Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[CH:9](O[BH-](OC(C)C)OC(C)C)(C)C.[K+].Cl[C:24]([O:26][C:27]1[CH:32]=CC=C[CH:28]=1)=[O:25].CC(C)([O-])C.[K+].C(O)(=O)C(O)=O>O1CCCC1>[C:27]([O:26][C:24]([N:6]1[CH:7]=[CH:8][C:3](=[O:2])[CH2:4][CH2:5]1)=[O:25])([CH3:32])([CH3:9])[CH3:28]
Reactant: CC(C)O[BH-](OC(C)C)OC(C)C
Reactant: COc1ccncc1
Reactant: O=C(Cl)Oc1ccccc1
Agent: CC(C)(C)[O-]
Agent: O=C(O)C(=O)O
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C=CC(=O)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59.2 %

Procedure:
A solution of 1.0 gm (9.16 mMol) 4-methoxypyridine in 15 mL tetrahydrofuran was cooled to −41° C. To this solution was added dropwise 12.6 mL (18.32 mMol) potassium tri(isopropoxy)borohydride (1.45 M in tetrahydrofuran). The resulting mixture was stirred for 15 minutes and then 1.58 gm (10.07 mMol) phenyl chloroformate were added and the resulting mixture stirred −41° C. After 2 hours, 7.19 gm (7.0 mMol) potassium tert-butoxide were added. After stirring at −41° C. for 30 minutes, the reaction mixture was allowed to warm to room temperature. After 2 hours at room temperature, the reaction mixture was cooled again to −41° C. and was then treated with saturated aqueous oxalic acid. The resulting mixture was extracted well with diethyl ether. The organic extracts were combined and washed sequentially with saturated aqueous oxalic acid, water, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride. The remaining organic phase was dried over magnesium sulfate and concentrated under reduced pressure. The residual oil was subjected to silica gel chromatography, eluting with a gradient of hexane containing from 10-40% ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide 1.07 gm of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C@@H:8]([NH:10][C:11]2[N:16]=[C:15]([N:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[N:19]=[CH:18]3)[CH:14]=[CH:13][N:12]=2)[CH3:9])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(Cl)Cl>[C:33]([NH:1][C:2]1[CH:3]=[C:4]([C@@H:8]([NH:10][C:11]2[N:16]=[C:15]([N:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[N:19]=[CH:18]3)[CH:14]=[CH:13][N:12]=2)[CH3:9])[CH:5]=[CH:6][CH:7]=1)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)c1cccc(N)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)c1cccc(NC(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-[(S)-1-(3-aminophenyl)ethylamino]-4-[benzimidazol-1-yl]pyrimidine (10.0 mg) in CH2Cl2 (2 mL) was added triethylamine (13 μL) and benzoyl chloride (3.5 μL). The resulting solution was stirred at room temperature for 30 min. then the volatiles removed in vacuo. The residue was purified on silica gel (2%(2M NH3 in MeOH)/CH2Cl2) then HPLC (Zorbax Rx-SIL, 70:30 hexanes:ethanol) to yield 1.8 mg of the title compound. 1H NMR (500 MHz, CDCl3, partial): δ 8.41 (d, J=5.5 Hz, 1H); 7.87 (m, 2H); 7.82 (m, 2H); 7.76 (s, 1H); 7.58 (m, 2H); 7.51 (m, 2H); 7.41 (t, J=7.9 Hz, 1H); 6.80 (d, J=5.5 Hz, 1H); 1.67 (d, J=6.9 Hz, 3H).
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[CH2:6]([N:8](CC)[CH2:9][CH3:10])[CH3:7].ClCC(Cl)=[O:16].C(N)C>CN(C=O)C>[NH2:4][C:3]1[N:8]([CH2:9][CH3:10])[CH2:6][C:7](=[O:16])[C:2]=1[C:1]#[N:5]
Reactant: O=C(Cl)CCl
Reactant: CCN(CC)CC
Reactant: N#CCC#N
Agent: CCN
Solvent: CN(C)C=O
Product: CCN1CC(=O)C(C#N)=C1N
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 97.6 %

Procedure:
19.8 g of malononitrile were dissolved in 30 ml of DMF and cooled to 0° C. While cooling, 61 g of triethylamine and 32 g of chloroacetyl chloride were simultaneously added dropwise to this, and the mixture was then stirred at 10° C. for 10 minutes. Subsequently, while cooling, 49 g of 70% by weight aqueous ethylamine solution were added dropwise, and the mixture was stirred at room temperature for 8 hours. The precipitate was filtered off with suction, washed and dried at 50° C. 41.8 g (92%) of impure crude product were obtained and were recrystallized from 1:1 isopropanol/water with the addition of active carbon. This resulted in 10.9 g (24% of theory) of the compound of the formula ##STR23## of melting point 278° to 280° C. The IR, NMR, UV and mass spectra and the elemental analysis are consistent with the structural formula.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:26])=[N:4][O:5][C:6]=1[N:7]([CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25])[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][CH:12]=1)(=[O:10])=[O:9].[Li]C(C)(C)C.[CH2:32]1[O:42][C:41]2[C:34](=[CH:35][C:36]([CH2:43][CH2:44][O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])=[C:37]([CH:40]=2)[CH:38]=[O:39])[O:33]1>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:26])=[N:4][O:5][C:6]=1[N:7]([CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25])[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[CH:38]([OH:39])[C:37]1[CH:40]=[C:41]2[O:42][CH2:32][O:33][C:34]2=[CH:35][C:36]=1[CH2:43][CH2:44][O:45][Si:46]([C:49]([CH3:51])([CH3:50])[CH3:52])([CH3:47])[CH3:48])(=[O:9])=[O:10]
Reactant: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1csc2ncccc12
Reactant: CC(C)(C)[Si](C)(C)OCCc1cc2c(cc1C=O)OCO2
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1c(C(O)c2cc3c(cc2CCO[Si](C)(C)C(C)(C)C)OCO3)sc2ncccc12
Yield: 46.8 %

Procedure:
The title compound was prepared by the method of Example 4(B) using N-(4-chloro-3-methyl-5-isoxazolyl)-N-(methoxyethoxymethyl)thieno[2,3-b]pyridine-3-sulfonamide (0.64 g, 1.5 mmoles) [Example 4(A)], THF (10 ml), t-BuLi (1.7M, 1.2 ml, 2.0 mmoles), and 4,5-(methylenedioxy)-2-(2-{[(1,1-dimethylethyl)dimethylsilyl]oxy}ethyl)benzaldehyde (0.71 g, 2.3 mmoles; prepared according to Lin, et al. (1994) J. Am. Chem. Soc. 116:9791-9792). Flash chromatography (40% EtOAc/hexanes) provided 0.51 g (46%) of the title compound as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[CH2:13])[CH2:10][CH:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])(C)C.Cl.[CH3:18]N1CCOCC1.ClC(OC[C:30]1[CH:35]=[CH:34]C=[CH:32][CH:31]=1)=O>CO.C(Cl)Cl>[CH3:18][O:16][C:14]([CH:9]1[CH2:10][C:11](=[CH2:13])[CH2:12][N:8]1[C:6]([O:5][CH2:1][C:4]1[CH:34]=[CH:35][CH:30]=[CH:31][CH:32]=1)=[O:7])=[O:15]
Reactant: CN1CCOCC1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C=C1CC(C(=O)O)N(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: C=C1CC(C(=O)OC)N(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.2 %

Procedure:
4-Methylene-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 601 (10.0 g, 44 mmol) was dissolved in MeOH (75 mL) at room temperature and HCl (4M in dioxane, 75 mL) was added. Stirring at room temperature was continued for 4 hours. All volatiles were removed in vacuo and a beige solid was obtained. The crude material was suspended in methylene chloride (100 mL) and N-Methyl morpholine (13.3 g, 132 mmol) was added. The mixture was cooled to 0° C. and benzyl chloroformate (8.26 g, 48.4 mmol) was added while stirring. After 30 minutes, the reaction was warmed to room temperature and the solution was washed with water and aqueous HCl (1 M). The solution was dried over sodium sulfate. Filtration and evaporation of solvents gave crude product, which was purified by silica gel chromatography (eluent:EtOAc/hexanes) to yield compound 602 (10.2 g). LCMS-ESI+: calc'd for C15H17NO4: 275.3 (M+). Found: 276.4 (M+H+).
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.[CH2:26]([O:33][C:34]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=1B(O)O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C>[CH2:26]([O:33][C:34]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=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)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: OB(O)c1ccc(F)cc1OCc1ccccc1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1Br
Solvent: CN(C)C=O
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccc(F)cc1OCc1ccccc1

Procedure:
The title compound was prepared in analogy to example 25, from N-(4-bromo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 25, intermediate a) and 2-benzyloxy-4-fluorophenylboronic acid (CAS RN 848779-87-3) and using DMF as reaction solvent. Off-white solid (29%). MS (ESI): m/z=549.0 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[O:14][C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:12][C:11]=2[CH2:21][O:22][CH2:23][O:24][CH3:25])=[CH:4][CH:3]=1.Cl[CH2:27][C:28]1[N:29]=[C:30]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:31][C:32]=1[CH3:33].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:33][C:32]1[O:31][C:30]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[N:29][C:28]=1[CH2:27][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[O:14][C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:12][C:11]=2[CH2:21][O:22][CH2:23][O:24][CH3:25])=[CH:4][CH:3]=1
Reactant: COCOCc1nc(-c2ccccc2)oc1CCc1ccc(O)cc1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCOCc1nc(-c2ccccc2)oc1CCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Temperature: 90 °C
Reaction time: 15 h
Yield: 100.1 %

Procedure:
A mixture of 5-[2-(4-hydroxyphenyl)ethyl]-4-methoxymethoxymethyl-2-phenyl-1,3-oxazole (3.12 g), 4-chloromethyl-5-methyl-2-phenyl-1,3-oxazole (2.28 g), potassium carbonate (1.27 g) and N,N-dimethylformamide (50 mL) was stirred at 90° C. for 15 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was washed successively with dilute hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 5-{2-[4-(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxyphenyl]ethyl}-4-methoxymethoxymethyl-2-phenyl-1,3-oxazole as colorless crystals (4.70 g, yield 85%) from a fraction eluted with ethyl acetate-hexane (1:3, v/v). The crystals were recrystallized from ethyl acetate-hexane. melting point: 124-125° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1F.[CH3:10][S-:11].[Na+]>CC(N(C)C)=O.O>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[S:11][CH3:10]
Reactant: C[S-]
Reactant: Cc1ccc(F)c(Br)c1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CSc1ccc(C)cc1Br
Temperature: 125 °C
Reaction time: 8 h

Procedure:
The 2-bromo-1-fluoro-4-methylbenzene (2.00 g, 10.6 mmol) was dissolved in dimethylacetamide (5.3 mL) and sodium thiomethoxide (0.82 g, 11.6 mmol) was added. The reaction was heated at 125° C. for 5.5 h. The reaction was then cooled to rt and stirred overnight. The reaction was then diluted with water (200 mL) and the mixture was extracted with ethyl acetate (3×125 mL). The combined organic layers were washed with water (1×150 mL) brine (1×100 mL) and dried over magnesium sulfate. The crude product was purified by medium pressure chromatography (silica gel, 0 to 40% EtOAc:hexanes) to give (2-bromo-4-methylphenyl)-(methyl)sulfane. 1H NMR (CDCl3) δ ppm 7.38 (1H, d, J=0.8 Hz), 7.09-7.13 (1H, m), 7.06 (1H, d), 2.47 (3H, s), 2.31 (3H, s).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[CH:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])=[C:16]([F:25])[CH:15]=2)=[O:11])=[CH:6][CH:5]=[C:4]([C:26]([F:29])([F:28])[F:27])[N:3]=1.CN(C=O)C.[NH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>CCOC(C)=O>[F:25][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=1[NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:13][NH:12][C:10](=[O:11])[CH:9]=[CH:8][C:7]1[C:2]([N:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)=[N:3][C:4]([C:26]([F:29])([F:28])[F:27])=[CH:5][CH:6]=1
Reactant: C1CCNC1
Reactant: CS(=O)(=O)Nc1ccc(CNC(=O)C=Cc2ccc(C(F)(F)F)nc2Cl)cc1F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1ccc(CNC(=O)C=Cc2ccc(C(F)(F)F)nc2N2CCCC2)cc1F
Temperature: 110 °C
Reaction time: 12 h
Yield: 93 %

Procedure:
To a suspension of 3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonylamino-benzyl)-acrylamide (40 mg, 0.088 mmol) in pyrrolidine (0.4 ml) was added DMF (0.5 ml). The mixture was stirred for 12 hours at 110° C. The reaction mixture was diluted with EtOAc and then washed two times with 1N-HCl and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was column-chromatographed to yield the title compound (40 mg, 93%).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:23])=[C:8]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:9]=2[C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[S:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:34]1[CH2:38]OC[CH2:35]1.ICCC>CN(C=O)C>[CH3:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:23])=[C:8]([CH:18]([CH2:35][CH2:34][CH3:38])[C:19]([O:21][CH3:22])=[O:20])[C:9]=2[C:11]2[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[S:4][CH:3]=1
Reactant: COC(=O)Cc1c(C)nc2scc(C)c2c1-c1ccc(C)cc1
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCCI
Product: CCCC(C(=O)OC)c1c(C)nc2scc(C)c2c1-c1ccc(C)cc1
Yield: 96.2 %

Procedure:
This compound was prepared according to the procedure C from methyl 2-(3,6-dimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)acetate (0.080 g; 0.246 mmol), LHMDS 1N in THF (0.280 mL; 0.280 mmol), 1-iodopropane (0.040 mL; 0.410 mmol) in DMF (3.5 mL) for 3.5 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-15%) in heptane furnished 0.087 g (96%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].[SH:6][CH:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:8](O)=[O:9].S(=O)(=O)(O)O>O.C1(C)C=CC=CC=1>[SH:6][CH:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:8]([O:4][CH2:3][CH2:2][CH2:1][O:5][C:8](=[O:9])[CH:7]([SH:6])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9]
Reactant: O=C(O)C(S)c1ccccc1
Reactant: OCCCO
Agent: O=S(=O)(O)O
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(OCCCOC(=O)C(S)c1ccccc1)C(S)c1ccccc1
Temperature: 25 °C
Yield: 98.6 %

Procedure:
1,3-Propanediol (9.50 g, 0.125 mol), a 55:45 mixture of the respective 4- and 3-isomers of mercaptophenylacetic acid (45.00 g, 0.268 mol), concentrated sulfuric acid (0.2 mL), and toluene (200 mL) were combined in a round-bottom flask equipped with a magnetic stirring bar, a water separator, and a condenser. During 6 h of heating under reflux with stirring, the solid organic acid isomers disappeared, and 4.46 mL (0.248 mol) of water was collected by the water separator. The mixture was allowed to cool to room temperature, washed in succession with 20 mL of saturated NaHCO3 solution and two 50-mL portions of brine, then dried over anhydrous MgSO4 and freed of solvent on a rotary evaporator. Dissolution of the residue in 400 mL of dichloromethane, followed by treatment at the boiling point with a small amount of decolorizing carbon, hot filtration, and rotary evaporation to remove solvent, gave 46.4 g (yield, 99%) of 1,3-propanediol bis(mercaptophenylacetate) as a viscous pale yellow oil that was shown by NMR analyses to contain the 4- and 3-isomers in a ratio of ca. 55:45, respectively: 1H NMR (in CDCl3 w/TMS, ppm): 1.91-1.96 (m, 2H, CH2CH2CH2); 3.44 (s, 4-isomer SH) and 3.47 (s, 3-isomer SH), 2H in toto; 3.53-3.63 (m, 4H, CH2C═O); 4.10-4.14 (m, 4H, CH2O); 7.03-7.44 (m, 8H, aromatic Ch); {1H}13C NMR (in CDCl3 w/TMS, ppm): 28.14 (CH2CH2CH2); 40.99 (4-isomer CH2C═O) and 41.31 (3-isomer CH2C═O); 61.64 (CH2O); 126.80-132.36 (at least 9 peaks, aromatic C); 171.20 (3-isomer C═O) and 171.41 (4-isomer C═O).
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([OH:31])[CH2:30][CH2:29][CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9](I)[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.[CH3:32][S:33]([C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1)(=[O:35])=[O:34].C(=O)(O)[O-]>CN(C)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>[F:1][C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([OH:31])[CH2:30][CH2:29][CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9]([C:40]3[CH:39]=[CH:38][CH:37]=[C:36]([S:33]([CH3:32])(=[O:35])=[O:34])[CH:41]=3)[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2c(I)cc3c(-c4cnc(C5(O)CCC5)s4)c(F)cnc32)cc1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2c(-c3cccc(S(C)(=O)=O)c3)cc3c(-c4cnc(C5(O)CCC5)s4)c(F)cnc32)cc1
Temperature: 70 °C

Procedure:
To a stirred ambient solution of 1-(5-(5-fluoro-2-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl)cyclobutanol (Example 59A) (200 mg, 0.351 mmol) and 3-(methylsulfonyl)phenyl boronic acid (105 mg, 0.527 mmol) in N,N-dimethylformamide (2.63 mL) was added saturated aqueous bicarbonate solution (880 μL) followed by bis(triphenylphosphine)palladium dichloride (17.26 mg, 0.025 mmol). The mixture was heated to 70° C. for 4 hours and was quenched by the addition of water and dichloromethane. The layers were separated, and the aqueous layer was extracted with additional dichloromethane. The combined organics were dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 0 to 100% ethyl acetate in hexane, to give the title compound MS ESI(+) m/z 598.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24](F)[CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:37][N:38]([CH3:63])[S:39]([N:42]1C2=C3C(=CC=C2[CH:44]=[N:43]1)C(=O)C(I)=C(C1C=CC=CC=1)O3)(=[O:41])=[O:40]>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21]([O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:22]3[N:42]([S:39](=[O:41])(=[O:40])[N:38]([CH3:63])[CH3:37])[N:43]=[CH:44][C:23]3=[CH:24][CH:25]=4)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)S(=O)(=O)n1ncc2ccc3c(=O)c(I)c(-c4ccccc4)oc3c21
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: CN(C)S(=O)(=O)n1ncc2ccc3c(=O)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(-c4ccccc4)oc3c21
Yield: 87 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 7-iodo-6-oxo-8-phenyl-6H-9-oxa-1,2-diaza-cyclopenta[a]naphthalene-1-sulfonic acid dimethylamide was reacted to give the title compound as a gummy solid (65 mg, 87%). LCMS (Method A): RT=4.81 min, [M+H]+=615.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.Cl.Cl[C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)[N:17]=[C:16]2[CH2:27][CH2:28][CH2:29][C:15]=12>CO.ClCCl>[Cl:26][C:22]1[CH:21]=[C:20]([C:18]2[N:17]=[C:16]3[CH2:27][CH2:28][CH2:29][C:15]3=[C:14]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=3)[CH:19]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Temperature: 150 °C
Yield: 86.4 %

Procedure:
An 18-mL vial was charged with methyl 4-aminobenzoate (20 mg, 0.13 mmol, 2 eq.) and 4-Chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine HCl salt (20 mg, 0.066 mmol, 1 eq. See step 1 of EXAMPLE 1). The mixture was dissolved in a mixture of MeOH (1 ml) and dichloromethane (2 ml). After the volatile material was removed under reduced pressure, the residue was heated at 150° C. under argon for 1 hr. After cooling to room temperature, the reaction mixture was partitioned between NaHCO3 aq. (10 ml) and ethyl acetate (10 ml). The organics was separated and dried over MgSO4. The solvent was removed under reduced pressure to give a residue, which was purified by chromatography on silica gel using dichloromethane followed by ethyl acetate as eluent to give the desired product methyl 4-[[2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]amino]benzoate (21.6 mg, 86% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:12]=2)[N:5]=[C:4]([NH2:21])[CH:3]=1.[CH3:22][N:23]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=[N:24]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:22][N:23]1[CH:27]=[C:26]([C:2]2[N:7]=[C:6]([C:8]3[CH:9]=[N:10][N:11]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:12]=3)[N:5]=[C:4]([NH2:21])[CH:3]=2)[CH:25]=[N:24]1
Reactant: C[Si](C)(C)CCOCn1cc(-c2nc(N)cc(Cl)n2)cn1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(-c2cc(N)nc(-c3cnn(COCC[Si](C)(C)C)c3)n2)cn1
Temperature: 100 °C
Yield: 54.7 %

Procedure:
6-Chloro-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyrimidin-4-amine (1.00 g, 3.07 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.958 g, 4.60 mmol), K3PO4 (1.95 g, 9.21 mmol), and Pd(PPh3)4 (0.355 g, 0.307 mmol) were suspended in dioxane (15.3 mL) and H2O (0.829 mL). After de-gassing with nitrogen, the reaction mixture was heated to 100° C. overnight. After cooling, the reaction mixture was diluted in EtOAc and washed with water and brine. The organics were dried with MgSO4, filtered and concentrated down to an orange oil. Purification of the resulting crude material by silica chromatography using a gradient of 0-10% MeOH/EtOAc afforded 6-(1-methyl-1H-pyrazol-4-yl)-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyrimidin-4-amine (0.623 g, 1.68 mmol, 54.7% yield) as a thick yellow oil. MS (apci) m/z=372.4 (M+H).
Reaction SMILES: Cl.[C:2]1([N:8]([CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:9]([C:11]2[CH:33]=[CH:32][C:14]3[N:15]([CH3:31])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][C:21]=4[O:29][CH3:30])=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:42]([O:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])=[O:43]>ClCCl.C(O)C>[C:2]1([N:8]([CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:9]([C:11]2[CH:33]=[CH:32][C:14]3[N:15]([CH3:31])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:42]([O:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])=[O:43])=[CH:22][C:21]=4[O:29][CH3:30])=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1OC)n2C)c1ccccc1
Reactant: CCCCCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: CCCCCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccc4)ccc3n2C)c(OC)c1
Yield: 53 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidino-2-methoxyphenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)amide hydrochloride and n-pentyl chloroformate. Yield: 53% of theory, C35H42N6O6 (642.7); Rf value: 0.54 (silica gel; dichloromethane/ethanol=9:1); EKA mass spectrum: (M+H)+=643; (M+H+Na)++=333.4.