Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[CH:2]1.[CH2:13]([OH:15])C>[OH-].[Na+]>[CH3:13][O:15][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[NH:1][CH:2]=[C:3]2[C:10]([OH:12])=[O:11]
Reactant: CCO
Reactant: O=C(O)c1c[nH]c2ccccc12
Agent: [Na+]
Agent: [OH-]
Product: COc1cccc2c(C(=O)O)c[nH]c12
Yield: 47 %

Procedure:
Preparation of 5 was based on a procedure for the synthesis of indole-3-carboxylic acid reported by R. K. Mackie et al. [supra]. To a 200-mL round bottom flask, 2.369 g of 4 (9.75 mmol) was added. Compound 4 was dissolved in 19 mL of absolute ethanol and 53 mL of 5N aqueous sodium hydroxide, refluxed overnight, and allowed to cool. The ethanol was removed by rotary evaporation, and the resulting solution was extracted with two 25-mL portions of diethyl ether. The aqueous solution was acidified with concentrated hydrochloric acid, and the peach-colored precipitate was collected. Recrystallization from hot aqueous ethanol (50:50 ethanol:water) yielded 0.883 g (47%) of 5 as cream-colored crystals: 1H NMR (acetone-d6) δ 3.95 (s, 3H, OCH3), 6.76 (d, 1H, J=7.3 Hz), 7.10 (app. t, 1H, J=8 Hz), 7.71 (d, 1H, J=8.5 Hz), 7.95 (m, 1H), 11.0 (br s, 1H).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#[N:17]>>[Cl:11][C:8]1[CH:9]=[N:10][C:2]([O:12][C:13]2[CH:20]=[CH:19][CH:18]=[C:15]([C:16]#[N:17])[CH:14]=2)=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: N#Cc1cccc(O)c1
Reactant: O=C(O)c1cc(Cl)cnc1Cl
Product: N#Cc1cccc(Oc2ncc(Cl)cc2C(=O)O)c1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 46 from 2,5-dichloronicotinic acid (Syn. Commun. 1989, 19, 553–9) and 3-hydroxybenzonitrile: 1H-NMR (CDCl3) δ 8.40–8.33 (2H, m), 7.74–7.52 (4H, m), a peak of COOH was not observed; MS (ESI) m/z 229 (M−COOH)−.
Reaction SMILES: [C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[C:11]([CH3:13])[C:10](Br)=[CH:9][N:8]=2)[CH:2]=1.[CH3:21]B1OB(C)OB(C)O1.O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2C=C(C3C(OC)=CC=CC=3OC)C=CC=2)CCCCC1.O>[C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[C:11]([CH3:13])[C:10]([CH3:21])=[CH:9][N:8]=2)[CH:2]=1
Reactant: CB1OB(C)OB(C)O1
Reactant: Cc1cc(-c2cccc(-c3ccccc3)c2)ncc1Br
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1cccc(P(C2CCCCC2)C2CCCCC2)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cnc(-c2cccc(-c3ccccc3)c2)cc1C
Yield: 86.9 %

Procedure:
2-([1,1′-Biphenyl]-3-yl)-5-bromo-4-methylpyridine 11.5 g (35.5 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (5.57 g, 44.3 mmol), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-3-yl)phosphine (1.2 g, 2.84 mmol), Pd2dba3 (0.650 g, 0.709 mmol) and potassium phosphate tribasic monohydrate, 250 mL toluene and 25 mL of water were placed in flask under nitrogen. The reaction mixture was degassed with nitrogen for 20 minutes and heated to reflux for 24 h. After cooling, the organic layer was separated and the aqueous layer extracted 3×50 mL with dichloromethane, dried over sodium sulfate and evaporated. The crude product was chromatographed on silica gel with 5% dichloromethane in hexane to give 8.0 g (87%) of the product. The product was confirmed by NMR and GC/MS.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][C:24]=1[N+:25]([O-])=O)[NH:7][C:8](=[O:21])[C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1)([O-])=O.[O:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=2)[CH:38]=O)[CH2:30][CH2:29]1>>[O:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[CH:36]=[C:37]([C:38]3[NH:25][C:24]4[CH:23]=[CH:22][C:6]([NH:7][C:8](=[O:21])[C:9]5[CH:14]=[CH:13][C:12]([N:15]6[CH2:20][CH2:19][O:18][CH2:17][CH2:16]6)=[CH:11][CH:10]=5)=[CH:5][C:4]=4[N:1]=3)[CH:40]=[CH:41][CH:42]=2)[CH2:30][CH2:29]1
Reactant: O=Cc1cccc(CN2CCOCC2)c1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)c1ccc(N2CCOCC2)cc1
Product: O=C(Nc1ccc2[nH]c(-c3cccc(CN4CCOCC4)c3)nc2c1)c1ccc(N2CCOCC2)cc1

Procedure:
Compound 419 was prepared according to the procedure similar to that described in Scheme III from 3,4-dinitro-N-(4-morpholinobenzoyl)aniline and 3-morpholinomethylbenzaldehyde. [M+H]+ calcd for C29H31N5O3: 498.24; found: 497.98.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[I:12]N1C(=O)CCC1=O.S([O-])([O-])=O.[Na+].[Na+]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([I:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1ccc(F)cc1F
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)O
Agent: O=S([O-])[O-]
Agent: [Na+]
Product: O=C(O)c1cc(I)c(F)cc1F
Temperature: 0 °C
Reaction time: 6 h
Yield: 215.8 %

Procedure:
2,4-Difluorobenzoic acid (100 g, 633 mmol) was dissolved in concentrated sulfuric acid (400 ml), and N-iodosuccinimide (142 g, 601 mol) was added by portions at not more than 5° C. After the completion of the addition, the mixture was stirred at the same temperature for 6 hr. The reaction mixture was poured into ice water (ca. 2400 ml), then saturated aqueous sodium sulfite solution was added, and the mixture was stirred. The precipitated solid was collected by filtration, washed with water, and vacuum dried to give crude crystals (188 g). The crude crystals obtained in the same manner were combined (total amount 568 g), and recrystallized from 50% aqueous ethanol (2600 ml) to give 2,4-difluoro-5-iodobenzoic acid (388 g, yield 68%) as a white solid.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][N:25]([CH2:33][C:34]2[NH:35][CH:36]=[CH:37][N:38]=2)[CH2:26][C:27]2[N:28]([CH3:32])[CH:29]=[CH:30][N:31]=2)=[CH:20][CH:19]=1)[CH3:16])C1C=CC=CC=1>CO.C(O)C.[C].[Pd]>[NH:38]1[CH:37]=[CH:36][N:35]=[C:34]1[CH2:33][N:25]([CH2:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][N:15]([CH3:16])[CH2:14][CH2:13][CH2:12][CH2:11][NH2:10])=[CH:19][CH:20]=1)[CH2:26][C:27]1[N:28]([CH3:32])[CH:29]=[CH:30][N:31]=1
Reactant: CN(CCCCNC(=O)OCc1ccccc1)Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: CN(CCCCN)Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.9 %

Procedure:
The compound (502.6 mg) obtained in Example 103-6 was dissolved in methanol (2.5 ml) and cooled with ice. Then, the solution was added with a suspension of 10% palladium-carbon (251.3 mg) in ethanol (2 ml), followed by stirring at room temperature for 2 hours under a hydrogen atmosphere. After the reaction, the solution was filtrated through Celite and the solvent was then distilled off, thereby obtaining the subject compound (382.4 mg) as a white solid.
Reaction SMILES: [NH2:1][CH:2]([CH3:16])[CH:3]([N+:13]([O-])=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].S(S([O-])=O)([O-])=O.[Na+].[Na+].Cl.S(=O)=O>O1CCOCC1.O>[NH2:13][CH:3]([CH:2]([NH2:1])[CH3:16])[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6]
Reactant: CC(N)C(CC(=O)c1ccccc1)[N+](=O)[O-]
Agent: Cl
Agent: O=S([O-])S(=O)[O-]
Agent: O=S=O
Solvent: C1COCCO1
Solvent: O
Product: CC(N)C(N)CC(=O)c1ccccc1

Procedure:
A suspension of 3.9 g of 4-amino-3-nitro-valerophenone in 35 ml of dioxane and 9 ml of water is heated to the reflux temperature and the resulting solution is treated, in the course of 10 minutes, while boiling, with 14 g of sodium dithionite in 60 ml of water. The reaction mixture is boiled under reflux for a further 15 minutes and 6 N hydrochloric acid is then added dropwise until the pH is 3, a little sulphur dioxide escaping. The pH value is adjusted to 2, the mixture is allowed to react for a few minutes and the organic solvent is then removed under reduced pressure. The residual aqueous suspension is rendered alkaline in the cold and extracted with 5 50 ml portions of chloroform. The combined organic extracts are washed twice with water, dried and filtered and the filtrate is evaporated. 3,4-Diamino-valerophenone is obtained in the form of brown crystals; melting point 106°-107°.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[F:20][C:21]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[CH:25][C:22]=1[CH:23]=O>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:23][C:22]2[CH:25]=[C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[CH:27]=[CH:28][C:21]=2[F:20])[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cc(-c2ccccn2)ccc1F
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cc(-c2ccccn2)ccc1F

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with 2-fluoro-5-(pyridin-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.66 min.; [M+H]+: 420.83 g/mol.
Reaction SMILES: [CH2:1]([O:4][N:5]1[C:11](=[O:12])[N:10]2[CH2:13][CH:6]1[C:7]([CH:17]([CH3:19])[CH3:18])=[CH:8][CH:9]2[C:14]([NH2:16])=O)[CH:2]=[CH2:3].C(ON1C(=O)N2C[C@H]1C(C(C)C)=C[C@H]2C(N)=O)C=C.C(ON1C(=O)N2C[C@H]1C(C)=C[C@H]2C#N)C=C>>[CH2:1]([O:4][N:5]1[C:11](=[O:12])[N:10]2[CH2:13][C@H:6]1[C:7]([CH:17]([CH3:19])[CH3:18])=[CH:8][C@H:9]2[C:14]#[N:16])[CH:2]=[CH2:3]
Reactant: C=CCON1C(=O)N2CC1C(C(C)C)=CC2C(N)=O
Agent: C=CCON1C(=O)N2C[C@H]1C(C(C)C)=C[C@H]2C(N)=O
Agent: C=CCON1C(=O)N2C[C@H]1C(C)=C[C@H]2C#N
Product: C=CCON1C(=O)N2C[C@H]1C(C(C)C)=C[C@H]2C#N

Procedure:
The title compound was prepared from 2S,5R)-6-(allyloxy)-4-isopropyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-ene-2-carboxamide (Intermediate 43, 143.9 mg, 0.54 mmol) following the procedure described for Intermediate 23. The desired product was obtained as a colorless oil (114 mg, 85%).
Reaction SMILES: [F:1][C:2]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[C:10](=[O:11])[NH:9][C:8]2[CH:12]=[N:13][N:14]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:7]=2[CH:6]=1.[H-].[Na+].[CH3:30]I>CN(C)C=O.C(OCC)(=O)C.O>[F:1][C:2]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[C:10](=[O:11])[N:9]([CH3:30])[C:8]2[CH:12]=[N:13][N:14]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:20])[CH3:21])[C:7]=2[CH:6]=1
Reactant: C[Si](C)(C)CCOCn1ncc2[nH]c(=O)c(Oc3ccc(F)cc3F)cc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1c(=O)c(Oc2ccc(F)cc2F)cc2c1cnn2COCC[Si](C)(C)C
Reaction time: 0.5 h

Procedure:
To a 0° C. solution of 6-(2,4-difluorophenoxy)-1-(2-trimethylsilanyl-ethoxymethyl)-1,4-dihydro-pyrazolo[4,3-b]pyridin-5-one (98 mg, 0.249 mmol) in dimethylformamide (1 mL) was added sodium hydride (60% dispersion in oil, Aldrich) (15 mg, 1.5 eq) and the resulting mixture was stirred at for 30 minutes, after which methyl iodide (25 μL, 1.5 eq) was added and the mixture was stirred additional 1 hour with warming from 0° C. to room temperature. The reaction mixture was diluted with ethyl acetate (35 mL) and water (25 mL). The organic layer was separated, washed with water (2×25 mL) and brine (1×25 mL), dried over magnesium sulfate, filtered and concentrated to give the title compound as a tan powder (118 mg, (M+H)+=408).
Reaction SMILES: [C:1]([N:6]([CH2:23][C:24]1[CH:36]=[CH:35][C:27]([O:28][CH2:29][C:30]([O:32]CC)=[O:31])=[C:26]([CH3:37])[CH:25]=1)[C:7]1[CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[CH:10]=[CH:11][CH:12]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CO.O1CCCC1>[C:1]([N:6]([CH2:23][C:24]1[CH:36]=[CH:35][C:27]([O:28][CH2:29][C:30]([OH:32])=[O:31])=[C:26]([CH3:37])[CH:25]=1)[C:7]1[CH:8]=[C:9]([C:13]2[CH:14]=[CH:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=2)[CH:10]=[CH:11][CH:12]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)N(Cc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCC(=O)N(Cc1ccc(OCC(=O)O)c(C)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.9 %

Procedure:
To a solution of ethyl [4-({butyryl[4′-(trifluoromethyl)-1,1′-biphenyl-3-yl]amino}methyl)-2-methylphenoxy]acetate (40 mg, 0.078 mmol) in methanol (2 mL) and tetrahydrofuran (2 mL), was added 2M sodium hydroxide (1 mL). After stirring for 1 h at room temperature the solvent was removed in vacuo and the residue acidified with 2M HCl, before extraction into ethyl acetate (2×15 mL). The organic solution was dried (MgSO4) and the solvents removed in vacuo to afford the title compound as a white solid (28 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24].C(=O)([O-])[O-].[K+].[K+].[CH2:35](Br)[CH2:36][OH:37]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:35][CH2:36][OH:37])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24]
Reactant: OCCBr
Reactant: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(O)c(OC)cc23)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(OCCO)c(OC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 22 %

Procedure:
N-{2-Chloro-4-[(7-hydroxy-6-methoxy-4-quinazolinyl)oxy]phenyl}-N′-propylurea (50 mg), potassium carbonate (30 mg), and ethylenebromohydrin (44 μl) were dissolved in N,N-dimethylformamide (4 ml), and the solution was stirred at room temperature for 3 hr. The solvent was removed by distillation under the reduced pressure. Water was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by chromatography on silica gel by development with chloroform/methanol to give 12 mg (yield 22%) of the title compound.
Reaction SMILES: [C:1]([C@:5]1([CH3:34])[C@@H:18]2[C@@:9]3([CH2:20][CH2:19][C@:16]4([CH2:17]2)[C@@:11]25[C:27]6[C:22](=[CH:23][CH:24]=[C:25]([OH:29])[C:26]=6[O:28][C@@H:10]32)[CH2:21][C@H:15]4[N:14]([CH2:30][CH:31]2[CH2:33][CH2:32]2)[CH2:13][CH2:12]5)[O:8][CH2:7][O:6]1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:41](Br)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>CC(C)=O>[CH2:41]([O:29][C:25]1[C:26]2[O:28][C@H:10]3[C@@:9]45[CH2:20][CH2:19][C@:16]6([CH2:17][C@@H:18]4[C@:5]([C:1]([CH3:4])([CH3:2])[CH3:3])([CH3:34])[O:6][CH2:7][O:8]5)[C@@:11]43[CH2:12][CH2:13][N:14]([CH2:30][CH:31]3[CH2:32][CH2:33]3)[C@@H:15]6[CH2:21][C:22]([C:27]=24)=[CH:23][CH:24]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)[C@@]1(C)OCO[C@]23CC[C@@]4(C[C@@H]21)[C@H]1Cc2ccc(O)c5c2[C@@]4(CCN1CC1CC1)[C@H]3O5
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)[C@@]1(C)OCO[C@]23CC[C@@]4(C[C@@H]21)[C@H]1Cc2ccc(OCc5ccccc5)c5c2[C@@]4(CCN1CC1CC1)[C@H]3O5
Temperature: 25 °C
Reaction time: 24 h
Yield: 55.2 %

Procedure:
To a suspension of compound 3 (1.0 g, 2.15 mMol) and K2CO3 (0.88 g, 6.45 mMol) in acetone (10 ml) was added benzyl bromide (0.31 mL, 2.15 mMol). The resulting suspension was stirred at ambient temperature for 24 h. All volatiles were removed by vacuum distillation. The crude product was purified by column chromatography on silica to give 0.66 g of the title compound 7 (54.5% yield) in a purity of 96.9% as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])[CH:2]=1.O[N:13]1[C:17](=[O:18])[CH2:16][CH2:15][C:14]1=[O:19].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CN(C=O)C>[CH2:16]1[C:17](=[O:18])[N:13]([O:10][C:9](/[CH:8]=[CH:7]/[C:3]2[CH:4]=[CH:5][CH:6]=[N:1][CH:2]=2)=[O:11])[C:14](=[O:19])[CH2:15]1
Reactant: O=C(O)C=Cc1cccnc1
Reactant: O=C1CCC(=O)N1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(/C=C/c1cccnc1)ON1C(=O)CCC1=O

Procedure:
A solution of 3-(3-pyridyl)acrylic acid (500 mg: commercially available from Aldrich Chemical Company), N-hydroxysuccinimide (463 mg), and EDCl (707 mg) in methylene chloride (20 mL) and DMF (10 mL) was stirred at ambient temperature for 18 hours. The product was isolated as described in Example 3a to yield 740 mg of the title compound as a white solid. MS (Cl/NH3) m/e 247 (M+H)+. 1H NMR(CDCl3, 300 MHz) δ2.87 (br s,4H), 7.15 (d,J=16 Hz,1H), 7.48-7.53 (m,1H), 8.02 (d,1H), 8.31 (dt,J=9 Hz,1H), 8.66 (dd,J=6 Hz,1H), 8.99 (d,J=2 Hz,1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][NH:8][C@@H:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]1)=[O:4].C(N(CC)CC)C.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>C(Cl)Cl>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][N:8]([S:33]([C:30]2[CH:29]=[CH:28][C:27]([O:26][CH3:25])=[CH:32][CH:31]=2)(=[O:35])=[O:34])[C@@H:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]1)=[O:4]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)[C@@H]1CCN[C@@H](C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1CCN(S(=O)(=O)c2ccc(OC)cc2)[C@@H](C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred, cold (0° C.) solution of (2R,4R)-piperidine-2,4-dicarboxylic acid 2-tert-butyl ester 4-methyl ester (2.7 g, 11.1 mmol) and triethylamine (4.6 ml, 33.3 mmol) in 30 mL of methylene chloride was added 4-methoxy-benzenesulfonyl chloride (2.3 g, 11.1 mmol). The mixture was warmed to ambient temperature and stirred for 4 hours. The reaction was quenched by the addition of aqueous ammonium chloride and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, and the organic mixture was dried over sodium sulfate. After filtration and concentration of the filtrate, the resulting crude product was purified by silica gel chromatography (elution with 3:8 ethyl acetate/hexanes) to provide (2R,4R)-1-(4-methoxy-benzenesulfonyl)-piperidine-2,4-dicarboxylic acid 2-tert-butyl ester 4-methyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:22])[N:7]3[CH2:14][CH2:13][C:12](=[CH:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:8]3=[N:9][C:10]=2[CH:11]=1.[C:23]1(=[O:33])[O:28][C:26](=[O:27])[C:25]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]12>O1CCCC1>[CH:15](=[C:12]1[C:8]2=[N:9][C:10]3[CH:11]=[C:2]([NH:1][C:23]([C:24]4[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=4[C:26]([OH:28])=[O:27])=[O:33])[CH:3]=[CH:4][C:5]=3[C:6](=[O:22])[N:7]2[CH2:14][CH2:13]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Nc1ccc2c(=O)n3c(nc2c1)C(=Cc1ccccc1)CC3
Solvent: C1CCOC1
Product: O=C(O)c1ccccc1C(=O)Nc1ccc2c(=O)n3c(nc2c1)C(=Cc1ccccc1)CC3
Reaction time: 14 h
Yield: 52.9 %

Procedure:
6-amino-3-benzylidene-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazoline-9-one (2 g) was reacted with phthalic anhydride (4.6 g) in tetrahydrofuran (150 ml) under stirring at the reflux temperature for 14 hours. After cooling the precipitate was filtered and washed with tetrahydrofuran and then with water to give 1.6 g of 2-[N-(3-benzylidene-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-6-yl)-aminocarbonyl]-benzoic acid, m.p. 302°-308° C.,
Reaction SMILES: Cl.[CH2:2]([NH:9][OH:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:18][C:19]([NH:21][C:22]1[C:39]([OH:40])=[C:38]2[C:25]([CH2:26][CH:27]3[C:36]([C:37]2=[O:41])=[C:35]([OH:42])[C:34]2([OH:43])[CH:29]([CH:30]([N:49]([CH3:51])[CH3:50])[C:31]([OH:48])=[C:32]([C:45]([NH2:47])=[O:46])[C:33]2=[O:44])[CH2:28]3)=[C:24]([N:52]([CH3:54])[CH3:53])[CH:23]=1)=[O:20]>CN1C(=O)N(C)CCC1.C(#N)C>[CH2:2]([N:9]([OH:10])[CH2:18][C:19]([NH:21][C:22]1[C:39]([OH:40])=[C:38]2[C:25]([CH2:26][C@@H:27]3[C:36]([C:37]2=[O:41])=[C:35]([OH:42])[C@@:34]2([OH:43])[C@H:29]([C@H:30]([N:49]([CH3:51])[CH3:50])[C:31]([OH:48])=[C:32]([C:45]([NH2:47])=[O:46])[C:33]2=[O:44])[CH2:28]3)=[C:24]([N:52]([CH3:53])[CH3:54])[CH:23]=1)=[O:20])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CN(C)c1cc(NC(=O)CBr)c(O)c2c1CC1CC3C(N(C)C)C(O)=C(C(N)=O)C(=O)C3(O)C(O)=C1C2=O
Reactant: ONCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Solvent: CC#N
Product: CN(C)c1cc(NC(=O)CN(O)Cc2ccccc2)c(O)c2c1C[C@H]1C[C@H]3[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]3(O)C(O)=C1C2=O
Yield: 36.8 %

Procedure:
The compound of the example is prepared by the procedure of Example 1 using 3 g of N-benzylhydroxylamine hydrochloride, 2 g of sodium carbonate, and 0.8 g of 9-(2-bromo-acetylamino)-4,7-bis-dimethylamino-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydro-naphthacene-2-carboxylic acid amide in 10 ml DMPU and 3 ml acetonitrile to give 0.315 g of the product.
Reaction SMILES: CO[C:3](=[O:27])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:11]=[C:12]3[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])=[N:17][NH:16][C:13]3=[N:14][CH:15]=2)[CH:5]=1.[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH3:26][O:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:18]1[C:12]2[C:13](=[N:14][CH:15]=[C:10]([C:6]3[CH:5]=[C:4]([C:3]([N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[O:27])[CH:9]=[CH:8][CH:7]=3)[CH:11]=2)[NH:16][N:17]=1
Reactant: COC(=O)c1cccc(-c2cnc3[nH]nc(-c4ccccc4OC)c3c2)c1
Reactant: C1CCNC1
Product: COc1ccccc1-c1n[nH]c2ncc(-c3cccc(C(=O)N4CCCC4)c3)cc12
Temperature: 90 °C
Reaction time: 16 h
Yield: 66.3 %

Procedure:
3-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-benzoic acid methyl ester (30 mg, 83 μmol) was dissolved in pyrrolidine (0.35 ml, 4.15 mmol) and the mixture was stirred at 90° C. for 16 h. The mixture was then concentrated and the crude product purified by flash silica gel chromatography using a gradient of 10% v/v of methanol in ethyl acetate to afford {3-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-pyrrolidin-1-yl-methanone as a yellow solid (22 mg, 55 μmol, 67% yield). 1H-NMR (500 MHz, d6-MeOH) δ 8.82 (d, 1H), 8.39 (d, 1H), 7.83 (t, 1H), 7.79 (td, 1H), 7.66 (dd, 1H), 7.55-7.59 (m, 2H), 7.48 (ddd, 1H), 7.20 (d, 1H), 7.11 (dt, 1H), 3.88 (s, 3H), 3.63 (t, 2H), 3.52 (t, 2H), 2.02 (m, 2H), 1.92 (m, 2H). MS: m/z 399 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:32][CH:33]=C)[CH:10]([C:21]2[N:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:24]=[N:23][CH:22]=2)[O:11][C:12](=[O:20])[NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[O:35]1CCCC1.I([O-])(=O)(=O)=O.[Na+].ClCCl.C(OCC)(=O)C>C(OCC)C.O.[Os](=O)(=O)(=O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:32][CH:33]=[O:35])[CH:10]([C:21]2[N:25]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:24]=[N:23][CH:22]=2)[O:11][C:12](=[O:20])[NH:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C=CCC(c1ccc(Cl)c(Cl)c1)C(OC(=O)Nc1ccccc1)c1cnnn1-c1ccccc1
Reactant: C1CCOC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: O
Product: O=CCC(c1ccc(Cl)c(Cl)c1)C(OC(=O)Nc1ccccc1)c1cnnn1-c1ccccc1
Yield: 65 %

Procedure:
To a stirred solution of 5-[(1RS,2SR)-2-(3,4-dichlorophenyl)-1-phenylcarbamoyloxy-4-pentenyl]-1-phenyl-1,2,3-(1H)-triazole (1.0 g) in diethyl ether (4 mL), water (4 mL), and tetrahydrofuran (2 mL) was added a solution of 0.16M osmium tetroxide in water (0.22 mL). After 5 minutes sodium periodate (0.96 g) was added portionwise. After 2 hours at room temperature water was added to the reaction mixture until most of the solids dissolve. The mixture was extracted with ethyl acetate (2×50 mL); the combined organic layers dried, filtered, and the solvent evaporated to yield crude product as an oil. Chromatography, with dichloromethane:ethyl acetate (9:1) as the eluent gave the title compound 0.65 g (65%) as a white solid; NMR: 3.12 (d,2), 3.71-3.75 (m,1), 5.84 (d,1) 6.8 (dd,1), 7.03 (t,1), 7.17-7.57 (m,11), 8.01 (s,1), 9.54 (s,1); MS (CI, CH4): 495(M+1).