Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:13]([Si:17](Cl)([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16].N1C=CN=C1.O>C(Cl)Cl>[CH2:22]([Si:17]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:18][CH2:19][CH2:20][CH3:21])[O:1][C:2]1[C:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1)[CH2:23][CH2:24][CH3:25]
Reactant: CCOC(=O)c1ncccc1O
Reactant: CCCC[Si](Cl)(CCCC)CCCC
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CCCC[Si](CCCC)(CCCC)Oc1cccnc1C(=O)OCC
Reaction time: 8 h
Yield: 49.7 %

Procedure:
A mixture of ethyl 3-hydroxypicolinate (15 g, 900 mmol), tributylsilyl chloride (16.23 g, 110 mmol), imidazole (8.0 g, 120 mmol) in methylene chloride was stirred overnight under a nitrogen atmosphere. Water was added and the methylene chloride layer was separated and concentrated in vacuo. Purification on a silica gel column using ethyl acetate-hexane (1:4) as the eluant gave ethyl 3-(tributylsilyloxy)picolinate as a solid (20 g).
Reaction SMILES: CO[C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[NH:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]3[NH:26][CH:27]=[CH:28][C:21]=23)=[O:13])=[CH:5][CH:4]=1.[C:31](C1C=CC=CC=1)(=O)C>>[C:6]1([CH:7]([NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[NH:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]3[NH:26][CH:27]=[CH:28][C:21]=23)=[O:13])[CH3:31])[CH:29]=[CH:30][CH:3]=[CH:4][CH:5]=1
Reactant: CC(=O)c1ccccc1
Reactant: COc1ccc(CNCCNC(=O)c2sccc2Nc2ccnc3[nH]ccc23)cc1
Product: CC(NCCNC(=O)c1sccc1Nc1ccnc2[nH]ccc12)c1ccccc1

Procedure:
This compound was prepared in an analogous manner as 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid [2-(4-methoxy-benzylamino)-ethyl]amide using acetophenone instead of 4-methoxy benzaldehyde. LCMS (ESI) 406 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.53 (1H, br. s.) 10.22 (1H, s) 8.02 (2H, d, J=5.37 Hz) 7.76 (1H, d, J=5.37 Hz) 7.45 (1H, d, J=5.47 Hz) 7.21-7.34 (5H, m) 7.08-7.20 (1H, m) 6.79 (1H, d, J=5.37 Hz) 6.43 (1H, d, J=2.73 Hz) 3.67 (1H, q, J=6.51 Hz) 3.18-3.38 (2H, m) 2.34-2.58 (2H, m) 2.14 (1H, br. s.) 1.19 (3H, d, J=6.64 Hz)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10](Br)=[CH:9][C:8]([CH3:12])=[CH:7][N:6]=1)=[O:4].[CH3:13][O:14][C:15](=[O:18])[CH:16]=[CH2:17].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.O>CCOC(C)=O.[CH2-]C=C.[CH2-]C=C.Cl[Pd+].Cl[Pd+].C1(C)C=CC=CC=1.CC(N(C)C)=O>[CH3:1][O:2][C:3]([C:5]1[C:10]([CH:17]=[CH:16][C:15]([O:14][CH3:13])=[O:18])=[CH:9][C:8]([CH3:12])=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1ncc(C)cc1Br
Reactant: C=CC(=O)OC
Agent: Cl[Pd+]
Agent: C=C[CH2-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)C=Cc1cc(C)cnc1C(=O)OC
Temperature: 115 °C
Reaction time: 18 h
Yield: 80.2 %

Procedure:
3-Bromo-5-methyl-pyridine-2-carboxylic acid methyl ester (1.6 g, 6.945 mmol), methylacrylate (1.50 g, 17.39 mmol), allylpalladium(II) chloride dimer (0.127 g, 0.348 mmol), tri-o-tolylphosphine (0.212 g, 0.695 mmol), water free sodium carbonate (2.211 g, 20.9 mmol), and N,N.dimethylacetamide (4.56 ml) were added to toluene (15 ml) and the reaction mixture was stirred for 18 h at 115° C. in a microwave apparatus. The mixture was diluted with EtOAc, washed with brine, dried over sodium sulfate, and the solvents were evaporated under reduced pressure. The residue was purified by chromatography on silica (Flashmaster, hex to hex/EtOAc 2/3 over 40 min, 20 min hex/EtOAc 2/3) to give the product as off-white solid (1.31 g, 80%). [1H-NMR (DMSO-d6, 600 MHz) δ 8.51 (s, 1H), 8.20 (s, 1H), 8.10 (d, 1H), 6.69 (d, 1H), 3.88 (s, 3H), 3.74 (s, 3H), 2.39 (s, 3H); LCMS RtL=2.753 min; [M+H]+=236.0]
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[CH:8]=1.Cl.C(=O)(O)[O-].[Na+]>O1CCCC1>[S:15]1[CH:16]=[CH:17][C:13]([C:9]2[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=2)[O:6][CH2:5][CH2:4][CH:3]=[O:2])=[CH:14]1
Reactant: COC(CCOc1cccc(-c2ccsc2)c1)OC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=CCCOc1cccc(-c2ccsc2)c1
Reaction time: 4 h
Yield: 72.9 %

Procedure:
0.46 g of the resulting ether compound was dissolved in 5 ml of tetrahydrofuran, and 2 ml of 2N hydrochloric acid was added. The mixture was allowed to stand at room temperature for 4 hours, and then the solution was made basic with an aqueous solution of sodium bicarbonate. The solution was extracted with s ethyl acetate, and the extract was worked up in a customary manner. The product was purified by silica gel column chromatography [hexane / ethyl acetate =20/1→10/1] to give 0.28 g of 3-[3-(3-thienyl)phenoxy]propanal as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([C:6]([N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])=[O:7])=[C:4]([Cl:15])[CH:3]=1.[C:16](=O)([O-])[O-].[K+].[K+].C[Zn]C.ClCCl>CN(C=O)C.C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:15][C:4]1[CH:3]=[C:2]([CH3:16])[CH:14]=[CH:13][C:5]=1[C:6]([N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])=[O:7]
Reactant: O=C([O-])[O-]
Reactant: CCN(CC)C(=O)c1ccc(Br)cc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: C[Zn]C
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCN(CC)C(=O)c1ccc(C)cc1Cl
Temperature: 90 °C
Reaction time: 18 h
Yield: 90 %

Procedure:
To a solution of 4-bromo-2-chloro-N,N-diethylbenzamide from Example 23, Part A (3.10 g, 10.67 mmol) in 50 mL of DMF was added potassium carbonate (3.68 g, 26.7 mmol) and dimethyl zinc (8.0 mL of a 2.0 M solution in toluene, 16.0 mmol). The solution was degassed with a stream of argon and then there was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (175 mg, 0.21 mmol). The reaction mixture was allowed to stir at 90° C. for 18 h. The reaction mixture was allowed to cool and was diluted with ethyl acetate. The organics were washed with water and brine, dried (MgSO4) and concentrated. The residue was purified (ISCO, elution with 0-50% EtOAc/hexane, 30 min) to afford 2.15 g (90%) of the title compound as a colorless oil. LRMS (ESI): 226.2/228.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[N:13]=[C:12]2[C:24]1[N:29]=[C:28]([O:30][C@H:31]2[CH2:38][N:37]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:36][CH2:35][C:32]32[CH2:34][CH2:33]3)[CH:27]=[N:26][CH:25]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1.C1(P(C2CCCCC2)C2C(OC)=CC=C(OC)C=2C2C(OC(C)C)=CC(OC(C)C)=CC=2OC(C)C)CCCCC1>[C:2]1([NH:1][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[N:13]=[C:12]3[C:24]2[N:29]=[C:28]([O:30][C@H:31]3[CH2:38][N:37]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:36][CH2:35][C:32]43[CH2:34][CH2:33]4)[CH:27]=[N:26][CH:25]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC2)[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(Br)cc34)n2)C1
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(OC(C)C)cc(OC(C)C)cc1OC(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CC2)[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(Nc5ccccc5)cc34)n2)C1
Temperature: 70 °C
Yield: 59.6 %

Procedure:
Aniline (0.019 ml, 0.205 mmol), dicyclohexyl(2′,4′,6′-triisopropoxy-3,6-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (brettphos) (5.00 mg, 8.55 μmol), brettphosprecatalyst (7.24 mg, 8.55 μmol), and (4R)-tert-butyl 4-((6-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yl)oxy)-6-azaspiro[2.5]octane-6-carboxylate (0.100 g, 0.171 mmol) were combined in 0.37 mL THF under argon. Lithium bis(trimethylsilyl)amide, 1.0 m solution in THF (0.376 ml, 0.376 mmol) was added. The dark red solution was sealed and heated in a 70° C. bath for 5 h. The reaction was cooled partitioned between saturated aqueous NH4Cl and DCM. The aqueous layer was extracted with DCM 3 times, and the combined organics were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The material was treated with DCM and purified by silica gel chromatography (25 g column) using 0-30% EtOAc/hexane. The product-containing fractions were combined and concentrated to give (4R)-tert-butyl 4-((6-(5-(phenylamino)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yl)oxy)-6-azaspiro[2.5]octane-6-carboxylate (0.061 g, 0.102 mmol, 59.8% yield) as a sticky brown oil. MS (ESI, pos. ion) m/z: 597 (M+1).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH2:5][C:6]([NH2:8])=[O:7].[NH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.O>C1(C)C=CC=CC=1>[N:9]1([CH2:2][CH2:3][O:4][CH2:5][C:6]([NH2:8])=[O:7])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1
Reactant: C1CNCCN1
Reactant: NC(=O)COCCCl
Solvent: O
Solvent: Cc1ccccc1
Product: NC(=O)COCCN1CCNCC1
Yield: 39.5 %

Procedure:
A mixture of 13.15 g of (2-chloroethoxy)acetamide (0.1 mol) and 43 g of anhydrous piperazine (0.5 mol) in 250 ml of toluene is introduced into a round-bottomed flask fitted with a water-cooled condenser and a mechanical stirrer. The mixture is heated at the reflux temperature for 4 hours. The precipitate formed is filtered off while hot and the solvent of the filtrate is evaporated off under reduced pressure to dryness. The evaporation residue is purified by chromatography on silica gel (eluent: 14/5/1 (v/v/v) of dichloromethane/methanol/28% aqueous ammonia solution). 7.4 g of 2-[2-(1-piperazinyl)ethoxy]acetamide are obtained in the form of a yellow oil
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:18]I>CN(C)C=O>[C:1]([O:5][C:6]([N:8]([CH3:18])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CI
Reactant: Cc1cccc(NC(=O)OC(C)(C)C)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(N(C)C(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.5 %

Procedure:
(tert-Butoxy)-N-(6-methyl(2-pyridyl))carboxamide (20.2 g, 102 mmol) dissolved in N,N-dimethylformamide (75 ml) was slowly added to a suspension of sodium hydride (3.67 g, 153 mmol) in DMF (150 ml) at 0° C. The reaction mixture was warmed to room temperature and stirred for 1 h. Methyl iodide (9.5 ml, 153 mmol) was added dropwise at 0° C. After stirring at room temperature for 16 h, the reaction mixture was poured over ice-water and extracted with ethyl acetate. The organic layer was washed with brine, dried with sodium sulfate, filtered, and evaporated under vacuum. The crude product was chromatographed over silica gel to yield 15.3 g (66%) of (tert-Butoxy)-N-methyl-N-(6-methyl(2-pyridyl))carboxamide. NMR 1H Cl3CD δ: 7.50 (t, 1H, J=7.6 Hz), 7.37 (d, 1H, J=7.6 Hz), 6.85 (d, 1H, J=7.6 Hz), 3.38 (s, 3H), 2.48 (s, 3H), 1.50 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([I:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:18])[CH:5]=[C:6]([C:13]([O:15]CC)=[O:14])[NH:7]2.ClC1C=C2C(C(=O)C=C(C(OCC)=O)N2)=C(I)C=1.[OH-].[Na+].ClC1C=C2C(C(=O)C=C(C(O)=O)N2)=C(I)C=1>>[Cl:1][C:2]1[CH:11]=[C:10]([I:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:18])[CH:5]=[C:6]([C:13]([OH:15])=[O:14])[NH:7]2
Reactant: CCOC(=O)c1cc(=O)c2c(Cl)cc(I)cc2[nH]1
Agent: CCOC(=O)c1cc(=O)c2c(I)cc(Cl)cc2[nH]1
Agent: O=C(O)c1cc(=O)c2c(I)cc(Cl)cc2[nH]1
Agent: [Na+]
Product: O=C(O)c1cc(=O)c2c(Cl)cc(I)cc2[nH]1

Procedure:
Treatment of a mixture of ethyl 5-chloro-7-iodo-4-oxo-1,4-dihydroquinoline-2-carboxylate and ethyl 7-chloro-5-iodo-4-oxo-1,4-dihydroquinoline-2-carboxylate (1.0 g) with sodium hydroxide as described in Example 1c, gave a mixture (0.930 g) of 5-chloro-7-iodo-4-oxo-1,4-dihydroquinoline-2-carboxylic acid and 7-chloro-5-iodo-4-oxo-1,4-dihydroquinoline-2carboxylic acid. Chromatography of this mixture (0.150 g) on a reverse phase carbon-18 column gave 5-chloro-7-iodo-4-oxo-1,4-dihydroquinoline-2-carboxylic acid (11 mg), mp 275° C. (dec). δ (360 MHz, DMSO-d6) 6.55 (1H, s, 3-H), 7.62 (1H, d, 6-H), 8.34 (1H, d, 8-H) and 11.91 (1H, bs, NH).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH2:18][C@@H:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)[OH:20])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1.[CH:28]([C:30]1[S:34][C:33](B(O)O)=[CH:32][CH:31]=1)=[O:29].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:27][C:23]1[CH:22]=[C:21]([C@@H:19]([OH:20])[CH2:18][N:10]([CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([C:33]3[S:34][C:30]([CH:28]=[O:29])=[CH:31][CH:32]=3)=[CH:3][CH:4]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:26]=[CH:25][CH:24]=1
Reactant: O=Cc1ccc(B(O)O)s1
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(Br)cc1)C[C@H](O)c1cccc(Cl)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: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N(CCc1ccc(-c2ccc(C=O)s2)cc1)C[C@H](O)c1cccc(Cl)c1
Temperature: 80 °C
Reaction time: 7 h
Yield: 35 %

Procedure:
To a solution of tert-butyl [2-(4-bromophenyl)ethyl][(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]carbamate (500 mg) in 1,2-dimethoxyethane (6 ml) was added 5-formyl-2-thiopheneboronic acid (206 mg), tetrakis(triphenylphosphine)palladium (63 mg) and aqueous solution of sodium carbonate (2M, 1.0 ml), and the mixture was stirred at 80° C. for 7 hours under nitrogen. The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=3/1) to give tert-butyl [(2R)-2-(3-chlorophenyl)-2-hydroxyethyl][2-[4-(5-formyl-2-thienyl)phenyl]ethyl]carbamate (187 mg).
Reaction SMILES: [Na].[CH:2]1([N:7]2[C:11]([NH2:12])=[C:10]([C:13]([NH2:15])=[O:14])[C:9]([CH2:16][CH3:17])=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH2:26][C:27](OCC)=O)[CH:23]=[CH:24][CH:25]=1.Cl>C(O)C.O>[CH:2]1([N:7]2[C:11]3=[N:12][C:27]([CH2:26][C:22]4[CH:23]=[CH:24][CH:25]=[C:20]([O:19][CH3:18])[CH:21]=4)=[N:15][C:13](=[O:14])[C:10]3=[C:9]([CH2:16][CH3:17])[NH:8]2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)Cc1cccc(OC)c1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CCc1[nH]n(C2CCCC2)c2nc(Cc3cccc(OC)c3)nc(=O)c1-2
Temperature: 25 °C
Yield: 55.4 %

Procedure:
Sodium (1.19 g) was dissolved in ethanol (85 mL) and 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (5.7 g, 26 mmol) and then ethyl 3-methoxyphenylacetate (10 g) were added. The reaction mixture was refluxed overnight, cooled to room temperature and the solvent was stripped. Water was added to the residue, followed by 2N HCl and the precipitate which formed was collected by filtration and recrystallized from ethyl acetate to afford 5.08 g of 1-cyclopentyl-3-ethyl-6-(3-methoxyphenylmethyl)pyrazolo[3,4-d]pyrimidin-4-one, m.p. 148°-150° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:19][NH2:20])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:12]=[N:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=1.F[C:22]1[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=1[N+:29]([O-:31])=[O:30].C(N(C(C)C)CC)(C)C>C(#N)C.O>[I:28][C:25]1[CH:26]=[CH:27][C:22]([NH:20][CH2:19][C:5]2[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]3[CH:12]=[N:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=3)=[C:3]([O:2][CH3:1])[CH:4]=2)=[C:23]([N+:29]([O-:31])=[O:30])[CH:24]=1
Reactant: COc1ccc(COc2ccc(CN)cc2OC)cn1
Reactant: O=[N+]([O-])c1cc(I)ccc1F
Solvent: CC#N
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(COc2ccc(CNc3ccc(I)cc3[N+](=O)[O-])cc2OC)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.9 %

Procedure:
To a stirred solution of (3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)methanamine (5.00 g, 18.23 mmol) in acetonitrile (75 mL) was added 1-fluoro-4-iodo-2-nitrobenzene (4.55 g, 17.04 mmol) and diisopropylethylamine (3.30 g, 25.56 mmol). The yellow solution was heated to reflux and stirred. After 4 h, the orange-brown mixture was allowed to cool to room temperature and was diluted with water (150 mL). The resulting bright orange precipitate was isolated by filtration and washed with water. The moist solids were dissolved in dichloromethane, and a small amount of water separated and was removed. The organic phase was dried over magnesium sulfate, filtered, and concentrated to provide 7.10 g (80%) of 4-iodo-N-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-2-nitroaniline as a bright orange solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:13].[CH3:14][N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=2[CH2:23][NH2:24])[CH2:17][CH2:16]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC(N(C)C)=O.CCOC(C)=O.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]>[Cl:13][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:24][CH2:23][C:22]3[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=3[N:18]3[CH2:17][CH2:16][N:15]([CH3:14])[CH2:20][CH2:19]3)[CH:3]=2)[C:8](=[O:12])[NH:7][N:6]=1
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Reactant: CN1CCN(c2ccccc2CN)CC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CN1CCN(c2ccccc2CNc2ccc3c(=O)[nH]nc(Cl)c3c2)CC1

Procedure:
A mixture 6-bromo-4-chloro-2H-phthalazin-1-one (150 mg, 0.58 mmol), 2-(4-methyl-piperazin-1-yl)-benzylamine (132 mg, 0.64 mmol), Pd2(dba)3 (53 mg, 0.058 mmol), rac-BINAP (132 mg, 0.17 mmol) and NaOt-Bu (140 mg, 1.45 mmol) in DMA (6 mL) was heated at 80° C. for 1 h. The mixture was allowed to cool, diluted with EtOAc (25 mL) and washed with water (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/hexanes) yielded the title compound. 4-Chloro-6-[2-(4-methyl-piperazin-1-yl)-benzylamino]-2H-phthalazin-1-one: 46 mg (20.7%): m/z (M+H)=384. 1H-NMR (DMSO-d6) δ: 12.31 (s, 1H), 7.89 (d, 1H), 7.77 (m, 1H), 7.33 (dd, 1H), 7.20 (m, 1H), 7.13 (m, 2H), 7.00 (m, 1H), 6.63 (s, 1H), 4.42 (d, 2H), 2.98 (m, 4H), 2.52 (m, 4H), 2.23 (s, 3H).
Reaction SMILES: [SH2:1].[CH2:2]([O:4][C:5]([NH:7][CH2:8][C:9]#[N:10])=[O:6])[CH3:3].N1C=CC=CC=1.C(N(CC)CC)C>>[CH2:2]([O:4][C:5]([NH:7][CH2:8][C:9]([NH2:10])=[S:1])=[O:6])[CH3:3]
Reactant: S
Reactant: CCOC(=O)NCC#N
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CCOC(=O)NCC(N)=S
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A stream of H2S is passed into a mixture of 27.5 g of ethoxycarbonylaminoacetonitrile (210 mmol), pyridine (21ml, 210 mmol) and triethylamine (14.5 ml, 105 mmol) according to the procedure of Example 23. After stirring for 4 hours at room temperature and washing with water, a beige precipitate is obtained which is filtered off to give 6.6 g of ethoxycarbonylaminothioacetamide, which is a beige powder melting at 116° C.
Reaction SMILES: [CH2:1]([N:8]1[C:18]2[C:13](=[CH:14][C:15]([CH3:19])=[CH:16][CH:17]=2)[C:11](=O)[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>CS(C)=O>[CH2:1]([N:8]1[C:18]2[C:13](=[CH:14][C:15]([CH3:19])=[CH:16][CH:17]=2)[CH2:11][C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2Cc1ccccc1
Agent: NN
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc2c(c1)CC(=O)N2Cc1ccccc1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a mixture of 5-methylisatin (8.05 g, 50 mmol) and K2CO3 (8.16 g, 60 mmol) in DMF (100 mL) was added BnBr (6.5 mL, 55 mmol) dropwise over 2 min. After addition, the resulting mixture was heated in an oil bath at 75° C. for 1.5 h. After cooling to rt, the reaction mixture was poured onto ice/cold water (250 mL), rinsed with H2O (50 mL) and stirred for 5 min. The resulting precipitates were collected by suction filtration and air dried to give 1-benzyl-5-methylisatin as dark red solid. MS ESI 252.0 [M+H]+, calcd for [C16H13NO2+H]+ 252.1. 1-Benzyl-5-methylisatin was suspended in DMSO (100 mL) and cooled to 0° C. Hydrazine hydrate (5 mL) was added dropwise over 5 min. After addition, the resulting clear red solution was heated at 120° C. for 2 h then 140° C. for 5 h. After cooling to rt, it was poured into a 1 L Erlenmeyer flask, rinsed with H2O (50 mL) and ice was added until a total volume about 300 mL. 2 M HCl (50 mL) was added and the mixture was extracted with EtOAc (200 mL×2, then 100 mL), and the organic layer was dried (Na2SO4). Removal of solvents followed by drying under high vacuum for 2 days gave the title compound as a dark red solid (12.53 g, quantitative yield over 2 steps, contained some DMSO residue). 1H NMR (400 MHz, CDCl3) δ 7.35-7.29 (m, 5H), 7.09 (s, 1H), 6.97 (d, J=7.6 Hz, 1H), 6.61 (d, J=8.0 Hz, 1H), 4.91 (s, 2H), 3.60 (s, 2H), 2.31 (s, 3H); MS ESI 238.0 [M+H]+, calcd for [C16H15NO+H]+ 238.1.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:14]=[C:15]([C:18](=[O:26])[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([I:25])[CH:20]=3)[CH:16]=[CH:17][C:4]=2[O:3]1.C1CCCCC1.C(OCC)(=[O:36])C>>[CH3:1][C:2]1([CH3:27])[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N+:9]=2[O-:36])[C:5]2[CH:14]=[C:15]([C:18](=[O:26])[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([I:25])[CH:20]=3)[CH:16]=[CH:17][C:4]=2[O:3]1
Reactant: CC1(C)CC(c2ccccn2)c2cc(C(=O)c3cccc(I)c3)ccc2O1
Reactant: CCOC(C)=O
Solvent: C1CCCCC1
Product: CC1(C)CC(c2cccc[n+]2[O-])c2cc(C(=O)c3cccc(I)c3)ccc2O1

Procedure:
In an analogous manner to that described in the first paragraph of Example 21, from 3,4-dihydro-2,2-dimethyl-6-(3-iodobenzoyl)-4-(2-pyridyl)-2H-1-benzopyran there was obtained 2-[3,4-dihydro-2,2-dimethyl-6-(3-iodobenzoyl)-2H-1-benzopyran-4-yl]pyridine N-oxide of melting point 128°-130° C. (from cyclohexane/ethyl acetate).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[C:11]([NH:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][CH:15]=2)[C:10]([C:24](=[O:32])[NH:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[CH:9][N:8]=1)=[O:5])[CH3:2].O.[OH-].[Na+].Cl>C(#N)C>[CH2:1]([NH:3][C:4](=[O:5])[NH:6][C:7]1[CH:12]=[C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:22][CH:23]=2)[C:10]([C:24](=[O:32])[NH:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[CH:9][N:8]=1)[CH3:2]
Reactant: CCNC(=O)Nc1cc(Nc2ccc(C(=O)OC)cc2)c(C(=O)Nc2cccnc2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CCNC(=O)Nc1cc(Nc2ccc(C(=O)O)cc2)c(C(=O)Nc2cccnc2)cn1
Temperature: 40 °C

Procedure:
Methyl 4-[[2-(ethylcarbamoylamino)-5-(3-pyridylcarbamoyl)-4-pyridyl]amino]benzoate (35 mg, 0.07 mmol) was suspended in acetonitrile (3 mL) and water (3 mL) and treated with NaOH (1 mL, 1 M). The mixture was heated to 40° C. for 40 minutes. The mixture was adjusted to pH ˜6 by addition of dilute aqueous HCl. The mixture was then freeze-dried. The crude product was dissolved in DMSO/water and purified by reverse phase chromatography (12 g Reveleris C18 cartridge, eluting with 0-100% acetonitrile in 0.1% aqueous formic acid). Compound 16 was isolated as a white solid (23 mg, 68%). 1H NMR (400 MHz, DMSO-d6): δ 10.53 (s, 1H), 10.04 (s, 1H), 9.24 (s, 1H), 8.86 (d, J=2.1 Hz, 1H), 8.64 (s, 1H), 8.32 (dd, J=4.7, 1.5 Hz, 1H), 8.12 (ddd, J=8.4, 2.5, 1.5 Hz, 1H), 7.93 (d. J=8.7 Hz, 2H), 7.87 (s, 1H), 7.51 (s, 1H), 7.40 (ddd, J=8.4, 4.7, 0.6 Hz, 1H), 7.36 (d. J=8.8 Hz, 2H), 3.20-3.12 (m, 2H), 1.07 (t, J=7.2 Hz, 3H). [M+H]+ m/z=421.14.