Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[Li].BrC1C=CC=CN=1.C([Li])CCC.[CH3:20][O:21][C:22]1[CH:38]=[CH:37][C:25]([C:26]([NH:28][C:29]2[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=2[CH:31]=[O:32])=[O:27])=[CH:24][CH:23]=1>O1CCCC1.CCCCCC.CCOCC>[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]([NH:28][C:29]2[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=2[CH:31]([OH:32])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[O:27])=[CH:37][CH:38]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2C=O)cc1
Reactant: [Li]c1ccccn1
Agent: Brc1ccccn1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(C(=O)Nc2ccccc2C(O)c2ccccn2)cc1
Reaction time: 0.33 h
Yield: 46 %

Procedure:
Pyridyl lithium, prepared by adding 2-bromopyridine (30.0 g., 0.19 mole) in 200 ml. of ether to 131 ml. of a hexane solution of 1.6 molar n-butyl lithium (0.2 mole) at -70°C., is added in 25 min. to a solution of o-(4-methoxybenzamido)benzaldehyde (8.6 g., 0.035 mole) in 300 ml. of tetrahydrofuran at -25°C. over a 20 min. period with stirring. Stirring is continued for 20 min. at -25°C. 1 hr. at -10°C. and then at 0°C. for 30 min. The reaction mixture is poured into 1500 ml. of cold 1N hydrochloric acid, the aqueous layer separated, washed with ethyl acetate, made strongly basic with concentrated ammonium hydroxide and extracted with ethyl acetate. The ethyl acetate extract is washed with water, brine, dried over sodium sulfate and concentrated and the residue thus obtained triturated with ether to provide a 46% yield of 4-methoxy-2'-[hydroxy(2-pyridyl)methyl]benzanilide, m.p. 127.5°-128.5°C. (corr.).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[NH:6][C:5](=[O:7])[N:4]([C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[O:9])[C:3]1=[O:20].[H-].[Na+].[C:24]([C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1)#[N:25].C(OCC)(=O)C>CN(C=O)C>[CH3:1][C:2]1([CH3:21])[N:6]([CH2:30][C:29]2[CH:32]=[CH:33][C:26]([C:24]#[N:25])=[CH:27][CH:28]=2)[C:5](=[O:7])[N:4]([C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[O:9])[C:3]1=[O:20]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: CC1(C)NC(=O)N(C(=O)c2cccc3ccccc23)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)C(=O)N(C(=O)c2cccc3ccccc23)C(=O)N1Cc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.7 %

Procedure:
5,5-Dimethyl-3-naphthylcarbonylimidazolidine -2,4-dione (35 mg) was dissolved in DMF (0.4 mL) and sodium hydride (60%, in oil) (5 mg) was added. Then, 4-cyanobenzyl bromide (25 mg) was added, and the mixture was stirred at room temperature overnight. Ethyl acetate (9.5 mL) was added to the reaction solution, separated out white precipitates were filtered, and the filtrate was concentrated and purified by silica gel chromatography (hexane:ethyl acetate=2:1) to obtain 24 mg of white crystals.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5].C(O[CH:10]=[CH2:11])=C.[CH2:12]([SiH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[CH3:13]>>[CH2:12]([Si:14]([CH2:10][CH3:11])([CH2:17][CH3:18])[CH2:15][CH2:16][O:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:6])[CH3:13]
Reactant: CC[SiH](CC)CC
Reactant: C=COC=C
Reactant: OCCCCO
Product: CC[Si](CC)(CC)CCOCCCCO
Temperature: 60 °C
Reaction time: 18 h

Procedure:
A 50 ml reaction flask was charged with 11.6 ml (100 mmol) of 1,4-butandiol-mono vinylether and a catalytic amount of divinyl-tetramethyl disiloxane platinum complex under inert atmosphere and heated to 60° C. 10.4 g (90 mmol) of triethylsilane was slowly added to the reaction flask through a dropping funnel. The exothermic reaction mixture was stirred at 75° C. for 18 hours, followed by distillation at 105° C. to 107° C./0.2 mbar over a 10 cm Vigreux column. This reaction yielded 15.2 g (66% of the theory) of a clear liquid. Purity according to gas chromatography was 98.7%.
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=O)[CH2:16][C:17](=O)[C:18]([F:21])([F:20])[F:19])=[CH:11][C:10]=1[CH2:24][CH3:25])(C(C)(C)C)(C)C.Cl.F[C:28]1[CH:33]=[C:32]([S:34]([CH3:37])(=[O:36])=[O:35])[CH:31]=[CH:30][C:29]=1[NH:38][NH2:39].O.[F-:41].C([N+](CCCC)(CCCC)CCCC)CCC>C(O)C>[CH2:24]([C:10]1[CH:11]=[C:12]([C:15]2[N:38]([C:29]3[CH:30]=[CH:31][C:32]([S:34]([CH3:37])(=[O:36])=[O:35])=[C:33]([F:41])[CH:28]=3)[N:39]=[C:17]([C:18]([F:19])([F:20])[F:21])[CH:16]=2)[CH:13]=[CH:14][C:9]=1[OH:8])[CH3:25]
Reactant: [F-]
Reactant: CCc1cc(C(=O)CC(=O)C(F)(F)F)ccc1O[Si](C)(C)C(C)(C)C
Reactant: CS(=O)(=O)c1ccc(NN)c(F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCc1cc(-c2cc(C(F)(F)F)nn2-c2ccc(S(C)(=O)=O)c(F)c2)ccc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.3 %

Procedure:
To a stirred solution of 1-(4-[[tert-butyl(dimethyl)silyl]oxy]-3-ethylphenyl)-4,4,4-trifluoro-1,3-butanedione (749 mg, 2.0 mmol) in ethanol (25 ml) was added (2-fluoro-4-methylsulfonylphenyl)hydrazine hydrochloride (530 mg, 2.2 mmol), and the mixture was heated at reflux temperature for 16 hours. The reaction mixture was cooled down to room temperature, and poured into water. The whole was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was dissolved in THF (5 ml). Tetrabutylammonium fluoride (1.0 M solution in THF; 2.5 ml, 2.5 mmol) was added, and the mixture was stirred for 1 hour. Then, the reaction mixture was poured into water. The whole was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate-hexane (1:2) to give title compound (140 mg, 16% yield).
Reaction SMILES: [CH3:1][C:2]1[Te:3][C:4]2[CH:14]=[C:13]([CH3:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:5]=2[N:6]=1.[F:16][C:17]([F:24])([F:23])[S:18]([O:21]C)(=[O:20])=[O:19]>ClCCl>[F:16][C:17]([F:24])([F:23])[S:18]([O-:21])(=[O:20])=[O:19].[CH3:17][N+:6]1[C:5]2[C:7]3[C:12]([C:13]([CH3:15])=[CH:14][C:4]=2[Te:3][C:2]=1[CH3:1])=[CH:11][CH:10]=[CH:9][CH:8]=3
Reactant: Cc1nc2c(cc(C)c3ccccc32)[te]1
Reactant: COS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc2[te]c(C)[n+](C)c2c2ccccc12
Product: O=S(=O)([O-])C(F)(F)F

Procedure:
2,5-Dimethylnaphtho[1,2-d]tellurazole (Example 28) (0.93 g=0.003 mole) was dissolved in dry dichloromethane, and methyl trifluoromethanesulfonate (0.33 ml=0.003 mole) was added. The flask was sealed and kept over a weekend. Bright yellow plates (0.88 g, 61% of theory) formed. The product was recrystallized from 10 ml of acetone by addition of 20 ml of diethyl ether. The melting point was 224°-230° C. The mass and nuclear magnetic resonance spectra were in agreement with that expected for the structural formula.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[S:8][C:9]=1[CH2:10][N:11]1[C:15]2=[N:16][CH:17]=[C:18]([OH:20])[CH:19]=[C:14]2[CH:13]=[CH:12]1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:37](Br)[CH:38]=[CH2:39].C(OCC)(=O)C>CN(C)C=O>[CH2:39]([O:20][C:18]1[CH:19]=[C:14]2[CH:13]=[CH:12][N:11]([CH2:10][C:9]3[S:8][C:7]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:30])[F:29])=[CH:23][CH:22]=4)=[N:6][C:5]=3[CH2:1][CH2:2][CH2:3][CH3:4])[C:15]2=[N:16][CH:17]=1)[CH:38]=[CH2:37]
Reactant: C=CCBr
Reactant: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1Cn1ccc2cc(O)cnc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCOc1cnc2c(ccn2Cc2sc(-c3ccc(C(F)(F)F)cc3)nc2CCCC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
730 mg 1-[4-Butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-1H-pyrrolo[2,3-b]pyridin-5-ol were dissolved in 20 ml dimethylformamide and 1.1 mg cesium carbonate and 410 mg allylbromide were added. The reaction mixture was stirred at room temperature for one hour then 100 ml ethyl acetate were added and the mixture was washed five times with portions of 20 ml of water The organic layer was dried over MgSO4 and the solvent removed under reduced pressure. This gives 800 mg 5-Allyloxy-1-[4-butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-1H-pyrrolo[2,3-b]pyridine as yellow oil.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:31])[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:17]=[C:16]([C:18]3[N:19]([CH3:30])[N:20]=[N:21][C:22]=3[C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[N:15]=[CH:14]2)=[CH:9][CH:8]=1>O.C1COCC1.CO>[F:29][C:26]1[CH:27]=[CH:28][C:23]([C:22]2[N:21]=[N:20][N:19]([CH3:30])[C:18]=2[C:16]2[N:15]=[CH:14][N:13]([C:10]3[CH:9]=[CH:8][C:7]([C:6]([OH:31])=[O:5])=[CH:12][CH:11]=3)[CH:17]=2)=[CH:24][CH:25]=1
Reactant: COC(=O)c1ccc(-n2cnc(-c3c(-c4ccc(F)cc4)nnn3C)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cn1nnc(-c2ccc(F)cc2)c1-c1cn(-c2ccc(C(=O)O)cc2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
A solution of lithium hydroxide monohydrate (85 mg, 2.01 mmol) in water (2.5 mL) was added dropwise to a suspension of 4-{4-[5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-yl]-imidazol-1-yl}-benzoic acid methyl ester (380 mg, 1.01 mmol) in THF (2.5 mL) and methanol (0.5 mL). The reaction mixture was then stirred at room temperature for 1 h and was then evaporated and the residue dissolved in water, acidified with HCl (1 N), and the resulting precipitate filtered off to afford the title product (315 mg, 86%) as a white solid. MS: m/e=362.3 [M−H]−.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH:9]1[C:14]1[N:19]=[C:18]([CH:20]2[CH2:25][NH:24][CH2:23][CH2:22][N:21]2[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:17]=[C:16](Cl)[N:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:34][NH2:35]>O1CCOCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH:9]1[C:14]1[N:19]=[C:18]([CH:20]2[CH2:25][NH:24][CH2:23][CH2:22][N:21]2[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:17]=[C:16]([NH:34][NH2:35])[N:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: Clc1cc(C2CNCCN2Cc2ccccc2)nc(C2CNCCN2Cc2ccccc2)n1
Solvent: C1COCCO1
Product: NNc1cc(C2CNCCN2Cc2ccccc2)nc(C2CNCCN2Cc2ccccc2)n1
Yield: 96.4 %

Procedure:
A solution of 2,4-di(N-benzylpiperazinyl)-6-chloropyrimidine (48.4 g, 104 mmol), hydrazine (96 g, 3 mol), in p-dioxane (1000 mL) was heated at 75° C. for 16 hours. The reaction was concentrated, dissolved in CH2Cl21 washed with H2O, and dried (MgSO4). Filtration and concentration of the resulting solution gave 46 g (97%) of the title compound as a foam. 1H NMR (CDCl3) δ 2.44 (m, 8H, piperazine), 3.52-3.59 (m, 8H, piperazine), 3.71 (m, 4H, CH2), 5.22 (s, 1H, C5H), 5.72 (bs, 2H, NH2)1 7.30 (m, 10H, Ar).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:27]1[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][N:28]=1>>[CH3:33][C:32]1[C:27]([C:4]([C:6]2[N:7]=[CH:8][N:9]([C:11]3[CH:12]=[C:13]([C:17]4[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:14]=[CH:15][CH:16]=3)[CH:10]=2)=[O:5])=[N:28][CH:29]=[CH:30][CH:31]=1
Reactant: Cc1cccnc1Br
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3C#N)c2)cn1
Product: Cc1cccnc1C(=O)c1cn(-c2cccc(-c3ccccc3C#N)c2)cn1

Procedure:
This compound is prepared by method C using compound 12d and 2-bromo-3-methylpyridine.
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]4[CH2:23][C:22]([CH3:25])([CH3:24])[NH:21][C:20]([CH3:27])([CH3:26])[CH2:19]4)[N:12]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH:28]([N:30]1[CH:34]=[CH:33][N:32]=[CH:31]1)=[CH2:29].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[N:30]1(/[CH:28]=[CH:29]/[C:2]2[CH:10]=[C:9]3[C:5]([C:6]([C:11]4[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]5[CH2:19][C:20]([CH3:27])([CH3:26])[NH:21][C:22]([CH3:24])([CH3:25])[CH2:23]5)[N:12]=4)=[CH:7][NH:8]3)=[CH:4][CH:3]=2)[CH:34]=[CH:33][N:32]=[CH:31]1
Reactant: C=Cn1ccnc1
Reactant: CC1(C)CC(Nc2nccc(-c3c[nH]c4cc(Cl)ccc34)n2)CC(C)(C)N1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CC1(C)CC(Nc2nccc(-c3c[nH]c4cc(/C=C/n5ccnc5)ccc34)n2)CC(C)(C)N1

Procedure:
The title compound was prepared by the general Heck procedure described in Example 256, using the SEM-protected intermediate of Example 229 and 1-vinyl-1H-imidazole, followed by TBAF deprotection of the SEM group.
Reaction SMILES: [OH:1][CH:2]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6](=[O:14])[CH2:5][CH2:4][CH2:3]1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>>[C:15]([O:1][CH:2]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6](=[O:14])[CH2:5][CH2:4][CH2:3]1)(=[O:17])[CH3:16]
Reactant: O=C1CCCC(O)c2ccccc2N1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OC1CCCC(=O)Nc2ccccc21
Temperature: 25 °C

Procedure:
A solution of 6-hydroxy-3,4,5,6-tetrahydro-1-benzazocin-2-(1H)one (9.2 g) in acetic anhydride (200 ml) is maintained at 80° C. for 3 hours. The reaction mixture is cooled to room temperature and the solvents removed under reduced pressure. Ether (300 ml) is added, and their resulting solution washed with water (150 ml) and dried over magnesium sulfate. The solvent is removed under reduced pressure to give 6-acetoxy-3,4,5,6-tetrahydro-1-benzazocin-2(1H)-one.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]3[N:14]=[CH:15][C:16]([C:17]([NH2:19])=[O:18])=[C:12]3[NH:11][CH2:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)=O.[H-].[Na+].[N:25]#[C:26]Br>O1CCCC1.O.CC(C)=O>[NH2:25][C:26]1[N:11]2[C:12]3[N:13]([C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH2:10]2)[N:14]=[CH:15][C:16]=3[C:17](=[O:18])[N:19]=1
Reactant: N#CBr
Reactant: NC(=O)c1cnn2c1NCC=C2c1cccc(F)c1
Agent: O=C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: Nc1nc(=O)c2cnn3c2n1CC=C3c1cccc(F)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 6.9 %

Procedure:
To a stirred suspension of 5.0 g of 7-(3-fluorophenyl)-4,5-dihydropyrazolo[1,5-a]pyrimidine-3-carboxamide (Example 6) in 250 ml of dry tetrahydrofuran, cooled to -78° C. (dry-ice, acetone) was added 1.70 g of sodium hydride (60% dispersion in mineral oil) in one portion. The reaction mixture was stirred at -78° C. for 30 minutes then 2.05 g of cyanogen bromide was added and the mixture was stirred for an additional 2 hours at -78° C., then slowly allowed to warm to room temperature over 16 hours. The reaction mixture was diluted with water and the solid was collected by filtration, washed with water, then ether to give 376 mg of the desired product as a white solid.
Reaction SMILES: [CH2:1]([CH:3]([O:6][C:7]1[C:12]([C:13](O)=[O:14])=[C:11]([NH:16][C:17]2[C:22]([CH3:23])=[CH:21][C:20]([Cl:24])=[CH:19][C:18]=2[CH3:25])[N:10]=[C:9]([CH3:26])[CH:8]=1)[CH2:4][CH3:5])[CH3:2].CSC>C1COCC1>[Cl:24][C:20]1[CH:19]=[C:18]([CH3:25])[C:17]([NH:16][C:11]2[C:12]([CH2:13][OH:14])=[C:7]([O:6][CH:3]([CH2:1][CH3:2])[CH2:4][CH3:5])[CH:8]=[C:9]([CH3:26])[N:10]=2)=[C:22]([CH3:23])[CH:21]=1
Reactant: CCC(CC)Oc1cc(C)nc(Nc2c(C)cc(Cl)cc2C)c1C(=O)O
Solvent: C1CCOC1
Solvent: CSC
Product: CCC(CC)Oc1cc(C)nc(Nc2c(C)cc(Cl)cc2C)c1CO
Reaction time: 0.5 h

Procedure:
To a solution of 4-(1-ethyl-propoxy)-6-methyl-2-(4-chloro-2,6-dimethyl-phenylamino)-nicotinic acid in dry THF was added BH3.DMS. The resulting mixture was heated at reflux overnight. The mixture was quenched with dilute HCl and stirred for 30 minutes, adjusted pH to 7.5-8.5, then extracted with ethyl acetate. The organic layer was separated, dried and concentrated to give a brown oil. After silica gel column chromatography, the title compound was obtained as a green oil. 1H NMR(CDCl3) d. 7.02(s,2H), 6.83(brs,1H), 4.78(s,2H), 4.14(m,1H), 2.2(s,3H), 2.13(s,6H), 1.66(m,4H), 0.93(9t,6H) ppm.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4](=[O:16])[NH:5][C:6]([CH3:15])=[CH:7][C:8]=1[CH:9]1CCC[CH2:11][CH2:10]1.CC1NC(=O)C(C#N)=C(CCC)C=1>>[NH2:1][CH2:2][C:3]1[C:4](=[O:16])[NH:5][C:6]([CH3:15])=[CH:7][C:8]=1[CH2:9][CH2:10][CH3:11]
Reactant: Cc1cc(C2CCCCC2)c(CN)c(=O)[nH]1
Agent: CCCc1cc(C)[nH]c(=O)c1C#N
Product: CCCc1cc(C)[nH]c(=O)c1CN

Procedure:
The title compound was prepared in the same manner as described for 3-(aminomethyl)-4-cyclohexyl-6-methyl-2(1H)-pyridinone (Intermediate 3) using 6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinecarbonitrile (2 g, 11.2 mmol). Obtained: 1.2 g (60%). LCMS E-S (M+H)=181.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.85-7.95 (br s, 3H), 5.99 (s, 1H), 3.80-3.85 (m, 2H), 2.42 (t, 2H), 2.14 (s, 3H), 1.43-1.49 (m, 2H), 0.86 (t, 3H).
Reaction SMILES: C([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:40])[CH2:14][CH2:15][N:16]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:17][CH2:18][C:19]([N:21]1[CH2:25][CH2:24][CH2:23][C@@H:22]1[C:26]([O:28]C(C)(C)C)=[O:27])=[O:20])=[O:7])(C)(C)C.[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44]>ClCCl.CCOCC>[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44].[CH2:33]([N:16]([CH2:15][CH2:14][C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:8]1[C:6]([OH:7])=[O:5])=[O:40])[CH2:17][CH2:18][C:19]([N:21]1[CH2:25][CH2:24][CH2:23][C@@H:22]1[C:26]([OH:28])=[O:27])=[O:20])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1C(=O)CCN(CCC(=O)N1CCC[C@@H]1C(=O)OC(C)(C)C)Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(O)[C@H]1CCCN1C(=O)CCN(CCC(=O)N1CCC[C@@H]1C(=O)O)Cc1ccccc1
Reaction time: 16 h
Yield: 80 %

Procedure:
To a stirred solution of 200 mg (0.36 mmol) (R)-1-[3-[benzyl-[3-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-3-oxo-propyl]-amino]-propionyl]-pyrrolidine-2-carboxylic acid tert-butyl ester in 5 ml dichloromethane at 0° C. was added dropwise 1.0 ml trifluoroacetic acid and stirring continued for 16 h at room temperature. Concentration in vacuo and azeotroping three times with chloroform on a rotary evaporator afforded, after trituration in ether, 160 mg (80%) of the title compound as a yellow crystalline solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][N:23]=1)[C:17]([O:19][CH3:20])=[O:18].[CH3:24][N:25]([CH2:37][CH2:38][N:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1)[C:26]([C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31](O)=[O:32])=[O:27].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[CH3:24][N:25]([CH2:37][CH2:38][N:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1)[C:26]([C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][N:23]=1)[C:17]([O:19][CH3:20])=[O:18])=[O:32])=[O:27]
Reactant: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)O)c1
Reactant: COC(=O)c1ccnc(-c2cc(N3CCCCC3)ccc2N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(C(=O)N(C)CCN3CCOCC3)c2)c1
Reaction time: 2 h
Yield: 81.9 %

Procedure:
A solution of 150 mg of methyl 2-(2-amino-5-(piperidin-1-yl)phenyl)isonicotinate 1.1h, 169 mg of 3-(methyl(2-morpholinoethyl)carbamoyl)benzoic acid, and 249 mg of diisopropylethylamine in 3 mL of DMF was treated with 202 mg of HATU. The mixture was stirred for 2 h and then it was diluted with 20 mL of water. The resulting precipitate was collected by filtration and dissolved in dichloromethane. The solution was washed with water and then dried over Na2SO4. The solvent was evaporated to give the product as 231 mg of an orange oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc(C)cn1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)cn1

Procedure:
To a mixture of methyl 5-methylpicolinate (1.25 g; 8.27 mmol) in carbon tetrachloride (45 mL) was added N-bromosuccinimide (1.78 g, 9.92 mmol) and benzoyl peroxide (0.205 g; 0.827 mmol). The mixture was refluxed for 18 hours and the resulting suspension was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent 0 to 8% ethyl acetate in dichloromethane) to 0.450 g (24%) of methyl 5-(bromomethyl)picolinate as a beige solid.
Reaction SMILES: [I-:1].[Cl:2][C:3]1[CH:4]=[C:5]([C:10]2[O:11][C:12](=[CH:17][I:18])[C:13]([CH3:16])([CH3:15])[NH+:14]=2)[CH:6]=[C:7]([Cl:9])[CH:8]=1.ClN1C(=[O:25])CCC1=O>CO.O>[I:1][CH:17]([I:18])[C:12](=[O:11])[C:13]([NH:14][C:10](=[O:25])[C:5]1[CH:4]=[C:3]([Cl:2])[CH:8]=[C:7]([Cl:9])[CH:6]=1)([CH3:16])[CH3:15]
Reactant: CC1(C)[NH+]=C(c2cc(Cl)cc(Cl)c2)OC1=CI
Reactant: [I-]
Reactant: O=C1CCC(=O)N1Cl
Solvent: CO
Solvent: O
Product: CC(C)(NC(=O)c1cc(Cl)cc(Cl)c1)C(=O)C(I)I
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.7 %

Procedure:
2-(3',5'-dichlorophenyl)-5-iodomethylene-4,4-dimethyloxazolinium iodide (5.0 gm, 0.0098 m) was disolved in methanol (200 ml) and N-chlorosuccinimide (3.3 gm, 0.025 m) was added. The mixture was stirred at room temperature for about 1 hour, then diluted with enough water to obtain a cloudy solution and stirred overnight. The reaction mixture was further diluted with water, then filtered and the solid obtained was dried and recrystallized from a mixture of ethyl acetate and hexane to yield 3.8 gm of the desired product.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].[OH-].[K+].I[C:13]1[C:18]([Cl:19])=[CH:17][C:16]([N+:20]([O-:22])=[O:21])=[CH:15][C:14]=1[Cl:23].CCOC(C)=O>CN1CCCC1=O>[Cl:19][C:18]1[CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=[C:14]([Cl:23])[C:13]=1[O:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([CH3:1])[CH:3]=1
Reactant: Cc1cc(O)ccc1F
Reactant: O=[N+]([O-])c1cc(Cl)c(I)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1cc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)ccc1F
Temperature: 130 °C
Reaction time: 2 h
Yield: 82.9 %

Procedure:
A mixture of 3-methyl-4-fluorophenol (99 mg, 0.79 mmol), potassium hydroxide (53 mg, 0.94 mmol), 4-iodo-3,5-dichloro-nitrobenzene (250 mg, 0.79 mmol) and 4A° molecular sieves (75 mg) in N-methylpyrolidinone (3 mL) was stirred at 130° C. for 2 h. The reaction mixture was poured into ice cold 1 N HCl (20 mL) and EtOAc (25 mL) was added. The EtOAc phase was separated and washed with 1N HCl (3×25 mL) and brine (25 mL). The EtOAc solution was dried over Na2SO4, filtered and concentrated. The residue was purified by preparative TLC (Hexanes: CH2Cl2=7:3) to afford 3,5-dichloro-4-(4-fluoro-3-methyl-phenoxy)-nitrobenzene (207 mg). MS Calc.: 315.0 Found: 315.0 (M).
Reaction SMILES: O[Li:2].O.C[O:5][C:6](=[O:47])[CH:7]([C:9]1[CH:46]=[CH:45][CH:44]=[CH:43][C:10]=1[CH2:11][CH2:12][C:13]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH:30]3[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]3)=[CH:26][CH:25]=2)[N:14]=1)[CH3:8]>C1COCC1.O.CO>[C:39]([O:38][C:36]([N:33]1[CH2:34][CH2:35][CH:30]([C:27]2[CH:26]=[CH:25][C:24]([NH:23][C:15]3[N:14]=[C:13]([CH2:12][CH2:11][C:10]4[CH:43]=[CH:44][CH:45]=[CH:46][C:9]=4[CH:7]([CH3:8])[C:6]([O-:47])=[O:5])[C:18]([C:19]([F:21])([F:20])[F:22])=[CH:17][N:16]=3)=[CH:29][CH:28]=2)[CH2:31][CH2:32]1)=[O:37])([CH3:40])([CH3:41])[CH3:42].[Li+:2]
Reactant: COC(=O)C(C)c1ccccc1CCc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Reactant: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C(=O)[O-])c1ccccc1CCc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Product: [Li+]
Temperature: 25 °C
Reaction time: 20 h

Procedure:
LiOH.H2O (17.3 mg, 0.413 mmol) was added to a solution of tert-butyl 4-(4-((4-(2-(1-methoxy-1-oxopropan-2-yl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I53) (0.084 g, 0.137 mmol) in THF (7 mL), water (1.5 mL) and methanol (1 mL). The resulting mixture was allowed to stir at room temperature for 20 hours. The volatiles were removed in vacuo and the residue diluted with EtOAc (50 mL) and sat. aq. NaHCO3(50 mL). The layers were separated and the aqueous layer was extracted with EtOAc (1×50 mL). The organic layers were combined, washed with brine (50 mL), dried with Na2SO4, filtered and concentrated under reduced pressure to give the title compound (I54) (86 mg) as a pale yellow viscous oil.