Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:6]([CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[C:5]2[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1.Br[CH2:33][C:34]([O:36][CH3:37])=[O:35].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:20]([O:19][C:18]([NH:17][CH2:16][C:6]1[C:7]([CH2:12][CH:13]([CH3:15])[CH3:14])=[N:8][C:9]2[C:4]([C:5]=1[C:25]1[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=1)=[CH:3][C:2]([O:1][CH2:33][C:34]([O:36][CH3:37])=[O:35])=[CH:11][CH:10]=2)=[O:24])([CH3:23])([CH3:21])[CH3:22]
Reactant: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(O)cc23)cc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1ccc2nc(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c3ccc(C)cc3)c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 110.2 %

Procedure:
A mixture of tert-butyl {[6-hydroxy-2-isobutyl-4-(4-methylphenyl)quinolin-3-yl]methyl}carbamate (1.5 g, 3.5 mmol), methyl bromoacetate (0.92 g, 6.0 mmol), potassium carbonate (0.55 g, 4.0 mmol) and N,N-dimethylformamide (5 ml) was stirred at room temperature for 4 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography to give methyl {[3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-4-(4-methylphenyl)quinolin-6-yl]oxy}acetate (1.9 g, yield 94%) as pale-yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]([CH2:9]C(O)=O)[CH:5]=[C:6]([F:8])[CH:7]=1.CO>C(#N)C>[NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N+:13]([O-:15])=[O:14]
Reactant: Nc1cc(F)cc(CC(=O)O)c1[N+](=O)[O-]
Solvent: CC#N
Solvent: CO
Product: Cc1cc(F)cc(N)c1[N+](=O)[O-]
Yield: 103.2 %

Procedure:
To the crude 3-Amino-5-fluoro-2-nitro phenyl acetic acid (3.6 g, 16.8 mmol) was added Cu2O (10.1 g, 70.6 mmol) in 120 mL of acetonitrile along with 50 uL of methanol and the suspension was refluxed for 12 hours. The reaction mixture was filtered through Celite and the Celite pad washed with water and ethyl acetate. The filtrate was extracted with ethyl acetate, washed with water and brine, dried over Na2SO4 and concentrated to give 2.95 g of material which by 1H NMR was 80% pure. ESIMS [M+Na]−193; 1H NMR (500 MHz, DMSO) δ 6.67 (s, 2H), 6.56 (dd, J=11, 2.8 Hz, 1H), 6.39 (dd, J=11, 2.8 Hz, 1H), 2.50 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:31])[C:10](=[C:28]([CH3:30])[CH3:29])[N:11]1[C:14](=[O:15])[C:13]([Br:17])([Br:16])[CH:12]1S(NCC1C=CC=CC=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:32]Br>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9](=[O:31])[C:10](=[C:28]([CH3:30])[CH3:29])[N:11]1[C:14](=[O:15])[C:13]([Br:17])([Br:16])[CH:12]1[Br:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrBr
Reactant: CC(C)=C(C(=O)OCc1ccccc1)N1C(=O)C(Br)(Br)C1S(=O)NCc1ccccc1
Solvent: ClC(Cl)Cl
Product: CC(C)=C(C(=O)OCc1ccccc1)N1C(=O)C(Br)(Br)C1Br
Temperature: 25 °C
Reaction time: 48 h
Yield: 55 %

Procedure:
3,3-dibromo-alpha-(1-methylethylidene)-2-[benzylaminosulfinyl]-4-oxo-1-azetidine acetic acid benzyl ester (5.7 g; 0.01 mole) was dissolved in chloroform (120 mL), bromine on a polymer carrier (18.75 g; the content of bromine bound to the polymer matrix with polyvinylpyrrolidone was 26%, 0.03 mole) was added and it was stirred at room temperature for 48 hours. Then the polymer was sucked off and the filtrate was evaporated to dryness. The evaporated residue was passed through a silica gel column with methylene chloride to isolate 2,3,3-tribromo-alpha-(1-methylethylidene)-4-oxo-1-azetidine acetic acid benzyl ester (2.73 g; 55.0%), which was subjected to a reaction with silver tetrafluoroborate in methanol analogously to the reaction described under 1a. After isolation 3,3-dibromo-2-methoxy-alpha-(1-methylethylidene)-4-oxo-1-azetidine acetic acid benzyl ester with spectroscopic data identical to those disclosed under 1a was obtained.
Reaction SMILES: Br[C:2]1[C:3]([CH2:19][CH:20]([CH3:22])[CH3:21])=[C:4]([C:15]([O:17][CH3:18])=[O:16])[C:5]([CH:12]([F:14])[F:13])=[N:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[S-2:23].[Li+].[Li+]>CN(C=O)C.Cl>[F:13][CH:12]([F:14])[C:5]1[C:4]([C:15]([O:17][CH3:18])=[O:16])=[C:3]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:2]([SH:23])=[C:7]([C:8]([F:11])([F:10])[F:9])[N:6]=1
Reactant: [S-2]
Reactant: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(Br)c1CC(C)C
Agent: Cl
Agent: [Li+]
Solvent: CN(C)C=O
Product: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(S)c1CC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
To a stirred solution of 10.11 g (0.026 mol) of methyl 5-bromo-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (example 122 of U.S. Pat. No. 5,019,153) in 75 mL dry DMF was added 1.42 g (0.031 mol) of lithium sulfide in one portion and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with 150 mL of 10% HCl solution and extracted with ether (3×100 mL). The combined extracts were washed with water, dried (MgSO4) and evaporated. The residue was purified by kugelrohr distillation (oven temperature 100-110° C., 1.5 torr) to give 7.35 g (83%) of product as a yellow-green oil:
Reaction SMILES: [OH:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.CCN(CC)CC.[NH2:37][CH2:38][CH2:39][OH:40].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C(Cl)Cl>[OH:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:37][CH2:38][CH2:39][OH:40])=[O:27])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: NCCO
Reactant: O=C(O)c1ccc(C[C@@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@H]2O)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCO)c1ccc(C[C@@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 68.7 %

Procedure:
To a solution of 4-(((1S,2S)-1-hydroxy-2,3-dihydro-1H,1′H-[2,2′-biinden]-2-yl)methyl)benzoic acid (100 mg, 0.26 mmol), Et3N (157 mg, 1.56 mmol) and 2-amino ethanol (40 mg, 0.65 mmol) in DCM (5 mL), was added T3P (0.33 mL, 50 wt % solution in ethyl acetate, 0.52 mmol) and then stirred at room temperature for 12 h. The reaction mixture was quenched with water (25 mL) and extracted with DCM (3×25 mL). The organic layer was washed with brine (25 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure. The residue was purified by CombiFlash using 20% ethyl acetate in chloroform as an eluent to yield 76 mg (68%) of the title compound as an off white solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][N:9]1[CH:13]([C:14]([O:16]C(C)(C)C)=[O:15])[CH2:12][N:11]([C:21]2[N:22]=[CH:23][N:24]([CH3:26])[CH:25]=2)[C:10]1=[O:27]>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][N:9]1[CH:13]([C:14]([OH:16])=[O:15])[CH2:12][N:11]([C:21]2[N:22]=[CH:23][N:24]([CH3:26])[CH:25]=2)[C:10]1=[O:27]
Reactant: CN1C(=O)N(c2cn(C)cn2)CC1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1C(=O)N(c2cn(C)cn2)CC1C(=O)O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred mixture of 1,1-dimethylethyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (200 mg, 0.999 mmol) (prepared as described in step (iii) of Example 13, starting from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) and 4-bromo-1-methyl-1H-imidazole (193 mg, 1.199 mmol) in 1,4-dioxane (8 ml) was added potassium phosphate (1060 mg, 4.99 mmol), copper(I) iodide (190 mg, 0.999 mmol) and trans-N,N-dimethylcyclohexane-1,2-diamine (0.158 ml, 0.999 mmol) and the reaction mixture was stirred at reflux under argon for 3 hours. The mixture was cooled to room temperature and diluted with dichloromethane (20 mL) and filtered and washed through with dichloromethane. The filtrate was concentrated under vacuum and taken up in dichloromethane. The solution was washed with 0.880 ammonia (×3), water then brine and separated by hydrophobic frit and the organic layer was reduced under vacuum. The residue was purified by Flashmaster automated silica gel chromatography eluting with 0-20% methanol in dichloromethane to leave an oil which crystallised on standing. The residue was dried under vacuum overnight to give 1,1-dimethylethyl 3-methyl-1-(1-methyl-1H-imidazol-4-yl)-2-oxo-4-imidazolidinecarboxylate (285 mg, 87% yield). LC/MS [M+H]+=281. (ii) Trifluoroacetic acid (1.0 ml, 12.98 mmol) was added to a solution of 1,1-dimethylethyl 3-methyl-1-(1-methyl-1H-imidazol-4-yl)-2-oxo-4-imidazolidinecarboxylate (220 mg, 0.785 mmol) in DCM (2 ml) and the reaction mixture was stirred at room temperature for 5 hours. The solvent was evaporated under vacuum, azeotroping with toluene and the residue was dried under vacuum over the weekend to give crude 3-methyl-1-(1-methyl-1H-imidazol-4-yl)-2-oxo-4-imidazolidinecarboxylic acid trifluoroacetate salt which was taken through to next step without further purification. LC/MS [M+H]+=225.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:5]2[CH:12]=[C:11]([C:13]3[CH2:14][CH2:15][NH:16][CH2:17][CH:18]=3)[NH:10][C:6]=2[N:7]=[CH:8][N:9]=1.[N:19]1([CH2:25][CH2:26][C:27](O)=[O:28])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:3][C:4]1[C:5]2[CH:12]=[C:11]([C:13]3[CH2:14][CH2:15][N:16]([C:27](=[O:28])[CH2:26][CH2:25][N:19]4[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)[CH2:17][CH:18]=3)[NH:10][C:6]=2[N:7]=[CH:8][N:9]=1
Reactant: O=C(O)CCN1CCCCC1
Reactant: Clc1ncnc2[nH]c(C3=CCNCC3)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCN1CCCCC1)N1CC=C(c2cc3c(Cl)ncnc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension/solution of 4-chloro-6-(1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidine bis-hydrochloride (19.1 mg, 0.0621 mmol, 1 eq), 1-piperidinepropanoic acid (24.5 mg, 0.156 mmol, 2.5 eq), 1-hydroxybenzotriazole (HOBt) (8.5 mg, 0.063 mmol, 1 eq), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC) (36.3 mg, 0.189 mmol, 3 eq) in anhydrous DMF (1.3 mL), DiPEA (64 μL, 0.37 mmol, 6 eq) was added and the reaction was stirred at rt, under N2, for 16 h. Solvent was concentrated in vacuo and the residue was dissolved in DCM, washed with NaHCO3 (2×) and brine (1×), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified on MDPS giving the title compound as a yellow solid. 1H NMR (400 MHz, MeOH-d4): δ=1.45-1.56 (s, br, 2H), 1.64 (sextet, J=5.6 Hz, 4H), 2.46-2.78 (m, 10H), 3.81 & 3.84 (t, J=5.6 Hz, rotamers, 2H), 4.29 & 4.33 (d, J=2.0 Hz, rotamers, 2H), 6.48 (s, br, 1H), 6.62 & 6.63 (s, rotamers, 1H), 8.50 (d, 1H). MS (ES+): m/z 373.99/376.00 (100/36) [MH+]. HPLC: tR=1.86 min (ZQ2000, polar—5 min).
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[C:7]([C:17]([O:19][CH3:20])=[O:18])=[CH:8][C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:10][C:4]=2[N:3]=1.Cl[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[C:25]([CH3:30])[CH:24]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:30][C:25]1[CH:24]=[C:23]([CH2:22][N:3]2[C:4]3[CH:10]=[C:9]([N:11]4[CH2:12][CH2:13][O:14][CH2:15][CH2:16]4)[CH:8]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[C:5]=3[N:6]=[C:2]2[CH3:1])[CH:28]=[CH:27][C:26]=1[CH3:29]
Reactant: Cc1ccc(CCl)cc1C
Reactant: COC(=O)c1cc(N2CCOCC2)cc2nc(C)[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(N2CCOCC2)cc2c1nc(C)n2Cc1ccc(C)c(C)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
To a solution of methyl 2-methyl-5-(4-morpholinyl)-1H-benzimidazole-7-carboxylate prepared as described in Example 26, step d (0.22 g, 0.799 mmol) in N,N-Dimethylformamide (DMF) (10 mL) was added in 4-(chloromethyl)-1,2-dimethylbenzene (0.185 g, 1.199 mmol) and potassium carbonate (0.331 g, 2.397 mmol). The resulting reaction mixture was stirred at 80° C. for 3 h. It was cooled to room temperature and poured into water (30 mL). The mixture was extracted with EtOAc (50 mL×3). The combined organic phases were washed with brine (50 mL) and concentrated. The crude material was subjected to normal phase purification (0→40% EtOAc/Hexane) then (0→1% MeOH/DCM) to give the product (0.24 g, 76%). MS (ES+) m/e 394.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH:23][C@H:24]3[CH2:28][N:27]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:26][C@H:25]3[C:33]([OH:35])=O)(=[O:22])=[O:21])=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[OH:36][N:37]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.NO>CN(C)C=O>[OH:36][NH:37][C:33]([C@H:25]1[C@@H:24]([NH:23][S:20]([C:17]2[CH:18]=[CH:19][C:14]([O:13][CH2:12][C:10]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=[C:2]([CH3:1])[CH:11]=3)=[CH:15][CH:16]=2)(=[O:22])=[O:21])[CH2:28][N:27]([S:29]([CH3:32])(=[O:30])=[O:31])[CH2:26]1)=[O:35]
Reactant: Cc1cc(COc2ccc(S(=O)(=O)N[C@H]3CN(S(C)(=O)=O)C[C@H]3C(=O)O)cc2)c2ccccc2n1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NO
Solvent: CN(C)C=O
Product: Cc1cc(COc2ccc(S(=O)(=O)N[C@H]3CN(S(C)(=O)=O)C[C@H]3C(=O)NO)cc2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 88.9 %

Procedure:
To a solution of 152 mg (0.24 mmol) of cis-4-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]-1-(methylsulfonyl)pyrrolidine-3-carboxylic acid and 97.3 mg (0.72 mmol) of 1-hydroxybenzotriazole in 3 mL of N,N-dimethylformamide at 0° C. was added 138 mg (0.72 mmol) of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride. The reaction mixture was stirred at room temperature for 1.5 h. To the 0° C. reaction mixture was added 0.12 mL of 50% hydroxylamine solution. The resulting reaction mixture was stirred at room temperature for 18 h. The volatile materials were removed under reduced pressure below 40° C. The residue was dissolved in 80 mL of ethyl acetate. The organic layer was washed with a saturated sodium bicarbonate solution (5×30 mL) and a saturated sodium chloride solution (2×30 mL), dried over sodium sulfate and filtered. After removal of the ethyl acetate, the residue was triturated with a 7:3 hexane:ethyl acetate mixture to give 114.1 mg of cis-N-hydroxy-4-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]-1-(methylsulfonyl)pyrrolidine-3-carboxamide as a yellow solid in 89% yield. MS: 535.2 (M+H)+
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)(=O)=O.[NH:24]1[CH:28]=[CH:27][N:26]=[CH:25]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:17]([O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][CH2:7][CH2:6][N:24]2[CH:28]=[CH:27][N:26]=[CH:25]2)=[CH:11][CH:12]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: c1c[nH]cn1
Reactant: CS(=O)(=O)OCCCCc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(COc2ccc(CCCCn3ccnc3)cc2)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 61.1 %

Procedure:
A mixture of 4-(4-benzyloxyphenyl)butyl methane sulfonate (25.0 g), imidazole (11.2 g), potassium carbonate (15.5 g) and N,N-dimethylformamide (200 ml) was stirred for 16 hours at 80° C. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography. From the fraction eluted with ethyl acetate-methanol (20:1, v/v), 1-[4-(4-benzyloxyphenyl)butyl]imidazole (14.0 g, 61%) was obtained. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 97-98° C.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH:15]=[N:16][CH:17]=3)[CH:10]=2)[N:5](C2CCCCO2)[N:4]=1)=O.[S].[F:32][C:33]1[CH:34]=[C:35]([C:39]2[C:40]([NH2:46])=[C:41]([NH2:45])[CH:42]=[N:43][CH:44]=2)[CH:36]=[CH:37][CH:38]=1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(O)CCC>[F:32][C:33]1[CH:34]=[C:35]([C:39]2[C:40]3[N:46]=[C:1]([C:3]4[C:11]5[C:6](=[N:7][CH:8]=[C:9]([C:12]6[CH:13]=[C:14]([NH:18][C:19](=[O:24])[C:20]([CH3:22])([CH3:21])[CH3:23])[CH:15]=[N:16][CH:17]=6)[CH:10]=5)[NH:5][N:4]=4)[NH:45][C:41]=3[CH:42]=[N:43][CH:44]=2)[CH:36]=[CH:37][CH:38]=1
Reactant: CC(C)(C)C(=O)Nc1cncc(-c2cnc3c(c2)c(C=O)nn3C2CCCCO2)c1
Reactant: Nc1cncc(-c2cccc(F)c2)c1N
Agent: CC[SiH](CC)CC
Agent: [S]
Solvent: CCCCO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C(=O)Nc1cncc(-c2cnc3[nH]nc(-c4nc5c(-c6cccc(F)c6)cncc5[nH]4)c3c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.2 %

Procedure:
A solution of N-(5-(3-formyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)pivalamide (LXV) (75 mg, 0.18 mmol), sulfur (64 mg, 0.20 mmol) and 5-(3-fluorophenyl)pyridine-3,4-diamine (XL) (41 mg, 0.20 mmol) in n-butanol (10 mL) was refluxed overnight under argon. The solution was cooled and filtered and dried under vacuum for 1 h. The residue was taken in dry DCM (5 mL). Triethylsilane (72 μL, 0.45 mmol) followed by TFA (2.5 mL) was added to the solution and stirred for 2 h at room temperature. The solvent was removed under vacuum. Water was added to the residue, sonicated briefly and basified with a 5N NH4OH solution. The solids formed were filtered, washed with cold water and dried at room temperature. The solids were boiled in DCM, cooled to room temperature and sonicated briefly. The solids were filtered, washed with DCM and dried under vacuum to give N-(5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)pivalamide (2) as a brown solid (66 mg, 0.13 mmol, 72% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 1.30 (s, 9H), 7.22 (t, 1H), 7.57-7.66 (m, 1H), 8.25 (d, 1H), 8.36 (d, 1H), 8.55 (s, 1H), 8.74 (s, 1H), 8.78 (s, 1H), 8.89 (s, 1H), 8.97 (s, 1H), 9.04 (s, 1H), 9.07 (s, 1H), 9.61 (s, 1H), 13.92 (brs, 1H), 14.63 (brs, 1H); ESIMS found C28H23FN8O m/z 507.5 (M+H).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][N:9]([CH:16]([CH3:18])[CH3:17])[C:10]=2[CH:11]=[C:12]([O:14][CH3:15])[CH:13]=1)=[O:4].O[Li].O>C1COCC1.O>[CH:16]([N:9]1[C:10]2[CH:11]=[C:12]([O:14][CH3:15])[CH:13]=[C:5]([C:3]([OH:4])=[O:2])[C:6]=2[CH:7]=[CH:8]1)([CH3:18])[CH3:17]
Reactant: COC(=O)c1cc(OC)cc2c1ccn2C(C)C
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)c2ccn(C(C)C)c2c1
Yield: 69.8 %

Procedure:
To a stirred solution of 1-isopropyl-6-methoxy-1H-indole-4-carboxylic acid methyl ester (320 mg, 1.29 mmol) in THF (2 mL) was added LiOH.H2O (160 mg, 3.88 mmol) in water (2 mL) at room temperature and heated at reflux for 2 h. The THF was removed under reduced pressure and the resulting aqueous layer was acidified with 1N HCl (pH 6) and extracted with ethyl acetate (2×5 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated to afford 1-isopropyl-6-methoxy-1H-indole-4-carboxylic acid (210 mg). 1H NMR (400 MHz, DMSO-d6): δ 1.42 (d, 6H), 3.88 (s, 3H), 4.85 (m, 1H), 6.81 (d, J=2.8 Hz, 1H), 7.26 (s, 2H), 7.45 (s, 1H), 12.68 (s, 1H).
Reaction SMILES: [C:1]([C:9]1[NH:10][CH:11]=[CH:12][C:13]=1[CH2:14][CH2:15][C:16](Br)([C:22]([O:24]CC)=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OO.C(B([CH2:35][CH3:36])CC)C.O=O>CS(C)=O.O>[C:1]([C:9]1[N:10]2[C:15](=[CH:14][CH:13]=1)[C:16]([C:22]([O:24][CH2:35][CH3:36])=[O:23])([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:12][CH2:11]2)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Br)(CCc1cc[nH]c1C(=O)c1ccccc1)C(=O)OCC
Reactant: CCB(CC)CC
Agent: O=O
Agent: OO
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C1(C(=O)OCC)CCn2c(C(=O)c3ccccc3)ccc21

Procedure:
To a mixture of a compound of formula VII, preferably 2-benzoyl-[3-bromo-3,3-di(ethoxycarbonyl)propyl]pyrrole, in a suitable solvent, is added an alkyl radical. A preferred alkyl radical, the methyl radical, is derived from the reaction of ferrous sulfate and hydrogen peroxide in dimethyl sulfoxide. In an alternative preferred embodiment, the alkyl radical is derived from a trialkylborane, preferably triethylborane, with oxygen (air) in a nonpolar solvent. The reaction mixture is allowed to stir until the reaction is complete. The reaction mixture is poured into water and extracted with a polar solvent, such as methylene chloride or diethyl ether. The combined organic extracts are washed, dried and concentrated under reduced pressure to yield a compound of formula I, preferably diethyl 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1,1-dicarboxylate, which may be isolated by conventional means.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.Br[CH2:17][C:18]([NH:20][C:21]1[C:26]([CH:27]([CH3:29])[CH3:28])=[CH:25][C:24]([OH:30])=[CH:23][C:22]=1[CH:31]([CH3:33])[CH3:32])=[O:19]>C(#N)C.O>[OH:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][N:13]([CH2:17][C:18]([NH:20][C:21]2[C:26]([CH:27]([CH3:29])[CH3:28])=[CH:25][C:24]([OH:30])=[CH:23][C:22]=2[CH:31]([CH3:33])[CH3:32])=[O:19])[CH2:12][CH2:11]1
Reactant: CC(C)c1cc(O)cc(C(C)C)c1NC(=O)CBr
Reactant: OCCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)c1cc(O)cc(C(C)C)c1NC(=O)CN1CCN(CCO)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 69 %

Procedure:
Potassium carbonate (1.52 g, 11 mmol) was added to a solution of 1-(2-hydroxyethyl)piperazine (1.43 g, 11 mmol) and 2-bromo-N-(2,6-diisopropyl-4-hydroxyphenyl)acetamide in acetonitrile (50 ml) and the mixture was stirred at room temperature for 12 hours. The reaction solution was diluted with water and extracted with chloroform. The organic layer was washed with water and a saturated sodium chloride solution successively and dried oven anhydrous sodium sulfate and the solvent was evaporated therefrom. The crude crystals were recrystallized from acetone-hexane to provide 2.5 g (yield 69%) of 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-(2,6-diisopropyl-4-hydroxyphenyl)acetamide as colorless needles.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[C:23]([C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1)#[N:24]>>[C:23]([C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH:30][C:20]([C:17]2[CH:18]=[CH:19][C:14]([C:3]3[CH:4]=[C:5]([C:8]4[O:9][C:10]([CH3:13])=[N:11][N:12]=4)[CH:6]=[CH:7][C:2]=3[CH3:1])=[CH:15][CH:16]=2)=[O:21])=[CH:27][CH:26]=1)#[N:24]
Reactant: N#Cc1ccc(CN)cc1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NCc4ccc(C#N)cc4)cc3)c2)o1

Procedure:
N-(4-Cyanobenzyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and 4-cyanobenzylamine using method N. NMR; δH [2H6]—DMSO 9.25,(1H, t), 8.01,(2H, d), 7.90,(1H, dd), 7.81,(2H, d), 7.77,(1H, d), 7.56-7.51,(5H, m), 4.58,(2H, d), 2.56,(3H, s), 2.31,(3H, s). LCMS; retention time 3.34 min, MH+ 409.