Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[C:14]([Br:16])[CH:13]=[CH:12][C:11]=2[Cl:17])=[O:9])=[CH:4][CH:3]=1.[CH2:18]([Al](CC)CC)[CH3:19].[Cl-].[Ce+3].[Cl-].[Cl-].C(=O)([O-])O.[Na+]>O1CCCC1.CO.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>[CH2:18]([C:2]1[N:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[C:14]([Br:16])[CH:13]=[CH:12][C:11]=2[Cl:17])=[O:9])=[CH:4][CH:3]=1)[CH3:19]
Reactant: CC[Al](CC)CC
Reactant: O=C(c1ccc(Br)nc1)c1cc(Br)ccc1Cl
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: [Ce+3]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1ccc(C(=O)c2cc(Br)ccc2Cl)cn1
Temperature: 30 °C
Reaction time: 1.5 h

Procedure:
5-Bromo-2-chlorophenyl 6-bromo-3-pyridyl ketone (3.2 g) from Reference Example 135-(2) was dissolved in tetrahydrofuran (80 ml), and added thereto were triethylaluminium (1.0 M hexane solution, 9.9 ml), tetrakis(triphenylphosphine)palladium(0) (570 mg) and cerium(III) chloride (7.3 g), and the mixture was stirred at 30° C. for 1.5 hours. The reaction mixture was diluted with methanol, and the reaction solution was basified with a saturated aqueous sodium hydrogen carbonate solution. The insoluble materials were filtered off and, the filtrate was extracted with ethyl acetate and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=99:1-85:15) to give 5-bromo-2-chlorophenyl 6-ethyl-3-pyridyl ketone (1.98 g) as a colorless solid. APCI-Mass m/Z 324/326 (M+H). (2) The above 5-bromo-2-chlorophenyl 6-ethyl-3-pyridyl ketone was treated in a manner similar to Reference Example 14-(1) to give the desired 5-bromo-2-chloro-1-(6-ethyl-3-pyridylmethyl)benzene as a colorless oil. APCI-Mass m/Z 310/312 (M+H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([CH:15]([N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)[CH3:16])#[N:14].[Cl:22][C:23]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:24]=1[CH:25]=[O:26].[Cl-].[NH4+]>O1CCCC1>[C:13]([C:15]([CH3:16])([N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)[CH:25]([OH:26])[C:24]1[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:23]=1[Cl:22])#[N:14]
Reactant: CC(C#N)n1cncn1
Reactant: O=Cc1ccc(Cl)cc1Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C#N)(C(O)c1ccc(Cl)cc1Cl)n1cncn1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a 3-neck, 250-ml flask equipped with an addition funnel, argon inlet and a septum were added 25 mls of anhydrous tetrahydrofuran and 5.7 mls of diisopropylamine (passed through activity I neutral alumina) under an argon atmosphere. The system was cooled to about 0° C. and 33 mls of 1.6M butyl lithium solution (in hexane) were then added via a syringe. The system was stirred at 0° C. for 5 minutes and then further cooled to -68° C. After cooling, 6.1 gms of 1-cyano-1-(1,2,4-triazol-1-yl)ethane in tetrahydrofuran were added to the system. The system was stirred at -68° C. for 1 hour and then 8.8 gms of 2,4-dichlorobenzaldehyde were slowly added to the system. The system was allowed to warm to room temperature over 30 minutes. Saturated aqueous ammonium chloride was then added to the system and the product was extracted with methylene chloride. The organic solution was washed with water, dried over sodium sulfate and filtered. The solvent was removed by stripping to yield a yellow oil. This oil was then taken up in diethyl ether resulting in the precipitation of 4.1 gms of the erythio isomer of the title compound. The mother liquors were concentrated and again taken up in diethyl ether resulting in the precipitation of 2.60 gms of the threo isomer of the title compound, m.p. 164° -168° C.
Reaction SMILES: [CH3:1][C:2]1([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[C:13]([N+:14]([O-])=O)=[CH:12][N:11]=[C:10]3[CH2:17][CH2:18][CH2:19][C:9]=23)[CH2:3]1.CC(O)=O>CCOC(C)=O.[Fe]>[NH2:14][C:13]1[C:8]([N:4]2[CH2:5][CH2:6][CH2:7][C:2]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:1])[CH2:3]2)=[C:9]2[CH2:19][CH2:18][CH2:17][C:10]2=[N:11][CH:12]=1
Reactant: CC1(NC(=O)OC(C)(C)C)CCCN(c2c([N+](=O)[O-])cnc3c2CCC3)C1
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC1(NC(=O)OC(C)(C)C)CCCN(c2c(N)cnc3c2CCC3)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
A mixture of tert-butyl [3-methyl-1-(3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)piperidin-3-yl]carbamate (100.0 mg, 0.27 mmol), AcOH (1.44 mL) and iron powder (222 mg, 3.98 mmol) was stirred at room temperature for 1 h. The reaction mixture was diluted with EtOAc, filtered through a short silica gel plug. The residue was rinsed with fresh EtOAc and filtered. The filtrate was concentrated under reduced pressure, diluted with EtOAc and neutralized with Na2CO3 solution. After vacuum filtration to remove insoluble impurities, the aqueous layer was extracted with EtOAc three times. The combined organic layers were dried, filtered and concentrated under reduced pressure to give the sub-title compound as off-white powder (80 mg, 90%). LCMS calc. for C19H31N4O2 (M+H)+: m/z=347.2. Found: 347.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:18][CH3:19])=[CH:5][C:6]2[C:15]3[CH2:14][CH2:13][NH:12][CH2:11][C:10]=3[C:9](=[O:16])[NH:8][C:7]=2[CH:17]=1.Cl.Cl[CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.C(N(CC)CC)C>C(O)C>[CH3:1][O:2][C:3]1[C:4]([O:18][CH3:19])=[CH:5][C:6]2[C:15]3[CH2:14][CH2:13][N:12]([CH2:22][CH2:23][N:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[CH2:11][C:10]=3[C:9](=[O:16])[NH:8][C:7]=2[CH:17]=1
Reactant: COc1cc2[nH]c(=O)c3c(c2cc1OC)CCNC3
Reactant: ClCCN1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1cc2[nH]c(=O)c3c(c2cc1OC)CCN(CCN1CCCCC1)C3

Procedure:
A solution of 4.2 g (0.02 m) of 1,2,3,4-tetrahydro-8,9-dimethoxybenzo[c][2,7]naphthyridin-5(6H)-one, 4.05 g (0.022m) of N-(2-chloroethyl)piperidine HCl and 4.45 g (0.044 m) of triethylamine in 125 cc of ethyl alcohol was refluxed for 18 hr. After evaporation, the residue was dissolved in 100 ml of water, made strongly basic with conc NH4OH solution and extracted with three 50 ml portions of chloroform. The chloroform extract was dried (Na2SO4) and evaporated in vacuo. The residue was crystallized from acetonitrile affording 3.3 g (44% of crude material. Recrystallization from 2-propanol afforded analytical material, mp 185°-188° C.
Reaction SMILES: [C:1]([C:3]1[C:7](I)=[CH:6][N:5]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[Cl:20])[N:4]=1)#[N:2].C([Li])CCC.[F:26][C:27]([F:36])([F:35])[C:28]([F:34])([F:33])[C:29](OC)=[O:30].O>O1CCCC1>[C:1]([C:3]1[C:7]([C:29](=[O:30])[C:28]([F:34])([F:33])[C:27]([F:36])([F:35])[F:26])=[CH:6][N:5]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[Cl:20])[N:4]=1)#[N:2]
Reactant: COC(=O)C(F)(F)C(F)(F)F
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1I
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C(=O)C(F)(F)C(F)(F)F
Temperature: -73 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-iodopyrazole (3.0 g) in tetrahydrofuran (80 ml) at -80° C. under an atmosphere of nitrogen was added, at such a rate that the temperature of the reaction mixture did not exceed -73° C., n-butyllithium (2.78 ml of a 2.5M solution in hexanes). The mixture was stirred at -73° C. for 10 minutes and then a solution of methyl pentafluoropropionate (0.89 ml) in tetrahydrofuran (5 ml) was then added at such a rate that the temperature of the reaction mixture did not exceed -75° C. Upon completion of the addition the mixture allowed to warm to room temperature over a period of 1.5 hours. Water (100 ml) was added and the mixture extracted twice with ethyl acetate (80 ml). The combined organic layers were dried (Na2SO4) and evaporated to give a pale yellow solid which was purified by column chromatography on silica gel (150 g) eluted with dichloromethane:hexane (9:1). Combination and evaporation of suitable fractions gave a yellow oil which was further purified by column chromatography on silica gel (50 g) eluted with dichloromethane:hexane (9:1). Combination and evaporation of suitable fractions gave the title compound as a white solid, m.p. 120° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:10]1([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21](Cl)=[O:22])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>C(Cl)Cl.N1C=CC=CC=1>[C:8]([C:7]1[C:2]([NH:1][C:21](=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:3][CH:4]=[CH:5][CH:6]=1)#[N:9]
Reactant: O=C(Cl)CCCCCc1ccccc1
Reactant: N#Cc1cccnc1N
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#Cc1cccnc1NC(=O)CCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
To 2-amino-3-cyanopyridine [24517-64-4] (200 mg, 1.7 mmol) in CH2Cl2 (3 ml) and pyridine (3 ml) was added a solution of 6-phenylhexanoic acid chloride (1.5 eq) in CH2Cl2 (1 ml) and the reaction mixture was stirred overnight at ambient temperature. Water was added, the phases were separated and the pH of the inorganic layer was adjusted (pH 7). The inorganic phase was extracted with EtOAc (3 times), the combined organic layers were washed with brine, dried over Na2SO4, filtrated and concentrated in vacuo. Trituration from diethyl ether yielded 6-phenyl-hexanoic acid (3-cyano-pyridin-2-yl)-amide 360 mg (73%) as a white solid, MS (m/e): 294.3 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]([O:15]C)=[O:14])[C:5]2[O:10][CH2:9][CH2:8][N:7]([CH3:11])[C:6]=2[CH:12]=1.[OH-].[Na+].CO.Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]([OH:15])=[O:14])[C:5]2[O:10][CH2:9][CH2:8][N:7]([CH3:11])[C:6]=2[CH:12]=1
Reactant: COC(=O)c1cc(Cl)cc2c1OCCN2C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN1CCOc2c(C(=O)O)cc(Cl)cc21
Temperature: 70 °C

Procedure:
7.1 Grams of methyl 6-chloro-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylate and 3.8 g of sodium hydroxide were dissolved in a mixed solvent obtained by mixing 50 ml of methanol and 100 ml of water, and the resulting solution was heated at 70° C. for 2 hours with stirring. The liquid reaction mixture was added to 300 ml of water, and 6 ml of concentrated hydrochloric acid was added thereto. The resulting insoluble substance was filtered off, washed with water, and dried, thereby obtaining 5.8 g of 6-chloro-4-methyl- 3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid. Melting point: 202°-204° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:20][CH2:21][OH:22])[CH:5]=[C:6]([Br:19])[C:7]=1[O:8][C:9]1[N:10]=[N:11][C:12]([Cl:18])=[C:13]([CH:15]([CH3:17])[CH3:16])[CH:14]=1.Cl([O-])=[O:24].[Na+].Cl[O-].[Na+].S(=O)(O)[O-].[Na+]>C(#N)C.C(Cl)Cl.P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:20][C:21]([OH:24])=[O:22])[CH:5]=[C:6]([Br:19])[C:7]=1[O:8][C:9]1[N:10]=[N:11][C:12]([Cl:18])=[C:13]([CH:15]([CH3:17])[CH3:16])[CH:14]=1
Reactant: [O-][Cl+][O-]
Reactant: CC(C)c1cc(Oc2c(Br)cc(CCO)cc2Br)nnc1Cl
Agent: O=P([O-])([O-])[O-]
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)c1cc(Oc2c(Br)cc(CC(=O)O)cc2Br)nnc1Cl
Reaction time: 0.5 h

Procedure:
A solution of 2-[3,5-dibromo-4-(6-chloro-5-isopropyl-pyridazin-3-yloxy)-phenyl]-ethanol (12) (111.4 g, 247 mmol) in acetonitrile (223 mL), methylene chloride (343 mL) and sodium phosphate buffer (343 mL of a 0.67 M solution, pH=6.7) was treated with 2,2,6,6-tetramethyl-1-piperidinyloxy free group (2.35 g, 14.83 mmol) at room temperature. A solution of sodium chlorite (44.71 g, 395.5 mmol) in water (135 mL) and a solution of sodium hypochlorite (28 mL, 24.5 mmol) in water (50 mL) were then added simultaneously to the reaction mixture over 45 min. The temperature of the reaction mixture rose to 40° C. during the addition and a cold water bath was used to prevent the temperature from going any higher. The brown reaction mixture was stirred for 30 min. While cooling with cold water, a solution of sodium bisulfite (28.42 g, 297 mmol) in water (86 mL) was added dropwise to the reaction mixture over 5 min. The yellow solution was diluted with methylene chloride (223 mL) and extracted. The layers were separated and the organic layer was extracted with water (2×200 mL), dried with sodium sulfate, filtered and concentrated under vacuum to afford [3,5-dibromo-4-(6-chloro-5-isopropyl-pyridazin-3-yloxy)-phenyl]-acetic acid (13). Glacial acetic acid (549 mL) and sodium acetate (40.56 g, 494 mmol) were added to [3,5-dibromo-4-(6-chloro-5-isopropyl-pyridazin-3-yloxy)-phenyl]-acetic acid (13). The reaction mixture was heated to 120° C. for 24 h. At this time, the reaction mixture was cooled to room temperature, diluted with toluene (200 mL) and concentrated under vacuum two times. The resulting residue was diluted with tetrahydrofuran (223 mL) and isopropyl acetate (892 mL) and was washed with water (3×150 mL). The organic layer was separated and concentrated under vacuum to about 600 mL. Isopropyl acetate (180 mL) was added and the mixture was concentrated under vacuum to about 450 mL. Heptane (300 mL) was added in portions over 10 min. The mixture was stirred under reflux for 15 min and then was cooled to room temperature. The resulting solid was filtered, washed with 50% isopropyl acetate in heptane (200 mL), and dried under high vacuum overnight to afford [3,5-dibromo-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-acetic acid (14) (80.4 g, 73%) as a white solid; LRMS for C15H14Br2N2O4 (M+H) m/z=446. Molecular Weight=446.0978; Exact Mass=443.9320
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12](=[O:14])[CH3:13])=[CH:9][C:8]=2[CH:15]=1)([O-])=O.[NH4+].[Cl-]>CCO.O.[Fe]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12](=[O:14])[CH3:13])=[CH:9][C:8]=2[CH:15]=1
Reactant: CC(=O)c1cc2cc([N+](=O)[O-])ccc2o1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(=O)c1cc2cc(N)ccc2o1
Yield: 54.3 %

Procedure:
Iron powder (0.680 g, 12.19 mmol) was added in portions to a solution of 1-(5-nitro-1-benzofuran-2-yl)ethanone (0.500 g, 2.44 mmol) and NH4Cl (0.652 g, 12.19 mmol) in EtOH (15 mL) and water (4 mL) and the mixture was refluxed for 1 h. The mixture was filtered through Celite and washed out with DCM. The solvents were evaporated and the residue was dissolved in DCM. The organic layer was washed with water, dried through a phase separator and evaporated. The product was purified by silica gel column chromatography using a EtOAc/hexane/MeOH (49:49:2) as eluant, to give the title compound (0.232 g, 54%) as a yellow solid; 1H NMR (500 MHz, CD3OD): δ 7.50 (ds, 1H), 7.33 (d, 1H), 6.95-7.00 (m, 2H), 2.54 (s, 3H); Mass Spectrum: M+H+ 176.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:36])[N:9]([C:13]3[CH:18]=[CH:17][C:16]([C@@H:19]4[CH2:26][CH2:25][C@H:24]5[C@@H:20]4[CH2:21][CH2:22][C@H:23]5[CH:27]([C:32]([O:34]C)=[O:33])[C:28]([O:30]C)=[O:29])=[CH:15][CH:14]=3)[CH2:10][CH2:11][O:12][C:6]=2[N:5]=[CH:4][N:3]=1.O.[OH-].[Li+]>O1CCOCC1.O>[NH2:1][C:2]1[C:7]2[C:8](=[O:36])[N:9]([C:13]3[CH:18]=[CH:17][C:16]([C@@H:19]4[CH2:26][CH2:25][C@H:24]5[C@@H:20]4[CH2:21][CH2:22][C@H:23]5[CH:27]([C:28]([OH:30])=[O:29])[C:32]([OH:34])=[O:33])=[CH:15][CH:14]=3)[CH2:10][CH2:11][O:12][C:6]=2[N:5]=[CH:4][N:3]=1
Reactant: COC(=O)C(C(=O)OC)[C@@H]1CC[C@H]2[C@@H]1CC[C@H]2c1ccc(N2CCOc3ncnc(N)c3C2=O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Nc1ncnc2c1C(=O)N(c1ccc([C@@H]3CC[C@H]4[C@@H]3CC[C@H]4C(C(=O)O)C(=O)O)cc1)CCO2

Procedure:
(±)-{(1R,3aS,4R,6aS)-4-[4-(4-Amino-5-oxo-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-6(5H)-yl)phenyl]octahydropentalen-1-yl}malonic acid was prepared as follows. A solution of dimethyl(±)-{(1R,3aS,4R,6aS)-4-[4-(4-amino-5-oxo-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-6(5H)-yl)phenyl]octahydropentalen-1-yl}malonate (190 mg, 0.38 mmol) and lithium hydroxide monohydrate (166 mg, 3.9 mmol) in p-dioxane/water (8:3-11 mL) was stirred at 50° C. for 3 hours. The reaction was concentrated to remove the p-dioxane, water (2 mL) added and the mixture extracted with EtOAc (5 mL). The aqueous layer was adjusted to pH˜3 with 2N aqueous hydrochloric acid, the solids filtered and dried in vacuo to afford the title compound as a white solid, 179 mg. 1H NMR (400 MHz, DMSO-d6) δ 8.17 (s, 1H), 7.58 (br s, 2H), 7.13 (d, 2H), 7.10 (d, 2H), 4.57 (m, 2H), 3.95 (m, 2H), 3.08 (d, 1H), 2.64 (m, 1H), 2.39 (m, 2H), 2.24 (m, 1H), 1.87-1.10 (m, 7H). m/z=467.3 (M+1).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([O:17]S(C4C=CC(C)=CC=4)(=O)=O)[CH:14]=[CH:15][CH:16]=3)[CH:9]=2)[N:4](S(C2C=CC(C)=CC=2)(=O)=O)[CH:3]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C.[CH:67]([C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][N:70]=1)=[CH2:68]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C>[N:70]1[CH:71]=[CH:72][CH:73]=[CH:74][C:69]=1[CH:67]=[CH:68][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=3)[CH:9]=2)[NH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2cccc(-c3cnc4c(c3)c(I)cn4S(=O)(=O)c3ccc(C)cc3)c2)cc1
Reactant: C=Cc1ccccn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Oc1cccc(-c2cnc3[nH]cc(C=Cc4ccccn4)c3c2)c1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 70.5 %

Procedure:
To toluene-4-sulfonic acid 3-[3-iodo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine-5-yl]-phenyl ester (50 mg, 0.077 mmol), tri-ortho-tolylphosphine (10 mg, 0.031 mmol), palladium (II) acetate (2 mg, 0.0077 mmol) was added DMF (0.5 mL), triethylamine (32 uL, 0.232 mmol), and 2-vinylpyridine (42 uL, 0.388 mmol). The vial was flushed with nitrogen, and the reaction was run in a Personal Chemistry® microwave reactor at 150° C. for 900 s. Water was added and the mixture was neutralized to pH 6 with 1 N aqueous HCl, then extracted with EtOAc three times. The extracts were combined and concentrated in vacuo. The crude was treated with 1 mL of EtOH and 1 mL of aqueous KOH (50 wt %). The reaction mixture was stirred at 80° C. for 15 h. The mixture was neutralized to pH 7 with 1 N aqueous HCl, and the resulting precipitate was filtered, washed with water, dried in vacuo, and adsorbed on silica gel. Purification on silica gel with a gradient of MeOH/CH2Cl2 afforded 3-[3-(2-pyridin-2-yl-vinyl)-1H-pyrrolo[2,3-b]pyridine-5-yl]-phenol as a yellow solid (17 mg, 35% yield). 1H NMR (500 MHz, DMSO-d6) δ 6.78 (dd, J=2.0, 8.0 Hz, 1H), 7.13 (s, 1H), 7.15-7.20 (m, 2H), 7.26 (d, J=16.0 Hz, 1H), 7.29 (t, J=8.0 Hz, 1H), 7.57 (d, J=7.5 Hz, 1H), 7.73 (dt, J=2.0, 8.0 Hz, 1H), 7.90 (d, J=16.0 Hz, 1H), 7.93 (d, J=2.0 Hz, 1H), 8.50 (d, J=2.0 Hz, 1H), 8.52 (d, J=5.0 Hz, 1H), 8.54 (d, J=2.5 Hz, 1H), 9.56 (s, 1H), 12.1 (s, 1H). MS: m/z 314 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:16](=[CH:17][CH:18]=1)[C:8]1([CH2:13][CH2:12][C:11](=[O:14])[NH:10][C:9]1=[O:15])[CH2:7][CH2:6][C:5]2=[O:19].[CH:20](O)(C)C>>[CH3:20][N:10]1[C:11](=[O:14])[CH2:12][CH2:13][C:8]2([C:16]3[C:4](=[CH:3][C:2]([CH3:1])=[CH:18][CH:17]=3)[C:5](=[O:19])[CH2:6][CH2:7]2)[C:9]1=[O:15]
Reactant: CC(C)O
Reactant: Cc1ccc2c(c1)C(=O)CCC21CCC(=O)NC1=O
Product: Cc1ccc2c(c1)C(=O)CCC21CCC(=O)N(C)C1=O
Yield: 80 %

Procedure:
Following the procedure noted in Example 5, 38.6 grams (0.15 M) of 2,3-dihydro-6-methylspiro-[naphthalene-1(4H),3'-piperidine]-2',4,6'-trione was methylated to give 32.5 grams (80%) of 1',6-dimethyl-2,3-dihydrospiro-[naphthalene-1(4H),3'-piperidine]-2',4,6'-trione, melting point 146°-147.5° C. from isopropyl alcohol.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[Li]CCCC.CCCCCC.CON(C)[C:24]([C@@H:26]1[CH2:31][CH2:30][CH2:29][N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27]1)=[O:25]>C1COCC1>[F:8][C:6]1[CH:5]=[CH:4][C:3]([CH3:9])=[C:2]([CH:7]=1)[C:24]([C@@H:26]1[CH2:31][CH2:30][CH2:29][N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27]1)=[O:25]
Reactant: CON(C)C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: Cc1ccc(F)cc1Br
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccc(F)cc1C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 88.3 %

Procedure:
To a solution of 2-bromo-4-fluoro-1-methylbenzene (10.6 g, 0.056 mol) in anhydrous THF (150 mL) at −78° C. under nitrogen was added dropwise a solution of 2.5 M n-BuLi in hexane (22 mL, 0.056 mol). After stirring for 1 hr at −78° C., a solution of (R)-tert-butyl 3-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (10 g, 0.037 mol) in anhydrous THF (120 mL) was added dropwise. After addition, the reaction mixture was allowed to warn to rt and stirred for 2 hr. The mixture was quenched with saturated NH4Cl (100 mL) solution and extracted with EtOAc (3×80 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to provide crude (R)-tert-butyl 3-(5-fluoro-2-methylbenzoyl)piperidine-1-carboxylate (10.5 g, yield 88%), which was used in the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[N:5]([CH2:16][CH2:17][CH3:18])[C:4]=2[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:26][CH2:27][CH2:28][OH:29]>CN(C=O)C>[Cl:1][C:2]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]2[C:8](=[O:14])[N:7]([CH2:26][CH2:27][CH2:28][OH:29])[C:6](=[O:15])[N:5]([CH2:16][CH2:17][CH3:18])[C:4]=2[N:3]=1
Reactant: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCC
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=CCn1c(Cl)nc2c1c(=O)n(CCCO)c(=O)n2CCC
Temperature: 60 °C
Yield: 71.7 %

Procedure:
A solution of 8-chloro-7-(2-propen-1-yl)-3-propyl-3,7-dihydro-1H-purine-2,6-dione (3.0 g, 11.1 mmol) in DMF (20 ml) was treated with caesium carbonate (3.7 g, 11.4 mmol) and 3-bromo-1-propanol (1.6 g, 11.5 mmol). The mixture was heated at 60° C. for 4 h and then cooled and evaporated. The residue was partitioned between EtOAc (60 ml) and saturated aqueous sodium bicarbonate (50 ml). The aqueous phase was extracted with EtOAc (60 ml), the combined organic phases were dried (MgSO4), filtered and evaporated. The product was purified using the Companion™ system and a gradient elution from cyclohexane to EtOAc. Product containing fractions were combined and evaporated to give the title compound as a colourless oil (2.6 g).