Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=2)([CH3:14])[N:13]=1)([CH3:4])([CH3:3])[CH3:2].[N-:23]=[N+:24]=[N-:25].[Na+].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+].CN[C@@H]1CCCC[C@H]1NC>C(O)C.O.[Cu](I)I>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:23]=[N+:24]=[N-:25])[CH:16]=2)([CH3:14])[N:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1=NC(C)(c2cccc(Br)c2)COC1
Reactant: [N-]=[N+]=[N-]
Agent: I[Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1=NC(C)(c2cccc(N=[N+]=[N-])c2)COC1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
[5-(3-Bromo-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester (5.03 g, 12.67 mmol), sodium azide (1.647 g, 25.3 mmol), sodium ascorbate (0.125 g, 0.63 mmol), copper iodide (0.241 g, 1.27 mmol) and (1R,2R)—N,N′-dimethyl-cyclohexane-1,2-diamine (0.270 g, 1.90 mmol) were dissolved in ethanol (17.7 ml) and water (7.6 ml). The mixture was stirred under N2 at 90° C. for 4 h and then poured into 1M aqueous KHCO3 solution. The mixture was extracted with EtOAc, and the organic phase was washed with brine, dried with Na2SO4 and evaporated under reduced pressure. The residue was purified by chromatography on silica gel (cyclohexane/EtOAc=7:3) to yield the title compound.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[OH:7][C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][N:14]3[C:21](=[O:22])[C:20]([C:23]([OH:25])=[O:24])=[CH:19][N:18]=[C:15]32)=[CH:10][CH:9]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:7][C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][N:14]3[C:21](=[O:22])[C:20]([C:23]([OH:25])=[O:24])=[CH:19][N:18]=[C:15]32)=[CH:10][CH:9]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: O=C(O)c1cnc2n(c1=O)CCc1ccc(O)cc1-2
Reactant: CC(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(=O)Oc1ccc2c(c1)-c1ncc(C(=O)O)c(=O)n1CC2
Temperature: 0 °C
Yield: 63.7 %

Procedure:
Isobutyryl chloride (455 mg., 4.26 mmoles) was added to a stirred, cooled (ice-water) mixture of 6,7-dihydro-10-hydroxy-4-oxo-4H-pyrimido[2,1-a]isoquinoline-3-carboxylic acid (1.03 g., 3.87 mmoles) and triethylamine (785 mg., 7.75 mmoles) in methylene chloride (20 ml.). The mixture was concentrated to dryness and the residue was triturated with cold 1N HCl, and then crystallized from benzene to give the title compound 0.81 g. (64% yield). The product was recrystallized successively from ethyl acetate and methanol to give the analytical sample, m.p. 183°-185°.
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH3:13])[C:7](=[NH:14])[S:6]1)([CH3:4])([CH3:3])[CH3:2].[C:15]1([C:21]2([C:26](O)=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:10]([C:8]1=[CH:9][N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[S:6]/[C:7]/1=[N:14]\[C:26]([C:21]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:27])[CH2:11][CH2:12][CH3:13]
Reactant: CCCCc1cn(C(C)(C)C)sc1=N
Reactant: O=C(O)C1(c2ccccc2)CCCC1
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)C1(c2ccccc2)CCCC1

Procedure:
The product from Example 92B and 1-phenylcyclopentanecarboxylic acid (Aldrich) were processed using the method described in Example 92C to afford the title compound. 1H NMR (DMSO-d6) δ 0.90 (t, J=7.3 Hz, 3H), 1.23-1.35 (m, 2H), 1.54 (s, 9H), 1.54-1.69 (m, 6H), 1.78-1.87 (m, 2H), 2.61-2.66 (m, 2H), 2.86-2.93 (m, 2H), 7.10-7.16 (m, 1H), 7.21-7.26 (m, 2H), 7.31-7.38 (m, 2H), 8.50 (s, 1H). MS (ESI+) m/z 385 (M+H)+. Anal. calcd. for C23H32N2OS: C, 71.83; H, 8.39; N, 7.28. Found: C, 71.58; H, 8.21; N, 7.05.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[N+:11]([CH2:13]S(C1C=CC(C)=CC=1)(=O)=O)#[C-:12].[N+:24]([C:27]1[CH:32]=[CH:31][C:30](/[CH:33]=[CH:34]/[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:29][CH:28]=1)([O-:26])=[O:25].C(=O)(O)[O-].[Na+]>C1COCC1>[N+:24]([C:27]1[CH:28]=[CH:29][C:30]([C:33]2[C:34]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:12][NH:11][CH:13]=2)=[CH:31][CH:32]=1)([O-:26])=[O:25]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CCOC(=O)/C=C/c1ccc([N+](=O)[O-])cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])O
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c[nH]cc1-c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 62.5 %

Procedure:
To a cooled (−77° C.) solution of 1M lithium hexamethyldisilazide in THF (102.4 mL, 102.4 mmol) was added 1-[(isocyanomethyl)sulfonyl]-4-methylbenzene (20.0 g, 102.4 mmol) as a solution in THF (100 mL) dropwise (30 min). The solution was allowed to stir for 15 min, and then ethyl (2E)-3-(4-nitrophenyl)acrylate (22.66 g, 102.4 mmol) was added dropwise (1 h) as a solution in THF (250 mL). The reaction was allowed to warm to rt over 17 h and the aqueous saturated sodium bicarbonate solution (200 mL) was added. The product was extracted with ethyl acetate (3×300 mL), and then the combined organic extracts were washed with water (100 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using 0-5% ethylacetate/dichlromethane to afford the desired product (16.65 g, 62%). 1H-NMR (300 MHz, DMSO-d6) δ 11.78 (br s, 1H), 8.15-8.19 (m, 2H), 7.73-7.76 (m, 2H), 7.55-7.79 (m, 1H), 7.19-7.24 (m, 1H), 4.16 (q, J=7.1 Hz, 2H), 1.21 (t, J=7.1 Hz, 3H); HPLC (Method A) 2.90 min; TLC Rf=0.47 (95:5 v/v CH2Cl2-EtOAc).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[CH:4][N:3]=1.[F:11][C@@H:12]1[C@H:16]([OH:17])[C@@H:15]([CH2:18][OH:19])[O:14][C@H:13]1N1C=CC(=O)NC1=O.[N-]=[N+]=[N-].[K+].[C@@H]1(N2C=C(C)C(=O)NC2=O)O[C@H](CO)[C@@H](O)C1>P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:13]2[O:14][C@H:15]([CH2:18][OH:19])[C@@H:16]([OH:17])[C@H:12]2[F:11])=[CH:4][N:3]=1
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2F)c(=O)[nH]1
Reactant: Nc1ncc2[nH]cnc2n1
Agent: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: Nc1ncc2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3F)c2n1
Temperature: 37 °C
Yield: 92.9 %

Procedure:
2-Aminopurine (Pacific Chemical Laboratories, 3.0 g, 22.2 mmoles) and 1-(2-deoxy-2-fluoro-β-D-ribofuranosyl)uracil (0.5 g; 2.0 mmoles) which may be prepared according to J. F. Codington et al., (J. Org. Chem. 29:558, 1964) were suspended in 25 ml of 5 mM potassium phosphate buffer, pH 7.0, which contained 0.04% (w/v) potassium azide. Thymidine phosphorylase (41,700 I.U.) and purine nucleoside phosphorylase (83,300 I.U.) (T. A. Krenitsky et al., Biochemistry 20:3615, 1981 and U.S. Pat. No. 4,381,344) which had been absorbed onto 10.5 g of DEAE-cellulose (25 ml) were added and the suspension shaken at 37° C. After 24 hours 3.0 g of 2,6-diaminopurine was added and the temperature increased to 50° C. After another 24 hours the reaction was filtered. The filter cake was washed with water and the filtrates combined and the solvent removed under vacuum. The residue was suspended in water and filtered. The filter cake was extracted with water (25° C.) until no product remained in the filter cake. The filtrates were combined, the pH was adjusted to pH 9.4 with NH4OH, and the solution applied to a 2.5×20 cm column of anion exchange resin (Bio-Rad AG1X2-hydroxide form). After washing the column with water, the product was eluted with methanol/water (9/1). Product containing fractions were combined and the solvent removed under vacuum. The residue was dissolved in chloroform/methanol/water (75:25:4) and applied to a 5×25 cm column of silica gel 60. The product was eluted with chloroform/methanl/water (75:25:4). Product containing fractions were combined and the solvent removed under vacuum. The residue was dissolved in hot water and filtered through a 0.22 μm-pore membrane filter. Lyophilization of the filtrate yielded 0.50 g of title compound that analyzed as a 0.5 hydrate.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([CH:13]2[CH2:17][CH2:16][C:15](=[O:18])[N:14]2[C:19]2[CH:24]=[CH:23][C:22]([CH2:25][O:26]C)=[CH:21][CH:20]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(S)C.[Cl-].[Cl-].[Cl-].[Al+3]>O>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([CH:13]2[CH2:17][CH2:16][C:15](=[O:18])[N:14]2[C:19]2[CH:20]=[CH:21][C:22]([CH2:25][OH:26])=[CH:23][CH:24]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCc1ccc(N2C(=O)CCC2C(=O)Nc2cc(C(C)(C)C)on2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CCS
Product: CC(C)(C)c1cc(NC(=O)C2CCC(=O)N2c2ccc(CO)cc2)no1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
1-(4-Methoxymethyl-phenyl)-5-oxo-pyrrolidine-2-carboxylic acid (5-tert-butyl-isoxazol-3-yl)-amide (0.130 g; 0.350 mmol) is diluted with ethanethiol (1.988 mL; 26.880 mmol) and cooled to 0° C. To this solution is added aluminum trichloride (0.793 g; 5.950 mmol). The solution is stirred for 3 hours, slowly warming to room temperature. The solution is added dropwise to a solution of water containing concentrated hydrochloric acid. The aqueous is extracted with ethyl acetate. The organics are combined and washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by preparative HPLC afforded title compound. ESI m/z 358 [M+H]+
Reaction SMILES: C([O:5][C:6](=[O:20])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][C:17](O)=O)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=1.[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32]>ClCCl>[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32].[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([N:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:22][CH2:30][CH3:31])[CH2:17][CH2:16][C:14]2[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:20])[S:12][CH:13]=2)=[N:23][CH:24]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CC(=O)O)cs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)c1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A compound obtained using {2-[(2-tert-butoxy-1,1-dimethyl-2-oxoethyl)thio]-1,3-thiazol-4-yl}acetic acid synthesized in Example 3 and 2-amino-5-chloropyridine as starting materials and by an operation similar to that of Example 293-1 was treated with dichloromethane and trifluoroacetic acid, and the mixture was stirred at room temperature for 12 hr. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (elution solvent; 0.05% trifluoroacetic acid-water:0.05% trifluoroacetic acid-acetonitrile=50:50 to 5:95) to give the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[CH3:18][C:19]([O:22][C:23]([NH:25][C@H:26]([C:33](O)=[O:34])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])([CH3:21])[CH3:20]>>[C:19]([O:22][C:23](=[O:24])[NH:25][C@H:26]([C:33](=[O:34])[N:9]([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=1)[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([CH3:21])([CH3:18])[CH3:20]
Reactant: Cc1ccc(NCCc2ccccn2)cc1C
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)c1ccccc1
Product: Cc1ccc(N(CCc2ccccn2)C(=O)[C@@H](NC(=O)OC(C)(C)C)c2ccccc2)cc1C

Procedure:
In analogy to the procedure described for the synthesis example 21, step 3, the title compound was prepared from (3,4-dimethyl-phenyl)-(2-pyridin-2-yl-ethyl)-amine and boc-L-alpha-phenylglycine. MS (m/e): 460.3 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][C@H:13]1[OH:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][C:13]1=[O:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@@H]1Cc2ccccc2C[C@H]1O)OCc1ccccc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=C(NC1Cc2ccccc2CC1=O)OCc1ccccc1
Reaction time: 3 h
Yield: 35.5 %

Procedure:
To a solution of trans 3-benzyloxycarbonylamino-2-hydroxy-1,2,3,4-tetrahydronaphthalene (850 mg) in dichloromethane (29 mL) stirring under nitrogen at room temperature was added pyridinium chlorochromate (740 mg). After 3 h, the reaction mixture was evaporated under vacuum onto silica gel and then purified by silica gel chromatography eluting with a step-wise gradient of 30-75% ethyl acetate in hexane to obtain the title compound (300 mg) as a white solid and starting material (350 mg).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH2:6][C:7]3[CH:11]=[CH:10][S:9][C:8]=3[C:2]1=2.[OH-].[K+].[I-].[Na+].[CH2:16]([CH:18]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:19]Br)[CH3:17]>CS(C)=O.O>[CH2:16]([CH:18]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:19][C:6]1([CH2:6][CH:3]([CH2:4][CH3:5])[CH2:2][CH2:8][CH2:7][CH3:11])[C:7]2[CH:11]=[CH:10][S:9][C:8]=2[C:2]2[S:1][CH:5]=[CH:4][C:3]1=2)[CH3:17]
Reactant: CCCCC(CC)CBr
Reactant: c1cc2c(s1)-c1sccc1C2
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCC(CC)CC1(CC(CC)CCCC)c2ccsc2-c2sccc21
Reaction time: 16 h

Procedure:
4H-Cyclopenta[2,1-b;3,4-b′]dithiophene (1.5 g, 0.00843 mol) was dissolved in DMSO (50 mL). After the solution was purged with nitrogen, and grounded KOH (1.89 g, 0.0337 mol), sodium iodide (50 mg), and 2-ethylhexyl bromide (3.25 g, 0.0169 mol) were sequentially added. The reaction mixture was stirred overnight under nitrogen (c.a. 16 hours). Water was added and the reaction was extracted with t-butylmethyl ether. The organic layer was collected, dried over magnesium sulfate, and concentrated. The residue was purified by chromatography using hexanes as eluent. Fractions containing pure 4,4-Bis-(2-ethyl-hexyl)-4H-cyclopenta[2,1-b;3,4-b′]dithiophene product were combined and concentrated. The product was obtained as a colorless oil after drying under vacuum. Yield: 2.68 g (79%). 1H NMR (CDCl3, 250 MHz): 7.13 (m, 2H), 6.94 (m, 2H), 1.88 (m, 4H), 0.94 (m, 16H), 0.78 (t, 6.4 Hz, 6H), 0.61 (t, 7.3 Hz, 6H).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8](F)[CH:9]=2)[N:4]([C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.CC([O-])=O.[K+].CC1(C)C(C)(C)OB(B2OC(C)(C)C(C)(C)O2)O1>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1
Reactant: Fc1cnc2c(c1)c(Br)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: Brc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncccc12
Temperature: 100 °C

Procedure:
A solution of 3-bromo-5-fluoro-1-trityl-pyrazolo[3,4-b]pyridine, 44, (16.86 g, 36.79 mmol), KOAc (10.83 g, 110.4 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (14.01 g, 55.18 mmol) in DMF (250 mL) was degassed under a nitrogen stream for 40 min. To the mixture was added Pd(dppf)2Cl2 (3.00 g, 3.68 mmol). The reaction mixture was heated at 100° C. for 90 minutes. The reaction mixture was filtered through a pad of florisil and celite. The filtrate was diluted with ether and brine. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. The product was dried on high vacuum pump 3 days. To the product was added 200 mL Et2O and the mixture was stirred and filtered. The filtrate was concentrated in vacuo. The crude residue was diluted with 150 mL hexanes and the suspension was stirred for 3 hours, filtered and concentrated in vacuo to afford 12.6 g of desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:10](=[N:12]O)[CH3:11])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>C1COCC1.CCOCC>[ClH:1].[NH2:12][CH:10]([CH:9]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:11]
Reactant: CC(=NO)C(Cc1ccc(Cl)cc1)N1CCCC1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(N)C(Cc1ccc(Cl)cc1)N1CCCC1
Reaction time: 8 h

Procedure:
At room temperature, to a solution of 4-(4-chlorophenyl)-3-pyrrolidin-N-yl-butan-2-one oxime (173 mg, 0.648 mmol, from Step C) in 1.8 mL anhydrous THF was added dropwise a 1M solution of lithium aluminum hydride in THF (0.778 mmole). The mixture was refluxed for 20 h. The reaction was quenched by addition of saturated aqueous sodium sulfate (0.1 mL), and stirred overnight. This mixture was filtered over a pad of CELITE diatomaceous earth, and the filtrate was concentrated to dryness. The mass spectrum of this material looked very messy, so the HCl salt was prepared (by addition of a HCl(g) in ether solution) in attempt to clean up the mess. By NMR, the reductive amination provided a ˜1:1 mixture of the two diastereomeric pairs of amines. This HCl salt was rather sticky and difficult to work with and therefore was used in the ensuing coupling experiment without further purification. LC/MS m/e=253 (M+1). 500 MHz 1H NMR (CD3OD) δ 1.56, 1.59 (2 d, J=7.2 Hz, 3H), 2.03 (m, 6H), 2.08 (m, 2H), 3.204.00 (m, 3H), 7.43 (m, 4H)
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:9]=[C:8]([Cl:10])[C:7]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:6][C:4]=1[NH2:5].[CH3:15][C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[CH2:18][C:19]#N.C>CO>[Cl:10][C:8]1[C:7]([S:11](=[O:13])(=[O:14])[NH2:12])=[CH:6][C:4]2[NH:5][C:19]([CH2:18][C:17]3[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=3[CH3:15])=[N:2][C:3]=2[CH:9]=1
Reactant: Nc1cc(Cl)c(S(N)(=O)=O)cc1N
Reactant: Cc1ccccc1CC#N
Agent: Cl
Solvent: CO
Product: Cc1ccccc1Cc1nc2cc(Cl)c(S(N)(=O)=O)cc2[nH]1
Reaction time: 0.08 h

Procedure:
To 50 ml of 6 N hydrochloric acid was added 11.8 g of 2-amino-4-chloro-5-sulfamylaniline and 10.4 g of 2-methylbenzyl cyanide. The reaction was refluxed for 22 hours and then concentrated in vacuo to a solid which was then added with stirring to 200 ml of 38% ammonium hydroxide. Filtration provided the free base as a semi-gum which was dissolved in 500 ml of methanol. The methanol solution was brought to a boil, charcoal added, and boiling continued for five minutes. Upon cooling, the suspension was filtered through Celite and the filtrate concentrated in vacuo to yield a solid, m.p. 226°-230°.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:22]=[CH:23][CH:24]=2)[CH2:10][NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[OH:34][C:35]1[C:40]([Cl:41])=[CH:39][C:38]([Cl:42])=[CH:37][C:36]=1[S:43](Cl)(=[O:45])=[O:44]>C(Cl)Cl>[Cl:41][C:40]1[C:35]([OH:34])=[C:36]([S:43]([N:11]([CH2:10][C:9]2[CH:22]=[CH:23][CH:24]=[C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:26][CH:25]=3)[CH:8]=2)[CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)(=[O:45])=[O:44])[CH:37]=[C:38]([Cl:42])[CH:39]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1O
Reactant: Fc1ccc(Oc2cccc(CNCCCCc3ccccc3)c2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(c1cc(Cl)cc(Cl)c1O)N(CCCCc1ccccc1)Cc1cccc(Oc2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 0.3 %

Procedure:
To a mixture of N-(3-(4-fluorophenoxy)benzyl)-4-phenylbutan-1-amine (100 mg, 28.6 mmol, 1.0 eq) in DCM (5 mL), was added triethylamine (86 mg, 85 mmol, 3 eq) followed by 2-hydroxy-3,5-dichlorobenzenesulfonyl chloride (75 mg, 28.6 mmol, 1.0 eq). The reaction mixture was stirred at ambient temperature for 4 h before being diluted with DCM (100 mL) and washed with water. The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure. The residue was purified by preparative HPLC to afford the title compound (45 mg, 28%); 1H NMR (400 MHz, CD3OD) δ 7.67-7.66 (d, 1H), 7.58-7.57 (d, 1H), 7.30-7.26 (t, 1H), 7.23-7.20 (t, 2H), 7.15-7.00 (m, 6H), 6.97-6.94 (m, 2H), 6.88-6.84 (m, 2H), 4.47 (s, 2H), 3.26-3.22 (t, 2H), 2.46-2.43 (t, 2H), 1.42-1.34 (m, 4H). MS (ESI): 574.0 (M−H)−.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)#[N:2].ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.[NH2:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[C:34]([OH:36])=[O:35]>CN(C=O)C.C(Cl)Cl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:30][C:31]2[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=2)[C:34]([OH:36])=[O:35])=[O:9])=[CH:10][CH:11]=1)#[N:2]
Reactant: Nc1cccc(C(=O)O)c1
Reactant: N#Cc1ccc(C(=O)O)cc1
Agent: COc1nc(Cl)nc(OC)n1
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: N#Cc1ccc(C(=O)Nc2cccc(C(=O)O)c2)cc1
Yield: 70 %

Procedure:
4-Cyanobenzoic acid is activated with 2-chloro-4,6-dimethoxy-1,3,5-triazine and N-methylmorpholine analogously to Example 1 and subsequently reacted with 3-aminobenzoic acid in DMF/CH2Cl2. There is obtained m-(p-cyanobenzamido)benzoic acid in the form of colourless crystals. Yield: 70%, m.p. 267° C. (ethyl acetate/acetonitrile).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9](=[O:11])[CH3:10])=[C:4]([CH3:12])[CH:3]=1.Cl[C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.[Cu]>[CH3:12][C:4]1[CH:3]=[C:2]([O:1][C:14]2[CH:19]=[N:18][CH:17]=[CH:16][N:15]=2)[CH:7]=[C:6]([CH3:8])[C:5]=1[C:9](=[O:11])[CH3:10]
Reactant: Clc1cnccn1
Reactant: CC(=O)c1c(C)cc(O)cc1C
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1c(C)cc(Oc2cnccn2)cc1C
Temperature: 100 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
A mixture of 1-(4-hydroxy-2,6-dimethylphenyl)ethanone (4-2, 4.66 g, 28.4 mmol), 2-chloropyrazine (2.50 g, 21.8 mmol), copper (27.7 mg, 4.36 mmol), and potassium carbonate (9.05 g, 65.5 mmol) in 43.7 mL of DMF was stirred at 100° C. overnight. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), concentrated under reduced pressure, and purified by column chromatography on silica gel (50% EtOAc in hexanes as eluant) to give 1-(2,6-dimethyl-4-(pyrazin-2-yloxy)phenyl)ethanone (7-1, 4.65 g) as brown oils: 1H NMR (500 MHz, CDCl3) δ 8.43 (bs, 1 H), 8.29 (bs, 1 H), 8.14 (bs, 1 H), 6.83 (s, 2 H), 2.49 (s, 3 H), 2.27 (s, 6 H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.S(Cl)([Cl:13])=O>ClCCl.CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:13])=[O:7])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(Br)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(Br)cc1

Procedure:
A mixture of 100 g (0.497 mole) of 4-bromobenzoic acid and 100 g of thionyl chloride in 300 ml of dichloromethane containing a few drops of N,N-dimethylformamide was heated at reflux for two days. The low boiling liquid were then removed by evaporation, and the remaining liquid was distilled to provide 4-bromobenzoyl chloride.