Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)[OH:4].[C:29]1([CH2:35][CH2:36][C:37](Cl)=[O:38])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[OH:4][CH:3]([C:5]1[CH:6]=[CH:7][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:9][CH:10]=1)[CH:2]([NH:1][C:37](=[O:38])[CH2:36][CH2:35][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:23][CH:24]=1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(Oc2ccccc2)cc1
Reactant: O=C(Cl)CCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(CCc1ccccc1)NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.7 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-phenoxyphenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (400 mg, 1.03 mmol) in ethyl acetate (20 ml) were added 3-phenylpropionyl chloride (230 ml, 1.55 mmol) and saturated aqueous sodium hydrogen carbonate (20 ml), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (416 mg, 78%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:18][C:19](=[O:25])[C:20]([O:22]CC)=O)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[CH:16][S:17][C:10]=12.[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>>[F:1][C:2]1[CH:3]=[C:4]([NH:18][C:19](=[O:25])[C:20](=[O:22])[N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[CH:16][S:17][C:10]=12
Reactant: C1CCNC1
Reactant: CCOC(=O)C(=O)Nc1ccc(Oc2ccnc3ccsc23)c(F)c1
Product: O=C(Nc1ccc(Oc2ccnc3ccsc23)c(F)c1)C(=O)N1CCCC1
Yield: 85.6 %

Procedure:
Prepared from ethyl 2-(3-fluoro-4-(thieno[3,2-b]pyridin-7-yloxy)phenylamino)-2-oxoacetate (Example 2; 36 mg, 0.10 mmol) and pyrrolidine (36 mg, 0.50 mmol) according to the procedure for Example 3. The product was purified on a pre-packed Isoelute silica gel column (10 g silica), eluting with a gradient of 20% EtOAc/hexanes, 1:1 EtOAc/hexanes, 2:1 EtOAc/hexanes, and then neat EtOAc. The product was obtained as a white powder (33 mg, 86%). 1H NMR (400 MHz, CDCl3) δ 9.74 (s, 1H), 8.52 (d, J=5 Hz, 1H), 7.87 (m, 1H), 7.75 (d, J=6 Hz, 1H), 7.58 (d, J=6 Hz, 1H), 7.37 (m, 1H), 7.26 (m, 1H), 6.52 (d, J=5 Hz, 1H), 4.09 (t, J=7 Hz, 2H), 3.63 (t, J=7 Hz, 2H), 2.02 (m, 2H), 1.91 (m, 2H). LRMS (ESI pos) m/e 386 (M+1). HPLC: 100% purity (220 nm).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([CH3:20])([CH3:19])[CH:13]=[C:12]2[CH3:21].[Br:22]N1C(=O)CCC1=O>C(#N)C>[Br:22][CH2:21][C:12]1[C:11]2[C:16](=[CH:17][CH:18]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH:10]=2)[NH:15][C:14]([CH3:20])([CH3:19])[CH:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccccc1-c1ccc2c(c1)C(C)=CC(C)(C)N2
Solvent: CC#N
Product: COc1ccccc1-c1ccc2c(c1)C(CBr)=CC(C)(C)N2
Yield: 75.6 %

Procedure:
A mixture of 800 mg of 6-(2-methoxyphenyl)-2,2,4-trimethyl-1,2-dihydroquinoline and 90 mL of acetonitrile was treated with 510 mg of N-bromosuccinimide (NBS) at −20° C. for 2 minutes. The reaction was quenched with water and extracted with EtOAc three times. The organic layers were combined and washed with 10% aqueous sodium thiosulfate (Na2S2O3) solution, water, and brine and then dried over magnesium sulfate. The residue was purified by flash chromatography to yield 776 mg of 4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline as a solid.
Reaction SMILES: [CH2:1]([N:8]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:22](=[O:26])(=[O:25])([OH:24])O.[OH:27][S:28](O)(=[O:30])=[O:29].O=S(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>>[S:22]([C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[CH2:15][N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([S:28]([OH:30])(=[O:29])=[O:27])[CH:7]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)([OH:24])(=[O:26])=[O:25]
Reactant: O=S(=O)(O)O
Reactant: c1ccc(CN(Cc2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)=O
Agent: [Na+]
Product: O=S(=O)(O)c1cccc(CN(Cc2cccc(S(=O)(=O)O)c2)c2ccccc2)c1

Procedure:
With stirring, 150.0 g of N,N-dibenzylaniline was added slowly over approximately two hours to 425.0 g of 100 percent sulfuric acid while maintaining a temperature in the range of 25° to 30° C. The resulting solution was set aside at ambient temperature for approximately fourteen hours. Then, 165 g of 65 percent oleum was added to the solution with stirring while maintaining a temperature in the range of 25° to 30° C. using an ice water bath. The resulting solution was stirred approximately 19 hours at ambient temperature and then was poured slowly onto ice with stirring. Sufficient sodium carbonate was added gradually to the drowned mixture to adjust the pH to approximately 7.0 and thus obtaining a solution of N,N-bis(3-sulfobenzyl)aniline.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[NH:1]([C:2]1[S:3][C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1cc(-c2ccccc2)sc1N
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1cc(-c2ccccc2)sc1Nc1ccccc1
Reaction time: 19 h

Procedure:
A vial was charged with copper acetate (77 mg, 0.425 mmol), ethyl 2-amino-5-phenylthiophene-3-carboxylate (100 mg, 0.404 mmol), phenylboronic acid (99 mg, 0.809 mmol), dichloromethane (2 ml), and triethylamine (0.113 ml, 0.809 mmol). The blue-green reaction mixture was magnetically stirred for 19 hours and then concentrated to a volume of 0.5 mL. The crude reaction mixture was purified by silica gel chromatography (7-60% dichloromethane/hexanes) to afford ethyl 2-anilino-5-phenylthiophene-3-carboxylate.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH:21]([CH3:23])[NH:20][CH2:19][CH2:18]2)=[O:12].[Br:24][C:25]1[C:26]([C:32]([O:34][CH3:35])=[O:33])=[N:27][C:28](F)=[CH:29][CH:30]=1.C(N(CC)CC)C>CS(C)=O.C(OCC)(=O)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH:21]([CH3:23])[N:20]([C:28]1[N:27]=[C:26]([C:32]([O:34][CH3:35])=[O:33])[C:25]([Br:24])=[CH:30][CH:29]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: CC1NCCc2cccc(C(=O)Nc3nc4ccccc4s3)c21
Reactant: COC(=O)c1nc(F)ccc1Br
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2C)ccc1Br
Temperature: 105 °C

Procedure:
A solution of EXAMPLE 163C (1 g), methyl 3-bromo-6-fluoropicolinate (0.715 g) and triethylamine (0.775 mL) in 12 mL DMSO was heated at 70° C. overnight followed by heating at 105° C. for 4 hours. The reaction mixture was diluted with ethyl acetate, washed three times with water and brine, dried over Na2SO4, filtered, and concentrated. The product was purified by flash chromotography (silica gel, 5-25% ethyl acetate/hexanes).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.CC1C=CC(S(O[CH2:23][C@H:24]2[O:26][CH2:25]2)(=O)=O)=CC=1.[H-].[Na+]>CN(C=O)C>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:23][C@@H:24]2[CH2:25][O:26]2)=[CH:7][CH:6]=1
Reactant: COCCc1ccc(O)cc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCc1ccc(OC[C@@H]2CO2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-(2-methoxyethyl)phenol (42 mg, 0.275 mmol) and (2S)-(+)-glycidyl tosylate (57 mg, 0.25 mmol) in 2 mL of DMF was added 15 mg (0.625 mmol) of sodium hydride (60% in mineral oil). The resulting mixture was allowed to stir for 16 hours at room temperature. The solution was then extracted three times with ethyl acetate, and the organic phase was washed sequentially with sodium hydroxide, water and brine, dried over sodium sulfate, and concentrated in vacuo to provide the product which was used without further purification. m/z 208 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[S:12][CH:13]=[CH:14][C:4]=2[N:3]=1.[BH4-].[Na+].FC(F)(F)C(O)=O>O1CCOCC1>[CH3:1][CH:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[S:12][CH:13]=[CH:14][C:4]=2[NH:3]1
Reactant: Cc1nc2ccsc2c2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: CC1Nc2ccsc2-c2ccccc21
Temperature: 23 °C
Yield: 132.5 %

Procedure:
5-Methylthieno[3,2-c]isoquinoline (12 g, 60 mmol) and sodium borohydride (9.0 g, 240 mmol) were combined in dry 1,4-dioxane (200 mL) at 23° C. Trifluoroacetic acid (9.2 mL, 120 mmol) was slowly added via syringe with gentle bubbling. After the addition was complete, the mixture was heated to reflux for 24 h. At this time the mixture was cooled to 23° C., quenched with de-gassed saturated aqueous sodium bicarbonate (450 mL) and extracted under nitrogen with de-gassed methylene chloride (3×ca. 150 mL). The combined extracts were washed under nitrogen with de-gassed brine (ca. 450 mL), dried (Na2SO4) under nitrogen and concentrated in vacuo to give the crude title compound (16 g) as an air-sensitive orange oil.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:8][CH2:9][C:10]#[N:11])=[CH:3][CH:2]=1.CN(P(N(C)C)(N(C)C)=O)C.[Li+].CC([N-]C(C)C)C.Cl[CH:38]([C:40]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[N:43]=[CH:42][CH:41]=1)[CH3:39]>C1COCC1>[C:7](=[N:8][CH:9]([CH:38]([C:40]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[N:43]=[CH:42][CH:41]=1)[CH3:39])[C:10]#[N:11])([C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: N#CCN=C(c1ccccc1)c1ccccc1
Reactant: CC(Cl)c1ccnc2ccccc12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CC(c1ccnc2ccccc12)C(C#N)N=C(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
To N-(Diphenylmethylene)aminoacetonitrile (2.26 g, 10.2 mmol) in 10 ml of anhydrous THF and HMPA (2.17 ml, 12.14 mmol), at −78° C. LDA (2.0 M, 6.0 ml, 12.14 mmol) was added dropwise over a period of 5 minutes. The color of solution turns from coloress to yellow to dark brown. It was then stirred at −78° C. for one hour. Then 4-(1-Chloroethyl)-quinoline (1.79 g, 9.34 mmol), was added dropwise and the reaction mixture was slowly brought to room temperature over a period of five minutes, quenched by addition of ice and partitioned between EtOAc (20 ml) and water (5 ml). The organic layer was dried over sodium sulfate, filtered, concentrated and column purified (hexanes:EtOAc; 3.5:1.5) to give 3.0 g (86%) of the product as a syrup which was used as such for the subsequent step.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:22])=[C:6]([NH:8][C:9]2[N:10]=[CH:11][C:12]3[N:17]=[C:16]([NH:18][C:19](=[O:21])[CH3:20])[S:15][C:13]=3[N:14]=2)[CH:7]=1.[F:23][C:24]([F:36])([F:35])[O:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](O)=[O:30].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[C:19]([NH:18][C:16]1[S:15][C:13]2[N:14]=[C:9]([NH:8][C:6]3[CH:7]=[C:2]([NH:1][C:29](=[O:30])[C:28]4[CH:32]=[CH:33][CH:34]=[C:26]([O:25][C:24]([F:23])([F:35])[F:36])[CH:27]=4)[CH:3]=[CH:4][C:5]=3[CH3:22])[N:10]=[CH:11][C:12]=2[N:17]=1)(=[O:21])[CH3:20]
Reactant: O=C(O)c1cccc(OC(F)(F)F)c1
Reactant: CC(=O)Nc1nc2cnc(Nc3cc(N)ccc3C)nc2s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2cnc(Nc3cc(NC(=O)c4cccc(OC(F)(F)F)c4)ccc3C)nc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.6 %

Procedure:
A solution of N-{5-[(5-amino-2-methylphenyl)amino][1,3]thiazolo[5,4-d]pyrimidin-2-yl}acetamide (120 mg, 382 μmol) produced in Example D35(v), 3-(trifluoromethoxy)benzoic acid (102 mg, 500 μmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (189 mg, 500 μmol) in pyridine (4 mL) was stirred at room temperature for 2 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (15 mL), and the mixture was extracted with ethyl acetate (20 mL, 5 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/methanol=100/0→95/5), and the fractions containing the object product were concentrated under reduced pressure. The obtained residue was recrystallized from tetrahydrofuran to give the title compound (78 mg, 40%) as colorless crystals.
Reaction SMILES: [C:1](Cl)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=C.[CH2:17]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.ClC1C=C(C=CC=1)CN(C)C>CC1C=CC(C)=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCN(CC)Cc1ccccc1
Solvent: Cc1ccc(C)cc1
Product: CCOC(=O)C=Cc1ccccc1
Temperature: 130 °C
Reaction time: 4 h

Procedure:
Ethyl cinnamate is prepared by the procedures described above, using different bases and the following reactants: 2.24 mg (10-5 mols) of palladium acetate, 5.77 ml (50 millimols) of benzoyl chloride, 5.42 ml (50 millimols) of ethyl acrylate and 50 millimols of N-benzyldiethylamine or N-(3-chlorobenzyl)-dimethylamine, in 100 ml of p-xylene. The reaction mixture is stirred for 4 hours at 130° C. Ethyl cinnamate is obtained in a yield of 67% of theory if N-benzyldiethylamine is used, and a yield of 56% of theory if N-(3-chlorobenzyl)-dimethylamine is used.
Reaction SMILES: [N+](=[CH:3]P(=O)(OC)OC)=[N-].CC(C)([O-])C.[K+].[CH:16]1([O:21][C:22]2[CH:23]=[C:24]([C:30]3([CH:40]=O)[CH2:35][CH2:34][C:33]4([O:39][CH2:38][CH2:37][O:36]4)[CH2:32][CH2:31]3)[CH:25]=[CH:26][C:27]=2[O:28][CH3:29])[CH2:20][CH2:19][CH2:18][CH2:17]1.O>O1CCCC1>[CH:16]1([O:21][C:22]2[CH:23]=[C:24]([C:30]3([C:40]#[CH:3])[CH2:31][CH2:32][C:33]4([O:36][CH2:37][CH2:38][O:39]4)[CH2:34][CH2:35]3)[CH:25]=[CH:26][C:27]=2[O:28][CH3:29])[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: COc1ccc(C2(C=O)CCC3(CC2)OCCO3)cc1OC1CCCC1
Reactant: COP(=O)(C=[N+]=[N-])OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C#CC1(c2ccc(OC)c(OC3CCCC3)c2)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of dimethyl (diazomethyl)phosphonate (0.516 g, 3.44 mmole, prepared as in Seyferth, D.; Marmor, R. S.; Hilbert, P. J. Org. Chem 1971, 36(10), 1379-1386) dissolved in dry tetrahydrofuran (10 mL) was added via cannulation to a solution of potassium t-butoxide (0.386 g, 3.4 mmol) dissolved in dry tetrahydrofuran (10 mL) at -78° C. under an argon atmosphere. To this was added rapidly a solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-1,1-(ethylenedioxy)-4-formylcyclohexane (0.62 g, 1.72 mmol) in dry tetrahydrofuran (10 mL). After 2 h, the reaction was warmed to room temperature, water was added and the mixture was extracted three times with ethyl acetate. The combined organic extract was washed with brine, was dried (sodium sulfate) and was evaporated. Purification by flash chromatography, eluting with 3:1 hexanes/ethyl acetate provided a white solid. mp 53.5°-55° C.
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:5]([NH:6][N:7]2[C:19](=[O:20])[C:18]3[C:17](=[O:21])[C:16]4[CH:15]=[CH:14][C:13]([Cl:22])=[CH:12][C:11]=4[NH:10][C:9]=3[C:8]2=[O:23])=[CH:4][CH:3]=1.CS(O)(=O)=O>CO>[Br:1][C:2]1[CH:25]=[CH:24][C:5]([N:6]2[C:8](=[O:23])[C:9]3[NH:10][C:11]4[CH:12]=[C:13]([Cl:22])[CH:14]=[CH:15][C:16]=4[C:17](=[O:21])[C:18]=3[C:19]([OH:20])=[N:7]2)=[CH:4][CH:3]=1
Reactant: O=C1c2[nH]c3cc(Cl)ccc3c(=O)c2C(=O)N1Nc1ccc(Br)cc1
Agent: CS(=O)(=O)O
Solvent: CO
Product: O=c1c2ccc(Cl)cc2[nH]c2c(=O)n(-c3ccc(Br)cc3)nc(O)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 22.2 %

Procedure:
A stirred suspension of 2-(4-bromoanilino)6-chloro-2,3,4,9 -tetrahydro-1H-pyrrolo[3,4-b]quinoline-1,3,9-trione (1.00 g, 2.39 mM) in asolution of methanol (500 mL) and methanesulfonic acid (50 mL) was refluxedfor 16 hours and cooled to room temperature. The resulting yellow suspension was filtered (the filtrate was saved for use in Example 28). The collected solids were washed with methanol and then ether to give the title compound (0.222 g, 22%) as a yellow powder, mp>400° C.; MS(CI): 420 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([Cl:12])[CH:3]=1.[N:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1>>[Cl:12][C:4]1[CH:3]=[C:2]([C:16]2[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=2)[CH:7]=[CH:6][C:5]=1[NH:8][C:9](=[O:11])[CH3:10]
Reactant: OB(O)c1ccncc1
Reactant: CC(=O)Nc1ccc(Br)cc1Cl
Product: CC(=O)Nc1ccc(-c2ccncc2)cc1Cl

Procedure:
The title compound was prepared from N-[4-bromo-2-chlorophenyl]acetamide and pyridin-4-ylboronic acid using a similar procedure to Description 3.
Reaction SMILES: [CH3:1][C:2]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>C1(C)C=CC=CC=1.[Zn]>[OH:3][C:2]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:1])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)CBr
Reactant: CC(=O)Cc1ccccc1
Agent: [Zn]
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(C)(O)Cc1ccccc1
Reaction time: 3 h
Yield: 68.7 %

Procedure:
A mixture of benzyl methyl ketone (134 g, 1 mole) and ethyl bromoacetate (168 g, 1 mole) was added to a mixture of mossy zinc (100 g) in toluene (500 cm3) in a large flask. When the vigorous exothermic reaction had subsided, the mixture was boiled for 3 hours. The solution was cooled, and washed sequentially with dilute sulfuric acid, 10% aqueous sodium hydroxide and then with water. The organic layer was separated, dried and filtered. The toluene solvent was removed, leaving the hydroxy ester, ethyl 3-hydroxy-3-benzylbutanoate (152.8 g), as an orange oil. The ester's structure and purity were established by NMR spectroscopy.
Reaction SMILES: C(OC([N:8]1[CH2:14][C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[N:11]([CH3:19])[C:10](=[O:20])[CH2:9]1)=O)(C)(C)C.[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24]>C(Cl)Cl>[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24].[CH3:19][N:11]1[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[CH2:14][NH:8][CH2:9][C:10]1=[O:20]
Reactant: CN1C(=O)CN(C(=O)OC(C)(C)C)Cc2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)CNCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a solution of 1-methyl-2-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepine-4-carboxylic acid tert-butyl ester (70 mg, 0.25 mmol) in dry DCM (10 mL), was added trifluoroacetic acid (0.75 mL, 3 mL/mmol). The mixture was stirred at r.t. for 1 h. After the completion of the reaction as confirmed by TLC, excess of TFA and DCM were evaporated in vacuo to afford trifluoroacetic acid salt of 1-methyl-1,3,4,5-tetrahydrobenzo[e][1,4]diazepin-2-one (70 mg, 95%) as a gummy solid which was used as such for next coupling.
Reaction SMILES: O=[C:2]([CH2:6][C:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH3:15])[C:3]([OH:5])=[O:4].S(O)(O)(=O)=O.[CH3:22][S:23][C:24](=[NH:26])[NH2:25].[O-]CC.[Na+].[OH-].[Na+]>C(O)C>[CH3:15][O:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:7]1[N:26]=[C:24]([S:23][CH3:22])[N:25]=[C:2]([C:3]([OH:5])=[O:4])[CH:6]=1
Reactant: COc1ccccc1C(=O)CC(=O)C(=O)O
Reactant: CSC(=N)N
Agent: CC[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: COc1ccccc1-c1cc(C(=O)O)nc(SC)n1
Temperature: 90 °C

Procedure:
A mixture of 2,4-dioxo-4-(2-methoxyphenyl)butyric acid (15.6 g, 70 mmol), 2-methyl-isothiourea sulfate (10.4 g, 73.5 mmol) and sodium ethoxide (26 mL, 21% by wt. in ethanol, 70 mmol) in ethanol (200 mL) was heated to reflux overnight. The resulting solution was reduced to approximately 50 mL using a rotary evaporator, water (200 mL) was added to give a suspension, which was adjusted to pH >9 with 10% NaOH. The mixture was extracted with diethyl ether (100 mL). The aqueous layer was taken to pH=3 with conc. HCI solution to give a suspension, which was heated to 90° C. for 10 minutes. Upon cooling in an ice bath for 1 h, a precipitate formed, which was filtered, washed with water (20 mL), and dried overnight under vacuum to give 6-(2-methoxyphenyl)-2-(methylthio)pyrimidine-4-carboxylic acid. 1H NMR (300 MHz, CDCl3) δ 8.45 (s, 1H), 8.10 (dd, J=7.5, 1.8 Hz, 1H), 7.48 (m, 1H), 7.09 (t, J=6.9 Hz, 1H), 7.02 (d, J=8.7 Hz, 1H), 3.94 (s, 3H), 2.67 (s, 3H). HPLC ret. time 2.02 min, 10-100% CH3CN, 5 min gradient; ESI-MS m/z 277.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:23][CH2:24][CH:25]=[C:26]([Cl:28])[Cl:27])[CH:5]=[C:6]([Cl:22])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH:15](O)[C:16]([C:19]#[N:20])(Cl)[Cl:17].N1C=CC=CC=1.C(OC(=O)C)(=O)C.Cl>CN(C1C=CN=CC=1)C.[Zn].CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([O:23][CH2:24][CH:25]=[C:26]([Cl:28])[Cl:27])[CH:5]=[C:6]([Cl:22])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH:15]=[C:16]([Cl:17])[C:19]#[N:20]
Reactant: N#CC(Cl)(Cl)C(O)COCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: N#CC(Cl)=CCOCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.4 %

Procedure:
A mixture of 0.26 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(4-(3-cyano-3,3-dichloro-2-hydroxypropyloxy)butyloxy)benzene, 0.079 g of pyridine, 0.077 g of acetic anhydride, 10 mg of N,N-dimethyl-4-aminopyridine and 10 ml of N,N-dimethylformamide was stirred at room temperature for 30 minutes, to which 0.065 g of zinc dust was added. The reaction mixture was further stirred at room temperature for 1 hour, poured into 20 ml of diluted hydrochloric acid and extracted twice with diethyl ether. The diethyl ether layers were combined, washed with water, dried over magnesium sulfate and then evaporated to give a crude product. The crude product was subjected to silica gel chromatography, which afforded 0.19 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(4-(3-chloro-3-cyano-2-propenyloxy)butyloxy)benzene (yield, 83%), nD23.0 1.5410.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH2:14])[CH2:11][CH2:10][N:9]1[C:15](=[O:24])[C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][O:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH:29]=O.S([O-])([O-])(=O)=O.[Mg+2].[BH4-].[Na+]>C1(C)C=CC=CC=1.CO>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=2[O:26][CH3:25])[CH2:11][CH2:10][N:9]1[C:15](=[O:24])[C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@H]1CCN(C(=O)c2cc(Cl)cc(Cl)c2)[C@H](Cc2ccccc2)C1
Reactant: COc1ccccc1C=O
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Mg+2]
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1ccccc1CN[C@H]1CCN(C(=O)c2cc(Cl)cc(Cl)c2)[C@H](Cc2ccccc2)C1

Procedure:
200 mg (0.551 mmol) of (2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-4-piperidinamine are reacted in analogy to Example 2g with 75 mg (0.551 mmol) of 2-methoxybenzaldehyde and 90 mg magnesium sulfate in 2 ml of toluene and subsequently reduced with 22 mg (0.584 mmol) of sodium borohydride in 2 ml of methanol. The title compound ##STR91## is obtained (170 mg, 64%) as white foam. TLC:methylene chloride/methanol/cone. ammonia (700:50:1) Rf =0.66, FD-MS:M+ =482, 482. IR:1620 cm-1.