Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[O:15][CH2:16][C:17](O)=[O:18]>C(Cl)(Cl)Cl.S(Cl)(Cl)=O>[N:1]1([C:17](=[O:18])[CH2:16][O:15][C:14]2[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:12]([O:11][CH3:10])[CH:13]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: COc1ccc(OCC(=O)O)cc1OC
Reactant: c1ccc2[nH]nnc2c1
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: COc1ccc(OCC(=O)n2nnc3ccccc32)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 109.2 %

Procedure:
To a solution of 1H-benzo[d][1,2,3]triazole (11.2 g) in CHCl3 (120 ml), thionyl chloride (1.7 ml) was added and after stirring at room temperature for 30 minutes, 2-(3,4-dimethoxyphenoxy)acetic acid (5.00 g) was added and the mixture was stirred at room temperature for 1.5 hours. The precipitate was filtered off and the filtrate was washed with an aqueous solution of 2 N NaOH; thereafter, the organic layer was dried (MgSO4), filtered and concentrated to give the titled compound (8.06 g, colorless solid.)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1/[C:13](=[CH:18]\[O:19][CH3:20])/[C:14]([O:16][CH3:17])=[O:15].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH2:24]([O:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1/[C:13](=[CH:18]\[O:19][CH3:20])/[C:14]([O:16][CH3:17])=[O:15])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CO/C=C(/C(=O)OC)c1ccccc1COc1cccc(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CO/C=C(/C(=O)OC)c1ccccc1COc1cccc(OCc2ccccc2)c1
Yield: 70.6 %

Procedure:
A solution of (E)-methyl 2-(2-((3-hydroxyphenoxy)methyl)phenyl)-3-methoxyacrylate (0.2 g, 0.63 mmol) obtained in Step 1, benzyl bromide (0.1 mL, 0.84 mmol) and cesium carbonate (0.31 g, 0.95 mmol) in 20 mL of acetonitrile (CH3CN) was stirred at room temperature for 3 hours after which the reaction solvent was removed by concentration in a vacuum. The residue was stirred in water (20 mL) and the aqueous layer was extracted twice with 20 mL of dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in a vacuum. The concentrate was purified by silica gel chromatography to afford (E)-methyl 2-(2-((3-(benzyloxy)phenoxy)methyl)phenyl)-3-methoxyacrylate as a white solid (0.18 g, yield 70%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=[O:12])[CH:2]=1.[BH4-].[Na+]>C(O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH2:11][OH:12])[CH:2]=1
Reactant: O=Cc1cnc2ccccc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1cnc2ccccc2c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In a 250 mL round bottom flask, quinoline-3-carbaldehyde (1.57 g, 10 mmol) was dissolved anhydrous ethanol (20 mL). The solution was cooled to 0° C. under nitrogen. NaBH4 (420 mg, 11 mmol) was added in one portion. The mixture was stirred at room temperature for 2 hours, and quenched by addition of water (3 mL). Na2SO4 (15 g) was added. After 10 minutes, the mixture was filtered. The filtrate was evaporated to provide quinolin-3-ylmethanol.
Reaction SMILES: [C:1]([C:4]1[CH:21]=[CH:20][C:7]([CH2:8][C:9]2[C:14]([Cl:15])=[CH:13][C:12]([N+:16]([O-])=O)=[CH:11][C:10]=2[Cl:19])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].O.O.[Sn](Cl)Cl>C(OC(=O)C)C>[C:1]([C:4]1[CH:21]=[CH:20][C:7]([CH2:8][C:9]2[C:14]([Cl:15])=[CH:13][C:12]([NH2:16])=[CH:11][C:10]=2[Cl:19])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(Cc2c(Cl)cc([N+](=O)[O-])cc2Cl)cc1
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)c1ccc(Cc2c(Cl)cc(N)cc2Cl)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
In 11 ml of ethylacetate were dissolved 1.1 g 4-(4-Acetylbenzyl)-3,5-dichloronitrobenzene and 3.8 g Tin (11) chloride dihydrate. The solution was allowed to proceed for one hour at temperatures ranging from 40-50° C. After completion of the reaction. The reaction mixture was poured into 100 ml ice-water, followed by extraction with 150 ml ethylacetate. The extract was washed with water and 25% ammonia solution, dried over anhydrous magnesium sulfate, and concentrated to afford the titled compound in a yield of 100%, m.p. 97-98° C.
Reaction SMILES: [Cl:1][C:2]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][N:5]1[C@@H:10]([CH3:11])[CH2:9][NH:8][C:7](=[O:12])[C:6]1=[O:13].C(=O)([O-])[O-].[Na+].[Na+].F[B-](F)(F)F.[CH2:33]([O+](CC)CC)[CH3:34]>C(Cl)Cl>[Cl:1][C:2]1[C:17]([C:18]([F:21])([F:19])[F:20])=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][N:5]1[C@@H:10]([CH3:11])[CH2:9][N:8]=[C:7]([O:12][CH2:33][CH3:34])[C:6]1=[O:13]
Reactant: CC[O+](CC)CC
Reactant: C[C@H]1CNC(=O)C(=O)N1Cc1cccc(C(F)(F)F)c1Cl
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC1=NC[C@H](C)N(Cc2cccc(C(F)(F)F)c2Cl)C1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 101.7 %

Procedure:
To an ice cooled solution of Intermediate 4 (1.0 g, 3.1 mmol) and sodium carbonate (6.6 g, 62 mmol) in DCM (45 mL) was added triethyloxonium tetrafluoroborate (1M in DCM, 15.6 mL, 15.6 mmol) dropwise. The ice bath was removed and the reaction was stirred at rt for 1.5 h. Water was added and the mixture was extracted with DCM (×3). The combined organic extracts were dried (Na2SO4), filtered, and concentrated to afford a yellow oil (1.1 g, 99%), which was used directly without further purification.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:9]=[C:8]([NH2:10])[NH:7][N:6]=1)=O.[NH3:11]>CO>[NH2:10][C:8]1[NH:7][N:6]=[C:5]([C:3]([NH2:11])=[O:2])[CH:9]=1
Reactant: COC(=O)c1cc(N)[nH]n1
Reactant: N
Solvent: CO
Product: NC(=O)c1cc(N)[nH]n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1.0 g (7 mmol) of 5-amino-1H-pyrazole-3-carboxylic acid methyl ester in 10 mL of methanol (MeOH) in a sealed tube was saturated with ammonia (NH3), and the sealed tube mixture was stirred at rt overnight. Since analysis by thin layer chromatography (TLC) revealed that the reaction was not complete, the mixture was then heated at 80° for 1 day. The reaction mixture was then cooled, the sealed tube was opened, and the solvent was evaporated to give 0.9 g of desired 5-amino-1H-pyrazole-3-carboxylic acid amide as indicated by 1H NMR; LC-MS—calcd for C4H6N4O [M++H]+: 127.05, found: 127.2.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([C:8]2[CH:9]=[C:10]([NH:14][S:15]([CH2:18][CH3:19])(=[O:17])=[O:16])[CH:11]=[CH:12][CH:13]=2)=[O:7])[N:3]=[CH:2]1.[CH2:20]([Mg]Br)[CH3:21].CCOCC>C1COCC1>[OH:7][C:6]([C:8]1[CH:9]=[C:10]([NH:14][S:15]([CH2:18][CH3:19])(=[O:17])=[O:16])[CH:11]=[CH:12][CH:13]=1)([C:4]1[N:3]=[CH:2][NH:1][CH:5]=1)[CH2:20][CH3:21]
Reactant: CCS(=O)(=O)Nc1cccc(C(=O)c2c[nH]cn2)c1
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC(O)(c1cccc(NS(=O)(=O)CC)c1)c1c[nH]cn1
Temperature: 25 °C

Procedure:
To a solution of Example 55E (84 mg, 0.3 mmol) in THF (10 mL) at 0° C. was added dropwise a 2M solution of ethyl magnesium bromide in ether (0.6 mL, 1.2 mmol) and the resulting mixture was allowed to warm to room temperature for 6 hours. The mixture was quenched with saturated NH4Cl and concentrated under vacuum. The residue was passed through a Dowex® 50×8-400 ion exchange resin with 5% NH4OH as eluent. The ammonia solution was concentrated under vacuum and purified again by chromatography (silica gel, 9:1 CH2Cl2:ethanol) to provide 20 mg of the desired product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[CH:5]2.[CH3:17][Si:18]([C:21]#[CH:22])([CH3:20])[CH3:19]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1COCC1.C(N(CC)CC)C>[O:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH:11]1[N:7]1[C:8]2[C:4](=[CH:3][C:2]([C:22]#[C:21][Si:18]([CH3:20])([CH3:19])[CH3:17])=[CH:10][CH:9]=2)[CH:5]=[N:6]1
Reactant: Brc1ccc2c(cnn2C2CCCCO2)c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc2c(cnn2C2CCCCO2)c1
Temperature: 80 °C

Procedure:
To a 250-mL pressure tube, 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (11.9 g, 42.3 mmol; Intermediate 1), Pd(Ph3P)2Cl2 (1.48 g, 0.05 mmol), CuI (0.8 g, 4.2 mmol) and THF/triethylamine (5:1, 85 mL) were added. This mixture was degassed with three vacuum/N2 cycles, and then trimethylsilylacetylene (9 mL, 63.5 mmol) was added. The pressure tube was sealed and heated at 80° C. for 2 days. Upon completion by LCMS, the reaction mixture was cooled down to room temperature and filtered through Celite with ethyl acetate (200 mL). The filtrate was concentrated to give the crude product that was used directly in the next step. LCMS: 299 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[Br:12]Br.S(=O)(O)[O-].[Na+]>C(O)(=O)C.O>[Br:12][C:7]1[CH:6]=[C:5]([O:8][CH3:9])[C:4]([O:10][CH3:11])=[CH:3][C:2]=1[I:1]
Reactant: COc1ccc(I)cc1OC
Reactant: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(Br)c(I)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
4-Iodoveratrole (26.0 g, 0.0985M) in acetic acid (25 ml) was treated with bromine (6.5 ml, 0.127M) in acetic acid (30 ml) and stirred at room temperature for one hour. The mixture was diluted with water (300 ml) and treated with sodium bisulfite to discharge the excess bromine. The white solid was filtered, washed with water and dried in vacuo over P2O5 to give 4-bromo-5-iodoveratrole (33.0 g, 95% yield) as a white solid, mp 98°-100° C. (literature: Baker et al., J. Chem. Soc. 3986 (1961), mp 102°-104° C.). NMR (CDCl3) δ 3.83 ppm (s, 6H, (2x) OCH3), 7.06 (s, 1H, ArH), 7.21 (s, 1H, ArH).
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.CO.Br[CH:16]([C:19]1[C:24]([CH3:25])=[C:23]([O:26][CH3:27])[C:22]([CH3:28])=[CH:21][N:20]=1)[C:17]#[N:18]>[OH-].[Na+]>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([S:1][CH:16]([C:19]3[C:24]([CH3:25])=[C:23]([O:26][CH3:27])[C:22]([CH3:28])=[CH:21][N:20]=3)[C:17]#[N:18])[NH:3][C:4]=2[CH:10]=1
Reactant: COc1c(C)cnc(C(Br)C#N)c1C
Reactant: COc1ccc2nc(S)[nH]c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2nc(SC(C#N)c3ncc(C)c(OC)c3C)[nH]c2c1
Yield: 58 %

Procedure:
To a solution of 2-mercapto-5-methoxybenzimidazole (15.1 g, 0.14 mole) dissolved in 40 ml of 8.4% sodium hydroxide, was added 170 ml of methanol, followed by bromo(4-methoxy-3,5-dimethyl-2-pyridyl)acetonitrile(21.4 g, 0.11 mole) at room temperature. The mixture was heated to reflux for 1 h under a nitrogen atmosphere. The resulting precipitate was removed by filtration and the methanol was evaporated. The residue obtained was extracted with chloroform, and the chloroform was washed 3 times with water and dried over magnesium sulfate. After evaporation of the solvent, the crude product was recrystallized from diethyl ether to give 22.6 g (90%) of the title compound as yellowish crystals: mp 193°-197° C.; 1H NMR (CDCl3) δ8.25 (s,1H), 7.65 (dd, 1H), 7.30 (m, 1H), 6.90 (m, 1H), 6.30 (br s, 2H), 3.95 (s, 3H), 3.75 (s, 3H), 2.50 (s, 3H), 2.20 (s, 3H) ppm.
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:7]=1)[CH2:3][CH2:4][OH:5].[C:20]1(=O)[O:25][C:23](=[O:24])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.CCOC(C)=O>C(Cl)Cl>[CH:15]1([O:14][C:8]2[CH:7]=[C:6]([CH:2]([N:1]3[C:23](=[O:24])[C:22]4=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]4[C:20]3=[O:25])[CH2:3][CH2:4][OH:5])[CH:11]=[CH:10][C:9]=2[O:12][CH3:13])[CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: COc1ccc(C(N)CCO)cc1OC1CCCC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(C(CCO)N2C(=O)c3ccccc3C2=O)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 0.1 h
Yield: 77 %

Procedure:
A mixture of 3-amino-3-(3'-cyclopentyloxy-4'methoxyphenyl)-1-propanol (4.31 grams, 16.24 mmol) and phthalic anhydride (2.41 grams, 16.27 mmol) was melted with a heat gun for 6 minutes. The mixture was allowed to cool to room temperature. Chromatography (silica gel 100 grams, 1:5 EtOAc:CH2Cl2) gave 3-(3'-cyclopentyloxy-4'-methoxyphenyl)-3-phthalimido-1-propanol as solid, (4.97 grams, 77% yield): mp, 59.0°-61.0° C.; 1H NMR (CDCl3)δ1.56-1.98 (m, 9H, OH, C5H8), 2.48-2.59 (m, 1H, CHH), 2.71-2.83 (m, 1H, CHH), 3.66-3.74 (m, 2H, OCH2), 3.80 (s, 3H, CH3), 4.74-4.80 (m, 1H, CH), 5.51 (dd, J=6.5, 9.4 Hz, 1H, NCH), 6.78 (J=8.3 Hz, 1H, Ar), 7.05-7.09 (m, 1H, Ar), 7.16-7.17 (m, 1H, Ar), 7.64-7.70 (m, 2H, Ar), 7.75-7.81 (m, 2H, Ar); 13C NMR (CDCl3)δ24.02, 32.71, 38.84, 51.44, 55.94, 59.75, 80.35, 111.58, 115.06, 120.54, 123.12, 131.60, 131.80, 133.86, 147.48, 149.55, 168.43; Anal Calcd for C23H25NO5 : C, 69.86; H, 6.37; N, 3.54. Found: C, 69.51; H, 6.41; N, 3.54.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([O:19][CH3:20])[C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1.C([Li])(C)(C)C.[I:26]I>C1COCC1>[I:26][C:6]1[C:7]([O:19][CH3:20])=[C:8]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[C:3]([O:2][CH3:1])=[CH:4][N:5]=1
Reactant: II
Reactant: COc1ccc(COc2c(OC)cncc2OC)cc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1ccc(COc2c(OC)cnc(I)c2OC)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 57.2 %

Procedure:
To a solution of 3,5-dimethoxy-4-(4-methoxy-benzyloxy)-pyridine (120 mg, 0.436 mmol) in dry THF (3 ml) at −78° C. was added t-butyllithium (0.48 mmol, 1.7 M solution in pentane) and the resulting orange mixture was stirred at low temperature for 10 minutes. A solution of iodine (166 mg, 0.654 mmol) in dry THF (2 ml) was added drop-wise and the reaction allowed to warm to room temperature and stir for 15 minutes, then quenched with 10% Na2S2O3 (aq) and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4 and concentrated onto silica-gel under reduced pressure. The solid residue was purified by flash chromatography (silica-gel, eluted with hexanes:EtOAc, 4:1) to give the product as a tan solid (100 mg, 57%). 1H-NMR (300 MHz, CDCl3) δ 7.83 (s, 1H), 7.33 (d, J=8.6 Hz, 2H), 6.86 (d, J=8.6 Hz, 2H), 5.11 (s, 2H), 3.88 (s, 3H), 3.85 (s, 3H), 3.79 (s, 3H).
Reaction SMILES: [F:1]F.[S:3]1(=[O:12])(=[O:11])[CH2:8][CH2:7][CH2:6][S:5](=[O:10])(=[O:9])[NH:4]1.[F-].[Na+]>C(#N)C>[F:1][N:4]1[S:5](=[O:10])(=[O:9])[CH2:6][CH2:7][CH2:8][S:3]1(=[O:12])=[O:11]
Reactant: O=S1(=O)CCCS(=O)(=O)N1
Reactant: FF
Agent: [F-]
Agent: [Na+]
Solvent: CC#N
Product: O=S1(=O)CCCS(=O)(=O)N1F

Procedure:
0.5 l of a mixture of 10 parts by volume of fluorine and 90 parts by volume of nitrogen is introduced into a solution of 370 mg of [1,3,2]dithiazinane-1,1,3,3-tetraoxide (Geisler and Kuschmiers, "Chem. Ber." 91, p. 1881, 1958) in 23 ml of acetonitrile at -40° C. in the presence of 82 mg of sodium fluoride powder within 9 minutes. Then, it is flushed with pure nitrogen, concentrated by evaporation in a vacuum, taken up with dichloromethane, chromatographed on 60 g of silica gel, concentrated by evaporation in a vacuum, and recrystallized from acetone/hexane. 331 mg of N-fluoromethanesulfonimide is obtained as crystals with a melting point of 171°-172° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH3:11])=[C:4]([CH2:12][N:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[N:15]([CH:22]([CH2:27][CH2:28][CH3:29])[CH2:23][C:24]([OH:26])=[O:25])[C:14]2=[O:30])[CH:3]=1.CC([OH:35])(C)C.C1C(=O)N(Br)C(=O)C1>C1COCC1.[Zn]>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:35])[N:8]2[CH3:11])=[C:4]([CH2:12][N:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[N:15]([CH:22]([CH2:27][CH2:28][CH3:29])[CH2:23][C:24]([OH:26])=[O:25])[C:14]2=[O:30])[CH:3]=1
Reactant: CCCC(CC(=O)O)n1c(=O)n(Cc2cc(Br)cc3c2ccn3C)c2ccccc21
Reactant: CC(C)(C)O
Agent: O=C1CCC(=O)N1Br
Agent: [Zn]
Solvent: C1CCOC1
Product: CCCC(CC(=O)O)n1c(=O)n(Cc2cc(Br)cc3c2CC(=O)N3C)c2ccccc21
Temperature: 25 °C
Yield: 25 %

Procedure:
To a solution of 3-[3-(6-bromo-1-methyl-1H-indol-4-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-hexanoic acid (71 mg, 0.15 mmol) in THF (11 mL) was added t-BuOH (1 mL). A solution of NBS (58 mg, 0.32 mmol) in THF (0.5 mL) was added and the resulting mixture was stirred at ambient temperature for 15 m, concentrated and used directly. This crude intermediate was dissolved in acetic acid (1.5 mL). Zn powder (70 mg, 1.1 mmol) was added and the resulting mixture was agitated for 15 m. The reaction mixture was filtered and the mother liquors were concentrated and purified directly by preparative HPLC using an acetonitrile/water/formic acid gradient to provide 12 mg (25%) of the title compound. LCMS (ESMS): m/z 486.88 (M+H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH2:13][CH2:12][C:11]([CH3:15])([CH3:14])[CH2:10][CH:9]=2)[C:5]([NH:16][C:17]([C:19]2[N:20]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:21]=[C:22]([C:24]#[N:25])[N:23]=2)=[O:18])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:39]([O:41][CH2:42][CH3:43])=[CH2:40])CCC.CN(C=O)C>CCOC(C)=O.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>[CH3:14][C:11]1([CH3:15])[CH2:12][CH2:13][C:8]([C:6]2[C:5]([NH:16][C:17]([C:19]3[N:20]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:21]=[C:22]([C:24]#[N:25])[N:23]=3)=[O:18])=[CH:4][CH:3]=[C:2]([C:39]([O:41][CH2:42][CH3:43])=[CH2:40])[N:7]=2)=[CH:9][CH2:10]1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CC1(C)CC=C(c2nc(Br)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=C(OCC)c1ccc(NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)c(C2=CCC(C)(C)CC2)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 38.3 %

Procedure:
To a round bottom flask containing 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [6-bromo-2-(4,4-dimethyl-cyclohex-1-enyl)-pyridin-3-yl]-amide (as prepared in Example 56, step (c), 32 mg, 0.060 mmol), Pd(PPh3)4 (7 mg, 0.006 mmol), and tributyl-(1-ethoxy-vinyl)-stannane (30 mg, 0.080 mmol) was added DMF (0.7 mL) and the resultant solution was allowed to stir at 100° C. overnight. The reaction was diluted with EtOAc (25 mL), washed with water (2×25 mL), dried (Na2SO4) and concentrated in vacuo. Purification of the residue by preparative TLC (20% EtOAc-hexanes) afforded 12 mg (43%) of the title compound as an oil. Mass spectrum (ESI, m/z): Calcd. for C28H39N5O3Si, 522.2 (M+H). found 522.3.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]3[CH2:14][CH2:15][CH2:16][CH2:17][CH:10]3[C:9]2=[O:18])=[CH:4][CH:3]=1.[CH3:19][N:20]([CH3:39])[C:21]([C:23]1[N:32]([CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)[C:26]2[N:27]=[C:28](Cl)[N:29]=[CH:30][C:25]=2[CH:24]=1)=[O:22]>>[CH3:19][N:20]([CH3:39])[C:21]([C:23]1[N:32]([CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)[C:26]2[N:27]=[C:28]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([N:8]4[CH2:13][CH2:12][N:11]5[CH2:14][CH2:15][CH2:16][CH2:17][CH:10]5[C:9]4=[O:18])=[CH:6][N:7]=3)[N:29]=[CH:30][C:25]=2[CH:24]=1)=[O:22]
Reactant: Nc1ccc(N2CCN3CCCCC3C2=O)cn1
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCN5CCCCC5C4=O)cn3)nc2n1C1CCCCC1
Yield: 16 %

Procedure:
Following general N—C coupling procedure 1, 2-(6-Amino-pyridin-3-yl)-hexahydro-pyrido[1,2-a]pyrazin-1-one (0.060 g, 0.244 mmol) was combined with 2-Chloro-7-cyclohexyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (0.075 g, 0.244 mmol, 1.0 eq) which gave 7-Cyclohexyl-2-[5-(1-oxo-octahydro-pyrido[1,2-a]pyrazin-2-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (0.020 g, 0.039 mmol) in 16% yield. 1H NMR (400 MHz, CDCl3) δ ppm 1.19-1.41 (m, 6H) 1.41-1.52 (m, 5H) 1.61-1.75 (m, 4H) 1.93 (br. s., 9H) 2.21 (td, J=11.37, 3.54 Hz, 2H) 2.40 (br. s., 2H) 2.52-2.81 (m, 7H) 2.93-3.05 (m, 4H) 3.16 (s, 11H) 3.47 (dd, J=11.37, 2.78 Hz, 2H) 3.93-4.09 (m, 2H) 4.26-4.42 (m, 2H) 6.44 (s, 2H) 7.68 (dd, J=8.84, 2.78 Hz, 2H) 8.00 (s, 2H) 8.23 (d, J=2.02 Hz, 2H) 8.63 (d, J=9.09 Hz, 2H) 8.71 (s, 2H) HRMS calc for m/z=517.3039 and found m/z=517.3046 (M+H)
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][N:12]=1>C(OCC)(=O)C>[N+:17]([C:14]1[CH:15]=[CH:16][C:11]2[N:12]([CH:2]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:10]=2)[CH:13]=1)([O-:19])=[O:18]
Reactant: Nc1ccc([N+](=O)[O-])cn1
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cn2cc([N+](=O)[O-])ccc2n1

Procedure:
Operations similar to Production Example 1-(2) were conducted using ethyl bromopyruvate and 2-amino-5-nitropyridine. The solid whereupon obtained was suspended in ethyl acetate, and washed with saturated aqueous sodium hydrogencarbonate to provide the title compound as brown solid.
Reaction SMILES: [C:1]1(=[O:22])[N:5]([CH:6]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7](O)=[O:8])[C:4](=[O:17])[C:3]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:2]12.O1CCCC1.[OH-].[NH4+:29]>O>[C:1]1(=[O:22])[N:5]([CH:6]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([NH2:29])=[O:8])[C:4](=[O:17])[C:3]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:2]12
Reactant: [NH4+]
Reactant: O=C(O)C(Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)C(Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 84 %

Procedure:
To a stirred solution of 2-phthalimido-3-phenylpropionic acid (2.95 g, 10.0 mmol) in tetrahydrofuiran (25 mL) are added carbonyldiimridazole (1.62 g, 10.0 mmol) and a few crystals of 4-N,N-dimethylaminopyridine, followed by 15 mL of tetrahydrofuran. The reaction mixture is stirred at room temperature for 45 minutes and 1 mL of concentrated ammonium hydroxide then is added. After 10 minutes, the reaction mixture is diluted with 50 mL water and the resulting slurry is partially concentrated to remove the tetrahydrofuran and filtered. The solid is washed with water and dried in vacuo (60° C., <1 mm) to afford 2.46 g (84%) of 2-phthalimido-3-phenylpropionamide as a white powder: mp 224°-226° C.; 1H NMR (DMSO-d6, 250 MHz) δ 7.79 (s, 4 H, Ar), 7.71 (br s, 1 H, CONH2), 7.32 (br s, 1 H, CONH2), 7.20-7.02 (m, 5H, Ar), 5.06-4.98 (m, 1H), 3.56-3.25 (m, 2H); 13C NMR (DMSO-d6, 250 MHz) d: 169.6, 168.0, 137.1, 134.3, 131.2, 129.5, 128.1, 126.3, 122.9, 54.2, 33.7. Anal. Calculated for C17H14N2O3. Theoretical: C, 69.38; H, 4.79; N, 9.52. Found: C, 69.37; H, 4.73; N, 9.43.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:22])[CH2:13][CH2:12][C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:14]#[N:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:23]N(C=O)C>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([O:22][CH3:23])[CH2:13][CH2:12][C:11]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)([C:14]#[N:15])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: N#CC1(c2ccccc2)CCC(O)(c2ccc(F)cc2)CC1
Reactant: CN(C)C=O
Product: COC1(c2ccc(F)cc2)CCC(C#N)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
300 mg of 4-(4-fluorophenyl)-4-hydroxy-1-phenylcyclohexanecarbonitrile were dissolved in 2.5 ml of dry DMF in a flask which had been dried and flushed with argon, treated under argon with 73 mg of sodium hydride (80% strength in mineral oil) and stirred for 30 min at room temperature. Subsequently, 0.14 ml of iodomethane was slowly added dropwise under argon. The reaction mixture was stirred for 3 h, then treated with water and extracted with EA. The combined organic phases were dried over magnesium sulfate and the solvent was removed in vacuo. The crude product, a brown oil, was purified by chromatography on silica gel using HEP/EA (2:1). 290 mg of the title compound were obtained as a white amorphous solid.