3:36])[CH3:35])=[CH:32][CH:31]=[C:30]2[C:25]=1[CH2:26][CH2:27][NH:28][CH2:29]2>>[O:1]([C:3]1[CH:4]=[C:5]([C:9]2[N:18]=[C:17]([C:19]([N:28]3[CH2:27][CH2:26][C:25]4[C:30](=[CH:31][CH:32]=[C:33]([N:34]([CH3:36])[CH3:35])[C:24]=4[OH:23])[CH2:29]3)=[O:20])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:6]=[CH:7][CH:8]=1)[CH3:2]
Reactant: CN(C)c1ccc2c(c1O)CCNC2
Reactant: COc1cccc(-c2nc(C(=O)O)c3ccccc3n2)c1
Agent: Cl
Product: COc1cccc(-c2nc(C(=O)N3CCc4c(ccc(N(C)C)c4O)C3)c3ccccc3n2)c1
Yield: 10 %

Procedure:
Reaction of 2-(3-methoxylphenyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-dimethylamino-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 50 (10% yield) as a brown solid. 1H NMR (300 MHz, CDCl3) δ 2.64 and 2.68 (2s, 6H), 2.87 and 3.09 (2t, 2H), 3.60 and 4.21 (2t, 2H), 3.94 and 3.97 (2s, 3H), 4.50 and 5.09 (2s, 2H), 6.34 and 6.82 (2d, 1H), 6.95-7.16 (m, 2H), 7.42-7.49 (m, 1H), 7.55-7.65 (m, 1H), 7.90-8.06 (m, 2H), 8.13-8.29 (m, 3H); MS (ESI) m/z 455 ([M+H]+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[CH2:18][C:17]3[CH:19]=[C:20](B4OC(C)(C)C(C)(C)O4)[CH:21]=[CH:22][C:16]=3[O:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br.Br[C:34]1[CH:39]=[CH:38][N:37]=[N:36][CH:35]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH:14]2[CH2:18][C:17]3[CH:19]=[C:20]([C:34]4[CH:39]=[CH:38][N:37]=[N:36][CH:35]=4)[CH:21]=[CH:22][C:16]=3[O:15]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(B4OC(C)(C)C(C)(C)O4)ccc3O2)CC1
Reactant: Brc1ccnnc1
Agent: Br
Product: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(-c4ccnnc4)ccc3O2)CC1

Procedure:
The title compound is prepared from 4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3-dihydro-benzofuran-2-yl]-piperidine-1-carboxylic acid tert-butyl ester and 4-bromopyridazine hydrobromide following a procedure analogous to that described in Example 1. LC (method 6): tR=1.19 min; Mass spectrum (ESI+): m/z=382 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15](=[O:24])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Br[CH2:32][C:33]#[N:34]>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15](=[O:24])[CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])[CH2:32][C:33]#[N:34])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CCBr
Reactant: Cc1ccccc1CC(=O)c1cccc(OCc2ccccc2)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccccc1C(CC#N)C(=O)c1cccc(OCc2ccccc2)c1
Reaction time: 0.5 h

Procedure:
A stirred solution of 1-(3-benzyloxyphenyl)-2-(2-methylphenyl)ethan-1-one (4 g) in tetrahydrofuran (100 mL) is treated with potassium tert-butoxide (200 mg). After stirring for 30 minutes, it is treated with bromoacetonitrile (0.98 mL), dropwise, and stirring is continued for a further 28 hours. The mixture is then treated with further quantities of potassium tert-butoxide (200 mg) and bromoacetonitrile (0.98 mL) and allowed to stand at room temperature overnight. It is then concentrated under reduced pressure and partitioned between water and ethyl acetate. The organic layer is dried over magnesium sulphate and evaporated, to give a brown oil, which is subjected to flash chromatography on silica gel, eluting with a mixture of ethyl acetate and pentane (1:9 v/v), to give 1-(3-benzyloxyphenyl)-3-cyano-2-(2-methylphenyl)propan-1-one, in the form of a colourless oil (0.67 g).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:14]1[CH:15]=[CH:16][C:17]([C:25]([OH:27])=[O:26])=[N:18][C:19]=1[O:20][CH2:21][CH:22]1[CH2:24][CH2:23]1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:22]1([CH2:21][O:20][C:19]2[N:18]=[C:17]([C:25]([OH:27])=[O:26])[CH:16]=[CH:15][C:14]=2[N:1]2[CH2:5][CH2:4][CH2:3][C:2]2=[O:6])[CH2:23][CH2:24]1
Reactant: O=C1CCCN1
Reactant: O=C(O)c1ccc(Br)c(OCC2CC2)n1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: O=C(O)c1ccc(N2CCCC2=O)c(OCC2CC2)n1
Temperature: 110 °C
Reaction time: 8 h
Yield: 54.3 %

Procedure:
Under nitrogen atmosphere, pyrrolidin-2-one (375 mg, 4.4 mmol), dimethylbisdiphenyl-phosphinoxanthene (CAS 161265-03-8, 127 mg, 2.4 mmol), tris(dibenzylideneacetone)dipalladium (CAS 51364-51-3, 67 mg, 0.1 mmol) and cesium carbonate (CAS 534-17-8, 1.8 g, 6 mmol) in 1,4-dioxane (100 mL) were added to a solution of 5-bromo-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 9 d, 1 g, 4 mmol) and the reaction mixture was stirred overnight at 110° C. The reaction mixture was concentrated in vacuo, dissolved in water and extracted with ethyl acetate (3×30 mL). The aqueous layer was adjusted to pH=2 with aqueous solution of hydrochloride (1N), the resulting precipitate was collected by filtration and dried. The crude product was purified by column chromatography (silica gel, 20 g, eluting with 30% ethyl acetate in petroleum ether) to give the desired product (600 mg) as a yellow solid; MS (EI): m/e=277.1 [M+H]+.