Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[C:7]([OH:15])[C:8](=[CH:13][CH:14]=1)[C:9]([O:11][CH3:12])=[O:10])=[N+]=[N-].[ClH:16].[H][H].[OH-].[K+]>CO.[Pd].O.C(O)C>[ClH:16].[NH2:1][CH2:4][C:5]1[CH:6]=[C:7]([OH:15])[C:8](=[CH:13][CH:14]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: [H][H]
Reactant: COC(=O)c1ccc(CN=[N+]=[N-])cc1O
Agent: [Pd]
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: CCO
Solvent: O
Product: COC(=O)c1ccc(CN)cc1O
Temperature: 25 °C
Yield: 65 %

Procedure:
Crude methyl 4-azidomethylsalicylate was dissolved in methanol (750 mL) in a 2L Parr hydrogenation flask. Palladium on carbon catalyst (10% [w/w], 3.8 g) in water (25 mL) was added, followed by concentrated hydrochloric acid (35 mL). The flask was affixed to a Parr hydrogenator, and the mixture was shaken at room temperature under 40 psi of hydrogen for 16 hours. The reaction mixture was then filtered through a 0.45 mm nylon filter. The retained solid was then washed with methanol (150 mL), water (100 mL), and methanol again (150 mL). The combined filtrates were evaporated to dryness to afford a tan solid. This solid was dissolved in hot denatured ethanol (150 mL) and the solution was allowed to cool to room temperature. White crystals formed quickly. Finally, the mixture was then chilled for 16-18 hours at 4° C. to complete crystallization. The solid was filtered, washed with a little cold ethanol (50 mL) and thendiethyl ether (150 mL), and dried in vacuo over potassium hydroxide pelletsto afford 51.5 g (65% yield based on methyl 4-bromomethylsalicylate) of methyl 4-aminomethylsalicylate hydrochloride (m.p. 225°-227°C., open capillary, uncorrected).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[C:16]2[C:19](C(C3C=CC(Cl)=CC=3)O)=[C:20](Cl)[N:21]=[CH:22][C:15]=2[N:14]([CH3:33])[C:13]1=[O:34])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].CN(C)CC(O)=O.[Cl:48][C:49]1[CH:50]=[C:51]([OH:55])[CH:52]=[CH:53][CH:54]=1>O1CCOCC1.[Cu]I>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[C:16]2[CH:19]=[C:20]([O:55][C:51]3[CH:52]=[CH:53][CH:54]=[C:49]([Cl:48])[CH:50]=3)[N:21]=[CH:22][C:15]=2[N:14]([CH3:33])[C:13]1=[O:34])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: Cn1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)c2c(C(O)c3ccc(Cl)cc3)c(Cl)ncc21
Reactant: Oc1cccc(Cl)c1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cn1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)c2cc(Oc3cccc(Cl)c3)ncc21
Temperature: 25 °C
Yield: 63 %

Procedure:
To a mixture of 3-(3-(tert-butyldimethylsilyloxy)propyl)-6-chloro-1-methylpyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione (See Compound 49, step 3, 383 mg, 1 mmol) CuI (24.7 mg, 0.13 mmol), Cs2CO3 (650 mg, 2 mmol), 2-(dimethylamino)acetic acid (51.5 mg, 0.5 mmol) in dioxane (6 mL) was added 3-chlorophenol (192 mg, 1.5 mmol). The reaction was heated at 140° C. (MW) for 2.5 h, cooled to RT and filtered through a pad of Celite. The filtrate was diluted with EA (20 mL) and water (20 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by chromatography eluted with PE/EA (2:1) to give 3-(3-(tert-butyldimethylsilyloxy)propyl)-6-(3-chlorophenoxy)-1-methylpyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione (300 mg, 63% yield) as a solid. LCMS: MH+ 476 and TR=2.377 min.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][OH:5].[C:10](Cl)(=[O:14])[CH2:11][CH2:12][CH3:13]>N1C=CC=CC=1>[C:10]([O:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][OH:5])(=[O:14])[CH2:11][CH2:12][CH3:13]
Reactant: CCCC(=O)Cl
Reactant: OCC(CO)(CO)CO
Solvent: c1ccncc1
Product: CCCC(=O)OCC(CO)(CO)CO
Yield: 47 %

Procedure:
In this example, the stoichiometry of Example 1 was modified using pentaerythritol (1.92 g; 14 mmol) and butyryl chloride (0.75 mL; 0.5 equiv) and pyridine (100 mL) to produce pentaerythritol monobutyrate (0.74 g; 47%).
Reaction SMILES: [CH3:1][C:2]1[C:14]([OH:15])=[C:13]([CH3:16])[CH:12]=[C:11]2[C:3]=1[CH2:4][CH2:5][C:6]1([O:10]2)[CH2:9][CH2:8][CH2:7]1.[CH3:17][O:18]C(Cl)Cl.O>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[OH:15][C:14]1[C:2]([CH3:1])=[C:3]2[C:11](=[C:12]([CH:17]=[O:18])[C:13]=1[CH3:16])[O:10][C:6]1([CH2:7][CH2:8][CH2:9]1)[CH2:5][CH2:4]2
Reactant: COC(Cl)Cl
Reactant: Cc1cc2c(c(C)c1O)CCC1(CCC1)O2
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: Cc1c(O)c(C)c2c(c1C=O)OC1(CCC1)CC2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a cooled solution of 5,7-dimethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-6-ol (1 g) in DCM (20 mL) was added TiCl4 (0.53 mL) which turned the solution a red color. To the solution was added dichloromethyl methyl ether (0.42 mL) and stirred at 0° C. for 30 min and then at room temperature for 30 min. The solution was poured into water and the DCM was separated, dried and evaporated. The residue was purified by silica gel column eluting with 20% ethylacetate in hexane to give 700 mg of 6-hydroxy-5,7-dimethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutane]-8-carbaldehyde as a yellow solid.
Reaction SMILES: [OH-].[K+].[CH3:3][Si:4]([CH3:24])([CH3:23])[C:5]1[CH:6]=[C:7](/[CH:11]=[CH:12]/[C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=2)[CH:8]=[CH:9][CH:10]=1.Cl>CCO>[CH3:24][Si:4]([CH3:3])([CH3:23])[C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([OH:19])=[O:18])=[CH:21][CH:22]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)c1ccc(/C=C/c2cccc([Si](C)(C)C)c2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C[Si](C)(C)c1cccc(C=Cc2ccc(C(=O)O)cc2)c1
Temperature: 25 °C
Yield: 100.3 %

Procedure:
A solution of 1.8 ml (3.6 mmol) of 2N-KOH was added to a solution of 143 mg (0.461 mmol) of trans-methyl 4-[(3-trimethylsilylphenyl)ethenyl]benzoate in 3 ml of EtOH. The mixture was stirred at room temperature. The reaction mixture was adjusted to acid pH with 2N hydrochloric acid, and then the aqueous solution was extracted with AcOEt. The extract was dried and evaporated to give 137 mg of the title compound as white crystals (yield 100%), which were recrystallized from a mixture of ethyl acetate, methylene chloride and n-hexane, and dried to give 116 mg of white crystals, m.p. 216°-218° C. (yield 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[C:11]([CH:17]2[C:22](=[O:23])[C:21]([CH3:25])([CH3:24])[S:20][C:19]([CH3:27])([CH3:26])[C:18]2=[O:28])[CH:10]=1.C(OO)(=[O:31])C>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[C:11]([CH:17]2[C:22](=[O:23])[C:21]([CH3:25])([CH3:24])[S:20](=[O:31])[C:19]([CH3:27])([CH3:26])[C:18]2=[O:28])[CH:10]=1
Reactant: CC(=O)OO
Reactant: CCc1ccc(-c2ccc(Cl)cc2Cl)cc1C1C(=O)C(C)(C)SC(C)(C)C1=O
Solvent: ClCCl
Product: CCc1ccc(-c2ccc(Cl)cc2Cl)cc1C1C(=O)C(C)(C)S(=O)C(C)(C)C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 40.1 %

Procedure:
A mixture of 4-(2′,4′-dichloro-4-ethylbiphenyl-3-yl)-2,2,6,6-tetramethylthiopyran-3,5-dione (79 mg, 0.1816 mmol), peracetic acid (1.8 g, 7.2 mmol, 36-40% solution in acetic acid) and dichloromethane (0.23 ml) is stirred for 4 hours at ambient temperature. The reaction mixture is partitioned between water and dichloromethane, and the organic phase is separated then concentrated under reduced pressure. The residue is purified by preparative reverse phase HPLC to give 4-(2′,4′-dichloro-4-ethylbiphenyl-3-yl)-2,2,6,6-tetramethyl-1-oxothiopyran-3,5-dione (32.9 mg) as a clear gum.
Reaction SMILES: [C@H:1]12[CH2:8][CH2:7][CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:9][NH:10][C:11]([C:13]1[N:14]=[C:15]2[N:19]([CH:20]=1)[CH:18]=[CH:17][S:16]2)=[O:12].[CH3:21][C:22]1[S:23][C:24]([C:30]2[CH:31]=[C:32]([CH3:36])[CH:33]=[CH:34][CH:35]=2)=[C:25]([C:27](O)=[O:28])[N:26]=1>>[CH3:21][C:22]1[S:23][C:24]([C:30]2[CH:31]=[C:32]([CH3:36])[CH:33]=[CH:34][CH:35]=2)=[C:25]([C:27]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:8][CH2:7][CH2:6]3)[C@H:2]2[CH2:9][NH:10][C:11]([C:13]2[N:14]=[C:15]3[N:19]([CH:20]=2)[CH:18]=[CH:17][S:16]3)=[O:12])=[O:28])[N:26]=1
Reactant: O=C(NC[C@H]1NC[C@@H]2CCC[C@@H]21)c1cn2ccsc2n1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)O)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CCC[C@@H]3[C@H]2CNC(=O)c2cn3ccsc3n2)c1

Procedure:
prepared by reaction of imidazo[2,1-b]thiazole-6-carboxylic acid-[(1S,2S,5R)-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 2-methyl-5-m-tolyl-thiazole-4-carboxylic acid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[C:3]=1[N+:9]([O-:11])=[O:10].Cl.[NH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(N(C(C)C)C(C)C)C>CC(N(C)C)=O.C(Cl)Cl>[Br:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([NH:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CN
Reactant: O=[N+]([O-])c1c(F)cccc1Br
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)CNc1cccc(Br)c1[N+](=O)[O-]
Temperature: 80 °C
Yield: 99 %

Procedure:
A mixture of 1-bromo-3-fluoro-2-nitrobenzene (10.25 g, 46.6 mmol; Ark Pharm, Inc., Libertyville, Ill.), ethyl 2-aminoacetate hydrochloride (6.50 g, 46.6 mmol; Aldrich), and N-ethyl-N-isopropylpropan-2-amine (24.35 ml, 140 mmol) in DMA (116 ml) was heated to 80° C. for 5 h. The mixture was diluted with DCM (400 ml), added to a separatory funnel, and washed with water (4×200 ml) before the organic layer was separated, dried over Na2SO4, and concentrated to give ethyl 2-((3-bromo-2-nitrophenyl)amino)acetate (210b, >99% yield) as a yellow oil (contaminated with DMA). MS (ESI, pos. ion) m/z: 303.0/305.0 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([N+:10]([O-])=O)[C:7]([NH:13][CH3:14])=[CH:6][C:3]=1[C:4]#[N:5]>CCO.[Pd]>[NH2:10][C:8]1[C:7]([NH:13][CH3:14])=[CH:6][C:3]([C:4]#[N:5])=[C:2]([F:1])[CH:9]=1
Reactant: CNc1cc(C#N)c(F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CNc1cc(C#N)c(F)cc1N

Procedure:
A stirred solution of 2-Fluoro-5-methylamino-4-nitro-benzonitrile (1.0 g, 0.0051 mol) in EtOH (20 mL) was hydrogenated using Pd/C for 3 h at room temperature. The reaction was filtered through CELITE® and the filter bed was thoroughly washed with EtOH. The resulting solution was concentrated to afford the crude 4-amino-2-fluoro-5-methylamino-benzonitrile as a brownish black solid. C8H8FN3; Crude LCMS (M+1): 166.2; LCMS Purity: 85.05%.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[NH:30]1[C:34]([CH:35]=O)=[N:33][N:32]=[N:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(O)(=O)C>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:35][C:34]4[NH:33][N:32]=[N:31][N:30]=4)[CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Reactant: O=Cc1nnn[nH]1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2nnn[nH]2)cc1
Temperature: 40 °C
Reaction time: 18 h
Yield: 79.3 %

Procedure:
In 1,2-dichloroethane (14 ml)/acetic acid (7 ml) was dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-2,3-dihydro-1-benzazepine-4-carboxylate (0.70 g). To the solution were added tetrazole-5-carbaldehyde (0.31 g) and sodium triacetoxyborohydride (1.5 g), and the mixture was stirred at 40° C. for 18 hours. The mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The resulting residue was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified with silica gel column chromatography (ethyl acetate/ethanol=15:1) to give methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(tetrazol-5-ylmethyl)-2,3-dihydro-1-benzazepine-4-carboxylate (0.67 g).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[N:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(COC)OC.O.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]>[CH3:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([C:14]2[CH:15]=[CH:16][N:11]=[CH:12][CH:13]=2)[C:3]=1[OH:10]
Reactant: OB(O)c1ccncc1
Reactant: Cc1cc(C)c(O)c(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: Cc1cc(C)c(O)c(-c2ccncc2)c1
Reaction time: 1 h
Yield: 30.1 %

Procedure:
2-Bromo-4,6-dimethylphenol (0.5 g, 2.5 mmol) was dissolved in dimethoxyethane/water (2:1). Pyridin-4-ylboronic acid (0.32 g, 2.5 mmol) and Pd(dppf)Cl2 (0.10 g, 0.13 mmol), sodium carbonate (1 g, 13 mmol) were added thereto, followed by stirring for 1 hour under reflux. After the completion of the reaction, the reaction mixture was added with water, and extracted with ethyl acetate. The obtained organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 2,4-dimethyl-6-(pyridin-4-yl)phenol (0.15 g, 30%).
Reaction SMILES: I[C:2]1[C:3](=[O:18])[NH:4][C:5](=[O:17])[N:6]([CH:16]=1)[C@@H:7]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]1[OH:9].C(N(CC)CC)C.[CH2:26]([NH:29][C:30](=[O:35])[C:31]([F:34])([F:33])[F:32])[C:27]#[CH:28]>CN(C=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.[Cu]I>[F:32][C:31]([F:34])([F:33])[C:30]([NH:29][CH2:26][C:27]#[C:28][C:2]1[C:3](=[O:18])[NH:4][C:5](=[O:17])[N:6]([CH:16]=1)[C@@H:7]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]1[OH:9])=[O:35]
Reactant: C#CCNC(=O)C(F)(F)F
Reactant: O=c1[nH]c(=O)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)cc1I
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NCC#Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]c1=O)C(F)(F)F
Temperature: 45 °C
Reaction time: 3.5 h
Yield: 95 %

Procedure:
This compound was prepared similarly. 5-Iodouridine (1.35 mmol, 500 mg) was dissolved in dry DMF (12 mL) and Ar was bubbled through the solution for 10 min. Then, (Ph3P)4Pd (0.1 equiv., 0.1351 mmol, 156 mg) was added and Ar was bubbled through the solution for another 5 min. Triethylamine (2.0 equiv., 2.703 mmol, 273 mg, 0.376 mL) was added via syringe followed by addition of N-propargyltrifluoroacetamide (2.5 equiv., 3.38 mmol, 510 mg and CuI (0.2 equiv., 0.27 mmol, 51.5 mg). The mixture was stirred at 45° C. for 3.5 h, then the solvent was evaporated, and the residue dissolved in MeOH/methylene chloride 1:1 (10 mL). Ion exchange resin (Bio-Rad AG1 X8, HCO3-form, 1.5 g) was added to remove Et3N.HI, and the mixture stirred at room temperature for 20 min. The mixture was then filtered through Celite, the solid washed with MeOH/methylene chloride 1:1 (10 mL) and the solvents removed by rotary evaporation. The residue was purified by column chromatography (chloroform/MeOH 8.25:1.75) to yield 5-(3-trifluoroacetamidopropyn-1-yl)-uridine (ca. 95%) as a yellow foam contaminated with some Et3N.HI. Rf:0.43 (chloroform/MeOH 8.25:1.75). 1H-NMR (DMSO-d6): 3.61 (m, 2H, 5′), 3.86 (m, 1H, 4′), 3.93-4.08 (m, 2H, 2′, 3′), 4.23 (m, 2H, H-9), 5.08 (d, 1H, OH), 5.19 (t, 1H, OH), 5.41 (d, 1H, OH), 5.75 (d, 1H, 1′), 8.48 (s, 1H, H-6), 10.10 (t, 1H, NH chain), 11.64 (s, 1H, NH cycl.). 13C-NMR (DMSO-d6): 29.5 (C-9), 60.5 (5′), 69.6 (3′), 73.8 (2′), 75.3 (C-8), 85.0 (4′), 87.6, (C-7), 88.3 (1′), 97.8 (C-5), 113.9, 117.7 (q, CF3, J=288.48 Hz), 144.4 (C-6), 149.7 (C-2), 155.9, 156.4 (q, COCF3, J=36.80 Hz), 161.6 (C-4).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[NH2:6].[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][N:14]=1.ClC1C=CC(C(NC2C=CC(I)=C(C)C=2)=O)=CN=1>>[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH:6][C:5]2[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:3]([O:2][CH3:1])[CH:4]=2)=[O:18])=[CH:15][N:14]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: COc1ccc(N)cc1OC
Agent: Cc1cc(NC(=O)c2ccc(Cl)nc2)ccc1I
Product: COc1ccc(NC(=O)c2ccc(Cl)nc2)cc1OC

Procedure:
6-Chloro-N-(3,4-dimethoxy-phenyl)-nicotinamide was prepared from 3,4-dimethoxy aniline and 6-chloronicotinoyl chloride following a procedure similar to the one described in the synthesis of 6-chloro-N-(4-iodo-3-methyl-phenyl)-nicotinamide, above. The product was isolated after precipitation out of a small volume of CH2Cl2 with hexanes. HRMS m/z calcd for C14H13N2O3Cl [M+H]+: 293.0688. Found: 293.0687.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=1)[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]#[N:22])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:26]=[N+:27]=[N-:28].[Na+].[Cl-].[NH4+]>CN(C)C=O.C(OCC)(=O)C>[O:1]([C:8]1[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=1)[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][C:21]2[NH:28][N:27]=[N:26][N:22]=2)=[CH:17][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CCCc1ccc(OCc2cccc(Oc3ccccc3)c2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: c1ccc(Oc2cccc(COc3ccc(CCc4nnn[nH]4)cc3)c2)cc1
Yield: 42.4 %

Procedure:
A solution of 3-(4-((3-phenoxybenzyl)oxy)phenyl)propanenitrile (0.5 g, 1.52 mmol), sodium azide (0.49 g, 7.54 mmol) and ammonium chloride (0.41 g, 7.66 mmol) in N,N-dimethylformamide (20 ml) was stirred at 110° C. for 28 hrs. The reaction solution was diluted with ethyl acetate, washed successively with aqueous citric acid solution, water and aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography (ethyl acetate:hexane=2:3-2:1) to give an oil, which was crystallized from ethyl acetate-tetrahydrofuran to give the title compound (0.24 g, 43%).
Reaction SMILES: [C:1]([NH:3][C:4](=[O:12])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)#[N:2].C1COCC1.Br[CH2:19][C:20]([N:22]([CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:23][C:24]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[O:25])=[O:21]>CN(C=O)C.CC(C)([O-])C.[K+]>[CH3:34][C:33]([CH3:36])([CH3:35])[CH2:32][N:22]([CH2:23][C:24]([N:26]1[CH2:27][CH2:28][O:29][CH2:30][CH2:31]1)=[O:25])[C:20]([CH2:19][N:3]([C:1]#[N:2])[C:4](=[O:12])[CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:21]
Reactant: CC(C)(C)CN(CC(=O)N1CCOCC1)C(=O)CBr
Reactant: N#CNC(=O)Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)CN(CC(=O)N1CCOCC1)C(=O)CN(C#N)C(=O)Cc1ccccc1
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 16.9 %

Procedure:
To a stirred solution of N-cyano-2-phenyl-acetamide (35 mg, 0.2 mmol) (see Example 1) in DMF (1.25 mL), potassium tert-butoxide (0.22 mL of a 1.0 M THF solution, 0.22 mmol) was added, dropwise at 0° C., under nitrogen. Upon complete addition, the cooling bath was removed and the reaction was stirred for 0.5 h. After this time, the resulting anion was added dropwise to a stirred solution of the above 2-bromo-N-(2,2-dimethyl-propyl)-N-(2-morpholin-4-yl-2-oxo-ethyl)-acetamide (88 mg, 0.24 mmol) in DMF (1.25 mL) at room temperature, under nitrogen. Upon complete addition, the reaction was stirred at room temperature for 0.5 h, then warmed to 45° C. for 15 h. The reaction was cooled to room temperature and concentrated to dryness. The remaining residue was dissolved in EtOAc and washed with 5% citric acid (aqueous). The layers were separated and the aqueous phase was extracted with EtOAc (2×). The combined organics were dried (MgSO4), filtered and concentrated to give the crude product which was purified via reverse phase HPLC (C18 column, 20-100% CH3CN/H2O over 20 min at a flow rate of 20 mL/minute, UV detection was at 220 nm). Retention time of the product was 14.7 min. Product-containing fractions were concentrated to give 14 mg (15%) of the title compound.
Reaction SMILES: [C:1]([NH:5][C:6](=O)[C:7](=[N:11][NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8](=O)[CH3:9])([CH3:4])([CH3:3])[CH3:2].NC1C=CC=CC=1.C(NC(=O)CC(C)=O)(C)(C)C.O.[NH2:39][NH2:40]>C(O)C>[C:1]([NH:5][C:6]1[C:7](=[N:11][NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([CH3:9])=[N:40][N:39]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)C(=NNc1ccccc1)C(=O)NC(C)(C)C
Reactant: NN
Agent: CC(=O)CC(=O)NC(C)(C)C
Solvent: Nc1ccccc1
Solvent: CCO
Solvent: O
Product: CC1=NN=C(NC(C)(C)C)C1=NNc1ccccc1
Temperature: 25 °C
Yield: 36.9 %

Procedure:
The title compound was prepared using 100 mg (0.4 mmol) of N-tert-butyl-3-oxo-2-(phenylhydrazono)butyramide which was synthesized using aniline (1.7 mmol) and N-tert-butyl acetoacetamide (393 mg, 2.5 mmol). Hydrazine hydrate (2.3 mmol) was added to a solution of N-tert-butyl-3-oxo-2-(phenylhydrazono)butyramide in ethanol. Very little solid had formed after heating the reaction at 75° C. for 1 hour, however, analysis of the reaction solution by TLC indicated that no starting material remained. The solution was allowed to cool to ambient temperature and the solvent was evaporated. The residue was recrystallized from ethanol/water. The resulting solid was isolated by filtration and dried to yield 38 mg (43%) of the title compound as a yellow solid. 1H NMR (ppm, 200 MHz, CDCl3) δ 1.42 (s, 9H), 2.20 (s, 3H), 5.35 (br s, 1H), 6.95 (t, 1H), 7.15-7.35 (m, 4H), 9.95 (br s, 1H); IR (cm−1, KBr pellet): 3368 (w), 3197 (w), 3038 (w), 2973 (w), 2928 (w), 1631 (m), 1602 (m), 1565 (m), 1516 (s), 1498 (s), 1391 (w), 1366 (m), 1225 (m), 1187 (w), 1166 (w), 1119 (w), 1074 (w), 1059 (w), 949 (w), 895 (w), 775 (w), 748 (w), 691 (m), 561 (w); MS (m/z, ES+): 276.2 (M+18, 5%), 259.2 (M+1, 1%), 203.1 (M-55, 5%).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:12][CH2:13][C:14]1[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=1[CH2:16][N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19]>>[Cl:11][C:9]1[N:10]=[C:3]2[C:2]([NH:12][CH2:13][C:14]3[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=3[CH2:16][N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: CN(Cc1ccccc1CN)S(C)(=O)=O
Reactant: Clc1nc2c(Br)cccn2n1
Product: CN(Cc1ccccc1CNc1cccn2nc(Cl)nc12)S(C)(=O)=O

Procedure:
156 c) N-{2-[(2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-methyl]-benzyl}-N-methyl-methanesulfonamide was prepared 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (500.0 mg, 2.151 mmol) and N-(2-aminomethyl-benzyl)-N-methyl-methanesulfonamide (540.0 mg, 2.365 mmol) in a manner analogous to Example 2d. 1H NMR (400 MHz, CDCl3, δ, ppm): 7.88 (d, J=6.7 Hz, 1H), 7.46-7.42 (m, 1H), 7.38-7.30 (m, 3H), 6.88 (t, J=7.6 Hz, 1H), 6.50 (d, J=7.9 Hz, 1H), 5.25-5.19 (m, 1H), 4.60 (d, J=5.5 Hz, 2H), 4.40 (s, 2H), 2.87 (s, 3H), 2.73 (s, 3H). MS=380 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:11]2[NH:19][C:14]3=[CH:15][N:16]=[CH:17][CH:18]=[C:13]3[CH:12]=2)[OH:10])=[CH:5][CH:4]=1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[NH:19][C:14]3=[CH:15][N:16]=[CH:17][CH:18]=[C:13]3[CH:12]=2)=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(O)c2cc3ccncc3[nH]2)cc1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2cc3ccncc3[nH]2)cc1
Yield: 99 %

Procedure:
(4-Methoxyphenyl)(1H-pyrrolo[2,3-c]pyridin-2-yl)methanone (87 mg, 99%) was prepared as an off-white solid following the procedure described for Example 100 using (4-methoxyphenyl)(1H-pyrrolo[2,3-c]pyridin-2-yl)methanol (Example 99) and tetrahydrofuran as a solvent: mp 225-228° C.; 1H NMR (300 MHz, CD3OD) δ3.92 (3H, s), 7.10-7.19 (3H, m), 7.75-7.76 (1H, m), 8.02-8.06 (2H, m), 8.16 (1H, d, J=5.6 Hz), 8.86 (1H, s); ESI MS m/z 253 [C15H12N2O2+H]+; HPLC (Method A) >99% (AUC), tR=15.3 min.