Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([NH:11][C:12]1[CH:43]=[CH:42][C:15]([C:16]([N:18]([CH3:41])[C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=2[O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([N:34]2[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]2)=[O:33])=[O:17])=[CH:14][C:13]=1[O:44][CH3:45])=[O:10].[CH:46]([CH:48]=O)=O.S([O-])(O)=O.[Na+]>C(O)C.C(Cl)(Cl)Cl>[CH3:45][O:44][C:13]1[CH:14]=[C:15]([CH:42]=[CH:43][C:12]=1[NH:11][C:9]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:2]=1[N:1]=[CH:46][CH:48]=[N:8]2)=[O:10])[C:16]([N:18]([CH3:41])[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([N:34]1[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]1)=[O:33])=[O:17]
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc(N)c1N
Reactant: O=CC=O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2nccnc12
Yield: 63.2 %

Procedure:
A mixture of 4-(2,3-diaminophenyl)carbonylamino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (200 mg), glyoxal (47 mg) and sodium hydrogen sulfite (169 mg) in ethanol (15 ml) was refluxed for 5 hours. The solution was diluted with chloroform (30 ml) and the solution was washed with water and brine. The organic solution was dried over magnesium sulfate and the solvent was evaporated in vacuo to give an oil. The crude product was purified by silica gal column (1% methanol in chloroform) to give 3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]-4-(quinoxalin-5-yl)carbonylaminobenzamide (131 mg).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:32](OCC)[O:33]CC)=[C:5]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:6]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[O:9].Cl.C(=O)(O)[O-].[Na+]>CC(C)=O>[CH3:1][C:2]1[NH:3][C:4]([CH:32]=[O:33])=[C:5]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:6]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[O:9]
Reactant: CCOC(=O)C1=C(C(OCC)OCC)NC(C)=C(C(=O)OCCN(CC)CC)C1c1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOC(=O)C1=C(C=O)NC(C)=C(C(=O)OCCN(CC)CC)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.4 %

Procedure:
To a mixture of a brown oil (2.46 g) of 2-(N,N-diethylamino)ethyl 2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylate in acetone (24.6 ml) was added 6N hydrochloric acid (2.46 ml) and this mixture was stirred for two hours at room temperature. The reaction mixture was adjusted to pH 7 with an aqueous solution of sodium bicarbonate and the acetone was distilled off. The residue was extracted with ethyl acetate, and the extract was washed with water, dried, and concentrated to give an oil (1.81 g) of 2-(N,N-diethylamino)ethyl 2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]([N:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][C:16]([NH:22][C:23](=[O:35])[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]4[CH2:34][CH2:33][CH2:32][NH:31]4)[CH:25]=3)=[CH:17][CH:18]=2)[CH2:13]1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CCN(CC)CC.[C:43]([C:45]1[CH:46]=[C:47]([N:51]=[C:52]=[O:53])[CH:48]=[CH:49][CH:50]=1)#[N:44].[N-]=C=O>CN(C=O)C>[CH2:2]([O:9][C:10]([N:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][C:16]([NH:22][C:23](=[O:35])[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]4[CH2:34][CH2:33][CH2:32][N:31]4[C:52](=[O:53])[NH:51][C:47]4[CH:48]=[CH:49][CH:50]=[C:45]([C:43]#[N:44])[CH:46]=4)[CH:25]=3)=[CH:17][CH:18]=2)[CH2:13]1)=[O:11])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: N#Cc1cccc(N=C=O)c1
Reactant: O=C(Nc1ccc2c(c1)CN(C(=O)OCc1ccccc1)CC2)c1cccc(C2CCCN2)c1
Agent: Cl
Agent: [N-]=C=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#Cc1cccc(NC(=O)N2CCCC2c2cccc(C(=O)Nc3ccc4c(c3)CN(C(=O)OCc3ccccc3)CC4)c2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 80.1 %

Procedure:
To a solution of 7-(3-pyrrolidin-2-yl-benzoylamino)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester HCl (238 mg, 0.387 mmol) in DMF (5 mL) add Et3N (0.082 mL, 0.581 mmol) followed by 3-cyanophenyl isocyanate (69 mg, 0.464 mmol). Stir the solution at room temperature for 48 h. LCMS analysis indicates the presence of starting material. Add more isocyanate (69 mg, 0.464 mmol) and stir the reaction at room temperature 24 h more. Quench the reaction with sat. NH4Cl (100 mL) and extract with EtOAc (2×150 mL). Wash the organic layers with water (100 mL), dry (Na2SO4) and concentrate to an oil. Purify the crude product by silica gel chromatography eluting with 10% to 75% EtOAc/hexane to afford 186 mg 7-{3-[1-(3-cyanophenylcarbamoyl)-pyrrolidin-2-yl]-benzoylamino}-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester as a solid foam.
Reaction SMILES: [OH:1][C:2]1[C:11]2[O:10][C:9]([C:12]([O:14]CC)=[O:13])=[CH:8][C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:18]([C:22]1[CH:32]=[CH:31][CH:30]=[CH:29][C:23]=1[O:24][CH2:25][CH:26]1[O:28][CH2:27]1)([CH3:21])([CH3:20])[CH3:19].[OH-].C([N+](C)(C)C)C1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.CN(C)C=O>[C:18]([C:22]1[CH:32]=[CH:31][CH:30]=[CH:29][C:23]=1[O:24][CH2:25][CH:26]([OH:28])[CH2:27][O:1][C:2]1[C:11]2[O:10][C:9]([C:12]([OH:14])=[O:13])=[CH:8][C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1)([CH3:19])([CH3:20])[CH3:21]
Reactant: CC(C)(C)c1ccccc1OCC1CO1
Reactant: CCOC(=O)c1cc(=O)c2cccc(O)c2o1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccccc1OCC(O)COc1cccc2c(=O)cc(C(=O)O)oc12

Procedure:
A mixture of 16.7 parts of ethyl 8-hydroxy-4-oxo-4H-1-benzopyran-2-carboxylate, 14.7 parts of 3-(2-t-butylphenoxy)-1,2-epoxypropane 50 parts of dimethyl formamide, and 0.1 parts of benzyltrimethyl ammonium hydroxide was boiled under reflux for 3 hours, evaporated to leave a dark brown oil, and treated with ethyl acetate, which was then washed with 2% sodium hydroxide solution, and water, dried, and evaporated to an oil. The oil was chromatographed on a silica column with chloroform as eluent to give a gummy solid, which was boiled with an aqueous ethanolic solution of sodium bicarbonate. The mixture was acidified to give a solid, which was recrystallised from ethanol after treatment with charcoal to give 4.6 parts of 8-(3-[2-t-butylphenoxy]-2-hydroxypropoxy)-4-oxo-4H-1-benzopyran-2-carboxylic acid as a cream solid, mp. 227-228 (decomp.).
Reaction SMILES: C(=O)C=CC1C=CC=CC=1.C(OCC)(=O)C=C.C(N)(=O)C=C.C1(C(=O)C=C)C=CC=CC=1.C1(=O)CCCC=C1.S[CH2:41][C:42]1[NH:43][C:44](C)=[C:45]([C:62]([O:64][CH2:65][CH3:66])=[O:63])[CH:46]([C:53]2[CH:58]=[CH:57][CH:56]=[C:55]([N+:59]([O-:61])=[O:60])[CH:54]=2)[C:47]=1[C:48]([O:50][CH2:51][CH3:52])=[O:49]>>[C:62]([C:45]1[CH:46]([C:53]2[CH:58]=[CH:57][CH:56]=[C:55]([N+:59]([O-:61])=[O:60])[CH:54]=2)[C:47]([C:48]([O:50][CH2:51][CH3:52])=[O:49])=[C:42]([CH3:41])[NH:43][CH:44]=1)([O:64][CH2:65][CH3:66])=[O:63]
Reactant: CCOC(=O)C1=C(C)NC(CS)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Agent: C=CC(=O)OCC
Agent: C=CC(=O)c1ccccc1
Agent: C=CC(N)=O
Product: CCOC(=O)C1=CNC(C)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1

Procedure:
Using in the procedure of Example 31 an α-β-unsatured-oxo compound selected from: cinnamaldehyde, ethyl acrylate, acrylamide, 1-phenyl-1-oxo-2-propene, 1-(p-imidazol-1-yl)phenyl-1-oxo-2-propene, 2-cyclohexen-1-one and 2-mercaptomethyl-3,5-dicarboethoxy-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine, the following 3,5-dicarboethoxy-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine are prepared:
Reaction SMILES: [CH2:1]([O:17][P:18](=[O:21])([OH:20])[OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(O)C.[OH-].[Na+].O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Zn+2:39]>O>[CH2:1]([O:17][P:18]([O-:21])([O-:20])=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Zn+2:39]
Reactant: CCCCCCCCCCCCCCCCOP(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCCCCCOP(=O)([O-])[O-]
Reaction time: 0.5 h

Procedure:
50 g of monocetylphosphoric acid and 100 g of ethanol were put into a 500 ml reaction vessel. Further, a solution of 6.29 g of 96% sodium hydroxide (purity was taken into consideration by calculating it from the degree of neutralization determined by titration) dissolved in 200 g of ion-exchanged water was added thereto. After the temperature was elevated to 80° C., it was confirmed that they were clearly dissolved. The solution was continuously stirred for 30 minutes. A solution of 22.3 g of zinc sulfate heptahydrate dissolved in 100 g of ion-exchanged water was added dropwise thereto to carry out a salt exchange reaction. After the completion of the addition, the mixture was stirred for 30 minutes. 13.20 g of an aqueous solution of 33.33% sodium hydroxide was added dropwise thereto to adjust the pH of the reaction mixture to 6.6. Further, the mixture was continuously stirred for one hour. After the completion of the reaction, the mixture was cooled and the product was collected by filtration, washed with water and dried, to obtain 49.3 g of the particles of zinc monocetylphosphate (zinc/sodium/phosphorus=0.77/1.42/2.00).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[CH3:7][O:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][CH2:12][NH:11]1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(#N)C>[CH3:6][O:5][C:3](=[O:4])[CH2:2][N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[CH2:9][O:8][CH3:7]
Reactant: COC(=O)CBr
Reactant: COC[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COC[C@@H]1CCCN1CC(=O)OC
Yield: 33.8 %

Procedure:
Methyl bromoacetate (199 μl, 2.10 mmol) was added to a mixture of (S)-2-methoxymethyl pyrrolidine (268 μl, 2.17 mmol), potassium carbonate (319 mg, 2.31 mmol) and sodium iodide (315 mg, 2.10 mmol) in acetonitrile (3 ml). The mixture was subjected to microwave irradiation for 5 min at 160° C., then partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane and the combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. Purification by flash column chromatography eluting with 0-10% (v/v) methanol in dichloromethane afforded (S)-(2-methoxymethyl-pyrrolidin-1-yl) acetic acid methyl ester (133 mg, 0.71 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]([O:14][CH3:15])=[O:13].[Br:16]Br>C(Cl)(Cl)Cl.CN(C=O)C>[NH2:1][C:2]1[C:11]([Br:16])=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[C:3]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1c(N)ccc2ccccc12
Reactant: BrBr
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1c(N)c(Br)cc2c1CCCC2
Yield: 101.2 %

Procedure:
Methyl 2-amino-1-naphthoate (0.5 g, 2.4 mmol) in chloroform (5 mL) and DMF (1 mL) was treated with bromine (0.125 mL, 2.4 mmol) for 30 minutes, concentrated, and dissolved in ethyl acetate. The organic layer was washed with NaHCO3 (3×), brine (3×) and water (3×), dried (Na2SO4), filtered, and concentrated to provide the desired product (0.69 g). MS (DCI) m/e 284, 286 (M+H)+.
Reaction SMILES: [I-].[CH2:2]([N+:6]1[C:10]([CH3:11])=[CH:9][S:8][C:7]=1[CH3:12])[CH2:3][CH2:4][CH3:5].[CH:13]1([C:19](Cl)=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>C(Cl)Cl.CN(C1C=CN=CC=1)C.CS(C)=O.CO>[CH2:2]([N:6]1[C:10]([CH3:11])=[CH:9][S:8]/[C:7]/1=[CH:12]\[C:19]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:20])[CH2:3][CH2:4][CH3:5]
Reactant: O=C(Cl)C1CCCCC1
Reactant: CCCC[n+]1c(C)csc1C
Agent: CN(C)c1ccncc1
Agent: [I-]
Solvent: CO
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCCCN1C(C)=CS/C1=C\C(=O)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial a solution of 3-butyl-2,4-dimethylthiazol-3-ium iodide (47.92 mg, 0.16 mmol) dissolved in CH2Cl2 (0.5 mL) was added, followed by the addition of DMAP (49.24 mg, 0.40 mmol) dissolved in CH2Cl2 (0.8 mL). Then, to the solution was added cyclohexanecarbonyl chloride (23.5 mg, 0.16 mmol) dissolved in CH2Cl2 (0.5 mL). The vial was capped and shaken overnight at room temperature. The residue was dissolved in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.92 (t, 3 H) 1.09-1.44 (m, 7 H) 1.51-1.70 (m, 3 H) 1.69-1.88 (m, 4 H) 2.21-2.36 (m, 4 H) 3.95-4.01 (m, 2 H) 5.79-5.91 (m, 1 H) 6.57-6.73 (m, 1 H) MS (ESI) positive ion 280 (M+H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)=O.[CH3:15][N:16]([CH3:20])[C:17]([NH2:19])=[O:18].C(OCC)(=O)C>CN(C)C=O>[CH3:15][N:16]([CH3:20])[C:17]1[O:18][CH:2]=[C:3]([C:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7][CH:6]=2)[N:19]=1
Reactant: CN(C)C(N)=O
Reactant: O=C(CBr)c1cccc2ccccc12
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)c1nc(-c2cccc3ccccc23)co1

Procedure:
1-(α-Bromoacetyl)naphthalene (5 g) and 1,1-dimethylurea (6 g) were stirred in anhydrous dimethylformamide (20 ml) at 105° C. overnight. The mixture was cooled, added to ethyl acetate, washed with sodium bicarbonate solution, water, brine, dried with sodium sulphate, filtered and evaporated in vacuo. The title compound was obtained (0.60 g; m.p. 30-32° C.) following silica gel column chromatography of the residue in dichloromethane.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])=[CH:13][CH:12]=2)=[C:6]([CH:9]=1)[C:7]#[N:8].C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1.[CH3:38][C:39]1[CH:40]=[C:41](B(O)O)[CH:42]=[CH:43][C:44]=1[CH3:45]>CO.C(Cl)Cl.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>[CH3:38][C:39]1[CH:40]=[C:41]([C:2]2[CH:3]=[CH:4][C:5]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[O:18])=[CH:13][CH:12]=3)=[C:6]([C:7]#[N:8])[CH:9]=2)[CH:42]=[CH:43][C:44]=1[CH3:45]
Reactant: N#Cc1cc(Br)ccc1Nc1ccc(C(=O)N2CCOCC2)cc1
Reactant: Cc1ccc(B(O)O)cc1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1ccc(-c2ccc(Nc3ccc(C(=O)N4CCOCC4)cc3)c(C#N)c2)cc1C
Temperature: 105 °C
Yield: 118.2 %

Procedure:
5-Bromo-2-(4-(morpholine-4-carbonyl)phenylamino)benzonitrile (300 mg, 0.777 mmol), Pd(Ph3P)4 (44.9 mg, 0.039 mmol), aqueous 2M Na2CO3 (0.882 mL, 1.763 mmol) were mixed with toluene (4 mL) in a sealed microwave tube. 3,4-dimethylphenylboronic acid (163 mg, 1.087 mmol) in MeOH (2.00 mL) was added to the above mixture. The mixture was heated at 105° C. for 4 hrs in an oil bath. The crude was diluted with CH2Cl2 (100 ml) and washed with water (2×50 ml), brine, dried with MgSO4 and concentrated. 378 mg of crude product (77% purity) was obtained and it will be used as it is.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:10])[CH:3]=1.[CH2:11](O)[CH2:12][OH:13].C(OCC)(OCC)OCC.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCCl>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]2[O:13][CH2:12][CH2:11][O:7]2)=[C:4]([F:10])[CH:3]=1
Reactant: OCCO
Reactant: O=Cc1ccc(Br)cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCCl
Solvent: CCOC(OCC)OCC
Product: Fc1cc(Br)ccc1C1OCCO1

Procedure:
4-bromo-2-fluorobenzaldehyde (9.4 g, 46.3 mmol), ethylene glycol (13.2 mL), triethyl orthoformate (6.6 mL) and p-toluenesulfonic acid (0.09 g, 0.473 mmol) were stirred in DCE (50 mL) at 80° C. for 2.5 hours. Room temperature was attained and the solution was washed successively with saturated NaHCO3, H2O and brine, dried over MgSO4 and concentrated in vacuo to give the product (pale yellow oil). 1H NMR (CDCl3) δ 7.41 (t, J=8.1 Hz, 1H), 7.30 (dd, J=8.1, 1.8 Hz, 1H), 7.25 (dd, J=9.6, 1.8 Hz, 1H), 6.02 (s, 1H), 4.13 (m, 2H), 4.04 (m, 2H).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1.ClCCl.CO.N>>[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:15](=[O:17])/[CH:14]=[CH:13]/[C:10]3[CH:9]=[CH:8][C:7]([CH2:6][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)=[CH:12][CH:11]=3)=[CH:28][CH:27]=2)=[CH:24][CH:25]=1
Reactant: COc1ccc(-c2ccc(N)cc2)cc1
Reactant: O=C(O)/C=C/c1ccc(CN2CCCC2)cc1
Agent: N
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(-c2ccc(NC(=O)/C=C/c3ccc(CN4CCCC4)cc3)cc2)cc1

Procedure:
Prepared analogously to Example 3.1.e. from (E)-3-(4-pyrrolidin-1-ylmethylphenyl)acrylic acid and 4′-methoxybiphenyl-4-ylamine. Yield: 74 mg (15.4% of theory); melting point: 199° C.-200° C.; C27H28N2O2 (M=412.53); calc.: molecular ion peak (M+H)+: 413; found: molecular ion peak (M+H)+: 413; Rf value: 0.77 (silica gel, dichloromethane/methanol/ammonia (80:20:1)).
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].C(O)(=O)C(C)(C)C>C(Cl)Cl.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[F:1][C:2]1[C:3]2[NH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:11]=2[CH:12]=[CH:13][CH:14]=1
Reactant: Fc1ccccc1Nc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)C(=O)O
Solvent: ClCCl
Product: Fc1cccc2c1[nH]c1ccccc12
Temperature: 120 °C
Yield: 46.5 %

Procedure:
A reaction vessel was charged with 2-fluoro-N-phenylaniline (0.4 g, 2.1 mmol), palladium diacetate (0.025 g, 0.1 mmol), potassium carbonate (0.030 g, 0.21 mmol), and pivalic acid (1.8 g), placed under an oxygen balloon, and heated at 120° C. Additional portions of palladium diacetate (0.025 g, 0.1 mmol) were added at 48 hours and 72 hours, and the mixture was heated for 4 days. The cooled reaction mixture was diluted with methylene chloride, washed with saturated aqueous sodium carbonate, dried (anhydrous sodium sulfate), filtered through a pad of silica gel, and concentrated. The crude product was purified by silica gel column chromatography (5-30% methylene chloride in hexanes) to give the desired product as a white solid (0.181 g, 46%). 1H NMR (d6-DMSO, 300 MHz) δ 11.65 (s, 1H), 8.13-8.11 (dd, 1H, J=0.6, 7.5 Hz), 7.94-7.91 (d, 1H, J=7.8 Hz), 7.50-7.38 (m, 2H), 7.25-7.07 (m, 3H). HPLC analysis (C18, 5-95% acetonitrile in H2O+0.1% trifluoroacetic acid over 20 min: retention time, % area at 254 nm): 9.65 min, 100%.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[Br:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[C:18]([CH3:25])[CH:17]=1.O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.C(Cl)(Cl)Cl>CO>[Br:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([N:12]2[CH2:11][CH2:10][N:9]([C:3]3[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][N:4]=3)[CH2:14][CH2:13]2)=[O:21])=[C:18]([CH3:25])[CH:17]=1
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3C)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
To a mixture of 1-(3,5-dimethylpyridin-2-yl)piperazine (3.8 g) described in Preparation Example 47, 4-bromo-2-methylbenzoic acid (4.3 g) and 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (DMT-MM) (8.8 g) were added chloroform (30 mL) and methanol (30 mL), and the mixture was stirred at room temperature overnight. After evaporation of the solvent, ethyl acetate was added, and insoluble materials were filtered off. The solvent in the filtrate was evaporated, and the residue was purified by column chromatography (hexane:ethyl acetate) to give the title compound (7 g).
Reaction SMILES: CS[C:3]1[S:7][C:6]([C:8]#[N:9])=[C:5]2[CH2:10][CH2:11][CH2:12][C:13](=[O:14])[C:4]=12.[CH3:15][NH:16][CH3:17]>C1COCC1>[CH3:15][N:16]([CH3:17])[C:3]1[S:7][C:6]([C:8]#[N:9])=[C:5]2[CH2:10][CH2:11][CH2:12][C:13](=[O:14])[C:4]=12
Reactant: CNC
Reactant: CSc1sc(C#N)c2c1C(=O)CCC2
Solvent: C1CCOC1
Product: CN(C)c1sc(C#N)c2c1C(=O)CCC2
Yield: 45 %

Procedure:
A solution of 3-methylsulfanyl-4-oxo-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carbonitrile (0.446 g) and dimethylamine (excess) in THF were heated in a sealed tube at 80° C. for 10 days. Aqueous work up and chromatographic purification afforded 0.2 g of 3-dimethylamino-4-oxo-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carbonitrile (45%).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]([NH:8][C@H:9]([C:14]([NH:16][C@H:17]([C:23]([NH:25][C@H:26]([C:35]([NH:37][C@H:38]([C:43]([NH:45][C@H:46]([C:51]([NH:53][C@H:54]([B:59]1[O:63][C@@H]2C[C@@H]3C[C@H]([C@]2(C)[O:60]1)C3(C)C)[CH2:55][CH2:56][CH2:57][CH3:58])=[O:52])[CH2:47][CH:48]([CH3:50])[CH3:49])=[O:44])[C:39]([CH3:42])([CH3:41])[CH3:40])=[O:36])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH3:34])=[O:24])[CH2:18][CH2:19][C:20](=[O:22])[OH:21])=[O:15])[CH2:10][C:11](=[O:13])[OH:12])=[O:7])([OH:3])=[O:2].C([O-])(=O)C.[NH4+].I([O-])(=O)(=O)=O.[Na+]>CC(C)=O.O>[C:1]([CH2:4][CH2:5][C:6]([NH:8][C@H:9]([C:14]([NH:16][C@H:17]([C:23]([NH:25][C@H:26]([C:35]([NH:37][C@H:38]([C:43]([NH:45][C@H:46]([C:51]([NH:53][C@H:54]([B:59]([OH:60])[OH:63])[CH2:55][CH2:56][CH2:57][CH3:58])=[O:52])[CH2:47][CH:48]([CH3:50])[CH3:49])=[O:44])[C:39]([CH3:42])([CH3:41])[CH3:40])=[O:36])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH3:34])=[O:24])[CH2:18][CH2:19][C:20](=[O:21])[OH:22])=[O:15])[CH2:10][C:11](=[O:12])[OH:13])=[O:7])([OH:3])=[O:2]
Reactant: CCCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](Cc1ccccc1C)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)CCC(=O)O)C(C)(C)C)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CCCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](Cc1ccccc1C)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)CCC(=O)O)C(C)(C)C)B(O)O
Temperature: 25 °C
Reaction time: 22 h
Yield: 96.8 %

Procedure:
0.2 g (0.2 mmol) of N2-[N-[N-[N-[N-(carboxypropionyl)-L-α-aspartyl]-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl -L-valyl]-N1-[1(R)-(3a(S),4(S),5,6(S),7,7a(R)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl)pentyl]-L-leucinamide was dissolved in 12 ml of acetone and 12 ml of 0.1M ammonium acetate in water were added. 0.21 g (1 mmol) of sodium periodate was added and the resulting mixture was stirred at room temperature for 22 hours. 7 ml of water were then added together with a small amount of sodium periodate. The resultingsolution was stirred for a further 5 hours. The acetone was removed under avacuum and the aqueous residue was acidified with 2N hydrochloric acid and then extracted with ethyl acetate. Saturated aqueous sodium chloride was added to the aqueous layer which was then extracted with ethyl acetate. The organic extracts were combined, dried over sodium sulphate and evaporated. The residue was trituated with diethyl ether, filtered off anddried to give 167 mg of 1(R)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-α-aspartyl]-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]pentylboronic acid as a white solid; MS: m/e 845.4 [M+H-H2O]+.