Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)=[O:11].[C:25]([CH2:29][O:30][CH2:31][CH2:32]Br)([O:27][CH3:28])=[O:26].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:25]([CH2:29][O:30][CH:31]([N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([CH:12]1[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17]1)=[O:11])[CH3:32])([O:27][CH3:28])=[O:26]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2nc3ccccc3[nH]2)CC1
Reactant: COC(=O)COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COC(C)n1c(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)nc2ccccc21
Temperature: 90 °C

Procedure:
Mix [1H-benzimidazol-2-yl][1-(t-butyloxycarbonyl)-4-piperidinyl]methanone (4.25 g, 12.91 mmol), carbomethoxy methoxy ethylbromide (3.01 g, 15.3 mmol), potassium carbonate (5.29 g, 38.25 mmol) and dimethylformamide (100 mL). Stir and heat and at 90° C. overnight. Allow to cool to room temperature, dilute with water and extract with ethyl acetate (2×). Wash the combined organic phases with water (3×), then brine and dry (MgSO4). Evaporate the solvent in vacuo to give and purify by chromatography to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][C@@:12]([CH2:17][CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])([C:14]([OH:16])=O)[CH:11]=[CH:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.Cl.Cl.[F:60][C:61]([F:73])([F:72])[C:62]1[CH:63]=[N:64][C:65]2[CH2:66][CH2:67][NH:68][CH2:69][C:70]=2[CH:71]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Si:20]([O:19][CH2:18][CH2:17][C@@:12]1([C:14]([N:68]2[CH2:67][CH2:66][C:65]3[N:64]=[CH:63][C:62]([C:61]([F:60])([F:72])[F:73])=[CH:71][C:70]=3[CH2:69]2)=[O:16])[CH2:13][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH:10]=[CH:11]1)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:21])[CH3:22]
Reactant: FC(F)(F)c1cnc2c(c1)CNCC2
Reactant: CC(C)(C)OC(=O)N[C@@H]1C=C[C@](CCO[Si](C)(C)C(C)(C)C)(C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1C=C[C@](CCO[Si](C)(C)C(C)(C)C)(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of the product of Step B (3.47 g, 8.99 mmol, 1 eq) in DCM (40 mL) at rt was added HOBt hydrate (2.34 g, 15.3 mmol, 1.7 eq) and EDCI (2.58 g, 13.5 mmol, 1.5 eq). After 15 min, DIEA (7.8 mL, 45.3 mmol, 5 eq) and 3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2 HCl (3.71 g, 13.5 mmol, 1 eq) were added and the solution stirred overnight at rt. Saturated NaHCO3 was added, the solution extracted with DCM, the organics combined, dried over MgSO4, and concentrated. Purification by chromatography (120 g column) eluting with 25 to 60% EtOAc/heptane afforded the title compound of Step C. 1H NMR (CHLOROFORM-d) δ: 8.71 (s, 1H), 7.69 (s, 1H), 6.19 (d, J=5.4 Hz, 1H), 5.76 (dd, J=5.6, 2.0 Hz, 1H), 4.68-4.86 (m, 4H), 3.85-4.07 (m, 2H), 3.54-3.65 (m, 2H), 3.13 (t, J=5.7 Hz, 2H), 2.58 (dd, J=13.3, 7.7 Hz, 1H), 1.98-2.16 (m, 2H), 1.85-1.97 (m, 1H), 1.42 (s, 9H), 0.84 (s, 9H), −0.02 (d, J=4.4 Hz, 6H). Calculated for C28H42F3N3O4Si: 570.3 (M+1). found: 570.3.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:38]=[CH:39][CH:40]=1)[C:5]([C:7]1[CH:8]=[C:9]2[C:15]3([CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[CH2:14][N:13]([C:28]3[C:29]4[C@H:36]([CH3:37])[CH2:35][CH2:34][C:30]=4[N:31]=[CH:32][N:33]=3)[C:10]2=[CH:11][CH:12]=1)=[O:6].[BH4-].[Na+]>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:5]([OH:6])[C:7]2[CH:8]=[C:9]3[C:15]4([CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]4)[CH2:14][N:13]([C:28]4[C:29]5[C@H:36]([CH3:37])[CH2:35][CH2:34][C:30]=5[N:31]=[CH:32][N:33]=4)[C:10]3=[CH:11][CH:12]=2)[CH:38]=[CH:39][CH:40]=1
Reactant: C[C@@H]1CCc2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4cc(C(=O)c5cccc(F)c5)ccc43)c21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[C@@H]1CCc2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4cc(C(O)c5cccc(F)c5)ccc43)c21
Reaction time: 1.5 h
Yield: 73.9 %

Procedure:
To a stirred solution of (R)-tert-butyl 5-(3-fluorobenzoyl)-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (0.047 g, 0.087 mmol) in MeOH (0.5 mL) was added NaBH4 (0.0036 g, 0.095 mmol) at about 0° C. The reaction was stirred for 1.5 hours and quenched by the addition of saturated NH4Cl solution. The solvent was evaporated under reduced pressure. The solid was dissolved in water and extracted with EtOAc. The combined extracts were washed with brine, dried MgSO4, filtered and concentrated. The crude residue was purified by column chromatography (1-3% MeOH/DCM) to yield tert-butyl 5-((3-fluorophenyl)(hydroxy)methyl)-1-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (0.035 g, 74%). LCMS (APCI+) m/z 545.3 [M+H]+; Rt=4.02 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:18]=[CH:17][N:16]=1)[CH2:9][CH2:10][CH2:11][CH:12]=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:26]([NH:33][CH:34]1[CH2:36][CH2:35]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([N:33]([CH:34]1[CH2:35][CH2:36]1)[CH2:12][CH2:11][CH2:10][CH2:9][N:8]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:18]=[CH:17][N:16]=1)[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: c1ccc(CNC2CC2)cc1
Reactant: CCOC(=O)c1ccnc(CN(CCCC=O)C(=O)OC(C)(C)C)c1
Product: CCOC(=O)c1ccnc(CN(CCCCN(Cc2ccccc2)C2CC2)C(=O)OC(C)(C)C)c1

Procedure:
By General Procedure A from ethyl 2-({[(tert-butoxy)carbonyl](4-oxobutyl)amino}methyl)pyridine-4-carboxylate and N-benzylcyclopropanamine. Purification by column chromatography (5% MeOH/DCM) gave the title compound as colorless oil. 1H-NMR (300 MHz, CDCl3): δ 8.60 (d, 1H), 7.70 (s, 1H), 7.60 (d, 1H), 7.10 (m, 5H), 4.50 (d, 2H), 4.40 (q, 2H), 3.50 (m, 2H), 3.15 (m, 2H), 2.50 (m, 2H), 1.60 (m, 1H), 1.45 (m, 16H), 0.4 (m, 4H) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.C1C=C[NH+]=CC=1.[Br:19][Br-]Br>C1COCC1.N1C=CC=CC=1>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][C:12]=1[Br:19]
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(N)c(Br)c1
Reaction time: 0.5 h
Yield: 76.6 %

Procedure:
To a mechanically stirred solution of ethyl 4-aminobenzoate (165 g, 1 mol) in THF (1.2 L) and pyridine (200 mL) at ˜10° C. was added portionwise (˜10–20 g each time) of pyridine hydrobromide perbromide (tech. 90%, 365 g, 1.02 mol) over a period of 1 h. Internal temperature was kept at 10–15° C. After completion of addition, the mixture was stirred for 30 min, then filtered through celite and the filter cake was washed with THF (1 L). The filtrate was diluted with Et2O, washed with 0.5 M of aqueous NaHSO3 (2×, 400 mL), brine, dried (MgSO4) and concentrated. The residue contained too much H2O and therefore was dissolved in EtOAc (1 L), washed with brine, dried (MgSO4) and concentrated to give a semi-solid residue. The residue was swished with hexanes-Et2O (2:1) to yield 187 g (77%) of the title compound as a white powder. The mother liquor was evaporated and swished again to give 19 g (8%) of additional title compound as a light brown powder.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5](=[O:13])[CH:4]=[C:3]1OC.[NH3:16]>CO>[NH2:16][C:3]1[C:2](=[O:1])[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5](=[O:13])[CH:4]=1
Reactant: N
Reactant: COc1cc(=O)c2ccccc2[nH]c1=O
Solvent: CO
Product: Nc1cc(=O)c2ccccc2[nH]c1=O
Temperature: -78 °C

Procedure:
2,5-Dihydro-2,5-dioxo-3-methoxy-1H-benz[b]azepine (0.4 g) was treated with 80 mL of liquid anhydrous ammonia chilled to -78° C. The mixture was sealed in a pressure vessel and warmed to 23° C. for 18 hours. The excess ammonia was evaporated to give a solid. The solid was dissolved in hot methanol (120 mL); the solution was filtered and evaporated to 60 mL; and crystallization was initiated by cooling the solution in an ice bath. The solid was filtered, washed (cold methanol) and dried under vacuum (25° C., 15 Pa) to give the title compound (0.28 g); mp 295.2°-296.5° C. (dec); NMR: 11.38 (s,1, NH), 8.09 (dd,1, J=8.2, 1.6), 7.54 (m,1), 7.44 (dd,1, J=8.2, 1.6), 7.21 (m,1), 6.23 (s,1). Analysis for C10H8N2O2 : Calculated: C, 63.82; H, 4.28; N, 14.89; Found: C, 63.80; H, 4.41; N, 14.87.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([C:15]([OH:17])=O)[CH:9]=[CH:8]2)(=[O:3])[CH3:2].P(Cl)(Cl)(Cl)(Cl)[Cl:19]>C1C=CC=CC=1>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([C:15]([Cl:19])=[O:17])[CH:9]=[CH:8]2)(=[O:3])[CH3:2]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CC(=O)Oc1ccc2cc(C(=O)O)ccc2c1
Solvent: c1ccccc1
Product: CC(=O)Oc1ccc2cc(C(=O)Cl)ccc2c1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
Then, in a 200 ml-reaction vessel, 17.1 g (7.43×10-2M) of 6-acetoxy-2-naphthoic acid and 85 ml of dry benzene were placed. To the mixture, 15.9 g (6.91×10-2M) of phosphorus pentachloride was added in 30 minutes at room temperature, followed by stirring for 4 hours at 60° C. After cooling, the solvent of the reaction mixture was distilled off to provide oily 6-acetoxy-2-naphthoyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.Cl[CH2:31][CH2:32][CH:33]1[CH2:37][CH2:36][CH2:35][N:34]1[CH3:38]>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH2:31][CH2:32][CH:33]5[CH2:37][CH2:36][CH2:35][N:34]5[CH3:38])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:27])([F:29])[F:28])[CH:3]=1
Reactant: CN1CCCC1CCCl
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CN1CCCC1CCN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and 2-(2-chloroethyl)-1-methylpyrrolidine following General Procedure H.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C@@H:4]([NH:8][C:9](=[O:18])[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:17])[CH2:5][CH:6]=[CH2:7].I[C:21]1[CH:26]=[CH:25][C:24]([C:27]2([O:33][CH3:34])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][O:2][C:3](=[O:19])[C@@H:4]([NH:8][C:9](=[O:18])[C:10]1[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5]/[CH:6]=[CH:7]/[C:21]1[CH:22]=[CH:23][C:24]([C:27]2([O:33][CH3:34])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[CH:25][CH:26]=1
Reactant: COC1(c2ccc(I)cc2)CCOCC1
Reactant: C=CC[C@H](NC(=O)c1c(Cl)cccc1Cl)C(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](C/C=C/c1ccc(C2(OC)CCOCC2)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 80 °C
Reaction time: 2 h
Yield: 79.2 %

Procedure:
Under an argon atmosphere, palladium acetate (295 mg) and tris(2-methylphenyl)phosphine (384 mg) were added to a suspension of (S)-2-(2,6-dichlorobenzamido)pent-4-enoic acid methyl ester (7.60 g), tetrahydro-4-(4-iodophenyl)-4-methoxy-2H-pyran (8.00 g) and potassium carbonate (5.21 g) in DMF (90 ml), and the resulting mixture was stirred at 80° C. for 2 hours. After cooling the reaction solution to room temperature, ethyl acetate was added thereto, and the resulting mixture was washed 3 times with water and once with saturated brine, followed by drying the organic layers over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent: cyclohexane/chloroform=2/1→1/4). The obtained crudely purified product was further purified by column chromatography (silica gel, eluent: cyclohexane/ethyl acetate=4/1) to obtain (S,E)-2-(2,6-dichlorobenzamido)-5-[4-(4-methoxytetrahydropyran-4-yl)-phenyl]pent-4-enoic acid methyl ester (9.80 g).
Reaction SMILES: [CH3:1][C:2]1[S:9][C:8]2[CH:7]=[C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[NH:5][C:4]=2[CH:3]=1.[Br:15]N1C(=O)CCC1=O.O>O1CCCC1>[Br:15][C:7]1[C:8]2[S:9][C:2]([CH3:1])=[CH:3][C:4]=2[NH:5][C:6]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)c1cc2sc(C)cc2[nH]1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1[nH]c2cc(C)sc2c1Br
Reaction time: 1 h
Yield: 69.7 %

Procedure:
To a solution of ethyl 2-methyl-4H-thieno[3,2-b]pyrrole-5-carboxylate (1.0 g) in tetrahydrofuran (10 mL) was added N-Bromosuccinimide (0.94 g) under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture was added water and the resulting mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=97/3−76/24) to give the title compound (0.96 g).
Reaction SMILES: [OH:1][C:2]1[C:3]2[C:8]([CH:9]=[C:10]([O:14]C)[C:11]=1[O:12]C)=[N:7][C:6](=[O:16])[C:5](=[O:17])[N:4]=2.[B].[OH-].[Na+].Cl>C(Cl)Cl>[OH:1][C:2]1[C:3]2[C:8]([CH:9]=[C:10]([OH:14])[C:11]=1[OH:12])=[N:7][C:6](=[O:16])[C:5](=[O:17])[N:4]=2
Reactant: COc1cc2c(c(O)c1OC)=NC(=O)C(=O)N=2
Agent: Cl
Agent: [B]
Agent: [Na+]
Solvent: ClCCl
Product: O=C1N=c2cc(O)c(O)c(O)c2=NC1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 80.8 %

Procedure:
To a suspension of 5-hydroxy-6,7-dimethoxy-2,3-quinoxalinedione (48) (50 mg, 0.22 mmol) in 2 mL of methylene dichloride was added 2 mL of a solution of boron tribomide in methylene dichloride (1M, Aldrich). The resulting mixture was stirred at room temperature for 12 hr. The mixture was poured into ice-water (5 g) to form a suspension. Aqueous sodium hydroxide (20%, 2 mL) was added to the suspension to form a red solution. Then the solution was acidified with 6N HCl (5 mL) to pH=1. The suspension was centrifuged, washed with methanol, and dried in vacuo giving 37 mg (80%) of the product as a brown solid; mp>350° C.; 1H NMR (DMSO-d6, 300 MHz) δ6.149 (s, 1H), 9.113 (s, 1H), 9.190 (s, 2H), 10.713 (s, 1H), 11.501 (s, 1H) (HPLC>98%).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].N1C=CC=CC=1.[C:15]([O:18][CH2:19][C:20](Cl)=[O:21])(=[O:17])[CH3:16]>C(Cl)Cl>[C:15]([O:18][CH2:19][C:20]([O:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8])=[O:21])(=[O:17])[CH3:16]
Reactant: CC(=O)OCC(=O)Cl
Reactant: O=C1CCC(=O)N1O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCC(=O)ON1C(=O)CCC1=O
Reaction time: 2.5 h
Yield: 93 %

Procedure:
A 3-neck round-bottom flask equipped with a mechanical stirrer, thermocouple and addition funnel with nitrogen inlet was charged with N-hydroxysuccinimide (commercially available from Sigma-Aldrich, St. Louis, Mo.) (211 g, 1.83 mol) and DCM (2.25 L) at room temperature, resulting in a suspension. Pyridine (178 mL, 2.2 mol) was added in one portion with no change in the internal temperature. A solution of acetoxyacetyl chloride (commercially available from Sigma-Aldrich, St. Louis, Mo.) (197 mL, 1.83 mol) in DCM (225 mL) was added dropwise over 60 minutes and the temperature rose to 35° C. Stirring was continued at room temperature for 2.5 hours. The reaction mixture was washed with water (1×1 L), 1N HCl (2×1 L) and brine (1×1 L). The organic layer was concentrated under vacuum and azeotroped with toluene (1×1 L) to obtain the product as a white solid (367 g, 93%). 1H NMR (400 MHz, CDCl3) δ 4.96 (2H, s), 2.86 (4H, s), 2.19 (3H, s) ppm; LCMS m/z: 238 (M+Na).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH3:12])[N:11]=1)[C:6]([OH:8])=O)[CH3:2].[CH3:13][C:14]1([CH3:28])[CH:16]2[CH2:17][C:18]3[C:22]([CH:15]12)=[C:21]([CH3:23])[S:20][C:19]=3[C:24]([NH:26][NH2:27])=[O:25].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[CH3:13][C:14]1([CH3:28])[CH:16]2[CH2:17][C:18]3[C:22]([CH:15]12)=[C:21]([CH3:23])[S:20][C:19]=3[C:24]([NH:26][NH:27][C:6](=[O:8])[C:5]1[CH:9]=[C:10]([CH3:12])[N:11]=[C:3]([CH2:1][CH3:2])[CH:4]=1)=[O:25]
Reactant: Cc1sc(C(=O)NN)c2c1C1C(C2)C1(C)C
Reactant: CCc1cc(C(=O)O)cc(C)n1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CCc1cc(C(=O)NNC(=O)c2sc(C)c3c2CC2C3C2(C)C)cc(C)n1
Reaction time: 15 h
Yield: 172.2 %

Procedure:
To a mixture of 2-ethyl-6-methyl-isonicotinic acid (87.9 mg, 0.53 mmol), 1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid hydrazide (141.8 mg, 0.6 mmol), HOBt (100 mg, 0.74 mmol) and TEA (0.42 mL) in DCM (5 mL) is added at 0° C. EDC (200 mg, 0.78 mmol). The mixture is stirred for 15 h during which time it warmed from 0° C. to rt. The mixture is quenched with EA (50 mL) and washed with 1M aq. NaOH (2×10 mL). The organic phase is dried (Na2SO4), filtered and evaporated to give crude 2-ethyl-6-methyl-isonicotinic acid N′-(1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carbonyl)-hydrazide (350 mg); LC-MS: tR=0.80 min, [M+1]=384.34.
Reaction SMILES: [NH2:1][CH:2]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:27][CH:26]=1)[C:3]([N:5]([CH2:14][C:15]1[C:20]2[N:21]=[CH:22][S:23][C:19]=2[CH:18]=[CH:17][CH:16]=1)[CH2:6][CH:7]([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])=[O:4].[CH2:36]([NH:43][C:44](=[O:54])[NH:45][C@H:46]([CH2:51][CH:52]=[CH2:53])[CH2:47][C:48](O)=[O:49])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O>[S:23]1[C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:14][N:5]([CH2:6][CH:7]([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])[C:3]([CH:2]([NH:1][C:48](=[O:49])[CH2:47][CH:46]([NH:45][C:44]([NH:43][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[O:54])[CH2:51][CH:52]=[CH2:53])[CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[CH:29][CH:30]=3)=[O:4])[C:20]=2[N:21]=[CH:22]1
Reactant: CCOC(CN(Cc1cccc2scnc12)C(=O)C(N)Cc1ccc(OC(C)(C)C)cc1)OCC
Reactant: C=CC[C@H](CC(=O)O)NC(=O)NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C=CCC(CC(=O)NC(Cc1ccc(OC(C)(C)C)cc1)C(=O)N(Cc1cccc2scnc12)CC(OCC)OCC)NC(=O)NCc1ccccc1
Reaction time: 0.67 h

Procedure:
To a solution of 2-Amino-N-benzothiazol-4-ylmethyl-3-(4-tert-butoxy-phenyl)-N-(2,2-diethoxy-ethyl)-propionamide in CH2Cl2(50 mL) was added a solution of (3R)-3-(3-Benzyl-ureido)-hex-5-enoic acid (1.6 g, 6.1 mmol), EDCl (1.17 g, 1.2 eq), HOBt (0.93 g, 1.2 eq), DIEA (2.13 mL, 12.2 mL) in CH2Cl2 (100 mL) stirred for 40 min. The reaction mixture was stirred at room temperature for 14 h, and then diluted with EtOAc, washed with water and brine. The organic layer was dried with Na2SO4 and concentrated in vacuo. The crude compound was used next step without further purification. MS ESI 744 (M+H), 766 (M+Na)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]=[C:19]3[N:21]([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][O:26]4)[N:22]=[C:23]([CH3:24])[C:18]3=[C:17]([C:31](=O)[CH3:32])[CH:16]=2)=[C:11]([F:34])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:35]([O:39][C:40]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)=[O:41])([CH3:38])([CH3:37])[CH3:36].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>ClCCl.C(O)(=O)C>[C:35]([O:39][C:40]([N:42]1[CH2:47][CH2:46][N:45]([CH:31]([C:17]2[CH:16]=[C:15]([C:12]3[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:10][C:11]=3[F:34])[N:20]=[C:19]3[N:21]([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][O:26]4)[N:22]=[C:23]([CH3:24])[C:18]=23)[CH3:32])[CH2:44][CH2:43]1)=[O:41])([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(=O)c1cc(-c2ccc(OCc3ccccc3)cc2F)nc2c1c(C)nn2C1CCCCO1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1nn(C2CCCCO2)c2nc(-c3ccc(OCc4ccccc4)cc3F)cc(C(C)N3CCN(C(=O)OC(C)(C)C)CC3)c12
Temperature: 40 °C
Reaction time: 8 h
Yield: 16.8 %

Procedure:
A mixture of 1-[6-(4-benzyloxy-2-fluoro-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-ethanone (390 mg), acetic acid (25 μL), piperazine-1-carboxylic acid tert-butyl ester (158 mg) and sodium triacetoxy borohydride (270 mg) in dichloromethane (7.5 mL) was stirred at 40° C. overnight. Then additional triacetoxy borohydride (90 mg) was added. The reaction mixture was concentrated in a membrane pump vacuum, and the residue was purified by flash chromatography (silica, heptane/ethyl acetate gradient) giving 4-{1-[6-(4-Benzyloxy-2-fluoro-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-ethyl}-piperazine-1-carboxylic acid tert-butyl ester (90 mg). This material was dissolved in methanol (5 mL), purged with argon, then with hydrogen and palladium (10% on charcoal, 8 mg) was added. The reaction mixture was stirred at 40° C. until the reaction was complete (according to HPLC/MS). The catalyst was filtered off and the filtrate was concentrated in a membrane pump vacuum. The residue was taken up in THF (2 mL), and conc. hydrochloric acid (1 mL) was added. The solution was stirred at r.t., then the solvents were evaporated and the residue was purified by preparative HPLC (C18 column, acetonitrile/water gradient) giving 3-fluoro-4-[3-methyl-4-(1-piperazin-1-yl-ethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl]-phenol (30 mg, 9%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[CH2:5]2.[CH3:20][N:21](C=O)C>C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[C-]#N.[Zn+2].[C-]#N>[O:19]=[C:13]1[CH:12]([N:6]2[CH2:5][C:4]3[C:8](=[CH:9][CH:10]=[C:2]([C:20]#[N:21])[CH:3]=3)[C:7]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: CN(C)C=O
Reactant: O=C1CCC(N2Cc3cc(Br)ccc3C2=O)C(=O)N1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: N#Cc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Temperature: 120 °C
Reaction time: 19 h

Procedure:
A mechanically stirred mixture of 3-(5-bromo-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (25.2 g, 78 mmol), bis(diphenylphosphino)ferrocene (2.0 g), tris(dibenzylideneacetone)dipalladium (2.0 g) and zinc cyanide (9.4 g, 80 mmol) in DMF (300 mL) was heated to 120° C. and stirred at this temperature for 19 hours. The reaction mixture was cooled to 40° C., and another 9.4 g of zinc cyanide, 2 g of bis(diphenylphosphino)ferrocene and 2 g of tris(dibenzylideneacetone)dipalladium were added. The mixture was stirred at 120° C. for 2 hours, cooled to room temperature and quenched with water (900 mL). The solid was filtered, washed with additional water and air dried overnight. The solid was stirred in hot acetic acid (200 mL) for 20 minutes. The solid was filtered, washed with additional acetic acid, ethyl acetate and hexanes, and air dried to give 30.8 g of crude 2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-carbonitrile as a gray solid; 1H NMR (DMSO-d6) δ 1.99-2.06 (m, 1H), 2.35-2.45 (m, 1H), 2.57-2.63 (m, 1H), 2.86-2.98 (m, 1H), 4.42 (d, J=17.7 Hz, 1H), 4.55 (d, J=17.7 Hz, 1H), 5.15 (dd, J=13.2 Hz, J=5.1 Hz, 1H), 7.91 (d, J=7.8 Hz, 1H), 7.99 (dd, J=7.8 Hz, J=0.9 Hz, 1H), 8.16 (s, 1H), 11.03 (s, 1H).