Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[CH:5]([C:28]1[CH:29]=[CH:30][C:31]2[N:35]=[C:34]3[S:36][CH2:37][CH2:38][CH2:39][N:33]3[C:32]=2[CH:40]=1)[C:6]1(Br)[C:12](=[O:13])[N:11]2[C@@H:7]1[S:8][CH:9]=[C:10]2[C:14]([O:16]CC1C=CC([N+]([O-])=O)=CC=1)=[O:15])(=O)C.[H][H]>C1COCC1.P([O-])([O-])([O-])=O>[S:36]1[C:34]2=[N:35][C:31]3[CH:30]=[CH:29][C:28](/[CH:5]=[C:6]4\[C@@H:7]5[N:11]([C:12]\4=[O:13])[C:10]([C:14]([OH:16])=[O:15])=[CH:9][S:8]5)=[CH:40][C:32]=3[N:33]2[CH2:39][CH2:38][CH2:37]1
Reactant: CC(=O)OC(c1ccc2nc3n(c2c1)CCCS3)C1(Br)C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CS[C@@H]21
Reactant: [H][H]
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Product: O=C(O)C1=CS[C@@H]2/C(=C\c3ccc4nc5n(c4c3)CCCS5)C(=O)N12
Yield: 18.4 %

Procedure:
4-nitrobenzyl (5R)-6-[(acetyloxy)(3,4-dihydro-2H-[1,3]thiazino[3,2-a]benzimidazol-7-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (700 mg, 1.1 mmol) was suspended in 20 ml THF and 20 ml pH=6.5 aqueous phosphate buffer. The mixture was then subjected to 45 psi hydrogen for two hours. Then it was filtered through a pad of celite and concentrated in vacuo to remove most of the THF. The solution was then cooled to zero degree and basified to pH=8 with 1 N sodium hydroxide. Then it was purified via reverse phase HPLC using 1 liter of water followed by 5%-25% acetonitrile and water. Water was then removed through concentrate in vacuo and 75 mg of product (Yield 18%) was collected. MP: >250° C., H-NMR (D2O): δ 7.08 (m, 6H), 3.70 (m, 2H), 4.05 (m, 2H), 3.13 (m, 2H), 2.22 (m, 2H); MS: 372.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([N:12]([C@@H:23]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[CH3:24])[C:13](=[O:22])[CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]([NH2:11])=[O:10])=[CH:4][CH:3]=1.[CH:32]1[CH:37]=[CH:36][C:35]([Se:38]Br)=[CH:34][CH:33]=1.CN(C)C=O>C(#N)C.[O-]S(C(F)(F)F)(=O)=O.[Ag+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[N:12]([C@@H:23]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)[CH3:24])[C:13](=[O:22])[CH:14]([Se:38][C:35]3[CH:36]=[CH:37][CH:32]=[CH:33][CH:34]=3)[CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[NH:11][C:9]2=[O:10])=[CH:6][CH:7]=1
Reactant: Br[Se]c1ccccc1
Reactant: C[C@H](c1ccc(Cl)cc1)N(C(=O)C=Cc1ccccc1)[C@H](C(N)=O)c1ccc(Cl)cc1
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CN(C)C=O
Solvent: CC#N
Product: C[C@H](c1ccc(Cl)cc1)N1C(=O)C([Se]c2ccccc2)C(c2ccccc2)NC(=O)[C@@H]1c1ccc(Cl)cc1
Reaction time: 6 h

Procedure:
Silver triflate (1.69 g, 6.6 mmol) was added to a stirred solution of (S)-α-(4-chlorophenyl)-α-[(R)-N-[1-(4-chlorophenyl)ethyl]-N-(cinnamoyl)amino]acetamide (1.5 g, 3.3 mmol), in acetonitrile (120 mL). To the resulting solution was successively added benzeneselenyl bromide (1.54 g, 6.53 mmol) and dimethylformamide (5.2 mL). After 6 h, the solvent was evaporated in vacuo. The residue was partitioned between ethyl acetate (100 mL) and 1N sodium hydrogenocarbonate (70 mL), dried (Na2SO4), and evaporated. Purification by column chromatography (AcOEt/hexanes, 1:3) afforded the title compound, which was recrystallized from Et2O to give colorless prisms (855 mg, 43%): 1H NMR (400 MHz, CDCl3) δ 1.68 (d, J=7.0 Hz, 3H, CH3), 4.29 (d, J=12.2 Hz, 1H, CH), 4.79 (d, J=12.2 Hz, 1H, CH), 5.28 (s, 1H, CH), 6.21–6.25 (m, 3H, ArH), 6.31 (q, J=7.0 Hz, 1H, CH), 6.71–6.76 (m, 4H, ArH), 6.93–7.11 (m, 6H, NH+5ArH), 7.34–7.40 (m, 4H, ArH), 7.50 (d, J=8.4 Hz, 2H, ArH). Mass spectrum (LCMS, ESI pos.): Calcd for C31H26Cl2N2O2Se: 608.0; found: 609.0 (M+H)+.
Reaction SMILES: N[C@H:2]([C:13](O)=O)[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)N[CH:5]=1.CN1[C:21](=O)[CH2:20][CH2:19][CH2:18]1>O>[CH:3]1[C:4]2=[C:12]3[C:7]([C:18]4[C:13]5[C:2](=[CH:3][CH:4]=[CH:5][C:5]2=5)[CH:21]=[CH:20][CH:19]=4)=[CH:8][CH:9]=[CH:10][C:11]3=[CH:13][CH:2]=1
Reactant: CN1CCCC1=O
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Solvent: O
Product: c1cc2cccc3c4cccc5cccc(c(c1)c23)c54

Procedure:
5.15 mg Trp were dissolved in a minimal amount of water by addition of a molar amount of NaCO3 and sonication. The Trp solution was added to the PDI-NMP-NHS solution and was stirred over night. The compound was transferred to a separating funnel and the aqueous phase was washed with DCM. Then the aqueous phase was acidified to pH 2 using 0.1 M HCl and extracted to DCM. The organic phase was washed 3 times with KCl brine. The extract was concentrated and precipitated from hexane and from diethyl-ether, the precipitant was filtered and re-dissolved in DCM. NMR and mass were measured.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[CH:9][S:8][C:7]=2[CH:11]=1.C([Li])CCC.[B:17](OC(C)C)([O:22]C(C)C)[O:18]C(C)C.Cl>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([B:17]([OH:22])[OH:18])[S:8][C:7]=2[CH:11]=1
Reactant: COc1ccc2ccsc2c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc2cc(B(O)O)sc2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
To a solution of 6-methoxybenzo[b]thiophene (18.13 g, 0.111 mol) in 150 mL of anhydrous tetrahydrofuran (THF) at -60° C. was added n-butyllithium (76.2 mL, 0.122 mol, 1.6M solution in hexanes), dropwise via syringe. After stirring for 30 minutes, triisopropyl borate (28.2 mL, 0.122 mol) was introduced via syringe. The resulting mixture was allowed to gradually warm to 0° C. and then distributed between 1N hydrochloric acid and ethyl acetate (300 mL each). The layers were separated, and the organic layer was dried over sodium sulfate. Concentration in vacuo produced a white solid that was triturated from ethyl ether hexanes. Filtration provided 16.4 g (71%) of 6-methoxybenzo[b]thiophene-2-boronic acid as a white solid. mp 200° C. (dec). 1H NMR (DMSO-d6) d 7.83 (s, 1H), 7.78 (d, J=8.6 Hz, 1H), 7.51 (d, J=2.0 Hz, 1H), 6.97 (dd, J=8.6, 2.0 Hz, 1H), 3.82 (s, 3H). FD mass spec: 208.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)C=N1.C[N+:11]([CH3:14])=CCl.[Cl-].C(Cl)(=O)[C:17](Cl)=[O:18]>CN(C)C=O>[NH:11]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]=[C:14]1[CH:17]=[O:18]
Reactant: C[N+](C)=CCl
Reactant: O=C(Cl)C(=O)Cl
Reactant: c1ccc2[nH]ncc2c1
Agent: [Cl-]
Solvent: CN(C)C=O
Product: O=Cc1nc2ccccc2[nH]1

Procedure:
In Step 1 of Scheme E, azaindole compound a is treated with the Vilsmeier reagent formed by mixing oxalyl chloride with dimethyl formamide to form azaindole aldehyde w, which in turn is reacted with Meldrum's acid in Step 2 to yield azaindole compound x. Azaindole x is then treated with Grignard reagent y in Step 3 to afford azaindole compound z. In Step 4 compound z is reacted with amine d in the presence of pyridine to give azaindole amide r, which is then reduced in Step 5 to provide aminopropyl azaindole compound s. Compound s is one of the compounds of formula I in accordance with the invention.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[C:11]([O:16][C@@H:17]3[O:25][C@H:24]([CH2:26][OH:27])[C@@H:22]([OH:23])[C@H:20]([OH:21])[C@H:18]3[OH:19])=[N:12][NH:13][C:14]=2[CH3:15])=[CH:5][CH:4]=1)[CH3:2].I[CH2:29][CH3:30]>>[CH2:29]([N:13]1[C:14]([CH3:15])=[C:10]([CH2:9][C:6]2[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)[C:11]([O:16][C@@H:17]2[O:25][C@H:24]([CH2:26][OH:27])[C@@H:22]([OH:23])[C@H:20]([OH:21])[C@H:18]2[OH:19])=[N:12]1)[CH3:30]
Reactant: CCc1ccc(Cc2c(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)n[nH]c2C)cc1
Reactant: CCI
Product: CCc1ccc(Cc2c(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)nn(CC)c2C)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Reference Example 63 using 4-[(4-ethylphenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-methyl-1H-pyrazole instead of 3-(β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-5-methyl-1H-pyrazole and using iodoethane instead of 1-iodopropane.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[C:16]([OH:18])=[CH:15][CH:14]=[CH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:21][O:22]CCl>CN(C)C=O>[CH2:1]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[C:16]([OH:18])=[C:15]([O:22][CH3:21])[CH:14]=[CH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCl
Reactant: Oc1cccc2cccc(Cc3ccccc3)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2cccc(Cc3ccccc3)c2c1O
Reaction time: 0.5 h
Yield: 91.3 %

Procedure:
100 g of 8-benzyl-1-naphthol was dissolved in 300 ml of N,N-dimethylformamide to give a solution. 18.6 g of sodium hydride (55% suspension in oil) was added to the solution under cooling with ice. After 30 minutes, 34.4 g of chloromethyl methyl ether was added to the obtained mixture under cooling with ice, followed by stirring for 10 minutes. The obtained mixture was further stirred at room temperature for 30 minutes. The resulting reaction mixture was poured onto ice-water and the obtained mixture was extracted with 1.2 l of ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated in a vacuum. The obtained residue was purified by silica gel column chromatography (developer: hexane to 9% ethyl acetate/hexane) to give 103 g of the title compound as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]#[N:12])=[N:4][CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1.[H][H]>CO.[Pd]>[NH2:8][C:6]1[CH:7]=[C:2]([CH3:1])[C:3]([C:11]#[N:12])=[N:4][CH:5]=1
Reactant: [H][H]
Reactant: Cc1cc([N+](=O)[O-])cnc1C#N
Agent: [Pd]
Solvent: CO
Product: Cc1cc(N)cnc1C#N
Yield: 92.8 %

Procedure:
A mixture of 3-methyl-5-nitropicolinonitrile (2.9 g, 17.8 mmol) and Pd/C (cat.) in MeOH (60 mL) was hydrogenated overnight with a balloon of hydrogen. Pd/C was removed through a pad of celite and the filtrate was evaporated to dryness to afford 2.2 g of 5-amino-3-methylpicolinonitrile as a greenish solid. 1H NMR (300 MHz, DMSO-d6) δ 7.83 (s, 1H), 6.79 (s, 1H), 6.32 (s, 2H), 2.29 (s, 3H).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:11][O:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH:15]([OH:19])[CH2:14]1.F[C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[N+:28]([O-:30])=[O:29]>C1COCC1>[F:27][C:25]1[CH:24]=[CH:23][C:22]([N+:28]([O-:30])=[O:29])=[C:21]([O:19][C@H:15]2[CH2:16][CH2:17][CH2:18][C@@H:13]([O:12][CH3:11])[CH2:14]2)[CH:26]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: COC1CCCC(O)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CO[C@@H]1CCC[C@H](Oc2cc(F)ccc2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
LiHMDS (1 M solution in THF; 5.0 ml) was added slowly to an ice/ethanol-cooled solution of 3-methoxy-cyclohexanol (7:3 mixture of cis- and trans-isomers; 601 mg) in THF (8 ml). Cooling was suspended after 5 minutes and the mixture was stirred for 15 minutes at room temperature before addition of 2,4-difluoro-1-nitro-benzene (482 μl). After 4 h another 1.5 ml of LiHMDS (1 M solution in THF) was added and the reaction mixture was stirred over night at room temperature. The reaction mixture was quenched by addition of hydrochloric acid (0.1 M), diluted with ethyl acetate, and filtered through celite. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was submitted to column chromatography (silica gel, cyclohexane/ethyl acetate 85:15) to give the cis-isomer (650 mg) and the trans-isomer (230 mg).
Reaction SMILES: Cl.O.[NH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.C(N(C(C)C)CC)(C)C.[F:19][C:20]1[CH:21]=[C:22]([N+:27]([O-:29])=[O:28])[CH:23]=[CH:24][C:25]=1F>C(#N)C>[F:19][C:20]1[CH:21]=[C:22]([N+:27]([O-:29])=[O:28])[CH:23]=[CH:24][C:25]=1[N:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1
Reactant: O=C1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC#N
Product: O=C1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 83.4 %

Procedure:
To a stirring solution of 4-piperidone monohydrate hydrochloride (258.7 g, 1.68 mol) and diisopropylethyl amine (590 ml, 3.39 mol) in acetonitrile (2.5 liter) is added 3,4-difluoronitrobenzene (186.3 ml, 1.68 mol). The mixture is heated to 80° C. and stirred overnight. The solvent is cooled to ambient temperature and removed in vacuo. The residue is partitioned between ethyl acetate and 10% aqueous HCl (1.20 liter each). The layers are shaken, the organic layer separated and washed with 10% HCl and brine (800 ml each). The organic layer is dried over MgSO4 and filtered. As the solvent is removed in vacuo a solid began to precipitate out (˜¼ volume). The resulting slurry is cooled to 0–5° C. and filtered to afford 333.7 g of the title compound. 1H NMR (400 MHz, CDCl3) δ 2.65 (m, 4 H), 3.65 (m, 4 H), 6.98 (m, 1 H), 7.26 (s, 1 H), 8.00 (m, 1 H); Anal. Calcd for C11H11FN2O3: C, 55.46; H, 4.65; N, 11.76. Found: C, 55.34; H, 4.60; N, 11.69.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[CH2:13]([S:15][C:16]1[C:17]([C:22]([NH2:24])=[O:23])=[N:18][CH:19]=[CH:20][CH:21]=1)[CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+].C1N2CCN(CC2)C1>O.CS(C)=O>[CH2:13]([S:15][C:16]1[C:17]([C:22]([NH:24][C:2]2[CH:7]=[CH:6][C:5]([S:8][C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=2)=[O:23])=[N:18][CH:19]=[CH:20][CH:21]=1)[CH3:14]
Reactant: FC(F)(F)Sc1ccc(Cl)nc1
Reactant: CCSc1cccnc1C(N)=O
Agent: C1CN2CCN1CC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: CCSc1cccnc1C(=O)Nc1ccc(SC(F)(F)F)cn1
Temperature: 70 °C
Reaction time: 1 h
Yield: 37.6 %

Procedure:
A mixture of 0.64 g of 2-chloro-5-trifluoromethylsulfanylpyridine, 0.54 g of 3-ethylsulfanylpicolinic acid amide, 1.96 g of cesium carbonate, 0.33 g of DABCO and 5 mL of DMSO was stirred at 70° C. for 1 hour. Water was added to the reaction mixture cooled to room temperature, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the resulting residue was applied to a silica gel column chromatography to obtain 0.40 g of 3-ethylsulfanyl-N-(5-trifluoromethylsulfanylpyridin-2-yl)picolinamide (hereinafter, referred to as Compound of Present Invention 48).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5](/[CH:7]=[CH:8]/[C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)=[N:4][C:3]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O1CCOCC1>[C].[Pd].CO>[CH3:1][C:2]1[S:6][C:5]([CH2:7][CH2:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)=[N:4][C:3]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)c1ccc(/C=C/c2nc(-c3ccccc3)c(C)s2)cc1
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)c1ccc(CCc2nc(-c3ccccc3)c(C)s2)cc1
Yield: 94.2 %

Procedure:
A mixture of methyl (E)-4-[2-(5-methyl-4-phenyl-2-thiazolyl)vinyl]benzoate (9.5 g), palladium-carbon (5%, 1.0 g) and dioxane (70 ml)-methanol (60 ml) was subjected to catalytic hydrogenation at 1 atm and room temperature. After the catalyst was filtered off, the filtrate was concentrated under reduced pressure to yield methyl 4-[2-(5-methyl-4-phenyl-2thiazolyl)ethyl]benzoate (9.0 g, 94%), which was then recrystallized from hexane to yield colorless plates having a melting point of 52°-53° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[C:7]2[CH3:12].[C:13](OC(=O)C)(=[O:15])[CH3:14]>N1C=CC=CC=1>[C:13]([O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[C:7]2[CH3:12])(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nccc2c(O)cccc12
Solvent: c1ccncc1
Product: CC(=O)Oc1cccc2c(C)nccc12

Procedure:
For example, 5-hydroxy-1-methylisoquinoline 64.9, prepared as described in J. Med. Chem., 1968, 11, 700, is reacted with acetic anhydride in pyridine to afford 5-acetoxy-1-methylisoquinoline 64.10. The latter compound is reacted with N-bromosuccinimide in refluxing ethyl acetate to yield 5-acetoxy-1-bromomethylisoquinoline 64.11. The product is then reacted with five molar equivalents of a trialkyl phosphite at 120° to give the phosphonate product 64.12. The acetoxy group is hydrolyzed by reaction with sodium bicarbonate in aqueous methanol as described in J. Am. Chem. Soc., 93, 746, 1971, to produce the phenol 64.13.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.C1(PCCCPC2C=CC=CC=2)C=CC=CC=1.CN([CH:34]=[O:35])C.[CH3:36][OH:37]>CC(O)=O.CC(O)=O.[Pd]>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([C:36]([O:35][CH3:34])=[O:37])=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: CO
Reactant: COc1ccc2c(Cl)ccnc2c1
Reactant: CN(C)C=O
Agent: [Pd]
Agent: c1ccc(PCCCPc2ccccc2)cc1
Solvent: CC(=O)O
Product: COC(=O)c1ccnc2cc(OC)ccc12
Temperature: 70 °C
Reaction time: 19 h

Procedure:
The following reagents were placed in a glass jacket inside of a Parr bomb: 4-chloro-7-methoxyquinoline (2 g, 10.33 mmol), Pd(OAC)2 (225 mg, 1.0 mmol), 1,3-diphenylphosphino propane [DPPE] (618 mg, 1.55 mmol), DMF (15 mL), MeOH (3 mL) and TEA (2.87 mL, 20.66 mmol) and the vessel sealed. The vessel was pressurized to 50 psi CO and stirred at 70° C. (internal temperature) for 19 h. The vessel was allowed to cool to RT, carefully opened and the contents transferred to a round bottom flask and concentrated in-vacuo. A solution of 2:1 EtOAc:hexanes was added to the residual solid and the solid filtered (and discarded). The filtrate was evaporated and the residue purified by column chromatography using a mixture of EtOAc/hexanes as the eluent. The title compound was obtained as a yellow solid.
Reaction SMILES: Br[C:2]1[C:3](=[O:35])[N:4]([CH2:19][C@H:20]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:5](=[O:18])[N:6]([CH2:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])[C:7]=1[CH3:8].[F:36][C:37]1[C:42]([O:43][CH3:44])=[CH:41][CH:40]=[CH:39][C:38]=1B(O)O>C1C=CC=CC=1.CCO.COCCOC.[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>[C:31]([O:30][C:28]([NH:27][C@H:20]([CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[CH2:19][N:4]1[C:3](=[O:35])[C:2]([C:38]2[CH:39]=[CH:40][CH:41]=[C:42]([O:43][CH3:44])[C:37]=2[F:36])=[C:7]([CH3:8])[N:6]([CH2:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])[C:5]1=[O:18])=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: Cc1c(Br)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)C2CCCCC2)c(=O)n1Cc1c(F)cccc1F
Reactant: COc1cccc(B(O)O)c1F
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: COCCOC
Solvent: CCO
Product: COc1cccc(-c2c(C)n(Cc3c(F)cccc3F)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)C3CCCCC3)c2=O)c1F
Temperature: 80 °C
Yield: 32.3 %

Procedure:
5-Bromo-3-[2(R)-tert-butoxycarbonylamino-2-cyclohexylethyl]-1-[2,6-difluorobenzyl]-6-methyl-pyrimidine-2,4(1H,3H)-dione 4b (1.0 g, 1.79 mmol) in benzene/EtOH/ethylene glycol dimethyl ether (20/2/22 mL) was added 2-fluoro-3-methoxyphenylboronic acid (382 mg, 2.24 mmol) and saturated Ba(OH)2/water (˜0.5 M, 15 mL). The reaction mixture was deoxygenated with N2 for 10 minutes, tetrakis(triphenylphosphine) palladium (0) (208 mg, 0.18 mmol) was added and the reaction mixture was heated at 80° C. overnight under N2. The reaction mixture was partitioned between brine and EtOAc. The organic layer was dried (sodium sulfate), evaporated, and purified by flash chromatography (silica, 30% EtOAc/hexanes) to give compound 4c (348 mg, 32.3% ). MS (CI) m/z 502.2 (MH+-Boc).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:28])[C:9]2[CH:27]=[CH:26][C:12]3[N:13]([CH3:25])[C:14]([NH:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=4)=[N:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:29][S:30]([CH2:33][CH2:34][C:35]1[CH:36]=[C:37]([NH2:41])[CH:38]=[CH:39][CH:40]=1)(=[O:32])=[O:31]>>[ClH:1].[CH3:29][S:30]([CH2:33][CH2:34][C:35]1[CH:36]=[C:37]([NH:41][C:2]2[N:7]=[C:6]([N:8]([CH3:28])[C:9]3[CH:27]=[CH:26][C:12]4[N:13]([CH3:25])[C:14]([NH:16][CH2:17][C:18]5[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=5)=[N:15][C:11]=4[CH:10]=3)[CH:5]=[CH:4][N:3]=2)[CH:38]=[CH:39][CH:40]=1)(=[O:31])=[O:32]
Reactant: CS(=O)(=O)CCc1cccc(N)c1
Reactant: Cc1ccc(CNc2nc3cc(N(C)c4ccnc(Cl)n4)ccc3n2C)cc1
Product: Cc1ccc(CNc2nc3cc(N(C)c4ccnc(Nc5cccc(CCS(C)(=O)=O)c5)n4)ccc3n2C)cc1
Product: Cl

Procedure:
The title compound was prepared following the procedure of example one with N5-(2-Chloro-pyrimidin-4-yl)-1,N5-dimethyl-N2-(4-methyl-benzyl)-1H-benzoimidazole-2,5-diamine (98 mg, 0.25 mmol) and 3-(2-methanesulfonyl-ethyl)-phenylamine (50 mg, 0.25 mmol) as a white solid (126 mg, 85%). 1H NMR (300 MHz, d6-DMSO+NaHCO3) δ 9.07 (s, 1H), 7.75-7.77 (m, 2H), 7.59 (d, J=8.1 Hz, 1H), 7.36 (t, J=6.0 Hz, 1H), 7.07-7.29 (M, 7H), 6.79-6.85 (M, 2H), 5.61 (d, J=5.7 Hz, 1H), 4.54 (d, J=5.7 Hz, 2H), 3.57 (s, 3H), 3.43 (s, 3H), 3.32-3.40 (m, 2H), 2.97 (s, 3H), 2.90-2.97 (M, 2H), 2.26 (s, 3H). MS (ESI) m/z=556 [M+H].
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[N:15][CH:16]=3)[CH:9]=2)[N:4]([S:30]([C:33]2[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[CH:3]=1.[CH2:40]([N:48]1[CH:52]=[C:51](B2OC(C)(C)C(C)(C)O2)[CH:50]=[N:49]1)[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.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>[CH2:40]([N:48]1[CH:52]=[C:51]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:12]=[CH:13][C:14]([N:17]5[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]5)=[N:15][CH:16]=4)[CH:9]=3)[N:4]([S:30]([C:33]3[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[CH:3]=2)[CH:50]=[N:49]1)[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)nc4)cnc32)cc1
Reactant: CC1(C)OB(c2cnn(CCc3ccccc3)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(CCc4ccccc4)c3)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)nc4)cnc32)cc1
Yield: 87.6 %

Procedure:
Using similar reaction conditions as described in step-i of example-1, tert-butyl 4-(5-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)piperazine-1-carboxylate (Intermediate 66K) (150 mg, 0.227 mmol) was coupled with 1-phenethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Intermediate 59) (101 mg, 0.34 mmol) using sodium carbonate (73 mg, 0.68 mmol) and Pd(PPh3)2Cl2 (10 mg, 0.011 mmol) in toluene/ethanol/water (3/5/1 ml) to afford 140 mg (88.0% yield) of the pure product after column purification using 5% methanol in dichloromethane as eluent. MS: m/z=704.3 (M+1).