Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH3:25][C:26]1([O:29][CH2:28]1)[CH3:27].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[N:15]([CH2:25][C:26]([OH:29])([CH3:28])[CH3:27])[N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Reactant: CC1(C)CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(O)Cn1nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn2c1=O
Temperature: 85 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
To a solution of 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (20 mg, 0.056 mmol), prepared as described in Example 1, in 0.6 mL of DMF was added isobutylene oxide (4.0 mg, 0.056 mmol), followed by K2CO3 (15.5 mg, 0.112 mmol). The mixture was heated to 85° C. After stirring overnight, the reaction was allowed to cool to RT The reaction mixture was filtered (to remove excess of K2CO3). The collected solution was concentrated under reduced pressure. The crude product was purified by reverse phase HPLC to give the title compound, 7,8-bis(4-chlorophenyl)-2-(2-hydroxy-2-methylpropyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (18.4 mg, 77% yield) as a yellow oil. MS [M+H]+: found 429; 1H NMR (CDCl3, 400 MHz) δ 8.28 (s, 1H), 7.39-7.27 (m, 6H), 7.16-7.12 (m, 2H), 4.16 (s, 2H), 4.00 (s, 1H), 1.34 (s, 6H).
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[N+:19]([O-])=O)(=[O:3])[CH3:2].N[C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[CH:26][C:27]([CH3:33])=[N:28]2>C(O)C>[C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[NH:19][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[CH:26][C:27]([CH3:33])=[N:28]2)(=[O:3])[CH3:2]
Reactant: CCn1nc(-c2ccccc2)c(C(C)=O)c([N+](=O)[O-])c1=O
Reactant: Cc1ccc2c(N)cccc2n1
Solvent: CCO
Product: CCn1nc(-c2ccccc2)c(C(C)=O)c(Nc2cccc3nc(C)ccc23)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.7 %

Procedure:
To a stirred solution of 100 mg (0.348 mmol) of 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417) in ethanol (5 mL), 5-amino-2-methylquinoline (83 mg, 0.522 mmol) was added. The resulting mixture was stirred at room temperature during three hours and the final product was collected by filtration and washed with diethylether to yield the title compound (80 mg, 57.6% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1C1NC(Br)=CN=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+]>O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(Br)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC1
Temperature: 90 °C
Reaction time: 16 h
Yield: 76.2 %

Procedure:
2,6-(bis-pinocolato)diboranonaphthalene (0.501 g), 2-(5-bromo-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.885 g), and NaHCO3 (0.562 g) were dissolved in a mixture of 1,2-dimethoxyethanedichloromethane (15 mL) and water (5 mL). The solution was degassed with nitrogen, and Pd(PPh3)4 (0.0935 g) was added. The reaction mixture was stirred at 90° C. for 16 hours and evaporated under vacuum. Solid was dissolved in DCM (20 mL) and extracted twice with water and once with brine. Solution was evaporated, recrystallized from ethyl acetate, and dried under vacuum, giving 2-(5-{6-[2-(1′-carboxylic acid tert-butyl ester-pyrrolidin-2-yl)-3H-imidazol-4-yl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.365 g, 46%) as a white solid.
Reaction SMILES: FC1C=CC(S(CCC)(=O)=O)=CC=1C#C[Si](C)(C)C.[Cl:20][C:21]1[CH:32]=[CH:31][C:24]([O:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])=[C:23]([C:33]#[CH:34])[CH:22]=1.Br[C:36]1[CH:41]=[C:40]([S:42]([CH2:44][CH2:45][CH3:46])=[O:43])[CH:39]=[CH:38][C:37]=1[CH3:47]>>[Cl:20][C:21]1[CH:32]=[CH:31][C:24]([O:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])=[C:23]([C:33]#[C:34][C:36]2[CH:41]=[C:40]([S:42]([CH2:44][CH2:45][CH3:46])=[O:43])[CH:39]=[CH:38][C:37]=2[CH3:47])[CH:22]=1
Reactant: CCCS(=O)c1ccc(C)c(Br)c1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC
Agent: CCCS(=O)(=O)c1ccc(F)c(C#C[Si](C)(C)C)c1
Product: CCCS(=O)c1ccc(C)c(C#Cc2cc(Cl)ccc2OCC(=O)OC)c1

Procedure:
Following the general method as outlined in Intermediate 107, starting from methyl (4-chloro-2-ethynylphenoxy)acetate (Intermediate 220) and 2-bromo-1-methyl-4-(propylsulfinyl)benzene (Intermediate 219), the title compound was obtained as a yellow oil after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)[C:5]([OH:7])=[O:6].[C:16]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)[C:5]([O:7][CH3:16])=[O:6]
Reactant: Nc1cc(C(=O)O)ccc1N1CCCC1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(=O)c1ccc(N2CCCC2)c(N)c1

Procedure:
3-Amino-4-(1-pyrrolidinyl)benzoic acid.hemioxalate (5.0 g) is suspended in methanol (40 ml) and thereto is added p-toluenesulfonic acid (2.5 g), and the mixture is refluxed for 3 hours. Mathanol is distilled off under reduced pressure, and the residue is extracted with ethyl acetate (100 ml). The extract is washed with 5% aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution in this order, dried over anhydrous sodium sulfate, and ethyl acetate is distilled off to give methyl 3-amino-4-(1-pyrrolidinyl)benzoate (3.4 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][C:22]=1[F:30])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CC=CC=1>ClCCl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:24]1[CH:25]=[CH:26][C:21]([O:20][CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[C:22]([F:30])[CH:23]=1)[N:6]=[CH:5]2
Reactant: OB(O)c1ccc(OCc2ccccc2)c(F)c1
Reactant: COc1c(Br)ccc2[nH]ncc12
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1c(Br)ccc2c1cnn2-c1ccc(OCc2ccccc2)c(F)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 51.6 %

Procedure:
A mixture of 5-bromo-4-(methyloxy)-1H-indazole (D19) (0.670 g, 2.95 mmol), 4-benzyloxy-3-fluorobenzeneboronic acid (1.45 g, 5.90 mmol), copper (II) acetate (0.804 g, 4.43 mmol), pyridine (0.447 mL, 5.90 mmol) and powdered 4A molecular sieves (3 g) in dichloromethane (30 mL) was stirred in an air atmosphere at room temperature. After 4 days, the mixture was diluted with ethyl acetate and filtered through celite. The filtrate was washed with water, dried (Na2SO4) and concentrated. Chromatography on silica gel (0-30% ethyl acetate in hexane and diethyl ether in hexane) gave the title compound (D20) (0.65 g)
Reaction SMILES: FC1C(N2CCNCC2)=C[C:9]2[NH:8][CH:7]=[C:6]3[C:18](=O)N(C4C=CC=CC=4)N=[C:5]3[C:4]=2[CH:3]=1.F[C:29]1[C:30]([F:49])=[CH:31][C:32]2[C:33]3[C:34]([C:39](=[O:48])[N:40]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[N:41]=3)=[CH:35][NH:36][C:37]=2[CH:38]=1.CC1CC(C)CNC1>>[CH3:18][CH:6]1[CH2:5][CH:4]([CH3:3])[CH2:9][N:8]([C:29]2[C:30]([F:49])=[CH:31][C:32]3[C:33]4[C:34]([C:39](=[O:48])[N:40]([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)[N:41]=4)=[CH:35][NH:36][C:37]=3[CH:38]=2)[CH2:7]1
Reactant: O=c1c2c[nH]c3cc(F)c(F)cc3c-2nn1-c1ccccc1
Reactant: O=c1c2c[nH]c3cc(N4CCNCC4)c(F)cc3c-2nn1-c1ccccc1
Agent: CC1CNCC(C)C1
Product: CC1CC(C)CN(c2cc3[nH]cc4c(=O)n(-c5ccccc5)nc-4c3cc2F)C1

Procedure:
The title compound was prepared following the procedure described in the synthesis of 28a using 27a and 3,5-dimethylpiperidine. 1H-NMR (DMSO-d6) δ (ppm): 0.99 (6H, d, J=6.33 Hz), 1.80 (4H, br), 2.47 (2H, t, J=8.62 Hz), 3.46 (2H, brd, J=11.81 Hz), 7.13 (1H, m), 7.26 (1H, d, J=7.97 Hz), 7.40 (2H, t, J=7.69 Hz), 7.79 (1H, d, J=13.18 Hz), 8.19 (2H, d, J=7.69 Hz), 8.65 (1H, s). m/z 391.5 (MH+).
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].Cl.C(OCC)(=O)C>O1CCOCC1.[OH-].[Na+]>[CH2:1]([S:3]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)Cl
Reactant: NCCCCCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)NCCCCCC(=O)O
Temperature: 25 °C
Yield: 38.3 %

Procedure:
A solution of ethanesulfonyl chloride (3.9 ml, 41.1 mmol) in dioxane (10 ml) was added to a solution of 6-aminohexanoic acid (2 g, 15.2 mmol) in 1N NaOH (56 ml) and dioxane (10 ml), while stirring at 0° C.-5° C. The pH of the reaction mixture was adjusted to 8-9 by addition of 25% sodium hydroxide solution. The mixture was allowed to warm to room temperature and stirred for 30 minutes. Further 25% NaOH solution was added to adjust the pH to about 11. After 3.5 h 1N hydrochloric acid (15 ml) and ethyl acetate (60 ml) were added. The organic layer was dried over sodium sulfate and concentrated. The residue was triturated with a mixture of diethyl ether (5 ml) and hexane (15 ml). The solid was collected by filtration and dried affording 1.3 g of the title compound (40% yield).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[CH:25][C:24](Cl)=[CH:23][CH:22]=3)[C@H:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:36][O:37][CH2:38][CH2:39][NH2:40].C1(C2C=CC=CC=2)C=CC=CC=1P(C1CCCCC1)C1CCCCC1>>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[CH:25][C:24]([NH:40][CH2:39][CH2:38][O:37][CH3:36])=[CH:23][CH:22]=3)[C@H:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: COCCN
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](c2ccc(Cl)cc2)[C@H](c2ccccc2)C1
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Product: COCCNc1ccc([C@H]2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)C[C@H]2c2ccccc2)cc1

Procedure:
The title compound, MS: m/e=551.1 (M+), was prepared in accordance with the general method of example 10 from rac-cis-(3,5-bis-trifluoromethyl-phenyl)-[4-(4-chloro-phenyl)-3-phenyl-piperidin-1-yl]-methanone, 2-methoxy-ethylamine and biphenyl-2-yl-dicyclohexyl-phosphane as ligand.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH2:12]O)=[CH:3]1.C(Br)(Br)(Br)[Br:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C>[Br:15][CH2:12][CH2:11][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:2]([CH3:1])[CH:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: Cn1cc(CCO)c2ccccc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: Cn1cc(CCBr)c2ccccc21
Temperature: 0 °C
Yield: 73 %

Procedure:
To a solution of 1-methyl-3-(2-hydroxyethyl)indole (4.00 g,0.023 mol) in 50 mL of acetonitrile at -20° C. under Ar was added a solution of CBr4 (10.16 g, 0.031 mol) in 25 mL of acetonitrile, followed by a solution of triphenylphosphine (8.00 g, 0.031 mol) in 125 mL of acetonitrile. The mixture was stirred and allowed to warm to 0° C. over 2 h. The resulting mixture was evaporated and the residue was chromatographed (SiO2 /hexane, then ethyl acetate-hexane=1:4) to give the product (4.00 g, 74%) as a brown oil: IR (neat) 2940, 1617, 1552 cm-1 ; 1Hnmr (200 MHz, CDCl3) δ 7.58 (d, J=7.6 Hz, 1H), 7.33-7.09 (m, 3H), 6.95 (s, 1H), 3.77 (s, 3H), 3.62 (t, J=7.9 Hz, 2 H), 3.32 (t, J=7.7 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[OH:15]O>C(O)(=O)C.O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[N:8]=[CH:7][C:6]([OH:15])=[CH:5]2
Reactant: OO
Reactant: O=[N+]([O-])c1cc(F)cc2cccnc12
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1cc(F)cc2cc(O)cnc12
Temperature: 70 °C
Reaction time: 5 h

Procedure:
A solution of 6-fluoro-8-nitro-quinoline (900 mg, 4.7 mmol) in acetic acid (10 ml) was treated at room temperature with hydrogen peroxide (30% in water (1.6 ml), then it was stirred at 70° C. for 5 hours. For the workup, the reaction mixture was cooled and poured into ice-water. The precipitate was filtered, washed with water, collected and dried. 6-Fluoro-8-nitro-quinolin-3-ol was obtained as a brown solid (285 mg, 29%); (calculated) C9H5FN2O3 [208.2]; (found) [M−H]−=207.
Reaction SMILES: [Mg].[CH2:2](Cl)[CH:3]=[C:4]([CH3:6])[CH3:5].[CH3:8][C:9]([CH3:14])=[CH:10][C:11](Cl)=[O:12]>O1CCCC1.CC(C)=CCCl>[CH3:5][C:4]([CH3:6])([C:11](=[O:12])[CH:10]=[C:9]([CH3:14])[CH3:8])[CH:3]=[CH2:2]
Reactant: CC(C)=CCCl
Reactant: CC(C)=CC(=O)Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: C=CC(C)(C)C(=O)C=C(C)C
Reaction time: 3 h

Procedure:
3 g of 3-methyl-but-2-enyl chloride (prenyl chloride) were added, under stirring, to a suspension of magnesium turnings (20 g; 0.83 M) in 100 ml of absolute tetrahydrofurane (THF). After initiation of the reaction, there were still added 900 ml of THF and the whole mixture was then cooled to -5°. A solution of 80 g of prenyl chloride in 400 ml of THF was then added to the above mixture which was finally kept at 10° for 3 hours. After cooling to 0°, a solution of 83 g. (0.7 M) of 3-methyl-but-2-en-1-oyl chloride in 350 ml of THF was added thereto and, after having been kept at room temperature for 3 further hours, the reaction mixture was poured onto ice-water. After evaporation of the volatile parts (THF) under reduced pressure, the concentrated residue was extracted twice with diethyl ether and the combined organic extracts washed with water, then neutralized with sodium hydrogencarbonate, dried and concentrated. The crude material thus obtained was finally distilled through a VIGREUX column to yield 55.0 g of 3,3,6-trimethyl-hepta-1,5-dien-4-one having b.p. 70°-75°/11 Torr.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10][C:11]2[NH:12][C:13]([CH3:30])=[C:14]([C:26]([O:28][CH3:29])=[O:27])[CH:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=3)[N:16]=2)=[CH:5][CH:4]=1.[C:31](Cl)(=[O:34])[CH2:32][CH3:33].N1C=CC=CC=1>ClCCl.CCOCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10][C:11]2[N:16]([C:31](=[O:34])[CH2:32][CH3:33])[CH:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=3)[C:14]([C:26]([O:28][CH3:29])=[O:27])=[C:13]([CH3:30])[N:12]=2)=[CH:5][CH:4]=1
Reactant: CCC(=O)Cl
Reactant: COC(=O)C1=C(C)NC(SCc2ccc(OC)cc2)=NC1c1cccc([N+](=O)[O-])c1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOCC
Product: CCC(=O)N1C(SCc2ccc(OC)cc2)=NC(C)=C(C(=O)OC)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1,4-Dihydro-2-[[(4-methoxyphenyl)methyl]thio]-6-methyl-4-(3-nitrophenyl)-5-pyrimidinecarboxylic acid, methyl ester (1.52 g., 3.5 mmole) in 15 ml of dichloromethane is cooled under argon to 0°-5° C. and treated with propionyl chloride (0.43 g., 4.7 mmole) and pyridine (0.55 g., 7.0 mmole). The mixture is then allowed to stir at room temperature for 3 hours, diluted with ether and the salt is filtered. The filtrate is washed with water, 1N hydrochloric acid, water, aqueous sodium bicarbonate, water and saturated brine. The aqueous fractions are back extracted with fresh ether. The combined organic solutions are dried (magnesium sulfate) and concentrated in vacuo to give 1.6 g. of a viscous oily product.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4](I)[CH:3]=1.[C:10]([OH:15])(=[O:14])[C:11]([CH3:13])=O.C1N2CCN(CC2)C1>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[CH:13]=[C:11]([C:10]([OH:15])=[O:14])[NH:8][C:5]2=[CH:6][N:7]=1
Reactant: Nc1cnc(Cl)cc1I
Reactant: CC(=O)C(=O)O
Agent: [Pd+2]
Agent: C1CN2CCN1CC2
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Temperature: 107 °C

Procedure:
Route A: To a solution of 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester (Preparation 17, 1.78 g, 7.9 mmol) in ethanol (70 mL) was added sodium hydroxide solution (5.2 mL, 2M, 10.3 mmol) and the mixture heated under reflux for 2 h. The solvent was removed in vacuo and the solid dissolved in water (150 mL) and acidified to pH 4 with acetic acid to give the title compound as a brown solid that was isolated by filtration. δH (CD3OD): 7.13 (1H, s), 7.68 (1H, s), 8.58 (1H, s); m/z (ES+)=197 [M+H]+. Route B: A mixture of 6-chloro-4-iodopyridin-3-ylamine (Preparation 106, 0.33 g, 1.30 mmol), pyruvic acid (0.27 mL, 3.89 mmol), DABCO (0.44 g, 3.89 mmol) and palladium acetate (0.015 g, 0.07 mmol) in dry DMF was stirred vigorously and degassed with argon for 15 min. The reaction mixture was heated to 107° C. for 5 h. The reaction mixture was allowed to cool to rt and stirred for 16 h. The volatiles were removed under reduced pressure and the residue partitioned between ethyl acetate (100 mL) and water (50 mL). The layers were separated and the aqueous extracted with ethyl acetate (2×50 mL). The combined organics were extracted with aqueous NaOH (2M, 3×70 mL). The combined aqueous extracts were acidified to pH 4 by careful addition of glacial acetic acid, then extracted with ethyl acetate (3×60 mL). The combined organics were washed with brine (50 mL), dried (MgSO4), filtered and concentrated in vacuo to give the title compound as a brown solid. RT=2.72 min, m/z (ES+)=197 [M+H]+
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.[N:12]12[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[C@@H:14]([NH:20][C:21]([C:23]1[O:24][C:25]3[CH:31]=[C:30](Br)[CH:29]=[CH:28][C:26]=3[CH:27]=1)=[O:22])[CH2:13]2.[OH-].[Na+]>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].CN(C=O)C>[N:12]12[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19]1)[C@@H:14]([NH:20][C:21]([C:23]1[O:24][C:25]3[CH:31]=[C:30]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][OH:1])[CH:4]=4)[CH:29]=[CH:28][C:26]=3[CH:27]=1)=[O:22])[CH2:13]2
Reactant: OCc1cccc(B(O)O)c1
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2ccc(Br)cc2o1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2ccc(-c3cccc(CO)c3)cc2o1
Temperature: 82.5 °C

Procedure:
A mixture of 130 mg (0.86 mmol) of 3-(hydroxymethyl)phenylboronic acid, 200 mg (0.57 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-bromo-1-benzofuran-2-carboxamide (Example 2A), 1.72 ml (1.72 mmol) of 1N sodium hydroxide solution, 40 mg (0.06 mmol) of 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) chloride and 2 ml of DMF is heated at 80-85° C. for 18 h. The solvent is removed under reduced pressure. The crude product is purified on silica gel 60 (Merck, Darmstadt; eluent: dichloromethane, dichloromethane/methanol 20:1, dichloromethane/methanol/ammonia 80:20:2). The solvent is removed under reduced pressure. Finally, the last residues of solvent are removed under high vacuum. 127 mg (54% of theory) of the title compound are isolated.
Reaction SMILES: C[Si]([Br:5])(C)C.Cl[C:7]1[C:12]2[S:13][C:14]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:23])=[N:15][C:11]=2[C:10]([F:24])=[CH:9][N:8]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)CC>[Br:5][C:7]1[C:12]2[S:13][C:14]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:23])=[N:15][C:11]=2[C:10]([F:24])=[CH:9][N:8]=1
Reactant: C[Si](C)(C)Br
Reactant: Fc1cccc(Cl)c1-c1nc2c(F)cnc(Cl)c2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC#N
Product: Fc1cccc(Cl)c1-c1nc2c(F)cnc(Br)c2s1
Temperature: 85 °C
Yield: 33.6 %

Procedure:
Trimethylsilyl bromide (0.4 mL, 3 mmol) was added to a solution of 4-chloro-2-(2-chloro-6-fluorophenyl)-7-fluorothiazolo[5,4-c]pyridine (0.317 g, 10 mmol) in propionitrile (10 mL) at room temperature under an argon atmosphere. The reaction mixture was heated at 85° C. in a sealed vial for three days then it was poured in an ice-cooled saturated solution of potassium carbonate. The resultant mixture was extracted with DCM (×2). The combined organic washings were dried (Na2SO4) and concentrated under reduced pressure to afford the title compound as an off-white solid (0.365 g, quantitative). 1H NMR (400 MHz, CDCl3): δ 8.39 (d, J=1.9 Hz, 1H), 7.51 (td, J=8.3, 5.8 Hz, 1H), 7.41 (dt, J=8.2, 1.1 Hz, 1H), 7.25-7.16 (m, 1H).
Reaction SMILES: Cl.O1CCOCC1.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]([N:30]2[CH2:44][C:33]3=[C:34]4[N:39]([N:40]=[C:32]3[CH2:31]2)[C:38]([CH3:41])=[C:37]([Cl:42])[C:36]([CH3:43])=[N:35]4)=[O:29])[CH:17]([F:45])[CH2:16]1)=O)(C)(C)C>>[ClH:42].[Cl:42][C:37]1[C:36]([CH3:43])=[N:35][C:34]2[N:39]([N:40]=[C:32]3[CH2:31][N:30]([C:28]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[O:21][CH:18]4[CH2:19][CH2:20][NH:15][CH2:16][CH:17]4[F:45])=[O:29])[CH2:44][C:33]3=2)[C:38]=1[CH3:41]
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1OC1CCN(C(=O)OC(C)(C)C)CC1F)C3
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1OC1CCNCC1F)C3
Temperature: 25 °C
Reaction time: 16 h
Yield: 201 %

Procedure:
A 4M solution of HCl in 1,4-dioxane (10 mL; 400 mmol; 136 eq.) was added to a solution of 4-[2-(6-chloro-5,7-dimethyl-1H,3H-2,4,7a,8-tetraaza-cyclopenta[a]indene-2-carbonyl)-phenoxy]-3-fluoro-piperidine-1-carboxylic acid tert-butyl ester (160 mg; 0.29 mmol; 1 eq.) and the reaction mixture was stirred at room temperature for 16 hours then concentrated in vacuo. The residue was triturated in Et2O and concentrated to dryness to afford the title compound (140 mg, 99%) as a pale yellow solid. UPLC/MS: (MS+) 444.4 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:22]=[CH:21][C:8]([CH:9]=[C:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][CH:6]=1>[Pd]>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][CH:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:21][CH:22]=1
Reactant: CCOC(=O)C(=Cc1ccc(OCOC)cc1)C(=O)OCC
Agent: [Pd]
Product: CCOC(=O)C(Cc1ccc(OCOC)cc1)C(=O)OCC
Yield: 99.7 %

Procedure:
In a similar manner to that described in Reference example 1(d), a reaction was carried out using diethyl 2-(4-methoxymethoxybenzylidene)malonate (4.98 g) and palladium on carbon (5%, 0.50 g) and the reaction mixture was treated to afford the desired compound (5.00 g) as a syrup.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6](B(O)O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Br[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20][CH3:21].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC>[CH3:21][S:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][CH:2]=[CH:3]2
Reactant: CSc1ccccc1Br
Reactant: OB(O)c1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CSc1ccccc1-c1ccc2[nH]ccc2c1
Reaction time: 0.33 h
Yield: 52.2 %

Procedure:
A solution of 5-indoleboronic acid (2.0 g, 12 mmol) and 2-bromothioanisole (1.6 mL, 12 mmol) in a mixture of ethylene glycol dimethyl ether (20 mL) and aqueous sodium carbonate (10 mL) was deoxygenated by a rapid stream of nitrogen applied to the system for 20 min, then treated with Pd(0) at once. The reaction was refluxed for 18 h, cooled down, filtered through Celite® and washed with THF (20 mL). The filtrate evaporated to dryness, taken up in water and extracted with EtOAc (3×). The EtOAc extracts were dried over sodium sulfate and concentrated. The crude residue was purified by flash chromatography (hexane/EtOAc, 1:3) to afford 5-[2-(methylthio)phenyl]-1H-indole (1.5 g, 52%).