Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[F:28][C:29]1[CH:30]=[C:31]([C:44]([OH:47])([CH3:46])[CH3:45])[CH:32]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:34]=1>>[F:28][C:29]1[CH:34]=[C:33]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=[C:6]([CH:21]=2)[C:7]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:17]([F:19])([F:20])[F:18])=[CH:14][CH:15]=2)=[O:8])[CH:32]=[C:31]([C:44]([OH:47])([CH3:45])[CH3:46])[CH:30]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: CC(C)(O)c1cc(F)cc(B2OC(C)(C)C(C)(C)O2)c1
Product: CC(C)(O)c1cc(F)cc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC[C@@H](O)C2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 53 using (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 35.1) and 2-(3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ol and to afford a yellow resin. HPLC (Condition 4) tR=5.18 min, UPLC-MS (Condition 3) tR=1.10 min, m/z=520.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.43 (d, J=1.96 Hz, 6H) 1.65-1.75 (m, 1H) 1.76-1.89 (m, 1H) 2.86 (d, J=10.95 Hz, 1H) 3.13-3.28 (m, 2H) 3.34-3.50 (m, 1H) 4.03-4.22 (m, 1H) 4.82 (d, J=2.74 Hz, 1H) 5.19 (d, J=0.78 Hz, 1H) 7.09 (d, J=9.38 Hz, 1H) 7.18-7.28 (m, 2H) 7.33 (d, J=8.99 Hz, 2H) 7.77-7.88 (m, 2H) 7.98 (m, J=2.30, 0.80 Hz, 1H) 8.67-8.76 (m, 1H) 10.16 (s, 1H).
Reaction SMILES: C(OC([NH:8][C@H:9]([CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1)[CH2:10][N:11]1[C:16](=[O:17])[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:19]=2[F:26])=[C:14]([CH3:27])[N:13]([CH2:28][C:29]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=2[F:36])[C:12]1=[O:37])=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:8][C@H:9]([CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1)[CH2:10][N:11]1[C:16](=[O:17])[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:19]=2[F:26])=[C:14]([CH3:27])[N:13]([CH2:28][C:29]2[C:30]([F:36])=[CH:31][CH:32]=[CH:33][C:34]=2[F:35])[C:12]1=[O:37]
Reactant: COc1cccc(-c2c(C)n(Cc3c(F)cccc3F)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)C3CCCCC3)c2=O)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(-c2c(C)n(Cc3c(F)cccc3F)c(=O)n(C[C@H](N)C3CCCCC3)c2=O)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To compound 2c (300 mg, 0.5 mmol) in dichloromethane (DCM, 2 mL) was added TFA (2 mL) and the reaction mixture was stirred at ambient temperature for 1 hour. Volatiles were evaporated and the residue was partitioned between saturated NaHCO3/water and EtOAc. The organic layer was dried (sodium sulfate), evaporated, purified by reverse phase HPLC (C-18 column, 15-75% ACN/water) to give compound 2d. MS (CI) m/z 502.20 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])[N:15]=3)[CH:12]=2)=[C:4]([F:24])[CH:3]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:37]([CH:38]([CH3:40])[CH3:39])=[CH:36][CH:35]=[C:34]([C:41](O)=[O:42])[C:33]2=[O:44])=[CH:28][CH:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:19]1([C:17]([NH:16][C:14]2[N:15]=[C:10]3[CH:9]=[CH:8][C:7]([O:6][C:5]4[CH:22]=[CH:23][C:2]([NH:1][C:41]([C:34]5[C:33](=[O:44])[N:32]([C:29]6[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=6)[C:37]([CH:38]([CH3:40])[CH3:39])=[CH:36][CH:35]=5)=[O:42])=[CH:3][C:4]=4[F:24])=[CH:12][N:11]3[CH:13]=2)=[O:18])[CH2:21][CH2:20]1
Reactant: CC(C)c1ccc(C(=O)O)c(=O)n1-c1ccc(F)cc1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)c1ccc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)c(F)c2)c(=O)n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 58.6 %

Procedure:
A mixture of N-[6-(4-amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (150 mg, 0.459 mmol), 1-(4-fluorophenyl)-6-(1-methylethyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (151 mg, 0.551 mmol), HATU (262 mg, 0.689 mmol), N,N-diisopropylethylamine (240 μL, 1.37 mmol) and N,N-dimethylformamide (3 mL) was stirred at room temperature for 4 days. After dilution with ethyl acetate, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH silica gel, 30 g, ethyl acetate/hexane=2/98-+80/20) to give the title compound (157 mg, 58%) as a white powder.
Reaction SMILES: C(#N)C.[CH3:4][C:5]([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)=[O:6].OI(C1C=CC=CC=1)[O:19][S:20]([C:23]1[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=1)(=[O:22])=[O:21]>C(OCC)(=O)C>[S:20]([O:22][CH2:4][C:5]([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)=[O:6])([C:23]1[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=1)(=[O:21])=[O:19]
Reactant: Cc1ccc(S(=O)(=O)OI(O)c2ccccc2)cc1
Reactant: CC(=O)c1ccc2ccccc2c1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OCC(=O)c2ccc3ccccc3c2)cc1
Yield: 68.5 %

Procedure:
Acetonitrile solution (40 mL) containing 2-acetonaphthone (1.70 g, 9.99 mmol) and [hydroxyl(tosyloxy)iodo]benzene (4.00 mg, 10.2 mmol) was heated under ref lux for 3 hours. The reaction mixture was cooled, and ethyl acetate was added thereto. The reaction solution was washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo to remove the solvent to obtain the title compound (2.33 g, 68.5%).
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.[F:6][C:7]1[CH:8]=[CH:9][C:10]([OH:16])=[C:11]([C:13](=[O:15])[CH3:14])[CH:12]=1.[OH-].[K+]>C(O)C.O>[O:5]1[CH2:4][CH:3]1[CH2:1][O:16][C:10]1[CH:9]=[CH:8][C:7]([F:6])=[CH:12][C:11]=1[C:13](=[O:15])[CH3:14]
Reactant: ClCC1CO1
Reactant: CC(=O)c1cc(F)ccc1O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(=O)c1cc(F)ccc1OCC1CO1
Reaction time: 1 h
Yield: 16.4 %

Procedure:
Epichlorohydrin (38 g) was added to a stirred solution of 5'-fluoro-2'-hydroxyacetophenone (20.9 g) in ethanol (20 ml). A solution of potassium hydroxide (9.5 g) in a mixture of ethanol (30 ml) and water (5 ml) was then added and stirring continued for one hour. The solvent was removed in vacuo and the residue poured into water then extracted with ethyl acetate. The combined extracts were washed with brine and dried over magnesium sulphate. The solvent was removed in vacuo and the residue purified by chromatography on silica, eluting with a 9:1 mixture, then a 3:2 mixture, of petroleum ether (b.p. 40-60° C.) and ethyl acetate. Appropriate fractions were combined and the solvent removed in vacuo to give 2'-(2,3-epoxypropoxy)-5'-fluoroacetophenone (4.68 g) as an oil.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH2:9][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:2]1.CCN(C(C)C)C(C)C.[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>C1COCC1>[CH2:7]([O:6][C:4]([CH:3]1[CH2:9][CH2:10][CH2:11][N:1]([C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:22]([F:21])=[CH:23][CH:24]=2)[CH2:2]1)=[O:5])[CH3:8]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCOC(=O)C1CCCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C1CCCN(C(=O)c2ccc(F)cc2)C1
Temperature: 0 °C
Reaction time: 24 h
Yield: 33 %

Procedure:
To a mixture of Ethyl nipecotate (2 g, 12.72 mmol) in THF (25 ml, 0.5M) was added DIEA (4.79 ml, 27.99 mmol). The reaction mixture was cooled to 0° C. and 4-Fluoro-benzoyl chloride (2.5 g-15.76 mmol) was slowly added. The reaction was to go up to R.T and stirred for 24 h. The solution was concentrated and DCM was added following by HCl 1N. The aqueous phase was separated and organic phase was extracted twice with HCl 1N and twice with water, dried over Na2SO4, filtered and concentrated to afford 1.15 g (33%) of 1-(4-Fluoro-benzoyl)-piperidine-3-carboxylic acid ethyl ester as a colorless oil which can be used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:35][CH3:36])=[C:5]([CH:32]=[CH:33][CH:34]=1)[C:6]([O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][OH:31])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.[C:44]1([CH3:54])[CH:49]=[CH:48][C:47]([S:50](Cl)(=[O:52])=[O:51])=[CH:46][CH:45]=1>ClCCl>[C:44]1([CH3:54])[CH:49]=[CH:48][C:47]([S:50]([O:31][CH2:30][CH2:29][O:28][CH2:27][CH2:26][O:25][CH2:24][CH2:23][O:22][CH2:21][CH2:20][O:19][C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:5]2[CH:32]=[CH:33][CH:34]=[C:3]([O:2][CH3:1])[C:4]=2[O:35][CH3:36])(=[O:52])=[O:51])=[CH:46][CH:45]=1
Reactant: COc1cccc(C(OCCOCCOCCOCCO)(c2ccccc2)c2ccccc2)c1OC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(C(OCCOCCOCCOCCOS(=O)(=O)c2ccc(C)cc2)(c2ccccc2)c2ccccc2)c1OC
Temperature: 0 °C

Procedure:
Compound 2 ( 5.0 g, 10.06 mmol) was dissolved in 50 mL of anhydrous dichloromethane and cooled to 0° C. Triethylamine (1.82 mL, 13.1 mmol) was added, followed by p-toluenesulfonyl chloride (1.92 g, 10.06 mmol) as a solid, with stirring. The reaction was stored in the refrigerator overnight. TLC Analysis indicated the reaction was approximately 80% complete. An additional 0.5 equivalents of triethylamine and 0.5 equivalents of p-toluenesulfonyl chloride were added, and the reaction was stirred at room temperature overnight. The reaction was filtered through Celite and concentrated. The residue was purified by flash chromatography using 300 mL of silica gel (wet-packed onto column using 5% triethylamine in hexane) eluting with 25-50-75% ethyl acetate in hexane containing 5% triethylamine, and then ethyl acetate containing 5% triethylamine. 5.7 g (87%) of 3 was collected as an orange oil. 1H NMR (300 MHz, CDCl3) d 7.75 (d, 2H), 7.44-7.12 (m, 11H), 6.78 (d, 4H), 4.12-4.09 (m, 2H), 3.73 (s, 6H), 3.66-3.54 (m, 13H), 3.22 (t, J=3.87 Hz, 2H), 2.41 (s, 3H).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:6]3[S:13][CH:12]=[C:11]([C:14]([NH:16][C:17]4[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=4[CH3:26])[C:20](O)=[O:21])=[O:15])[C:7]=3[N:8]=[CH:9][N:10]=2)[CH2:3][CH2:2]1.[O:27]1[CH2:32][CH2:31][N:30]([C:33]2[N:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=2)[CH2:29][CH2:28]1>>[CH:1]1([NH:4][C:5]2[C:6]3[S:13][CH:12]=[C:11]([C:14]([NH:16][C:17]4[CH:18]=[C:19]([C:20](=[O:21])[NH:39][C:36]5[CH:37]=[N:38][C:33]([N:30]6[CH2:29][CH2:28][O:27][CH2:32][CH2:31]6)=[CH:34][CH:35]=5)[CH:23]=[CH:24][C:25]=4[CH3:26])=[O:15])[C:7]=3[N:8]=[CH:9][N:10]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=O)O)cc1NC(=O)c1csc2c(NC3CC3)ncnc12
Reactant: Nc1ccc(N2CCOCC2)nc1
Product: Cc1ccc(C(=O)Nc2ccc(N3CCOCC3)nc2)cc1NC(=O)c1csc2c(NC3CC3)ncnc12

Procedure:
The procedure of Step 5 of Example 1 was repeated except for using 3-(4-(cyclopropylamino)thieno[3,2-d]pyrimidine-7-carboxamido)-4-methylbenzoic acid obtained in Step 3 of Example 21 and 6-morpholinopyridine-3-amine to obtain the title compound (see Table 1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[CH:13][O:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10].[Br:16]C1CC(=O)NC1=O.C1(=O)NC(=O)CC1>N(C(C)(C)C#N)=NC(C)(C)C#N.C(Cl)(Cl)(Cl)Cl>[Br:16][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[CH:13][O:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10]
Reactant: O=C1CC(Br)C(=O)N1
Reactant: COC=C(C(=O)OC)c1ccccc1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1
Solvent: ClC(Cl)(Cl)Cl
Product: COC=C(C(=O)OC)c1ccccc1CBr
Temperature: 90 °C
Yield: 97.3 %

Procedure:
20.6 g of the methyl α-(2-methylphenyl)-β-methoxyacrylate obtained as described in Method A, 17.65 g of bromosuccinimide, 0.2 g of azobisisobutyronitrile and 150 ml of CCl4 are slowly heated to 90° C. and kept at this temperature until all the succinimide floats on the solvent. The mixture is filtered, the filtrate is evaporated down, the remaining oil is dissolved in about 5 ml of acetone and the solution is brought to crystallization with n-hexane. 27.5 g of colorless crystals of melting point 86°-87° C. are obtained.
Reaction SMILES: C(O[C:4](=O)[CH2:5][C:6]([CH:8]=[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH2:10]1)=O)C.[CH2:20]([O:22][C:23](=[O:28])[CH2:24][C:25](=[NH:27])[NH2:26])[CH3:21]>C(O)C>[CH2:20]([O:22][C:23]([C:24]1[CH:8]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH:10]=2)[C:6]([C:23]([O:22][CH2:20][CH3:21])=[O:28])=[C:5]([CH3:4])[NH:27][C:25]=1[NH2:26])=[O:28])[CH3:21]
Reactant: CCOC(=O)CC(=N)N
Reactant: CCOC(=O)CC(=O)C=C1CC=Cc2ccccc21
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(N)=C(C(=O)OCC)C1c1cccc2ccccc12
Yield: 62 %

Procedure:
Boiling a solution of 13.4 g of (1-naphthylidene)acetoacetic acid ethyl ester and 6.5 g of amidinoacetic acid ethyl ester in 100 ml of ethanol for 8 hours yields 2-amino-6-methyl-4-(1-naphthyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of melting point 174°C (ethanol).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[CH2:12]Br.Cl.[CH2:15]([NH2:17])[CH3:16].CCN(CC)CC>CN(C=O)C>[CH2:15]([N:17]1[CH2:12][C:4]2[C:3](=[CH:8][CH:7]=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=2)[CH2:2]1)[CH3:16]
Reactant: CCN
Reactant: O=[N+]([O-])c1ccc(CBr)c(CBr)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN1Cc2ccc([N+](=O)[O-])cc2C1
Temperature: 20 °C
Reaction time: 1.5 h
Yield: 55.7 %

Procedure:
A mixture of dibromide 118 (9.27 g, 30.0 mmol), ethylamine hydrochloride (2.45 g, 30.0 mmol) and Et3N (21 mL, 150 mmol) in DMF (100 mL) was stirred at 20° C. for 90 min. The mixture was partitioned between EtOAc and aqueous Na2CO3 solution. The organic fraction was washed with water, dried and the solvent evaporated to give isoindole 245 (3.21 g, 56%) as a dark oil: 1H NMR δ 8.11 (dd, J=8.1, 2.1 Hz, 1H, H-6), 8.05 (d, J=2.1 Hz, 1H, H-4), 7.34 (d, J=8.1 Hz, 1H, H-7), 3.99 (s, 4H, H-1, H-3), 2.82 (q, J=7.2 Hz, 2H, CH2), 1.22 (t, J=7.2 Hz, 3H, CH3); HRMS (FAB+) calcd for C10H13N2O2 (MH+) m/z 193.0977, found 193.0983.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][S:8](Cl)(=[O:10])=[O:9].[Cl:12][C:13]1[CH:14]=[C:15]([C:19]#[C:20][C:21]2[CH:22]=[CH:23][C:24]([F:28])=[C:25]([NH2:27])[CH:26]=2)[CH:16]=[N:17][CH:18]=1>ClCCl>[Cl:12][C:13]1[CH:14]=[C:15]([C:19]#[C:20][C:21]2[CH:22]=[CH:23][C:24]([F:28])=[C:25]([NH:27][S:8]([CH3:7])(=[O:10])=[O:9])[CH:26]=2)[CH:16]=[N:17][CH:18]=1
Reactant: Nc1cc(C#Cc2cncc(Cl)c2)ccc1F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cc(C#Cc2cncc(Cl)c2)ccc1F
Temperature: 25 °C
Reaction time: 20 h
Yield: 91.5 %

Procedure:
Add pyridine (193 mg, 2.44 mmol) followed by methanesulfonyl chloride (127 mg, 1.11 mmol) to a solution of 5-(5-chloropyridin-3-ylethynyl)-2-fluorophenylamine, (prepared as described in EXAMPLE 190), (275 mg, 1.11 mmol) in dichloromethane (10 mL) at 0° C. under nitrogen. Warm to room temperature and stir 20 h. Add additional methanesulfonyl chloride (32 mg, 0.28 mmol). Stir at room temperature for 2 h. Concentrate and purify by silica gel chromatography, eluting with 3:1 ethyl acetate:hexanes, to give the title compound as a white solid (330 mg, 92%).
Reaction SMILES: [CH:1]1([C:4]2[C:12](B3OC(C)(C)C(C)(C)O3)=[CH:11][CH:10]=[C:9]3[C:5]=2[CH2:6][C:7](=[O:23])[N:8]3[CH3:22])[CH2:3][CH2:2]1.[Br:24][C:25]1[CH:26]=[N:27][CH:28]=[C:29](Br)[CH:30]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.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>[Br:24][C:25]1[CH:30]=[C:29]([C:12]2[C:4]([CH:1]3[CH2:2][CH2:3]3)=[C:5]3[C:9](=[CH:10][CH:11]=2)[N:8]([CH3:22])[C:7](=[O:23])[CH2:6]3)[CH:28]=[N:27][CH:26]=1
Reactant: CN1C(=O)Cc2c1ccc(B1OC(C)(C)C(C)(C)O1)c2C1CC1
Reactant: Brc1cncc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Product: CN1C(=O)Cc2c1ccc(-c1cncc(Br)c1)c2C1CC1
Temperature: 120 °C

Procedure:
To 4-cyclopropyl-1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one, prepared as described in Example 40d (50 mg, 0.16 mmol) was added 3,5-dibromopyridine (CAS#625-92-3, 113 mg, 0.479 mmol), 1,2-dimethoxyethane (1.5 mL), and 2 M aqueous sodium carbonate (0.2 mL, 0.4 mmol). The reaction mixture was degassed and placed under an argon atmosphere, at which time resin bound tetrakis(triphenylphosphine)palladium(0), specifically polystyrene triphenylphosphine palladium (0) [PS—PPh3-Pd(0) (Biotage), 0.11 mmol/g loading, (43.5 mg, 4.79 μmol)] was added. The reaction vessel was sealed and was heated by microwave irradiation at 120° C. for 3 hours. The reaction mixture was then cooled to room temperature, diluted with dichloromethane and filtered through glass wool. The filtrate was further diluted with saturated aqueous sodium bicarbonate and the layers were separated. The aqueous layer was extracted two times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (ethyl acetate-heptane, 10 to 75%) to furnish 5-(5-bromo-pyridin-3-yl)-4-cyclopropyl-1-methyl-1,3-dihydro-indol-2-one; HRMS: (ESI) m/z 343.0451 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 0.18-0.26 (m, 2H), 0.78-0.88 (m, 2H), 1.87-1.99 (m, 1H), 3.25 (s, 3H), 3.64 (s, 2H), 6.82 (d, J=8.0 Hz, 1H), 7.22 (d, J=8.0 Hz, 1H), 7.98 (s, 1H), 8.62 (d, J=1.4 Hz, 1H), 8.67 (d, J=2.0 Hz, 1H).
Reaction SMILES: C1(CS(O[CH2:12][CH2:13][C@H:14]([NH:16][S:17]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:19])=[O:18])[CH3:15])(=O)=O)C=CC=CC=1.[Cl-:27].[Na+].CN(C)C=O>CCOC(C)=O>[Cl:27][CH2:12][CH2:13][C@H:14]([NH:16][S:17]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:19])=[O:18])[CH3:15]
Reactant: [Cl-]
Reactant: C[C@H](CCOS(=O)(=O)Cc1ccccc1)NS(=O)(=O)Cc1ccccc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@H](CCCl)NS(=O)(=O)Cc1ccccc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 38.9 %

Procedure:
To the crude (R)-3-(phenylmethylsulfonamido)butyl phenylmethanesulfonate (23.6 mmol) was added sodium chloride (984 mg, 16.8 mmol) and dimethylformamide (37 mL) and the reaction was stirred at 80° C. for 16 hours. The reaction was then diluted with EtOAc, washed with water (×2) and brine, dried with MgSO4, concentrated and purified by silica gel column chromatography (0-50% Acetone in Heptane, 216 nM) to give (R)—N-(4-chlorobutan-2-yl)-1-phenylmethanesulfonamide (1.71 g, 6.53 mmol, 58% yield over 2 steps). LCMS (ESI), m/z, 261 [M+H]+.
Reaction SMILES: COC1C=CC([N:9]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:11]([CH3:20])([CH3:19])[C:10]2=[O:21])=CC=1>C(#N)C.O>[CH3:19][C:11]1([CH3:20])[CH:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:9][C:10]1=[O:21]
Reactant: COc1ccc(N2C(=O)C(C)(C)C2c2ccccc2)cc1
Solvent: O
Solvent: CC#N
Product: CC1(C)C(=O)NC1c1ccccc1

Procedure:
A solution of 24.4 g of N-(4-methoxy-phenyl)-3,3-dimethyl-4-phenylazetidin-2-one and 16.5 g of lithium 25 perchlorate in a mixture of 500 cm3 of acetonitrile and 50 cm3 of water, is subjected to electrolysis in a unseparated cell, using a graphite anode and a stainless steel grille as cathode and maintaining a constant potential difference of 1.5 V. At the end of the reaction the solution is concentrated to 1/4 of volume. An extraction is made with ethyl acetate and the organic phase is washed with a solution of aqueous sodium sulphite at 10% and then with water; it is dried with sodium sulphate and then evaporated. The raw product is purified on silica gel, using a mixture of ethyl acetate/hexane as eluant in a ratio of 3/7 and 15.4 g of 3,3-dimethyl-4-phenylazetidin-2-one are obtained (yield (98%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][N:12]=1.N#N.C(=O)([O-])[O-].[Cs+].[Cs+]>O.O1CCOCC1>[F:10][C:11]1[N:12]=[CH:13][C:14]([C:2]2[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:15][CH:16]=1
Reactant: OB(O)c1ccc(F)nc1
Reactant: N#Cc1cccnc1Cl
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1cccnc1-c1ccc(F)nc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 84.5 %

Procedure:
To an oven-dried, N2-purged, 250-mL, round-bottomed flask containing a magnetic stir bar were added the commercially available 2-chloro-3-cyanopyridine (1.25 g, 9.00 mmol), the commercially available 2-fluoropyridine-5-boronic acid (845 mg, 6.00 mmol), and dichlorobis(triphenylphosphine)pallalium(II) (211 mg, 0.300 mmol). The flask was sealed with a septum and purged with N2 atmosphere. Anhydrous dioxane (45 mL) and a N2-purged solution of cesium carbonate (5.86 g, 18.0 mmol) in water (45 mL) were added via syringe. The reaction mixture was heated to ˜90° C. in an oil bath and stirred for 2 hours. The reaction was monitored by LC-MS. After cooling to room temperature, the solvent/volatiles were removed by rotary evaporator to give a thick brown oil. Water (75 mL) was added and the mixture was transferred to a separatory funnel. The mixture was extracted with ethyl acetate (4×30 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated by rotary evaporator to give a brown solid. The product was recrystallized from ethyl acetate/hexanes to give 1.01 g (84%) of the title compound as a tan powder. MS (ESI+) m/z 200.0 (M+H)+; 1H NMR (DMSO-d6) δ 7.43 (dd, J=8.6, 2.9 Hz, 1H), 7.70 (dd, J=8.1, 5.1 Hz, 1H), 8.49 (d, J=1.7 Hz, 1H), 8.51 (d, J=1.7 Hz, 1H), 8.74 (d, J=2.7 Hz, 1H), 8.98 (dd, J=4.7, 1.7 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[C:5]([C:6](O)=[O:7])=[C:4]([F:12])[CH:3]=1.CSC>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([F:12])[C:5]([CH2:6][OH:7])=[C:9]([F:11])[CH:10]=1
Reactant: O=C(O)c1c(F)cc(Br)cc1F
Solvent: C1CCOC1
Solvent: CSC
Product: OCc1c(F)cc(Br)cc1F
Temperature: 60 °C
Reaction time: 16 h
Yield: 94.9 %

Procedure:
To a solution of 4-bromo-2,6-difluorobenzoic acid (5 g, 21.10 mmol) in THF (100 mL) was added BH3.DMS (20.03 mL, 211 mmol) dropwise at rt. The resulting mixture was stirred at 60° C. for 16 h. After LCMS analysis showed the starting material had disappeared, the mixture was quenched by MeOH. The solvent was removed in vacuo to yield a white solid of (4-bromo-2,6-difluorophenyl)methanol (4.5 g, 20.02 mmol, 95.2% yield), which was used in the next step without further purification: ES-LCMS m/z 222.1 (M+1).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[NH:9][C:8]3[CH:10]=[C:11]([Cl:16])[C:12]([Cl:15])=[C:13]([Cl:14])[C:7]=3[N:6]=2)[CH2:3][CH2:2]1.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C(O[CH:45]1[O:57][C@@H:56]([CH2:58][O:59][C:60](=[O:62])[CH3:61])[C@H:51]([O:52][C:53](=[O:55])[CH3:54])[C@@H:46]1[O:47][C:48](=[O:50])[CH3:49])(=O)C>ClCCCl>[CH:1]1([NH:4][C:5]2[N:9]([C@H:45]3[O:57][C@@H:56]([CH2:58][O:59][C:60](=[O:62])[CH3:61])[C@H:51]([O:52][C:53](=[O:55])[CH3:54])[C@@H:46]3[O:47][C:48](=[O:50])[CH3:49])[C:8]3[CH:10]=[C:11]([Cl:16])[C:12]([Cl:15])=[C:13]([Cl:14])[C:7]=3[N:6]=2)[CH2:3][CH2:2]1
Reactant: Clc1cc2[nH]c(NC3CC3)nc2c(Cl)c1Cl
Reactant: CC(=O)OC[C@@H]1OC(OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCCl
Product: CC(=O)OC[C@@H]1O[C@H](n2c(NC3CC3)nc3c(Cl)c(Cl)c(Cl)cc32)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Yield: 51.9 %

Procedure:
2-(Cyclopropylamino)-4,5,6-trichloro-1H-benzimidazole (1.32 g, 4.00 mmol), N,O-bis(trimethylsilyl)acetamide (1.0 mL, 0.82 g, 4.05 mmol), trimethylsilyl trifluoromethanesulfonate (0.5 mL, 0.58 g, 2.59 mmol), 1,2,3,5-tetra-O-acetyl-L-ribofuranose (1.70 g, 5.34 mmol) and 1,2-dichloroethane (12 mL) were used according to general procedure II. The product was purified by silica gel chromatography using 60:1 dichloromethane/methanol to afford 1.11 g (52%) of a yellow foam. MS (CI): m/z 534 (M+1).