Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[NH:8][CH:7]=[C:6]2[CH:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1.[H-].[K+].[CH2:22](OS(C1C=CC(C)=CC=1)(=O)=O)[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1OCCOCCOCCOCCOCCOC1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]([CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:7]=[C:6]2[CH:13]1[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccccc2)cc1
Reactant: COc1cc(C)c2[nH]cc(C3CCN(C)CC3)c2c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [K+]
Product: COc1cc(C)c2c(c1)c(C1CCN(C)CC1)cn2CCc1ccccc1
Yield: 14.7 %

Procedure:
By a method similar to Preparation 26, using 5-methoxy-7-methyl-3-(1-methylpiperidin-4-yl)-1H-indole (5.81 mmol, 1.50 g), 35% potassium hydride (5.81 mmol, 0.665 g), toluene-4-sulfonic acid phenethyl ester (5.81 mmole, 1.60 g), additional 18-crown-6 (5.22 mmol,1.38 g) and additional toluene-4-sulfonic acid phenethyl ester (2.90 mmole, 0.802 g) were added to afford 0.31 g (15%) of the title compound: mass spectrum (ion spray): m/z=363 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH3:22][N:23]([CH3:26])C=O>C1C2C(=CC=CC=2)CCN1.C(O)C>[CH2:22]1[C:20]2[C:5](=[CH:4][CH:3]=[CH:2][CH:21]=2)[CH2:6][CH2:26][N:23]1[CH2:19][C@@H:17]([OH:18])[CH2:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[C:5]3[CH:20]=[CH:21][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)=[CH:10][CH:11]=1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Reactant: CN(C)C=O
Agent: c1ccc2c(c1)CCNC2
Solvent: CCO
Product: O[C@@H](COc1ccc(-c2noc3cc(F)ccc23)cc1)CN1CCc2ccccc2C1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 1,2,3,4-tetrahydroisoquinoline in ethanol essentially as described above in Example 21. Purity by LC/MS=99%, [M+H]+=419.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:37]=[CH:36][C:20]([C:21]([N:23]([CH3:35])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30](OCC)=[O:31])=[O:22])=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.Cl>O1CCCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([N:23]([CH3:35])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH2:30][OH:31])=[O:22])=[CH:36][CH:37]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccccc1N(C)C(=O)c1ccc(NC(=O)c2ccccc2-c2ccc(C)cc2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccccc3CO)cc2)cc1
Reaction time: 2 h
Yield: 54.3 %

Procedure:
A solution of 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-(2-ethoxycarbonylphenyl)benzamide (493 mg) in tetrahydrofuran (20 ml) was cooled in an ice bath. Lithium aluminum hydride (1M solution in tetrahydrofuran, 2.5 ml) was added dropwise to the solution and the mixture was stirred at the same temperature for 2 hours. Water was slowly added to the solution and resulting mixture was acidified with 1N hydrochloric acid. The solution was extracted with chloroform and the organic solution was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was subjected to silica gel column (20 g, 2% methanol in chloroform). The product was solidified with diethyl ether to give 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-(2-hydroxymethylphenyl)benzamide (245 mg) as a white powder.
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:10]2[CH:11]=[C:12]([C:16]([O:18]C)=[O:17])[S:13][C:14]=2[CH3:15])[N:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[N:5]2.C1COCC1.[OH-].[K+]>CO>[N:1]1[CH:2]=[C:3]([C:10]2[CH:11]=[C:12]([C:16]([OH:18])=[O:17])[S:13][C:14]=2[CH3:15])[N:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[N:5]2
Reactant: COC(=O)c1cc(-c2cnc3cccnn23)c(C)s1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1sc(C(=O)O)cc1-c1cnc2cccnn12
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Methyl 4-(imidazo[1,2-b]pyridazin-3-yl)-5-methylthiophene-2-carboxylate (0.54 g, 1.98 mmol) was dissolved in methanol (9.88 mL) and THF (9.88 mL) and a solution of KOH in methanol was added (1 M, 5.93 mL, 5.93 mmol). The reaction mixture was left to stir overnight at 60° C. The reaction mixture was then cooled to room temperature, concentrated, and acidified with aqueous 1N HCl. The aqueous layer was extracted three times with ethyl acetate, then extracted one time with a 3:1 CHCl3:isopropanol mixture. The combined organics were dried with magnesium sulfate, filtered, and concentrated to afford the title compound. 1H NMR (500 MHz, CD3SOCD3) δ 8.77 (d, 1H); 8.34 (d, 1H); 8.25 (s, 1H); 8.11 (s, 1H); 7.51 (dd, 1H); 2.56 (s, 3H). LRMS (APCI) calc'd for (C12H9N3O2S) [M+H]+, 260.0. found 260.0.
Reaction SMILES: [CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:2]([CH3:4])[CH3:3].[CH3:25][O:26][C:27]1[C:37]([O:38][CH3:39])=[CH:36][CH:35]=[CH:34][C:28]=1[CH:29]=[CH:30][C:31](O)=[O:32]>>[CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:31](=[O:32])[CH2:30][CH2:29][C:28]1[CH:34]=[CH:35][CH:36]=[C:37]([O:38][CH3:39])[C:27]=1[O:26][CH3:25])[CH:2]([CH3:3])[CH3:4]
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCN)C(=O)O)cc1
Reactant: COc1cccc(C=CC(=O)O)c1OC
Product: COc1cccc(CCC(=O)NCCCC[C@@H](C(=O)O)N(CC(C)C)S(=O)(=O)c2ccc(C)cc2)c1OC
Yield: 18 %

Procedure:
Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-L-lysine was reacted with 2,3-dimethoxycinnamic acid under the conditions described in example 86. The crude material was purified by flash chromatography (CH2Cl2:MeOH, 49:1 to 9:1) to yield 18% of the desired product.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][C@H:7]([CH3:9])[N:6]2[C:10]([C:20](=O)[C:21]([O:23][CH3:24])=[O:22])=[C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:12]([O:13][CH3:14])=[C:5]2[C:4]1=[O:26])[CH3:2].[OH-].[Na+].[CH2:29]1COCC1>C1(C)C=CC=CC=1.CCOCC.[CH3-].C[Al+]C.[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Cl-].[Ti+3]>[CH2:1]([N:3]1[CH2:8][C@H:7]([CH3:9])[N:6]2[C:10]([C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH2:29])=[C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:12]([O:13][CH3:14])=[C:5]2[C:4]1=[O:26])[CH3:2]
Reactant: C1CCOC1
Reactant: CCOC(=O)c1c(OC)c2n(c1C(=O)C(=O)OC)[C@@H](C)CN(CC)C2=O
Agent: [Ti+3]
Agent: C[Al+]C
Agent: [CH3-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: C=C(C(=O)OC)c1c(C(=O)OCC)c(OC)c2n1[C@@H](C)CN(CC)C2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cold (0° C.) solution of ethyl (4S)-2-ethyl-8-(methoxy)-6-[methoxy(oxo)-acetyl]-4-methyl-1-oxo-1,2,3,4-tetrahydro-pyrrolo[1,2-a]-pyrazine-7-carboxylate (1.0 g, 2.73 mmol) in anhydrous THF (100 mL), a solution of Tebbe reagent (6.0 mL, 0.5 M) in toluene was added. The reaction mixture was stirred at room temperature for one hour. The product mixture was diluted with ether (100 mL) and treated with aq sodium hydroxide (4 mL, 1M). The mixture was filtered. The organic extract was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluted with ethyl acetate-hexane gradient. Collection and concentration of appropriate fractions provided the olefination product.
Reaction SMILES: [NH4+].[Cl-].[Cl:3][C:4]1[C:5]([C:29]2[CH:30]=[N:31][N:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=23)=[N:6][C:7]([NH:10][C:11]2[CH:16]=[C:15]([N+:17]([O-])=O)[C:14]([N:20]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH3:21])=[CH:13][C:12]=2[O:27][CH3:28])=[N:8][CH:9]=1>O.C(O)C.[Fe]>[Cl:3][C:4]1[C:5]([C:29]2[CH:30]=[N:31][N:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=23)=[N:6][C:7]([NH:10][C:11]2[CH:16]=[C:15]([NH2:17])[C:14]([N:20]([CH2:22][CH2:23][N:24]([CH3:25])[CH3:26])[CH3:21])=[CH:13][C:12]=2[O:27][CH3:28])=[N:8][CH:9]=1
Reactant: COc1cc(N(C)CCN(C)C)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1cc(N(C)CCN(C)C)c(N)cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Temperature: 105 °C
Reaction time: 3 h
Yield: 93.8 %

Procedure:
A solution of NH4Cl (45 mg, 0.85 mmol) in water (10 mL) was added in one portion to a stirred mixture of N-(5-chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)-N′-(2-dimethylaminoethyl)-2-methoxy-N′-methyl-5-nitrobenzene-1,4-diamine (Intermediate 34, 600 mg, 1.21 mmol) and iron (405 mg, 7.24 mmol) in ethanol (30 mL). The resulting mixture was stirred at 105° C. for 3 h. The mixture was then concentrated in vacuo and the resulting residue was mixed with DMF (10 mL) and purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 0.35M methanolic ammonia in CH2Cl2 and pure fractions were concentrated in vacuo to give the title compound (530 mg, 94%) as a brown gum; 1H NMR: 2.16 (6H, d), 2.38 (2H, t), 2.66 (3H, d), 2.92 (2H, t), 3.66 (3H, s), 4.60 (2H, s), 6.78 (1H, s), 6.92 (1H, s), 7.12 (1H, t), 7.27-7.4 (1H, m), 8.38 (1H, s), 8.43 (1H, d), 8.49 (1H, s), 8.83 (1H, d), 8.95 (1H, s); m/z: ES+ MH+ 467.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][NH:9][CH:10]=1)=[O:5])[CH3:2].[H-].[Na+].[CH2:13](I)[CH:14]([CH3:16])[CH3:15].O>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH:10]=1)=[O:5])[CH3:2]
Reactant: CC(C)CI
Reactant: CCOC(=O)c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(CC(C)C)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1H-Pyrazole-4-carboxylic acid ethyl ester (5.0 g) was dissolved in DMF (50 mL), 60% sodium hydride (1.57 g) was added, and the mixture was stirred at 0° C. for 30 min. Then, isobutyl iodide (4.7 mL) was added, and the mixture was stirred for 14 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=8:2) to give 1-(2-methylpropyl)-1H-pyrazole-4-carboxylic acid ethyl ester (6.0 g) as an oil. The obtained compound was subjected to reactions in the same manner as in Reference Examples 17 to 18 to give the title compound.
Reaction SMILES: N[C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])=[CH:4][C:3]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N([O-])=O.[Na+].[C-:27]#[N:28].[K+]>Cl>[CH2:16]([O:15][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][C:2]=1[C:27]#[N:28])[C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccc(C(=O)CCC(=O)O)cc1OCc1ccccc1
Reactant: [C-]#N
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Product: N#Cc1ccc(C(=O)CCC(=O)O)cc1OCc1ccccc1

Procedure:
3-(4-Amino-3-benzyloxybenzoyl)propionic acid was diazotised in aqueous hydrochloric acid with sodium nitrite and the resultant solution was treated with cuprous cyanide in aqueous potassium cyanide solution to give 3-(3-benzyloxy-4-cyanobenzoyl)propionic acid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[CH:21]=[C:22]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH:23]=[CH:24][C:25]=1[CH3:26]>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:20]1[CH:21]=[C:22]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH:23]=[CH:24][C:25]=1[CH3:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(NS(C)(=O)=O)cc1Br
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Product: Cc1ccc(NS(C)(=O)=O)cc1C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C

Procedure:
Following the general method as outlined in Intermediate 20, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and N-(3-bromo-4-methylphenyl)methanesulfonamide, the title compound was obtained after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][CH:14]([CH3:33])[CH2:15][CH:16]=[C:17]1[CH2:32][CH2:31][C:20]2([S:24][CH2:23][C:22](=[O:25])[N:21]2[CH2:26][CH2:27][C:28]([OH:30])=[O:29])[CH2:19][CH2:18]1.Br[CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37].Cl>CCCCCC.O1CCCC1.C(OCC)(=O)C>[C:39]([O:38][C:36](=[O:37])[CH2:35][CH:23]1[C:22](=[O:25])[N:21]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])[C:20]2([CH2:31][CH2:32][C:17](=[CH:16][CH2:15][CH:14]([CH3:33])[CH3:13])[CH2:18][CH2:19]2)[S:24]1)([CH3:42])([CH3:41])[CH3:40]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)CC=C1CCC2(CC1)SCC(=O)N2CCC(=O)O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)CC=C1CCC2(CC1)SC(CC(=O)OC(C)(C)C)C(=O)N2CCC(=O)O
Temperature: -70 °C
Reaction time: 0.17 h

Procedure:
In an atmosphere of nitrogen, 1.97 ml of N,N-diisopropylamine was added to 10 ml of anhydrous tetrahydrofuran, to which was dropwise added 9.50 ml of a solution of n-butyllithium in hexane (1.58 mol/L) at −30° C. The mixture was stirred at the same temperature for 10 minutes and then cooled to −70° C., to which was dropwise added a solution of 1.56 g of 3-[8-(3-methylbutylidene)-3-oxo-1-thia-4-azaspiro[4.5]decan-4-yl]-propionic acid in 20 ml of anhydrous tetrahydrofuran. After stirring the resulting mixture at the same temperature as above for 30 minutes, 0.89 ml of tert-butyl bromoacetate was dropwise added at the same temperature. After elevating the temperature to 0° C., the reaction mixture was poured into a mixture of ice water and ethyl acetate, pH was adjusted to 2.0 with 2 mol/L hydrochloric acid, and the organic layer was separated. The organic layer was washed successively with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Thus, 2.23 g of 3-[2-[2-(tert-butoxy)-2-oxoethyl]-8-(3-methylbutylidene)-3-oxo-1-thia-4-azaspiro[4.5]decan-4-yl]-propionic acid was obtained as a yellow oily product.
Reaction SMILES: I[C:2]1[C:3]([NH2:14])=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][CH:7]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[C:29](=O)([O-])[O-:30].[Cs+].[Cs+]>CO.[Cu]I>[CH3:29][O:30][C:2]1[C:3]([NH2:14])=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: Nc1cc(-c2ccccc2)ncc1I
Reactant: O=C([O-])[O-]
Agent: [Cu]I
Agent: [Cs+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: CO
Product: COc1cnc(-c2ccccc2)cc1N
Temperature: 130 °C
Yield: 44.7 %

Procedure:
A stirred suspension of 6.20 g (20.9 mmol) 5-iodo-2-phenyl-pyridin-4-ylamine, 319 mg (1.68 mmol) copper(I) iodide, 453 mg (2.51 mmol) 1,10-phenanthroline and 13.6 g (41.9 mmol) cesium carbonate in 40 ml methanol was heated at 130° C. for 20 min in a microwave oven. The resulting mixture was then cooled to room temperature and concentrated in vacuo. The residue was resuspended in 500 ml dichloromethane and extracted three times with 200 ml portions of 1 M aq. hydrochloric acid. The combined acid extracts were then made basic by addition of 5 N aq. sodium hydroxide solution and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (methanol/dichloromethane 3/97-5/95) afforded 1.87 g (45%) 5-methoxy-2-phenyl-pyridin-4-ylamine as a dark red oil. ES-MS m/e (%): 201 (M+H+, 100).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:20][CH2:19][CH2:18][C@H:17]([N:21]([CH2:28][C:29]3[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[C:31]([C:39]([F:42])([F:41])[F:40])[CH:30]=3)[C:22]3[N:23]=[N:24][N:25]([CH3:27])[N:26]=3)[C:16]3[CH:43]=[C:44]([CH3:51])[C:45]([C:47]([F:50])([F:49])[F:48])=[CH:46][C:15]2=3)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>[Pd].CO>[F:38][C:35]([F:36])([F:37])[C:33]1[CH:34]=[C:29]([CH:30]=[C:31]([C:39]([F:40])([F:41])[F:42])[CH:32]=1)[CH2:28][N:21]([C@H:17]1[CH2:18][CH2:19][CH2:20][N:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[C:15]2[CH:46]=[C:45]([C:47]([F:48])([F:49])[F:50])[C:44]([CH3:51])=[CH:43][C:16]1=2)[C:22]1[N:23]=[N:24][N:25]([CH3:27])[N:26]=1
Reactant: [H][H]
Reactant: Cc1cc2c(cc1C(F)(F)F)N(C1CCN(Cc3ccccc3)CC1)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Agent: [Pd]
Solvent: CO
Product: Cc1cc2c(cc1C(F)(F)F)N(C1CCNCC1)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Reaction time: 5 h
Yield: 48.3 %

Procedure:
Subject a mixture of (S)-[1-(1-benzyl-piperidin-4-yl)-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl]-(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amine (0.130 g, 0.179 mmol) and palladium on carbon (10% by weight, wet, 0.050 g) in methanol (10 mL) to an atmosphere of hydrogen gas (35 psi) at room temperature on a Parr shaker apparatus. After 5 h, filter the mixture through celite and the concentrate the filtrate under reduced pressure. Purify the resulting residue using flash column chromatography on silica gel, eluting with hexanes/ethyl acetate (80:20), to provide the title compound as white solid (0.055 g, 48%): 1H NMR (CDCl3, 300 MHz) δ 1.63-2.13 (m, 10H), 2.34 (s, 3H), 2.82-3.0 (m, 3H), 3.10-3.22 (m, 1H), 3.33-3.41 (m, 1H), 4.09-4.13 (m, 1H), 4.14 (s, 3H), 4.74-4.97 (m, 2H), 5.12 (bs, 1H), 5.34-5.49 (m, 1H), 6.89 (s, 1H), 7.32 (s, 1H), 7.60 (s, 1H), 7.71 (s, 1H); ESI MS m/z 726 [C28H30F9N7+H]+.
Reaction SMILES: Cl.Br[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[C:9]([C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2)#[CH:10]>[Cu]I.CN(C=O)C.CCN(CC)CC>[CH3:28][O:27][C:26]1[CH:25]=[CH:24][NH:23][C:22]=1/[CH:21]=[C:13]1\[C:14](=[O:20])[NH:15][C:16]2[C:12]\1=[C:11]([C:9]#[C:10][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)[CH:19]=[CH:18][CH:17]=2
Reactant: C#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2
Reactant: Brc1ccncc1
Agent: [Cu]I
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#Cc3ccncc3)c21

Procedure:
Using Method J above, 4-bromopyridine hydrochloride (110 mg, 0.57 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-4-ethynyl-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (Starting Material 5) (100 mg, 0.38 mmol) using DPPFPdCl2 (15.4 mg) (Aldrich) and CuI (4 mg) (Aldrich) as catalyst in DMF (5 mL) and Et3N (5 mL) as solvent and heating at reflux for 1 day, yielding (Z)-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-4-[(4-pyridinyl)ethynyl]-2H-indol-2-one. (Yield 70 mg, 54%).
Reaction SMILES: [N:1]1([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[C:23]4=[N:24][CH:25]=[CH:26][CH:27]=[C:22]4[NH:21][C:20]3=[O:28])=[CH:15][CH:14]=2)[C:5]2=[N:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:4]2[CH2:3][CH2:2]1.[CH2:29](I)[CH3:30].[H-].[Na+].O>CN(C=O)C>[N:1]1([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[C:23]4=[N:24][CH:25]=[CH:26][CH:27]=[C:22]4[N:21]([CH2:29][CH3:30])[C:20]3=[O:28])=[CH:15][CH:14]=2)[C:5]2=[N:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:4]2[CH2:3][CH2:2]1
Reactant: CCI
Reactant: O=c1[nH]c2cccnc2n1-c1ccc(N2CCn3c2nc2ccccc23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(=O)n(-c2ccc(N3CCn4c3nc3ccccc34)cc2)c2ncccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of 3-[4-(2,3-dihydro-1H-imidazo[1,2-a]benzimidazol-1-yl)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (150 mg) and ethyl iodide (0.1 mL) in DMF (4.0 mL) was added sodium hydride (62 mg) (60% in mineral oil) at 0° C. The mixture was stirred at 0° C. for 1 h, and then H2O was added. The precipitate was collected and washed with MeOH to give 3-[4-(2,3-dihydro-1H-imidazo[1,2-a]benzimidazol-1-yl)phenyl]-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (23 mg) as white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:14]([C:23]([OH:25])=[O:24])[CH2:15][CH2:16][CH2:17][N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[CH2:9][N:8]=[C:7]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:6]=2[CH:32]=1.[N+](=[CH2:35])=[N-]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:14]([C:23]([O:25][CH3:35])=[O:24])[CH2:15][CH2:16][CH2:17][N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[CH2:9][N:8]=[C:7]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:6]=2[CH:32]=1
Reactant: C=[N+]=[N-]
Reactant: CCN(CC)CCCC(=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1)C(=O)O
Solvent: ClCCl
Product: CCN(CC)CCCC(=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1)C(=O)OC

Procedure:
A solution of 7-chloro-2-[[1-carboxy-4-(diethylamino)butylidene]hydrazino]-5-phenyl-3H-1,4-benzodiazepine in CH2Cl2 (10 ml.) is treated with stirring under N2, with an ethereal solution of diazomethane (5 ml., 0.3 M). After 1/2 hour the solution is concentrated in vacuo giving 7-chloro-2-[[1-(methoxycarbonyl)-4-(diethylamino)-butylidene]hydrazino]-5-phenyl-3H-1,4-benzodiazepine as an oil, the nmr of which confirmed the structure. Nmr (CDCl3) δ 0.95 (t, 3, CH2CH3) 1.82 (m, 2, CH2CH2CH2); 2.50 (m, 6, CH2CH3 and CH2CH2N), 2.27 (m, z, CCH2CH2), 3.77 (s, 3, OCH3), 4.50 (broad s, z, 3--CH2), between 6.80 and 7.85 (m, 8, arom H's).
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH2:13][CH:14]=[C:15]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:8][C:7]=1[O:30][CH3:31].[OH-].[Na+].Cl>C(O)C>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([C:15]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[CH:14][CH2:13][S:12][C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:32])=[O:2])=[C:7]([O:30][CH3:31])[CH:8]=2)=[CH:21][CH:20]=1
Reactant: COC(=O)COc1ccc(SCC=C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(SCC=C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)ccc1OCC(=O)O
Reaction time: 2 h

Procedure:
{4-[3,3-Bis-(4-chlorophenyl)-allylsulfanyl]-2-methoxy-phenoxy}-acetic acid methyl ester (280 mg, 0.57 mmol) was dissolved in warm ethanol (10 ml). 1N NaOH (1 ml) was added at room temperature and the reaction mixture was stirred for 2 h after which it was evapo-rated. The residue was treated with 1N HCl (1.2 ml) and extracted with dichloromethane (3×25 ml). The combined organic phases were dried and evaporated to give the title compound in 245 mg (90%) yield.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:27])[C:17]#[C:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][OH:26])=[CH:21][CH:20]=2)=[CH:11][CH:10]=1)#[C:7][CH3:8].C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:26][CH2:25][C:22]1[CH:21]=[CH:20][C:19]([C:18]#[C:17][C:16](=[O:27])[NH:15][C:12]2[CH:11]=[CH:10][C:9]([C:6]#[C:7][CH3:8])=[CH:14][CH:13]=2)=[CH:24][CH:23]=1)(=[O:4])=[O:3]
Reactant: CC#Cc1ccc(NC(=O)C#Cc2ccc(CO)cc2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC#Cc1ccc(NC(=O)C#Cc2ccc(COS(C)(=O)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.14 mL (1.8 mmol) of methanesulfonic acid chloride is slowly added dropwise at ambient temperature to a solution of 0.5 g (1.72 mmol) of 3-(4-hydroxymethylphenyl)propynoic acid (4-prop-1-ynylphenyl)amide and 0.49 mL (3.6 mmol) of triethylamine in 20 mL of dichloromethane and the reaction mixture is stirred for 2 hours at ambient temperature. It is extracted three times with water and the organic phase is dried over sodium sulfate. The solvent is distilled off and the residue is stirred with diisopropyl ether. Yield: 0.48 g (75.6% of theory); C20H17NO4S (M=367.42); calc.: molecular ion peak (M+H)+: 368; found: molecular ion peak (M+H)+: 368; Rf value: 0.48 (silica gel, dichloromethane/ethanol (20:1)).