Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[N:4]1)[CH3:2].S(Cl)(Cl)=O.[NH2:15][C:16]1[CH:17]=[C:18]([CH:31]=[CH:32][CH:33]=1)[C:19]([C:21]1[CH:29]=[C:28]2[C:24]([CH2:25][C:26](=[O:30])[NH:27]2)=[CH:23][CH:22]=1)=[O:20]>C1COCC1>[O:30]=[C:26]1[CH2:25][C:24]2[C:28](=[CH:29][C:21]([C:19]([C:18]3[CH:17]=[C:16]([NH:15][C:8]([C:7]4[N:3]([CH2:1][CH3:2])[N:4]=[CH:5][CH:6]=4)=[O:10])[CH:33]=[CH:32][CH:31]=3)=[O:20])=[CH:22][CH:23]=2)[NH:27]1
Reactant: Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Reactant: CCn1nccc1C(=O)O
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCn1nccc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Temperature: 79 °C
Reaction time: 3 h
Yield: 67.4 %

Procedure:
A dry flask was charged with 2-Ethyl-2H-pyrazole-3-carboxylic acid (0.111 g, 0.792 mmol) and thionyl chloride (5 mL) and allowed to stir at 79° C. for 3 h. The thionyl chloride was then removed by concentration in vacuo. The crude acid chloride was cooled to room temperature, and then dissolved in THF (8 mL). 6-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 40, 0.200 g, 0.793 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux overnight. The reaction mixture was then allowed to cool to room temperature and subsequently vacuum filtered. The solid was washed with 0° C. THF (˜5 mL) and collected to afford the 2-Ethyl-2H-pyrazole-3-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide as a solid (0.200 g, 0.534 mmol, 68%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[CH3:11][Mg]Cl>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:10])([CH3:11])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[Mg]Cl
Reactant: CC(=O)c1ccc(Br)cc1
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 1-(4-bromophenyl)ethanone (8 g, 40.2 mmol) in 150 mL of THF was added MeMgCl (3.0 M in THF, 40 mL, 120 mmol) at −78° C. The reaction was stirred at rt overnight, and quenched with 150 mL of aqueous NH4Cl. The product was extracted with 250 mL of EtOAc, and the extracts were dried over anhydrous MgSO4, and concentrated to give 2-(4-bromophenyl)propan-2-ol, which was used without further purification.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][C:6](=[O:8])[CH2:5][CH2:4][NH:3]1.[CH:9]([O-])([O-])OC.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:9][O:8][C:6]1[CH2:5][CH2:4][NH:3][C:2](=[O:1])[CH:7]=1
Reactant: COC([O-])[O-]
Reactant: O=C1CCNC(=O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC1=CC(=O)NCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.5 %

Procedure:
A mixture of 2,4-dioxopiperidine (15.1 g), methyl orthoformate (30 ml) and p-toluenesulfonic acid (3.0 g) in methanol (300 ml) is refluxed for 1 hour. After evaporating the solvent, the residue is dissolved in benzene and refluxed for 5 hours. To the solution is added potassium carbonate (9.0 g), and the mixture is stirred overnight at room temperature and then filtered. The filtrate is distilled to remove the solvent. The residue is recrystallized from ethyl acetate-isopropyl alcohol to give 4-methoxy-5,6-dihydro-2(1H)-pyridone (12.3 g, 72.5%) as colorless prisms. m.p. 115°-117° C.
Reaction SMILES: [N+:1]([C:4]1[CH:29]=[CH:28][C:7]([C:8](=[O:27])[CH2:9][NH:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:21])=[CH:17][C:18]=3[Cl:20])[NH:13][C:12]=2[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:6][CH:5]=1)([O-])=O.O.[Sn](Cl)Cl.C(OCC)(=O)C.O.C(=O)([O-])O.[Na+]>C(O)C>[NH2:1][C:4]1[CH:29]=[CH:28][C:7]([C:8](=[O:27])[CH2:9][NH:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:21])=[CH:17][C:18]=3[Cl:20])[NH:13][C:12]=2[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1NCC(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1NCC(=O)c1ccc(N)cc1
Temperature: 70 °C

Procedure:
Dissolve 3-[(4-nitrophenacyl)amino]-2-carbethoxy-4,6-dichloroindole (0.5 g,1.184 mmol) in ethanol (20 mL) and add tin (II) chloride monohydrate (1.60 g, 7.1 mmol). Heat to 70° C. overnight. Pour into ethyl acetate/water (200 mL) and add solid sodium hydrogen carbonate to obtain pH 7. Filter and evaporate the solvent in vacuo to give the title compoundas a pale yellow oil (0.477, 100%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C(N(CC)CC)C.S=[C:19]1[CH2:23][S:22][C:21](=[O:24])[NH:20]1>C(O)C>[O:24]=[C:21]1[N:20]=[C:19]([NH:2][CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[CH2:23][S:22]1
Reactant: O=C1NC(=S)CS1
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)CNC1=NC(=O)SC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.9 %

Procedure:
To a solution of tert-butyl glycinate hydrochloride (4.00 g) and triethylamine (3.33 mL) in ethanol (20 mL) was added 4-thioxo-1,3-thiazolidin-2-one (2.65 g), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.70 g).
Reaction SMILES: C([O:3][C:4](=[O:15])[C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Br:14])[CH:9]=1)([OH:7])[CH3:6])C.[OH-].[K+].Cl>CO>[Br:14][C:10]1[CH:9]=[C:8]([C:5]([OH:7])([CH3:6])[C:4]([OH:15])=[O:3])[CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)C(C)(O)c1cccc(Br)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(O)(C(=O)O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97.4 %

Procedure:
To a solution of 2-(3-Bromo-phenyl)-2-hydroxy-propionic acid ethyl ester (1.87 g, 6.7 mmol) in methanol (10 mL) was added potassium hydroxide (50% in water, 2 mL) and the solution was stirred at room temperature for 15 minutes. Hydrochloric acid (1 N) was added to adjust the pH to 4. The resulting mixture was extracted with ethyl acetate (10 ml×3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to afford the crude 2-(3-bromo-phenyl)-2-hydroxy-propionic acid as a white solid (1.6 g, 97%). MS: m/z 245 (M+H+).
Reaction SMILES: CN(C)C=O.[CH3:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12]([CH3:19])=[CH:13][C:14](=[O:18])[NH:15]2)=[CH:10][CH:9]=1.[H-].[Na+].CS(O[CH2:27][CH2:28][CH:29]1[CH2:38][CH2:37][C:32]2([O:36][CH2:35][CH2:34][O:33]2)[CH2:31][CH2:30]1)(=O)=O>C(OCC)(=O)C.O>[O:33]1[C:32]2([CH2:31][CH2:30][CH:29]([CH2:28][CH2:27][N:15]3[C:16]4[C:11](=[CH:10][CH:9]=[C:8]([O:7][CH3:6])[CH:17]=4)[C:12]([CH3:19])=[CH:13][C:14]3=[O:18])[CH2:38][CH2:37]2)[O:36][CH2:35][CH2:34]1
Reactant: CS(=O)(=O)OCCC1CCC2(CC1)OCCO2
Reactant: COc1ccc2c(C)cc(=O)[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(C)cc(=O)n(CCC3CCC4(CC3)OCCO4)c2c1
Temperature: 62.5 °C
Reaction time: 0.5 h

Procedure:
To 3 mL of an N,N-dimethylformamide solution containing 0.12 g of 7-methoxy-4-methylquinolin-2(1H)-one, 28 mg of a 60% aqueous sodium hydride solution was added at 50° C., and the mixture was stirred at 60 to 65° C. for 30 minutes. Thereto was added 2 mL of an N,N-dimethylformamide solution containing 0.18 g of 2-(1,4-dioxaspiro[4.5]decan-8-yl)ethyl methanesulfonate at 50° C., and the mixture was stirred at 60 to 65° C. for 1 hour and 20 minutes. Thereto was added 14 mg of a 60% aqueous sodium hydride solution at the same temperature, and the mixture was stirred for 1 hour and 45 minutes. The reaction mixture was cooled to room temperature, and then water and ethyl acetate were then added thereto. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by flash silica gel column chromatography [hexane:gradient elution of ethyl acetate=40:60 to 30:70] to obtain 65 mg of a colorless oily substance, 1-(2-(1,4-dioxaspiro[4.5]decan-8-yl)ethyl)-7-methoxy-4-methylquinolin-2(1H)-one.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=1[O:23][CH3:24])(=[O:14])=[O:13])[C:7](=[O:25])[C:6]2([OH:35])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH2:33][CH3:34])#[N:2].Cl[C:37]([O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:38]>N1C=CC=CC=1.C(Cl)Cl>[C:37](=[O:38])([O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[O:35][C:6]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH2:33][CH3:34])[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([C:1]#[N:2])[CH:4]=2)[N:8]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=2[O:23][CH3:24])(=[O:14])=[O:13])[C:7]1=[O:25]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCOc1ccccc1C1(O)C(=O)N(S(=O)(=O)c2ccc(OC)cc2OC)c2ccc(C#N)cc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOc1ccccc1C1(OC(=O)Oc2ccccc2)C(=O)N(S(=O)(=O)c2ccc(OC)cc2OC)c2ccc(C#N)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.1 %

Procedure:
1.5 g (3.0 mmol) of the product 1c were dissolved in 30 ml of pyridine. At 0° C., 1.7 g (10.6 mmol) of phenyl chloroformate were rapidly added dropwise. This reaction solution was stirred for 60 minutes before being stirred into ice-water. The resulting precipitate was isolated, dissolved in methylene chloride, dried and concentrated in vacuo. The resulting residue was crystallized with Et2O/n-pentane. 1.2 g of the intermediate were obtained.
Reaction SMILES: [OH:1][C:2]1[C:11]2[CH:10]3[CH:12]=[C:13]([CH3:16])[CH2:14][CH2:15][CH:9]3[C:8]([CH3:18])([CH3:17])[O:7][C:6]=2[CH:5]=[C:4]([C:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([CH3:23])[CH2:20][CH2:21][CH3:22])[CH:3]=1.[ClH:30].[O:31]1[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][CH2:39][C:40](O)=[O:41])[CH2:33][CH2:32]1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[ClH:30].[O:31]1[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][CH2:39][C:40]([O:1][C:2]2[C:11]3[CH:10]4[CH:12]=[C:13]([CH3:16])[CH2:14][CH2:15][CH:9]4[C:8]([CH3:18])([CH3:17])[O:7][C:6]=3[CH:5]=[C:4]([C:19]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)([CH3:23])[CH2:20][CH2:21][CH3:22])[CH:3]=2)=[O:41])[CH2:33][CH2:32]1
Reactant: O=C(O)CCCN1CCOCC1
Reactant: CCCC(C)(c1ccccc1)c1cc(O)c2c(c1)OC(C)(C)C1CCC(C)=CC21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Product: CCCC(C)(c1ccccc1)c1cc(OC(=O)CCCN2CCOCC2)c2c(c1)OC(C)(C)C1CCC(C)=CC21

Procedure:
0.7 g. (2.33 mmoles) of 1-Hydroxy-3-(phenyl- 1-methylbutyl)-6,6,9-trimethyl-6a,7,8,10a-tetrahydrodibenzo [b,d]pyran, prepared according to the method of Example 48, 0.48 g. (2.28 mmoles) of γ-morpholinobutyric acid hydrochloride (Cruichshank and Sheehan, J. Am. Chem. Soc. 83, 2891 (1961), m.p. 180°-182° ) and 0.48 g. (2.35 mmoles) of dicyclohexylcarbodiimide (Aldrich) are combined with 35 ml. of methylene chloride and stirred at room temperature for a total of 40 hours. The insoluble by-product of dicyclohexylurea is removed using a rotary evaporator. The resulting residue is dissolved in about 20 ml. of benzene and a small amount of insoluble material is removed by filtration. The benzene is evaporated and the residue dried in vacuo to give 0.7 g. of material. Crystallization from benzene/pet ether yields the crystalline product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH:10]=CC)[N:5]=[C:4]([N:13]2[CH2:17][CH2:16][CH2:15][CH:14]2[C:18]2[O:22][N:21]=[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[CH:19]=2)[N:3]=1.I([O-])(=O)(=O)=[O:30].[Na+].[BH4-].[Na+]>C(O)(C)(C)C.C1COCC1.O.C(OCC)(=O)C.[Os](=O)(=O)(=O)=O>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][OH:30])[N:5]=[C:4]([N:13]2[CH2:17][CH2:16][CH2:15][CH:14]2[C:18]2[O:22][N:21]=[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[CH:19]=2)[N:3]=1
Reactant: CC=CCCc1cc(Cl)nc(N2CCCC2c2cc(-c3ccccn3)no2)n1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Solvent: O
Product: OCCCc1cc(Cl)nc(N2CCCC2c2cc(-c3ccccn3)no2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36 %

Procedure:
A solution of 2.5% w/v osmium tetroxide in tert-butanol (0.47 ml) was added to a vigorously stirred solution of 4-chloro-6-(pent-3-en-1-yl)-2-{2-[3-(pyrid-2-yl)isoxazol-5-yl]pyrrolidin-1-yl}pyrimidine (prepared as described in Example 34) in THF (10.5 ml) and water (2.8 ml). Solid sodium periodate (951 mg, 4.44 mmol) was then added. The reaction was stirred at ambient temperature for 2 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine, dried (Na2SO4), and the solvent removed by evaporation. The residue was dissolved in THF (13.5 ml) and distilled water (5.0 ml) and sodium borohydride (59 mg, 1.59 mmol) was added. The reaction was stirred at ambient temperature for 18 hours. The reaction mixture was diluted with ethyl acetate and water and the layers partitioned and separated. The ethyl acetate layer was washed with water and saturated brine, dried (Na2SO4) and the solvent removed by evaporation. The residue was purified by flash chromatography on silica gel eluting with methanol/DCM (1.5:98.5) to give the title compound (205 mg, 36%).
Reaction SMILES: [C:1](=[O:21])([O:5][CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)[O:2][CH2:3]Cl.[I-:22].[Na+]>CC(C)=O>[C:1](=[O:21])([O:5][CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)[O:2][CH2:3][I:22]
Reactant: CC(C)(C)OC(=O)N1CCC(CCOC(=O)OCCl)CC1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CCOC(=O)OCI)CC1
Temperature: 40 °C
Reaction time: 2.5 h

Procedure:
Chloromethyl 2-(1-(tert-butoxycarbonyl)-4-piperidyl)-ethyl carbonate (4.9 g) was added to a solution of sodium iodide (9 g) in acetone (20 ml). After stirring at 40° C. for 2.5 hours the reaction mixture was cooled to room temperature, filtered and evaporated in vacuo. The residue was taken up in dichloromethane, washed with aqueous sodium bicarbonate and sodium thiosulfate, dried over magnesium sulfate, filtered and evaporated in vacuo. Purification on silica gel with hexane/ethyl acetate (2:1) as eluent gave the title compound as a light yellow oil.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([O:15][C:16]2[CH:25]=[CH:24][C:19]([C:20](OC)=[O:21])=[CH:18][CH:17]=2)[CH2:12][CH2:13][CH3:14])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[CH3:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C(O)(=O)C>O1CCCC1.C(OCC)(=O)C>[N:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[CH2:26][C:20]([C:19]1[CH:18]=[CH:17][C:16]([O:15][C@H:11]([C:8]2[CH:9]=[CH:10][C:5]([CH2:1][CH:2]([CH3:3])[CH3:4])=[CH:6][CH:7]=2)[CH2:12][CH2:13][CH3:14])=[CH:25][CH:24]=1)=[O:21]
Reactant: Cc1ccccn1
Reactant: CCC[C@H](Oc1ccc(C(=O)OC)cc1)c1ccc(CC(C)C)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCC[C@H](Oc1ccc(C(=O)Cc2ccccn2)cc1)c1ccc(CC(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methyl 4-[1-(S)-(4-isobutylphenyl)-butoxy]benzoate (283 mg) and 2-methylpyridine (0.09 ml) in tetrahydrofuran (5 ml) was added 1.0M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (2.7 ml) at 0° C. The mixture was stirred for 18 hours at room temperature. Acetic acid (0.18 ml) and ethyl acetate (15 ml) was added to the mixture. The mixture was washed with water and aqueous solution of sodium bicarbonate, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel eluting with a mixture of n-hexane and ethyl acetate (2:1) to give 4-[1-(S)-(4-isobutylphenyl)butoxy]phenyl 2-pyridylmethyl ketone as a yellow oil (216 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][C:10]2[C:11]3[N:34]([CH3:35])[CH:33]=[CH:32][C:12]=3[N:13]=[C:14]([N:16]([C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[N:15]=2)=[C:4]([CH3:36])[CH:3]=1.[N:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1.C1COCC1.C([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C.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>[CH3:36][C:4]1[CH:3]=[C:2]([C:40]2[CH:41]=[CH:42][N:37]=[CH:38][CH:39]=2)[CH:7]=[C:6]([CH3:8])[C:5]=1[S:9][C:10]1[C:11]2[N:34]([CH3:35])[CH:33]=[CH:32][C:12]=2[N:13]=[C:14]([N:16]([C:24]2[CH:25]=[CH:26][C:27]([C:30]#[N:31])=[CH:28][CH:29]=2)[C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])[N:15]=1
Reactant: Cc1cc(Br)cc(C)c1Sc1nc(N(C(=O)OC(C)(C)C)c2ccc(C#N)cc2)nc2ccn(C)c12
Reactant: OB(O)c1ccncc1
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: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(-c2ccncc2)cc(C)c1Sc1nc(N(C(=O)OC(C)(C)C)c2ccc(C#N)cc2)nc2ccn(C)c12
Temperature: 80 °C
Reaction time: 10 h

Procedure:
tert-Butyl 4-(4-bromo-2,6-dimethylphenylthio)-5-methyl-5H-pyrrolo[3,2-d]pyrimidin-2-yl(4-cyanophenyl)carbamate (0.729 mmol) is combined with pyridine-4-boronic acid (1.46 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.0729 mmol) in a two dram vial. The vial is sealed and flushed with argon. Degassed THF (5.0 mL) and aqueous Na2CO3 (2 M, 1.5 mL, 3.0 mmol) are injected, and the mixture agitated on a shaker at 80° C. for 10 h. The mixture is diluted with ethyl acetate and extracted with aqueous Na2CO3 (0.5 M, ×2). The organic layer is collected, concentrated, and the residue purified by chromatography (SiO2, 1:4 hexanes/EtOAc).
Reaction SMILES: [C:1]([C:3]1[C:21]([N+:22]([O-])=O)=[CH:20][CH:19]=[CH:18][C:4]=1[O:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][N:8]1[C:13]([NH:15][CH2:16][CH3:17])=[O:14])#[N:2].C1CCCCC=1>CCO.[Pd]>[NH2:22][C:21]1[C:3]([C:1]#[N:2])=[C:4]([CH:18]=[CH:19][CH:20]=1)[O:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][N:8]1[C:13]([NH:15][CH2:16][CH3:17])=[O:14]
Reactant: CCNC(=O)N1CCCCC1COc1cccc([N+](=O)[O-])c1C#N
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: CCNC(=O)N1CCCCC1COc1cccc(N)c1C#N
Temperature: 100 °C
Yield: 92.2 %

Procedure:
To a solution of 2-((2-cyano-3-nitrophenoxy)methyl)-N-ethylpiperidine-1-carboxamide (Example 26c, 0.458 g, 1.46 mmol) in EtOH (20 mL) was added cyclohexene (0.74 mL, 7.3 mmol) and catalytic amount of 10% Pd/C (0.146 mg). Reaction mixture was heated at 100° C. for 40 minutes, then filtered through Cellite, washed with EtOH (100 mL) and evaporated to give 2-((3-amino-2-cyanophenoxy)methyl)-N-ethylpiperidine-1-carboxamide (0.407 g, 92%) which was used in to next step without further purification. MS 303 (MH+).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1>CCCC[N+](CCCC)(CCCC)CCCC.C1C=CC([Si-](F)(F)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C.[CH2-]C=C.[CH2-]C=C.Cl[Pd+].Cl[Pd+]>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:3][CH:4]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccc(I)cc1
Agent: Cl[Pd+]
Agent: C=C[CH2-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(-c2ccccc2)cc1
Temperature: 95 °C
Yield: 174 %

Procedure:
To a solution of 0.101 g (0.410 mmol) of 4′-iodoacetophenone and 1.113 g (2.062 mmol) of TBAT in 10 mL of DMF was added 12 mg (0.033 mmol) of allyl palladium chloride dimer. The reaction mixture was degassed to remove oxygen via one freeze-pump-thaw cycle. The red-brown mixture was heated at 95° C. for 5 h. The resulting brown mixture was quenched by the addition of 50 mnL of H2O; the aqueous layer was then extracted with 4×50 mL of Et2O, and the combined organic layers were dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography (25 mm, 17 cm, 0-10% EtOAc/hexane) gave 70 mg (86%) of 4-acetylbiphenyl as a yellow solid and 7 mg 14%) of 4,4′-diacetylbiphenyl, the homocoupled product. Recrystallization from absolute EtOH yielded pale yellow needles: TLC Rf=0.29 (10% EtOAc/hexane); mp 119-119.5° C. (lit. mp 119-120° C. (EtOH) Echavarren, A. M. and Stille, J. K., J. Am. Chem. Soc. 109:5478-5486 (1987)); IR (CCl4) 3081 (w), 3038 (w), 3000 (w), 2931 (m), 2850 (w), 1691 (m), 1569 (s), 1538 (s); 1H NMR δ2.63 (s, 3H), 7.88 (t, J=7.3, 1H), 7.46 (t, J=7.4, 2H), 7.61 (d, J=7.2, 2H), 7.67 (A of AB quartet, JAB=8.4, 2H), 8.02 (B of AB quartet, JAB=8.4, 2H); 13C NMR δ26.6, 127.2, 128.2, 128.9, 135.9, 139.9, 145.8, 197.7; LRMS (EI) 197 ((M+1), 10), 196 ((M+), 59), 181 (100), 158 (35), 152 (41); HRMS (EI) calcd for C14H12O 196.0888 (M+); found 196.0883. The IR and 1H NMR are identical to the spectral reported by Echavarren and Stille.
Reaction SMILES: [CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].P(Cl)(Cl)(Cl)(Cl)[Cl:15].P(Br)(Br)(Br)(Br)Br.S(Cl)(Cl)=O>C1C=CC=CC=1>[CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: Cc1c(C(=O)O)cccc1[N+](=O)[O-]
Agent: BrP(Br)(Br)(Br)Br
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: Cc1c(C(=O)Cl)cccc1[N+](=O)[O-]

Procedure:
The conversion of 2-methyl-3-nitrobenzoic acid (II) to a 2-methyl-3-nitrobenzoyl halide (III) may be effected by reacting II with a suitable halogenating agent, such as phosphorus pentachloride, phosphorus pentabromide, thionyl chloride, and the like, preferably thionyl chloride, in a suitable inert solvent, such as dry benzene, at a temperature from room temperature to reflux until the reaction is complete and removing the solvent under reduced pressure. Preferably, II is converted to 2-methyl-3-nitrobenzoyl chloride by simply refluxing it in pure thionyl chloride for about 2- 6 hours and removing the excess thionyl chloride under reduced pressure. The preferred 2-methyl-3-nitrobenzoyl chloride is obtained in yields of 95- 100% of theoretical.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]Br.O(CCCCCCCBr)C1C=CC=CC=1>>[C:1]1([S:7][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][Br:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCCCCCCCBr
Reactant: Sc1ccccc1
Agent: BrCCCCCCCOc1ccccc1
Product: BrCCCCCCCSc1ccccc1
Yield: 46 %

Procedure:
7-Phenylthioheptyl bromide was prepared from thiophenol (4.40 g, 40 mmol) and 1,7-dibromoheptane (10.32 g, 40 mmol) as described above for 7-phenoxyheptyl bromide. Yield: 46% bp; 132-136° C./0.05 torr; 1H-NMR: 1.30-1.85 (m, 10H), 2.90 (t, 2H), 3.35 (t, 2H), 7.25 (s, 5H)).