Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]([C:10]3[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([S:23](=[O:34])(=[O:33])[N:24]([CH2:29][CH2:30][O:31][CH3:32])[C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:19][CH:18]=4)[N:11]=3)=[CH:8][N:7]=[C:6]2[CH3:35])[CH2:3][CH2:2]1.C([Li])CCC.[CH3:41][C:42]([CH3:44])=[O:43].O>C1COCC1>[CH:1]1([CH2:4][N:5]2[C:9]([C:10]3[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([S:23](=[O:33])(=[O:34])[N:24]([CH2:29][CH2:30][O:31][CH3:32])[C:25]([CH3:27])([CH3:28])[CH3:26])=[CH:21][CH:22]=4)[N:11]=3)=[CH:8][N:7]=[C:6]2[CH2:35][C:42]([OH:43])([CH3:44])[CH3:41])[CH2:3][CH2:2]1
Reactant: CC(C)=O
Reactant: COCCN(C(C)(C)C)S(=O)(=O)c1ccc(Nc2nccc(-c3cnc(C)n3CC3CC3)n2)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COCCN(C(C)(C)C)S(=O)(=O)c1ccc(Nc2nccc(-c3cnc(CC(C)(C)O)n3CC3CC3)n2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 36.2 %

Procedure:
4-(1-Cyclopropylmethyl-2-methylimidazol-5-yl)-2-{4-[N-(2-methoxyethyl)-N-(t-butyl)sulphamoyl]anilino}pyrimidine (Method 78; 1.15 g, 2.31 mmol) was dissolved in anhydrous THF (80 ml), under nitrogen. The solution was cooled to −78° C. and n-butyl lithium (2.88 ml of a 1.6 N solution in hexanes, 4.62 mmol), was added slowly, maintaining the temperature at less than −65° C. The reaction mixture was then stirred at −78° C. for 30 minutes, then acetone (1187 μl, 2.54 mmol) was added and mixture allowed to warm to ambient temperature and stirred for 1 hour. The reaction mixture was then poured into water (100 ml), and extracted with EtOAc (2×50 ml). The organic extracts were combined, washed with water (50 ml), brine (50 ml), and dried. The volatiles were removed and the residue was purified by chromatography on silica gel eluting with EtOAc to give the title compound (465 mg, 36%) as a yellow solid. NMR: 0.10 (m, 2H) 0.18 (m, 2H) 0.89 (m, H) 1.07 (s, 6H) 1.12 (s, 9H) 2.75 (s, 2H) 3.15 (s, 3H) 3.38 (m, 4H) 4.54 (d, 2H) 7.11 (d, H) 7.58 (m, 3H) 7.75 (d, 2H) 8.34 (d, H) 9.8 (s, H); m/z 557.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][O:5][CH2:4][CH:3]1[O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[C:11]#[N:12].[H-].[Na+].[CH3:20]I>CN(C)C=O>[CH3:17][O:16][C:15]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1[O:7][CH:3]1[CH:2]([O:1][CH3:20])[CH2:6][O:5][CH2:4]1
Reactant: CI
Reactant: COc1ccc(C#N)cc1OC1COCC1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C#N)cc1OC1COCC1OC
Temperature: 60 °C
Reaction time: 2 h
Yield: 72.6 %

Procedure:
1.0 g (4.2 mmol) of 3-(4-hydroxytetrahydrofuran-3-yloxy)-4-methoxybenzonitrile (A15) in 5 ml of dimethylformamide is added dropwise under a nitrogen atmosphere to a solution of 140 mg (4.6 mmol) of 80% strength sodium hydride in 5 ml of dimethylformamide and the mixture is heated at 60° C. for 20 min. 315 μl (5.0 mmol) of methyl iodide, dissolved in 1 ml of dimethylformamide, are then added dropwise at RT. The mixture is stirred at RT for 2 h, concentrated, treated with 20 ml of water and acidified with 2 N hydrochloric acid. After extraction with 3×30 ml of ethyl acetate, the combined organic phases are dried over magnesium sulfate, concentrated and the crude product is recrystallized from 10 ml of isopropanol. 760 mg of the title compound of m.p. 98-100° C. are obtained.
Reaction SMILES: [S:1]([CH2:5][CH2:6][OH:7])([OH:4])(=[O:3])=[O:2].C1C=CC(NC2C=CC(NC3C=C[CH:25]=[CH:26][CH:27]=3)=CC=2)=CC=1.[C:28]1(C=CC(O)=CC=1)[OH:29].COC>>[C:28]([O:7][CH2:6][CH2:5][S:1]([OH:4])(=[O:3])=[O:2])(=[O:29])[C:26]([CH3:25])=[CH2:27]
Reactant: O=S(=O)(O)CCO
Reactant: c1ccc(Nc2ccc(Nc3ccccc3)cc2)cc1
Reactant: Oc1ccc(O)cc1
Agent: COC
Product: C=C(C)C(=O)OCCS(=O)(=O)O

Procedure:
To the reactor containing the concentrated isethionic acid solution of Example 1 is added 95.2 Kg. (209.5 lbs.) of MAA to achieve a MAA/ITA molar ratio of about 5:1 along with 14 grams of N,N' diphenyl-p-phenylene diamine and 140 grams of monomethyl ether hydroquinone, both serving as polymerization inhibitors. The mixture is heated for about 6 hours under a vacuum of about 90 mm. Hg. at a temperature of about 80° C. to form sulfoethyl methacrylate according to the reaction: ##STR9## with water of reaction and residual water from the oxidation reaction being continuously removed by azeotropic distillation of a water/MAA mixture under vacuum. At the completion of the reaction, as shown by the cessation of the azeotropic distillation and an increase in the pot temperature, any remaining MAA is removed by vacuum distillation at a pressure of about 10 mm. Hg. The resultant product is sulfoethyl methacrylate having a purity of about 90-95% with methacrylic acid as the major impurity.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:8][C:9]1([CH3:33])[C:18]2[CH:17]=[C:16]([C:19]#[C:20][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=3)[CH:15]=[CH:14][C:13]=2[C:12](=[O:32])[CH2:11][CH2:10]1>C1C=CC=CC=1.[Zn]>[OH:32][C:12]1([CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:11][CH2:10][C:9]([CH3:8])([CH3:33])[C:18]2[CH:17]=[C:16]([C:19]#[C:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:30][CH:31]=3)[CH:15]=[CH:14][C:13]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3=O)cc1
Reactant: CCOC(=O)CBr
Agent: [Zn]
Solvent: c1ccccc1
Product: CCOC(=O)CC1(O)CCC(C)(C)c2cc(C#Cc3ccc(C(=O)OCC)cc3)ccc21
Temperature: 25 °C

Procedure:
To a refluxing solution of 1.00 g (15.30 mmol) of 20 mesh, granular zinc (activated prior to use by washing with 2% HCl, water, 95% ethanol, acetone, anhydrous Et2O and then dried in vacuum for several hours) in 20 ml of dry benzene was slowly added a mixture of 0.23 ml (1.62 mmol) of ethyl bromoacetate, 0.28 g (0.81 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl]benzoate (Compound 1) in 10 ml of dry benzene. The resulting mixture was refluxed for 2 hours, cooled to room temperature and the precipitate filtered through celite. The filtrate was washed with cold 15% H2SO4, sat. aqueous NaHCO3 and brine. The organic phase was dried over Na2SO4 and concentrated in vacuo to a yellow oil. Purification by flash chromatography (silica, 10% EtOAc-hexane) yielded the title compound as a light yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([O:8][CH:9]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:10]([F:13])([F:12])[F:11])=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:29]([O:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2[CH:49]=[CH:48][C:47]([C:50](Cl)=[O:51])=[CH:46][CH:45]=2)=[CH:40][CH:39]=1)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>C(Cl)Cl.O>[CH2:29]([O:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2[CH:49]=[CH:48][C:47]([C:50]([O:1][C:2]3[CH:3]=[CH:4][C:5]([C:6]([O:8][CH:9]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:10]([F:11])([F:12])[F:13])=[O:7])=[CH:20][CH:21]=3)=[O:51])=[CH:46][CH:45]=2)=[CH:40][CH:39]=1)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCCCOc1ccc(-c2ccc(C(=O)Cl)cc2)cc1
Reactant: CCCCCCC(OC(=O)c1ccc(O)cc1)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCCCCOc1ccc(-c2ccc(C(=O)Oc3ccc(C(=O)OC(CCCCCC)C(F)(F)F)cc3)cc2)cc1
Reaction time: 8 h

Procedure:
To a mixture of the 1,1,1-trifluoro-2-octyl 4-hydroxybenzoate prepared above (0.53 g) and triethylamine (0.18 g) in methylene chloride (10 ml) was slowly added c under ice cooling a solution of 4-n-octyloxybiphenyl-4'-carboxylic acid chloride (0.73 g) in methylene chloride (10 ml). After the mixture was left to stand until it reached room temperature, it was stirred overnight. The mixture was poured in water and extracted with methylene chloride. The extracted layer was washed with dilute aqueous hydrochloric acid solution, water, 1N aqueous sodium carbonate solution and water, in this order, and dehydrated over anhydrous magnesium sulfate. After the solution was distilled under reduced pressure to remove the solvent, the residue was purified by silica-gel column chromatography to obtain the titled compound (0.4 g, [α]D20 =+32.2).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:12][N:13]([CH3:18])[CH2:14][CH2:15][CH2:16]Cl>CN(C)C=O.C1(C)C=CC=CC=1>[CH3:12][N:13]([CH3:18])[CH2:14][CH2:15][CH2:16][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: CN(C)CCCCl
Reactant: O=Cc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CN(C)CCCOc1ccc(C=O)cc1

Procedure:
A stirred solution of 61.0 g (0.50 mole) of 4-hydroxybenzaldehyde in 400 ml of dimethylformamide (nitrogen atmosphere) is gradually treated with 24.0 g of 50% NaH. The temperature is kept below 35° using an ice water bath. When the addition is completed, the thick mixture is heated to 70° for several minutes, then cooled to 35° before the addition of 417 ml of 1.8N (0.75 mole) of 3-dimethylaminopropyl chloride in toluene.
Reaction SMILES: Br[C:2]1[N:6]([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:5]2[CH:15]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[S:17][C:4]=2[C:3]=1[CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.[C:28]([O:32][C:33](=[O:50])[NH:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1B1OC(C)(C)C(C)(C)O1)([CH3:31])([CH3:30])[CH3:29].C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.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>[C:28]([O:32][C:33]([NH:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:2]1[N:6]([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:5]2[CH:15]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[S:17][C:4]=2[C:3]=1[CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:50])([CH3:31])([CH3:29])[CH3:30]
Reactant: COC(=O)c1cc2c(s1)c(C1CCCCC1)c(Br)n2CC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)Nc1ccccc1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2c(s1)c(C1CCCCC1)c(-c1ccccc1NC(=O)OC(C)(C)C)n2CC(=O)OC(C)(C)C
Yield: 89 %

Procedure:
A solution (0.15 M) of methyl 5-bromo-4-(2-tert-butoxy-2-oxoethyl)-6-cyclohexyl-4H-thieno[3,2-b]pyrrole-2-carboxylate (from Step 2) in dioxane was treated with tert-butyl-N-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (1.5 eq.) and 2 N Na2CO3 solution (6 eq.) and degassed. PdCl2(PPh3)2 (0.2 eq.) was added and the suspension refluxed for 30 mins. After cooling, EtOAc was added and the solution was washed with water, brine, dried over sodium sulfate and evaporated in vacuo to give a residue which was purified by flash chromatography (PE:EtOAc, 95:5) to afford the title compound (89%) as a solid. 1H-NMR (400 MHz, DMSO-d6, 300 K, δ) 8.00 (s, 1H), 7.73 (m, 2H), 7.47-7.43 (t, J 8.6, 1H), 7.27-7.23 (m, 2H), 4.73-4.49 (dd, J 20, 2H), 3.82 (s, 3H), 2.17-2.11 (m, 1H), 1.82-1.21 (m, 10H), 1.37 (s, 9H), 1.28 (s, 9H). MS (ES+) m/z: 569 [M+H]+.
Reaction SMILES: [K].[Cl:2][C:3]1[CH:4]=[C:5]([NH:10][C:11](=[O:15])[N:12]([CH3:14])[CH3:13])[CH:6]=[CH:7][C:8]=1[OH:9].[CH3:16][C:17]([O:21][CH:22](Cl)[CH3:23])([CH3:20])[C:18]#[CH:19].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[Cl:2][C:3]1[CH:4]=[C:5]([NH:10][C:11](=[O:15])[N:12]([CH3:13])[CH3:14])[CH:6]=[CH:7][C:8]=1[O:9][CH:22]([O:21][C:17]([CH3:20])([CH3:16])[C:18]#[CH:19])[CH3:23]
Reactant: C#CC(C)(C)OC(C)Cl
Reactant: CN(C)C(=O)Nc1ccc(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K]
Agent: [Na+]
Solvent: CC(C)=O
Product: C#CC(C)(C)OC(C)Oc1ccc(NC(=O)N(C)C)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a well-stirred suspension of the potassium salt of 3-chloro-4-hydroxyphenyl-1,1-dimethylurea (0.04 mole) in dry acetone (150 ml.) is added dropwise 1-chloroethyl 1,1-dimethyl-2-propynyl ether (5.9 grams, 0.04 mole). During the addition, an exotherm to 35° C. is observed; the reaction is stirred at room temperature overnight, then poured into an aqueous 10% sodium carbonate solution containing 200 grams of ice, and the mixture stirred vigorously for 30 minutes. The resulting solid is filtered off, water-washed and dried to give 8.5 grams, melting point 99° to 101° C., crystallization from hexane-cyclohexane-benzene gave 4.69 grams (36%), melting point 101° to 103° C.
Reaction SMILES: C[O:2][C:3](=[O:41])[C@@H:4]([NH:11][C:12]([C:14]1[CH:18]=[C:17]([O:19][CH2:20][C:21]([N:23]2[CH2:27][CH2:26][CH2:25][C@H:24]2[C:28](=[O:34])[NH:29][CH:30]2[CH2:33][CH2:32][CH2:31]2)=[O:22])[N:16]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:15]=1)=[O:13])[CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[OH-].[Li+].Cl>C1COCC1.O>[CH:30]1([NH:29][C:28]([C@@H:24]2[CH2:25][CH2:26][CH2:27][N:23]2[C:21](=[O:22])[CH2:20][O:19][C:17]2[N:16]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[N:15]=[C:14]([C:12]([NH:11][C@@H:4]([CH:5]3[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]3)[C:3]([OH:41])=[O:2])=[O:13])[CH:18]=2)=[O:34])[CH2:33][CH2:32][CH2:31]1
Reactant: COC(=O)[C@@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1)C1CCCCC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(N[C@H](C(=O)O)C1CCCCC1)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Reaction time: 4 h

Procedure:
To a solution of 428 mg (S)-({5-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-cyclohexyl-acetic acid methyl ester in 20 ml THF and 5 ml water were added 30 mg lithium hydroxide at 0° C. After stirring for 4 h it was acidified with 1 N HCl and concentrated in vacuo to give the crude product as colorless oil. Yield: 380 mg.
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)(=[O:8])=[O:7])#[N:2].[N+:20]([O-])([OH:22])=[O:21]>C(OC(=O)C)(=O)C>[C:1]([C:3]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:4]=1[NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)(=[O:8])=[O:7])#[N:2]
Reactant: Cc1ccc(S(=O)(=O)Nc2ccccc2C#N)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Product: Cc1ccc(S(=O)(=O)Nc2ccc([N+](=O)[O-])cc2C#N)cc1
Temperature: 25 °C
Yield: 98 %

Procedure:
To a suspension of 2′-cyano-p-toluenesulfonanilide (2.67g (9.80 mmol) in acetic anhydride (7.0 ml), 97% fuming nitric acid (0.45 ml (10.5 mmol) was added with stirring at room temperature. After stirring for one hour at 50° C., crystals began to separate. Water was added to decompose excess acetic anhydride, and the crystals were filtered, washed with water, dried in the air and then, washed with diethyl ether and collected by filtration to give 3.05 g (98%) of 2′-cyano-4′-nitro-p-toluenesulfonanilide as pale yellow crystals.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].S(Cl)([Cl:13])=O>>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([Cl:13])=[O:6]
Reactant: O=C(O)c1cccc(I)c1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cccc(I)c1
Yield: 67 %

Procedure:
2.21 g (0.00891 mol) of 3-iodobenzoic acid were dissolved in 25 ml of thionyl chloride under argon and boiled under reflux for 2 hrs. The excess thionyl chloride was distilled off and the residue was taken up twice with 50 ml of toluene and concentrated each time. 1.6 g (67%) of 3-iodobenzoyl chloride were obtained as a yellow solid.
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:10]1[CH:11]=[CH:12][C:13]([CH3:16])=[N:14][CH:15]=1)#[CH:9].Br[C:18]1[C:26]2[NH:25][C:24]3[CH2:27][CH2:28][N:29]([CH3:31])[CH2:30][C:23]=3[C:22]=2[CH:21]=[CH:20][CH:19]=1>O1CCCC1.C(P([Pd]P(C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C)(C)C.[Cu]I>[CH3:31][N:29]1[CH2:28][CH2:27][C:24]2[NH:25][C:26]3[C:18]([C:9]#[C:8][C:10]4[CH:15]=[N:14][C:13]([CH3:16])=[CH:12][CH:11]=4)=[CH:19][CH:20]=[CH:21][C:22]=3[C:23]=2[CH2:30]1
Reactant: C#Cc1ccc(C)nc1
Reactant: CN1CCc2[nH]c3c(Br)cccc3c2C1
Agent: CC(C)(C)[PH]([Pd][PH](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(C#Cc2cccc3c4c([nH]c23)CCN(C)C4)cn1
Temperature: 75 °C
Reaction time: 2 h

Procedure:
Triethylamine (1.5 mL) was added to a mixture of bis(tri-t-butylphosphino)palladium (12.3 mg, 0.024 mmol; Aldrich), 5-ethynyl-2-methylpyridine (85 mg, 0.72 mmol; International Publication No. WO2005090333), CuI (4.6 mg, 0.024 mmol; Aldrich) and the product of Example 1A (128 mg, 0.48 mmol) in anhydrous tetrahydrofuran (1.5 mL). The mixture was purged with a nitrogen stream for 2 minutes, then stirred under nitrogen at 75° C. for 2 hours and then at 35° C. for 18 hours in a sealed tube. The mixture was filtered through a glass microfiber frit, rinsed with CH3OH (3 mL) and purified by reverse-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 30×100 mm, flow rate 40 mL/minute, 50-99% gradient of methanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)]. Fractions containing the product were concentrated under vacuum and the residue was further purified by flash chromatography (silica gel, eluted with CHCl3—CH3OH-14.8 M aqueous NH4OH (90:10:1)) to provide the title compound: 1H NMR (400 MHz, methanol-d4) δ ppm 2.55 (s, 3H), 2.56 (s, 3H), 2.89 (t, J=5.8 Hz, 2H), 2.98 (t, J=5.5 Hz, 2H), 3.69 (s, 2H), 6.97-7.04 (m, 1H), 7.25 (dd, J=7.3, 0.9 Hz, 1H), 7.33 (d, J=7.9 Hz, 1H), 7.41 (dd, J=7.8, 1.1 Hz, 1H), 7.94 (dd, J=7.9, 2.1 Hz, 1H), 8.68 (d, J=1.8 Hz, 1H); MS (DCI) m/z 302 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]([NH:9][C:10]1[C:14]([C:15]([O:17]C)=O)=[CH:13][S:12][CH:11]=1)=[O:8].Cl.[F:20][C:21]1[CH:34]=[CH:33][C:24]([C:25]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[O:26])=[CH:23][CH:22]=1.NC1C(C(OC)=O)=CSC=1.BrCCCCN=C=O>C1(C)C=CC=CC=1>[F:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([CH:27]2[CH2:32][CH2:31][N:30]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:15](=[O:17])[C:14]4=[CH:13][S:12][CH:11]=[C:10]4[NH:9][C:7]3=[O:8])[CH2:29][CH2:28]2)=[O:26])=[CH:33][CH:34]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: COC(=O)c1cscc1NC(=O)NCCCCBr
Agent: COC(=O)c1cscc1N
Agent: Cl
Agent: O=C=NCCCCBr
Solvent: Cc1ccccc1
Product: O=C(c1ccc(F)cc1)C1CCN(CCCCn2c(=O)[nH]c3cscc3c2=O)CC1

Procedure:
The title compound was prepared by the procedure of Example 10 using N-(4-bromobutyl)-N'-(4-carbomethoxythien-3-yl)urea (6.92 g, 21 mmol) and 4-(4-fluorobenzoyl)piperidine hydrochloride (10.16 g, 42 mmol). The urea was prepared by reacting methyl 4-aminothiophene-3-carboxylate with 4-bromobutylisocyanate in toluene at room temperature for 12 hours to produce the urea as a tan solid, mp 85°-86° C. There was obtained 3.62 g (40.8% yield) of the title compound as a brown solid. This material was recrystallized from CH2Cl2 /ether, mp 190°-192° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([N:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13](=[O:20])[NH:12][C:11]3[CH:21]=[CH:22][CH:23]=[CH:24][C:10]2=3)=[O:8])=[CH:3][CH:2]=1.[BH4-].[Na+].[CH3:27]O>>[OH2:8].[CH3:27][N:1]1[CH2:2][CH2:3][C:4]([C:7]([N:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13](=[O:20])[NH:12][C:11]3[CH:21]=[CH:22][CH:23]=[CH:24][C:10]2=3)=[O:8])=[CH:5][CH2:6]1.[CH3:27][N:1]1[CH2:2][CH2:3][C:4]([C:7]([N:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13](=[O:20])[NH:12][C:11]3[CH:21]=[CH:22][CH:23]=[CH:24][C:10]2=3)=[O:8])=[CH:5][CH2:6]1
Reactant: CO
Reactant: O=C1Nc2ccccc2N(C(=O)c2ccncc2)c2ccccc21
Agent: [BH4-]
Agent: [Na+]
Product: CN1CC=C(C(=O)N2c3ccccc3NC(=O)c3ccccc32)CC1
Product: O
Temperature: 0 °C

Procedure:
2.3 g (0.005 mol) of 5,10-dihydro-5-[(4-pyridinyl)carbonyl]-11H-dibenzo[b,e][1,4]diazepin-11-one methoiodide were suspended in 200 ml of methanol and at 0° C. 0.25 g (0.006 mol) of sodium borohydride were added in batches. The mixture was stirred for a further hour in the ice bath. It was then stirred into 1 liter of ice-cold water and extracted exhaustively with methylene chloride. The combined extracts were washed with water, dried over sodium sulphate and concentrated by evaporation in vacuo. After recrystallization from diisopropylether/methanol, the colorless crystals melted at 233°-234° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:30]=[CH:29][C:13]([CH2:14][NH:15][C:16]3[CH:28]=[CH:27][C:19]4[O:20][C:21]([CH3:26])([CH3:25])[O:22][C:23](=[O:24])[C:18]=4[CH:17]=3)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH2:31]([C:38]1[CH:46]=[CH:45][C:41]([C:42](Cl)=[O:43])=[CH:40][CH:39]=1)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][C:10]2[CH:30]=[CH:29][C:13]([CH2:14][N:15]([C:16]3[CH:28]=[CH:27][C:19]4[O:20][C:21]([CH3:26])([CH3:25])[O:22][C:23](=[O:24])[C:18]=4[CH:17]=3)[C:42](=[O:43])[C:41]3[CH:45]=[CH:46][C:38]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:39][CH:40]=3)=[CH:12][CH:11]=2)=[CH:6][CH:7]=1
Reactant: CCCCCCCc1ccc(C(=O)Cl)cc1
Reactant: CC1(C)OC(=O)c2cc(NCc3ccc(C#Cc4ccc(Cl)cc4)cc3)ccc2O1
Product: CCCCCCCc1ccc(C(=O)N(Cc2ccc(C#Cc3ccc(Cl)cc3)cc2)c2ccc3c(c2)C(=O)OC(C)(C)O3)cc1

Procedure:
The titled compound was prepared following the procedure E using 6-({4-[(4-chlorophenyl)ethynyl]benzyl}amino)-2,2-dimethyl-4H-1,3-benzodioxin-4-one and 4-heptylbenzoyl chloride as a yellow oil (94%). HPLC, Rt: 6.8 min (Purity: 96.4%).
Reaction SMILES: ON1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=O.[CH:9]1([N:15]=C=NC2CCCCC2)CCCC[CH2:10]1.N=C=N.C(NC1CCCCC1)(N[CH:30]1CCCC[CH2:31]1)=O>>[NH2:15][CH2:9][CH2:10][C:3]1[CH:4]=[CH:5][C:6]([OH:7])=[CH:31][CH:30]=1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(NC1CCCCC1)NC1CCCCC1
Reactant: O=C1CCC(=O)N1O
Agent: N=C=N
Product: NCCc1ccc(O)cc1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
Formation of the tyramide of compound III, is as follows. N-hydroxysuccinimide (33 mg) is dissolved In the reaction mixture prepared above by heating to 70° C., then dicyclohexylcarbodiimide (61 mg) is added. This is reacted at 70° C. for 90 minutes, an additional amount (6 mg) of the carbodimide is added and the reaction is continued for another 30 minutes. The mixture is cooled to 0° C. and the precipitated dicyclohexylurea is settled by centrifugation. The supernatant, containing 6-(-4′-N-hydroxysuccinimidyl carboxy phenyl)-3,8-bis bromoacetamidyl-5-methylphenanthridinium chloride (IV) is recovered. A solution of tyramine [4-(2′-amino)ethylphenol] (1.0 g) in water (5 ml) is formed by bringing it to pH 7 by addition of concentrated HCl. This solution is added to the supernatant containing compound IV and reacted at room temperature for one hour. This mixture is then reduced to a red oil by evacuation at 60° C., and is then extracted with water to remove excess tyramine. Compound (VI) is then recrystalized from ethanol-acidified with HCl.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@@H:13]([C:24](O)=[O:25])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+]>C(COC)OC.O>[OH:25][CH2:24][C@H:13]1[CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:16][CH2:15][N:14]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C[C@@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CN1CCOCC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C[C@@H]1CO
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 87.8 %

Procedure:
(2R)-4-[(Benzyloxy)carbonyl]-1-(tert-butoxycarbonyl)piperazine-2-carboxylic acid (1.4 g, 3.9 mmol) was dissolved in dimethoxyethane (10 mL) and to the cooled resultant solution was added N-methylmorpholine (0.4 g, 3.9 mmol) followed by isobutyl chloroformate (0.54 g, 3.9 mmol) by means of drops. The mixture was stirred at 0° C. for 20 min and then the mixture was filtered. The filtrate was transferred to a 500 mL flask and then cooled again. Sodium borohydride (0.22 g, 5.9 mmol) dissolved in water (5 mL) was added and the external cooling bath was removed. The reaction mixture was stirred until the temperature of it had reached RT whereupon water (120 mL) was added. The mixture was extracted trice with ethyl acetate and the combined organic solutions were dried and then evaporated. The product was purified by column chromatography on silica gel (ethyl acetate-heptane 10% to 70%). There was obtained 1.2 g (84%) of 4-benzyl 1-tert-butyl (2R)-2-(hydroxymethyl)piperazine-1,4-dicarboxylate as a colorless oil. 1H NMR (500 MHz, CDCl3): 1.4 (s, 9H), 2.7-3.2 (b, 4H), 3.5 (b, 2H), 3.8-4.2 (m, 4H), 5.1 (m, 2H), 7.2-7.4 (m, 5H); LCMS: m/z 349 (M−1)−.