Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]([F:7])([F:6])[CH2:4]N.N([O-])=O.[Na+].[C:12]1([CH3:21])[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][CH:19]=[O:20].C([O-])(O)=O.[Na+]>ClCCl.O.[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4].CO>[F:2][C:3]([F:7])([F:6])[CH2:4][CH:19]([OH:20])[CH2:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH3:21]
Reactant: Cc1ccccc1CC=O
Reactant: NCC(F)(F)F
Agent: [Zr+4]
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: Cc1ccccc1CC(O)CC(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of 2,2,2-trifluoroethylamine hydrochloride (0.271 g) in dichloromethane/water (15/0.5 mL) at 0° C. was added sodium nitrite (0.166 g) and the resulting yellow solution was stirred for 1 hour at 0° C. The reaction mixture was then cooled to −78° C. and 2-o-tolylacetaldehyde (0.134 g) was added, followed by zirconium(IV)tetrachloride. After stirring for 2 hrs at −78° C. cooling was stopped and methanol (3 mL) and saturated solution of NaHCO3 (10 mL) were added. The mixture was extracted with dichloromethane and the extracts were dried and concentrated. Evaporation residue (194 mg) was dissolved in methanol (3 ml) and solution was cooled to 0° C. Sodium borohydride (44 mg) was added and the reaction mixture was stirred for 25 minutes. K2CO3-solution (2M, 5 mL) was added to the reaction mixture, followed by water (5 mL) after 5 min and the resulting solution was extracted with EtOAc. Extracts were dried and concentrated and the residue was purified by separation method E (EtOAc/heptane). (Yield 121 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][CH2:16][C:17]#[N:18])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.[Ni]>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][CH2:15][CH2:16][CH2:17][NH2:18])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CCCOC1CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: NCCCOC1CCN(Cc2ccccc2)CC1

Procedure:
10.0 g (40.9 mmol) 3-(1-benylpiperidin-4-yloxy)-propionitrile are dissolved in 100 ml ethanol and added to a spatula tip of Raney-Nickel. The mixture is stirred at RT under hydrogen atmosphere until the uptake of the theoretical amount of hydrogen (ca. two days). The mixture is filtered from the catalyst and the solvent is removed under vacuum. The residue is distilled in a bulb tube apparatus. Yield of colorless oil: 7.5 g (73%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([C:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[CH2:21][OH:22])=[CH:15][CH:14]=1)[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[CH2:11]([C:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[CH:21]=[O:22])=[CH:15][CH:14]=1)[CH3:12]
Reactant: CCc1ccc(/C=C/CO)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCc1ccc(/C=C/C=O)cc1
Reaction time: 1 h

Procedure:
General Procedure H. To a solution of oxalyl chloride (5.9 ml, 11.8 mmol, 2 M in CH2Cl2) in CH2Cl2 (20 ml) was added a solution of DMSO (1.1 ml, 15.7 mmol) in CH2Cl2 (3 ml) dropwise at −60° C. A solution of (E)-3-(4-ethylphenyl)prop-2-en-1-ol (Compound 40, 1.3 g, 7.8 mmol) in CH2Cl2 (5 ml) was cannulated slowly into the above mixture at −60° C. After the reaction was stirred at the same temperature for 1 hour, a solution of triethylamine (4.4 ml, 31.4 mmol) in CH2Cl2 (5 ml) was added into the reaction, which was stirred an additional 1 hour at −60° C. The reaction was quenched with water, and the products were extracted with CH2Cl2. The organic layer was washed with 5% aqueous NaHCO3, and brine, and dried over MgSO4. The filtered solution was concentrated in vacuo, and the residue was purified by column chromatography (silica gel, 15% ethyl acetate in hexane) to obtain the title compound as a clear oil.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:19]=[C:18](Cl)[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].[NH:27]1[C:35]2[C:30](=[N:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][CH2:28]1.F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1COCC1.O1CCOCC1>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:19]=[C:18]([N:27]3[C:35]4[C:30](=[N:31][CH:32]=[CH:33][CH:34]=4)[CH2:29][CH2:28]3)[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: c1cnc2c(c1)NCC2
Reactant: CC(C)OC(=O)N1CCC(Oc2cc(Cl)ncn2)CC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CC(C)OC(=O)N1CCC(Oc2cc(N3CCc4ncccc43)ncn2)CC1
Temperature: 80 °C

Procedure:
A mixture of 2b (100 mg, 0.33 mmol), potassium tert-butoxide (0.1 g, 2.7 eq), 1-1 (0.35 mmol, 1.05 eq), tris(dibenzylideneacetone)dipalladium (32 mg, 0.1 eq), tri-t-butylphosphonium tetrafluoroborate (40 mg, 0.4 eq) and dioxane (1 mL) was heated at 80° C. for 18 h in a sealed vial. After allowing the reaction to cool down to room temperature, THF was added and the mixture was filtered. The filtrate was concentrated under a stream of nitrogen and the residue was taken up with 1 mL of THF and purified by preparative HPLC to afford 2-1.
Reaction SMILES: [NH2:1][O:2][C@@H:3]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)=[O:5].[C:24]([O:28][C:29]([NH:31][C:32]1[S:33][C:34]([Cl:42])=[C:35]([C:37](=O)[C:38]([OH:40])=[O:39])[N:36]=1)=[O:30])([CH3:27])([CH3:26])[CH3:25]>CO>[C:20]([O:19][C:17](=[O:18])[CH2:16][C@H:3]([O:2]/[N:1]=[C:37](/[C:35]1[N:36]=[C:32]([NH:31][C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30])[S:33][C:34]=1[Cl:42])\[C:38]([OH:40])=[O:39])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)=[O:5])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)Nc1nc(C(=O)C(=O)O)c(Cl)s1
Reactant: COc1ccc(COC(=O)[C@H](CC(=O)OC(C)(C)C)ON)cc1
Solvent: CO
Product: COc1ccc(COC(=O)[C@H](CC(=O)OC(C)(C)C)O/N=C(\C(=O)O)c2nc(NC(=O)OC(C)(C)C)sc2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.5 %

Procedure:
To a solution of (S)-4-tert-butyl 1-(4-methoxybenzyl) 2-(aminooxy)succinate (39.7 g, 122 mmol) in Methanol (300 mL) was added a solution of 2-(2-((tert-butoxycarbonyl)amino)-5-chlorothiazol-4-yl)-2-oxoacetic acid (Example 21b) (34 g, 111 mmol) at 0° C. Then the mixture was allowed to warm up to rt and stirred for 2 h. LCMS indicated completion of the reaction and the product as a mixture of Z/E isomer (19:1). The reaction mixture was concentrated and the residue was purified by reverse phase automatic C18 column chromatography (Combinflash RF, 150 g column, six runs), eluting with Acetonitrile/Water (0-90%) to afford (S,Z)-2-(((4-(tert-butoxy)-1-((4-methoxybenzyl)oxy)-1,4-dioxobutan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)-5-chlorothiazol-4-yl)acetic acid (46 g, 74.9 mmol, 67.6% yield) as pale yellow solid. LCMS: (M+H)+: 614.4. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.44 (s, 9 H) 1.55 (s, 9 H) 2.74-2.96 (m, 2 H) 3.78 (s, 3 H) 5.06-5.13 (m, 1 H) 5.17 (s, 2 H) 6.86 (d, J=8.84 Hz, 2 H) 7.32 (d. J=8.59 Hz, 2 H)
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([CH2:15][NH:16][C:17]1[CH:18]=[C:19]([C:23]2[N:28]=[CH:27][C:26](/[CH:29]=[C:30](\[O:36][CH2:37][CH3:38])/[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:25][CH:24]=2)[CH:20]=[CH:21][CH:22]=1)=O)(C)(C)C.O>ClCCl>[CH2:37]([O:36]/[C:30](=[CH:29]\[C:26]1[CH:27]=[N:28][C:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([NH:16][CH3:15])[CH:18]=2)=[CH:24][CH:25]=1)/[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH3:38]
Reactant: CCOC(=O)/C(=C/c1ccc(-c2cccc(NCC(=O)OC(C)(C)C)c2)nc1)OCC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)/C(=C/c1ccc(-c2cccc(NC)c2)nc1)OCC
Temperature: 25 °C
Reaction time: 20 h
Yield: 83.2 %

Procedure:
0.62 mL (7.0 mmol) of trifluoroacetic acid is added to a solution of 0.30 g (0.7 mmol) of ethyl (Z)-3-{6-[3-(tert-butoxycarbonylmethylamino)phenyl]pyrid-3-yl}-2-ethoxyacrylate in 10 mL of dichloromethane. The reaction mixture is stirred at room temperature for 20 hours. The reaction is stopped by addition of 10 mL of water and extraction with dichloromethane. The organic phases are combined and then dried over magnesium sulfate. After filtration, the solvents are evaporated off. The crude product obtained is purified by chromatography on a column of silica eluted with an 80/20 heptane/ethyl acetate mixture to give 0.19 g (86%) of ethyl (Z)-2-ethoxy-3-[6-(3-methylaminophenyl)pyrid-3-yl]acrylate in the form of a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([C:6](OCC)=[O:7])=[CH:4][C:3]=1[CH3:13].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.Cl>CCOCC.O>[Br:1][C:2]1[CH:12]=[CH:11][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[CH3:13]
Reactant: CCOC(=O)c1ccc(Br)c(C)c1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: Cc1cc(CO)ccc1Br
Reaction time: 1 h
Yield: 91.4 %

Procedure:
Ethyl 4-bromo-3-methylbenzoate (14 g, 0.058 mol) was dissolved in ether (200 ml). Under ice-cooling, to the obtained solution was added lithium aluminium hydride (1.8 g, 0.046 mol) little by little, and under this state, the mixture was stirred for 1 hour. After decomposing excessive lithium aluminium hydride with ethyl acetate, water and 10% hydrochloric acid were added, and the mixture was extracted with ethyl acetate. After washing with water and saturated aqueous sodium chloride solution, the extract was dried over anhydrous sodium sulfate, and the solvent was distilled away. The residue was separated and purified by using a column chromatography (ethyl acetate:n-hexane=1:3) to give the title compound (10.6 g, 0.053 mol).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])[CH2:10][C:6]=2[C:5]([F:23])=[C:4](Cl)[N:3]=1.[NH2:25][C@@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@@H:27]1[NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36].C(N(C(C)C)CC)(C)C.O>C(#N)C.CCOC(C)=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])[CH2:10][C:6]=2[C:5]([F:23])=[C:4]([NH:25][C@@H:26]2[CH2:31][CH2:30][CH2:29][CH2:28][C@@H:27]2[NH:32][C:33](=[O:39])[O:34][C:35]([CH3:37])([CH3:36])[CH3:38])[N:3]=1
Reactant: COc1ccc(CN2Cc3c(F)c(Cl)nc(Cl)c3C2=O)c(OC)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1ccc(CN2Cc3c(F)c(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)nc(Cl)c3C2=O)c(OC)c1
Temperature: 100 °C
Reaction time: 72 h
Yield: 46.6 %

Procedure:
A mixture of 4,6-dichloro-2-(2,4-dimethoxybenzyl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one (4.8 g, 12.93 mmol) and tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (4.16 g, 19.40 mmol) and diisopropylethylamine (3.39 mL, 19.40 mmol) in ACN (20 mL) was stirred at 100° C. for 3 days. Water and EtOAc were added and the aqueous phase was extracted with EtOAc. The organic phases were combined, washed with brine, dried over MgSO4, and evaporated. The residue was purified by chromatography on SiO2 (Hexane/EtOAc=1/1) to give the title compound as a brown amorphous solid (3.31 g, 46.6%). 1H NMR (500 MHz, CDCl3) δ ppm 1.35-2.02 (m, 17H), 3.80 (s, 3H), 3.84 (s, 3H), 4.01 (br s, 1H), 4.20 (s, 2H), 4.23 (br s, 1H), 4.66 (s, 2H), 4.91 (br s, 1H), 6.40-6.52 (m, 2H), 7.20-7.28 (m, 1H). [M+H] calc'd for C27H34ClFN4O5, 549. found, 549.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([C:13]#[N:14])[C:11]#[N:12])=[CH:5][CH:4]=1)[CH3:2].O.[NH2:16][NH2:17]>C(O)C>[NH2:12][C:11]1[C:10]([CH2:9][C:6]2[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=2)=[C:13]([NH2:14])[NH:17][N:16]=1
Reactant: NN
Reactant: CCc1ccc(CC(C#N)C#N)cc1
Solvent: O
Solvent: CCO
Product: CCc1ccc(Cc2c(N)n[nH]c2N)cc1
Temperature: 25 °C

Procedure:
A mixed solution of 4-ethylbenzyl bromide (10.0 g), malononitrile (6.64 g), potassium carbonate (6.94 g) and tetra-n-butylammonium bromide (648 mg) in toluene (100 ml) was agitated at room temperature for 17 hours. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate twice. The extract was washed successively with water and brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=6:1) to give 2-(4-ethylphenylmethyl)malononitrile (3.28 g) as a colorless solid. (2) A solution of the above 2-(4-ethylphenylmethyl) malononitrile (1.30 g) and hydrazine hydrate (0.86 ml) in ethanol (35 ml) was heated under reflux for 4 hours. Hydrazine hydrate (0.43 ml) was further added thereto and the mixture was further heated under reflux for 4 hours. The reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was crystallized from ethyl acetate-diethyl ether to give 3,5-diamino-4-(4-ethylphenylmethyl)pyrazole (2.63 g) as pale pink powder. APCI-Mass m/Z 217 (M+H). (3) The above 3,5-diamino-4-(4-ethylphenylmethyl)pyrazole (1.30 g) was added to 50% aqueous phosphoric acid solution (19 ml), and further added thereto was water (10 ml). The mixture was cooled to 0° C., and thereto was added dropwise an aqueous solution (4 ml) of sodium nitrite (912 mg). The mixture was stirred at the same temperature for 30 minutes, and further stirred at room temperature for 4 hours. The reaction mixture was cooled again to 0° C., 10% aqueous sodium hydroxide solution was added thereto to adjust pH of the reaction mixture to 7. The mixture was extracted with ethyl acetate, washed successively with water and brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol=100:0-90:10) to give the desired 4-(4-ethylphenylmethyl)pyrazole (414 mg) as a pale brown semisolid. APCI-Mass m/Z 187 (M+H).
Reaction SMILES: C(O[C:6]([N:8](C)[CH2:9][C:10](O)=[O:11])=O)(C)(C)C.Cl.CN(C)CCCN=C=NCC.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]1[CH:38]=[CH:37][C:36]([O:39][C:40]2[C:54]([CH:55]3[CH2:59][CH2:58][CH2:57][NH:56]3)=[CH:53][C:43]3[NH:44][C:45]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=4)=[N:46][C:42]=3[CH:41]=2)=[CH:35][CH:34]=1.Cl.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl.N1C=CC=CC=1>[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]1[CH:34]=[CH:35][C:36]([O:39][C:40]2[C:54]([CH:55]3[CH2:59][CH2:58][CH2:57][N:56]3[C:10](=[O:11])[CH2:9][NH:8][CH3:6])=[CH:53][C:43]3[NH:44][C:45]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=4)=[N:46][C:42]=3[CH:41]=2)=[CH:37][CH:38]=1
Reactant: Fc1ccccc1-c1ccc(Oc2cc3nc(-c4ccccn4)[nH]c3cc2C2CCCN2)cc1
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: CNCC(=O)N1CCCC1c1cc2[nH]c(-c3ccccn3)nc2cc1Oc1ccc(-c2ccccc2F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
19 mg of N-(t-butoxycarbonyl)-N-methylglycine and 24 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide monohydrochloride were added in order to a pyridin (1 ml) solution of 37 mg of 5-((2′-fluorobiphenyl-4-yl)oxy)-2-pyridin-2-yl-6-pyrrolidin-2-yl-1H-benzimidazole, and the reaction liquid was stirred at room temperature for 3 hours. 2 ml of 4 N hydrochloric acid-dioxane solution was added to the reaction liquid, and the reaction liquid was stirred at room temperature for 1 hour. The reaction liquid was diluted with chloroform, and made basic with aqueous saturated sodium carbonate added thereto, and the organic layer was washed with saturated saline and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: chloroform/methanol=10/1) to obtain the entitled compound as a pale yellow solid.
Reaction SMILES: [CH3:1][P:2]([CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:29])[C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[C:23](I)[CH:22]=3)=[CH:15][C:14]=2[C:30]([F:33])([F:32])[F:31])[CH2:8][CH2:7]1)([CH3:4])=[O:3].N#N.C(N(CC)C(C)C)(C)C.[CH3:45][Si:46]([C:49]#[CH:50])([CH3:48])[CH3:47]>[Cu]I.CCOC(C)=O.O.CN(C=O)C>[CH3:1][P:2]([CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:29])[C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([C:50]#[C:49][Si:46]([CH3:48])([CH3:47])[CH3:45])[CH:22]=3)=[CH:15][C:14]=2[C:30]([F:33])([F:32])[F:31])[CH2:8][CH2:7]1)([CH3:4])=[O:3]
Reactant: C#C[Si](C)(C)C
Reactant: Cc1ccc(C(=O)Nc2ccc(CN3CCN(CP(C)(C)=O)CC3)c(C(F)(F)F)c2)cc1I
Agent: [Cu]I
Agent: N#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)Nc2ccc(CN3CCN(CP(C)(C)=O)CC3)c(C(F)(F)F)c2)cc1C#C[Si](C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
N-[4-({4-[(dimethylphosphoryl)methyl]piperazin-1-yl}methyl)-3-(trifluoromethyl)phenyl]-3-iodo-4-methylbenzamide (5 mmol), Pd[(PPh3)]4 (289 mg, 0.25 mmol), CuI (71 mg, 0.375 mmol) is placed in a schlenk flask. The flask is subjected to 3 cycles of vacuum-refilling with N2. To this mixture is added anhydrous N,N-diisopropylethylamine (1.1 mL, 6 mmol), DMF (5 mL), and trimethylsilylacetylene (0.92 mL, 6.5 mmol). This solution is stirred at rt for 24 h. Water and EtOAc are added to the reaction mixture to facilitate the extraction. The combined organic layers are dried over Na2SO4, filtered, and then concentrated on a rotavap and the crude product is purified on a silica gel column (eluent: 5% MeOH in CH2Cl2, MeON is pre-saturated with ammonia gas).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2=[O:12].[N+:13]([CH3:16])([O-:15])=[O:14]>O>[OH:12][C:7]1([CH2:16][N+:13]([O-:15])=[O:14])[C:6]2[C:10](=[C:2]([I:1])[CH:3]=[CH:4][CH:5]=2)[NH:9][C:8]1=[O:11]
Reactant: O=C1Nc2c(I)cccc2C1=O
Reactant: C[N+](=O)[O-]
Solvent: O
Product: O=C1Nc2c(I)cccc2C1(O)C[N+](=O)[O-]
Temperature: 30 °C
Reaction time: 24 h

Procedure:
7-iodoisatin (0.136 g) and nitromethane (0.15 ml) were added to water and the reaction mixture was vigorously stirred at a temperature of 30° C. for 24 hours. The obtained product was extracted with ethyl acetate and purified by silica gel column chromatography using ethyl acetate/hexane as eluents to afford pure product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:23]3[C:18]([CH2:19][CH2:20][CH2:21][CH2:22]3)=[C:17]([C:24](O)=[O:25])[CH:16]=2)=[C:11]([C:27]([N:29]2[C@H:38]([CH2:39][N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)[CH2:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:30]2)=[O:28])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(N(C)C)=C(C)C.C1(C)C=CC=CC=1.[Si:61]([O:68][C:69]1[CH:74]=[CH:73][C:72]([NH:75][C:76]2[CH:77]=[C:78]3[CH:84]=[CH:83][N:82]([CH3:85])[C:79]3=[N:80][CH:81]=2)=[CH:71][CH:70]=1)([C:64]([CH3:67])([CH3:66])[CH3:65])([CH3:63])[CH3:62]>ClCCCl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:23]3[C:18]([CH2:19][CH2:20][CH2:21][CH2:22]3)=[C:17]([C:24]([N:75]([C:72]3[CH:71]=[CH:70][C:69]([O:68][Si:61]([C:64]([CH3:67])([CH3:65])[CH3:66])([CH3:63])[CH3:62])=[CH:74][CH:73]=3)[C:76]3[CH:77]=[C:78]4[CH:84]=[CH:83][N:82]([CH3:85])[C:79]4=[N:80][CH:81]=3)=[O:25])[CH:16]=2)=[C:11]([C:27]([N:29]2[C@H:38]([CH2:39][N:40]3[CH2:41][CH2:42][O:43][CH2:44][CH2:45]3)[CH2:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:30]2)=[O:28])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc(-c2ccc(OCc3ccccc3)cc2C(=O)N2Cc3ccccc3C[C@H]2CN2CCOCC2)n2c1CCCC2
Reactant: Cn1ccc2cc(Nc3ccc(O[Si](C)(C)C(C)(C)C)cc3)cnc21
Agent: CC(C)=C(Cl)N(C)C
Solvent: Cc1ccccc1
Solvent: ClCCCl
Product: Cn1ccc2cc(N(C(=O)c3cc(-c4ccc(OCc5ccccc5)cc4C(=O)N4Cc5ccccc5C[C@H]4CN4CCOCC4)n4c3CCCC4)c3ccc(O[Si](C)(C)C(C)(C)C)cc3)cnc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The acid obtained in Step B (9 g, 11.8 mmol) is dissolved in 90 mL of 1,2-dichloroethane. 1.9 mL of 1-chloro-N,N,2-trimethylpropenylamine (14 mmol) are added thereto. After stirring for 3 hours at ambient temperature, 90 mL of toluene and 4.62 g of N-[4-[tert-butyl(dimethyl)silyl]oxyphenyl]-1-methyl-1H-pyrrolo[2,3-b]pyridin-5-amine (Preparation 3″, 13 mmol) are added. The reaction mixture is heated at 110° C. for 20 hours. After returning to ambient temperature, the reaction mixture is washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue obtained is purified by chromatography over silica gel (dichloromethane/ethanol gradient) to yield the expected product.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([NH:11][C@H:12]([C:16]([NH:18][C@H:19]([C:21]([O:23]C)=[O:22])[CH3:20])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[OH-].C(OC(=O)C)C.CN(C=O)C>CO>[C:1]1([CH2:7][CH2:8][C:9]([NH:11][C@H:12]([C:16]([NH:18][C@H:19]([C:21]([OH:23])=[O:22])[CH3:20])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)CCc1ccccc1)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)[C@H](NC(=O)CCc1ccccc1)C(=O)N[C@@H](C)C(=O)O

Procedure:
By the same procedure used to prepare AcTyr(O-t-butyl)ValAlaOH, PhCH2CH2COValAlaOCH3 (508 mg, 1.52 mmole) and LiOH.OH (319 mg, 7.6 mmole) in 10% aqueous CH3OH (15 mL) gave, after quenching with sulfonic acid ion exchange resin (17.0 g, 38 meq), 511 mg (100%) of pure product as a white powder. Recyrstallization of a portion from ethylacetate gave an analytical sample: mp 205°-206° C.; 1H NMR (DMSO-d6) δ 0.76 (d, J=6.7 Hz, 3H), 0.81 (d, J=6.8 Hz, 3H), 1.24 (d, J=7.3 Hz, 3H), 1.8-1.95 (m, 1H), 2.35-2.55 (m, 2H, partially obscured by the DMSO-d5 peak), 2.75-2.85 (m, 2H), 4.1-4.25 (m, 2H), 7.1-7.3 (m, 5H), 7.84 (d, J=9.1 Hz, 1H), 8.23 (d, J=6.5 Hz, 1H); MS (LSIMS) m/e 321 (45, M+ +1), 232 (29), 204 (11), 157 (100); [α]D20 -2.0° (c=1.0, DMF); Analysis calculated for C17H24N2O4 : C, 63.73; H, 7.55; N, 8.75; found: C, 63.78; H, 7.30; N, 8.60.
Reaction SMILES: [CH3:1][C:2]1([CH2:7]/[CH:8]=[CH:9]/[C:10]23[CH2:17][CH2:16][C:13]([C:18]([O:20][CH3:21])=[O:19])([CH2:14][CH2:15]2)[CH2:12][CH2:11]3)[O:6][CH2:5][CH2:4][O:3]1.[H][H]>C(O)C.[Pd]>[CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][C:10]23[CH2:11][CH2:12][C:13]([C:18]([O:20][CH3:21])=[O:19])([CH2:16][CH2:17]2)[CH2:14][CH2:15]3)[O:3][CH2:4][CH2:5][O:6]1
Reactant: COC(=O)C12CCC(/C=C/CC3(C)OCCO3)(CC1)CC2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COC(=O)C12CCC(CCCC3(C)OCCO3)(CC1)CC2
Reaction time: 3 h

Procedure:
Methyl 4-[(1E)-3-(2-methyl-1,3-dioxolan-2-yl)prop-1-enyl]bicyclo[2.2.2]octane-1-carboxylate (4-B) (1.1 g) was stirred in ethanol (75 mL). A spatula tip scoop of 10% Pd on carbon (150 mg) was added. A hydrogen balloon was added and the mixture was stirred under hydrogen atmosphere for 3 h. The palladium-on-carbon was filtered and the ethanol was removed in vacuo to yield methyl 4-[3-(2-methyl-1,3-dioxolan-2-yl)propyl]bicyclo[2.2.2]octane-1-carboxylate (4-C).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][N:15]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.C(O)C.O.O.NN>C(OCC)C>[N:1]1[CH:2]=[CH:3][C:4]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][NH2:15])[CH2:9][CH2:8]2)=[CH:5][CH:6]=1
Reactant: O=C1c2ccccc2C(=O)N1CCN1CCN(c2ccncc2)CC1
Agent: NN
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: NCCN1CCN(c2ccncc2)CC1
Yield: 62.2 %

Procedure:
A stirred mixture of 2-[2-(4-pyridin-4-yl-piperazin-1-yl)-ethyl]-isoindole-1,3-dione (1.52 g, 4.52 mmol), ethanol (47.5 mL), water (2.5 mL) and hydrazine hydrate (98%, 0.438 mL, 9.04 mmol) was refluxed for 3 h, then cooled and diluted with diethyl ether (100 mL). The precipitated crystals were filtered off, washed with diethyl ether and filtrate was concentrated. The residue was dissolved N sodium hydroxide (25 mL), extracted with dichloromethane (4×25 mL), the combined organic layers were washed with brine (25 mL), dried over sodium sulfate, filtered and concentrated to yield 0.58 g (62%) of the title compound as a colorless oil.