Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]([CH3:6])=O)([CH3:3])[CH3:2].Br.CC(O)=O.BrBr.[C:14]([CH2:17][O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=[O:23])(=[S:16])[NH2:15].C(=O)([O-])O.[Na+]>CO.O>[CH:1]([C:4]1[N:15]=[C:14]([CH2:17][O:18][C:19]2[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=2)[CH:22]=[O:23])[S:16][CH:6]=1)([CH3:3])[CH3:2]
Reactant: NC(=S)COc1cccc(C=O)c1
Reactant: CC(=O)C(C)C
Agent: Br
Agent: BrBr
Agent: O=C([O-])O
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: CC(C)c1csc(COc2cccc(C=O)c2)n1
Reaction time: 2 h
Yield: 68 %

Procedure:
Then, 32.9 g (0.38 mol) of methyl isopropyl ketone was dissolved in 291 ml of methanol and mixed with 2.9 ml of 25% HBr-AcOH under cooling with ice. 18.7 ml (0.36 mol) of bromine was added dropwise under cooling with ice, and the reaction solution was stirred for 2 hours. The reaction solution was stirred together with water at room temperature for 30 minutes and then together with 3-(thiocarbamoylmethoxy)benzaldehyde at room temperature for 5.5 hours. Water and saturated sodium hydrogen carbonate were added to adjust the pH to 8.0, and the reaction solution was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo for removal of the solvent, and the residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=20:1) to give 64.3 g of t he title compound in a yield of 68%.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:18])[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.[CH:19]1([N:24]2[C:33]3[N:32]=[C:31]([NH:34][C:35]4[CH:36]=[CH:37][C:38]([C:44](O)=[O:45])=[C:39]5[C:43]=4[O:42][CH2:41][CH2:40]5)[N:30]=[CH:29][C:28]=3[N:27]([CH3:47])[C:26](=[O:48])[C@H:25]2[CH2:49][CH3:50])[CH2:23][CH2:22][CH2:21][CH2:20]1.C(N(C(C)C)CC)(C)C.N>ClCCl.O>[CH:19]1([N:24]2[C:33]3[N:32]=[C:31]([NH:34][C:35]4[CH:36]=[CH:37][C:38]([C:44]([NH:1][CH2:2][C@H:3]([OH:18])[CH2:4][N:5]5[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])[CH2:7][CH2:6]5)=[O:45])=[C:39]5[C:43]=4[O:42][CH2:41][CH2:40]5)[N:30]=[CH:29][C:28]=3[N:27]([CH3:47])[C:26](=[O:48])[C@H:25]2[CH2:49][CH3:50])[CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)O)c4c3OCC4)nc2N1C1CCCC1
Reactant: CC(C)(C)OC(=O)N1CCN(C[C@@H](O)CN)CC1
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)NC[C@H](O)CN4CCN(C(=O)OC(C)(C)C)CC4)c4c3OCC4)nc2N1C1CCCC1
Reaction time: 2 h
Yield: 32.3 %

Procedure:
Tert-butyl 4-[(2S)-3-amino-2-hydroxy-propyl]piperazine-1-carboxylate 7c (355 mg, 1.37 mmol), 7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,3-dihydrobenzofuran-4-carboxylic acid 1q (600 mg, 1.37 mmol), O-(benzotriazol-1-yl)-N,N,N′-tetra methyluronium tetrafluoroborate (440 mg, 1.37 mmol) and diisopropylethylamine (390 mg, 3.01 mmol) were dissolved in 40 mL of dichloromethane. The reaction solution was stirred for 2 hours. The resulting solution was added with 50 mL of water and 10 mL of aqueous ammonia successively, stirred for 0.5 hours, extracted with dichloromethane (50 mL×3). The combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound tert-butyl 4-[(2S)-3-[[7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,3-dihydrobenzofuran-4-carbonyl]amino]-2-hydroxy-propyl]piperazine-1-carboxylate 7d (300 mg, yield: 32.3%) as a white solid.
Reaction SMILES: C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C.S(OOS([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].[C:25]([C:33]1[N:34]([CH2:38][CH2:39][CH:40]([C:46]([O:48][CH2:49][CH3:50])=[O:47])[C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH:35]=[CH:36][CH:37]=1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(O)(=O)C.O.O.O.O.C([O-])(=O)C.[Mn+2].C([O-])(=O)C.[N+]([O-])([O-])=O.[Ag+].O>[C:25]([C:33]1[N:34]2[C:35](=[CH:36][CH:37]=1)[C:40]([C:46]([O:48][CH2:49][CH3:50])=[O:47])([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:39][CH2:38]2)(=[O:32])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCOC(=O)C(CCn1cccc1C(=O)c1ccccc1)C(=O)OCC
Agent: [Ag+]
Agent: [Mn+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)C1(C(=O)OCC)CCn2c(C(=O)c3ccccc3)ccc21
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 95.5 %

Procedure:
A mixture of manganese(II) acetate tetrahydrate (343 mg, 1.40 mmol), silver nitrate (23.8 mg, 0.140 mmol), sodium acetate (420 mg, 5 mmol), acetic anhydride (542 mg, 4.20 mmol) and sodium persulfate (333 mg, 1.4 mmol) in acetic acid (8 mL) was stirred at 80° C. for 30 minutes. To this mixture was added a solution of 2-benzoyl-1-[3,3-di(ethoxycarbonyl)propyl]pyrrole (500 mg, 1.40 mmol) in acetic acid (2 mL). To the reaction mixture was then added additional sodium persulfate (333 mg, 1.4 mmol). The resulting mixture was stirred at 80° C. for 12 hours, cooled, poured into water (25 mL), and extracted with toluene (3×25 mL). The combined toluene extracts were washed with water (25 mL) and concentrated under reduced pressure, providing 475 mg (95%) of diethyl 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1,1-dicarboxylate.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][N:3]=1.S(Cl)([Cl:13])=O>C(#N)C.N1C=CC=CC=1>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:13])=[O:7])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(O)nc1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: O=C(Cl)c1ccc(O)nc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
13.92 g (0.1 mol) of 6-hydroxynicotinic acid and 0.04 g (0.5 mmol) of pyridine were heated in 60 ml of acetonitrile to 80° C. 12.49 g (0.105 mol) of thionyl chloride was instilled and the reaction again stirred for 30 minutes at 80° C. After cooling, the precipitate was filtered off, washed twice each with 10 ml of cold acetonitrile and concentrated by evaporation in a vacuum. 13.38 g (0.085 mol) of 6-hydroxynicotinoyl chloride was obtained as a light yellowish powder, corresponding to a yield of 85 percent relative to the 6-hydroxynicotinic acid. Further data concerning the product was:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][C:3]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:20][C:21](Cl)=[O:22].O>CN(C)C=O>[CH3:11][O:10][C:8]([C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:21](=[O:22])[CH2:20][O:12][C:3]=2[CH:4]=1)=[O:9]
Reactant: O=C(Cl)CCl
Reactant: COC(=O)c1ccc(N)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)OCC(=O)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.3 %

Procedure:
To a solution of 2 -amino-5 -methoxycarbonylphenol [Tetrahedron, 46(15), 5177-5186 (1990)] (2.20 g) in dimethylformamide (30 ml) were added potassium carbonate (4.00 g) and 2-chloroacetyl chloride (1.50 g) and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into water to give precipitates, which were taken by filtration and dried to give 7-methoxycarbonyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (2.00 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:22]3[C:21](=O)[CH2:20][CH2:19][CH2:18][C:17]=3[NH:16][C:15]3[CH2:14][CH2:13][CH2:12][C:11](=[O:24])[C:10]2=3)[CH:5]=[CH:6][C:7]=1[F:8].[BH4-].[Na+].C(O)C>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:10]3[C:11](=[O:24])[CH2:12][CH2:13][CH2:14][C:15]=3[NH:16][C:17]3[CH2:18][CH2:19][CH2:20][CH2:21][C:22]2=3)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1CCCC2=C1C(c1ccc(F)c(Br)c1)C1=C(CCCC1=O)N2
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCO
Product: O=C1CCCC2=C1C(c1ccc(F)c(Br)c1)C1=C(CCCC1)N2
Temperature: 70 °C
Yield: 63.4 %

Procedure:
A mixture of 9-(3-bromo-4-fluorophenyl)-3,4,6,7,9,10-hexahydro-1,8(2H,5H)-acridinedione (1.8 g), sodium borohydride (1.74 g), ethanol (40 mL) and pyridine (14 mL) was heated at 70° C. for three and one half hours. The solvent was removed, the residue partitioned between water and ethyl acetate, the organic layer dried and the solvent removed. Chromatography (methylene chloride/ethyl acetate; 7/3) gave the title compound (1.1 g), as a yellow solid, mp 254°-257° C.; NMR: 1.41-1.51 (m,3, CH2), 1.60-1.88 (m,5, CH2), 2.03-2.13 (m,4, CH2), 2.38-2.44 (m,2, CH2), 4.18 (s,1, CH), 7.13-7.24 (m,2, Ar), 7.38 (dd,1, J=6.9, 2.0, Ar), 8.45 (s,1, NH); (CI, CH4) MS: m/z=378(M+1). Analysis for C19H19FBr: Calculated: C, 60.65; H, 5.09; N, 3.72; Found: C, 60.68; H, 5.09; N, 3.65.
Reaction SMILES: Br[C:2]1[C:3]([F:20])=[CH:4][C:5]2[CH:17]3[CH2:18][CH:15]([CH2:16]3)[C:8]3[NH:9][C:10]([C:12]([NH2:14])=[O:13])=[N:11][C:7]=3[C:6]=2[CH:19]=1.CN(C)C=O.C(N(CC)CC)C.[CH3:33][C:34]([OH:38])([C:36]#[CH:37])[CH3:35]>C(#N)C.[Cu]I.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>[F:20][C:3]1[C:2]([C:37]#[C:36][C:34]([OH:38])([CH3:35])[CH3:33])=[CH:19][C:6]2[C:7]3[N:11]=[C:10]([C:12]([NH2:14])=[O:13])[NH:9][C:8]=3[CH:15]3[CH2:16][CH:17]([C:5]=2[CH:4]=1)[CH2:18]3
Reactant: NC(=O)c1nc2c([nH]1)C1CC(C1)c1cc(F)c(Br)cc1-2
Reactant: C#CC(C)(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CN(C)C=O
Product: CC(C)(O)C#Cc1cc2c(cc1F)C1CC(C1)c1[nH]c(C(N)=O)nc1-2
Temperature: 80 °C
Reaction time: 0.03 h
Yield: 27.1 %

Procedure:
Into a pressure tube containing a solution 9-bromo-8-fluoro-3,4,5,6-tetrahydro-4,6-methanobenzo[3,4]cyclohepta[1,2-d]imidazole-2-carboxamide (47 mg, 0.14 mmol) in 1:1 N,N-dimethylformamide/triethylamine (0.8 mL) was introduced 2-methyl-3-butyn-2-ol (235 mg, 2.80 mmol), copper(I) iodide (2 mg, 0.01) and nitrogen gas bubbled through the solution for 3 minutes. Bis(triphenylphosphine)palladium(II) chloride (10 mg, 0.01 mmol) was added and nitrogen bubbling continued a further two minutes before the pressure tube was closed under nitrogen. The reaction mixture was warmed to 80° C. for 8 hr. After cooling to room temperature, the reaction mixture was evaporated in vacuo and the residue re-dissolved in ethyl acetate (15 mL). This solution was washed with water (2×5 mL) and brine (5 mL). The organic extract was dried over sodium sulfate, filtered and the filtrate absorbed onto silica gel. Purification by silica gel flash column chromatography (eluent: dichloromethane containing a 0-8% gradient of methanol) furnished partially purified product as a brown oil. After several acetonitile solubilisation-evaporation (in vacuo) cycles, a grey-brown solid was obtained which was slurried in acetonitrile (0.4 mL) and collected by filtration to furnish the title compound (13 mg, 0.038 mmol, 27%) as a grey solid: 1H NMR (500 MHz, d4-methanol) δ 1.59 (s, 6H), 1.63 (d, J=11.03 Hz, 2H), 2.85-2.95 (m, 2H), 3.44 (td, J=6.94, 3.78 Hz, 1H), 3.63 (td, J=8.04, 3.78 Hz, 1H), 6.86 (d, J=10.40 Hz, 1H), 8.25 (d, J=7.57 Hz, 1H); M+1=340.
Reaction SMILES: [F:1][CH:2]([F:23])[C:3]1[CH:4]=[N:5][CH:6]=[C:7]([N:16]2C(C)=CC=C2C)[C:8]=1[N:9]1[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]1.NO.C(N(CC)CC)C.C(O)C>O>[F:23][CH:2]([F:1])[C:3]1[C:8]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)=[C:7]([NH2:16])[CH:6]=[N:5][CH:4]=1
Reactant: Cc1ccc(C)n1-c1cncc(C(F)F)c1N1CCN(C)CC1
Agent: NO
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN1CCN(c2c(N)cncc2C(F)F)CC1
Temperature: 25 °C

Procedure:
A solution of 1-[3-(difluoromethyl)-5-(2,5-dimethylpyrrol-1-yl)-4-pyridyl]-4-methyl-piperazine (80 mg, 0.2497 mmol) and NH2OH (165.0 mg, 4.994 mmol) in a mixture of triethylamine (101.1 mg, 139.3 μL, 0.9988 mmol), ethanol (1 mL) and H2O (0.25 mL) was heated at reflux for 20 h. After cooling to RT the reaction was quenched by loading directly onto an SCX-2 cartridge and eluted with MeOH followed by NH3/MeOH. The basic fraction was concentrated in vacuo yielding 5-(difluoromethyl)-4-(4-methylpiperazin-1-yl)pyridin-3-amine that was used in next step without further purification. MS (ES+) 243.1.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:12][CH:13]([O:19][CH2:20][CH3:21])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[CH3:22][S:23]([O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34]OS(C)(=O)=O)=[CH:29][CH:28]=1)(=[O:25])=[O:24].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[C:1]([C:5]1[CH:6]=[C:7]([CH2:12][CH:13]([O:19][CH2:20][CH3:21])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:8]=[CH:9][C:10]=1[O:11][CH2:34][CH2:33][C:30]1[CH:29]=[CH:28][C:27]([O:26][S:23]([CH3:22])(=[O:24])=[O:25])=[CH:32][CH:31]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CS(=O)(=O)OCCc1ccc(OS(C)(=O)=O)cc1
Reactant: CCOC(=O)C(Cc1ccc(O)c(C(C)(C)C)c1)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)C(Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)c(C(C)(C)C)c1)OCC
Yield: 22.1 %

Procedure:
Ethyl 3-(3-tert-butyl-4-hydroxyphenyl)-2-ethoxypropanoate (0.15 g, 0.44 mmole) and 4-{2-[(methylsulfonyl)oxy]ethyl}phenyl methanesulfonate (0.26 g, 0.89 mmole) were dissolved in 2-butanone (4 ml). Polyethyleneglycol 400 (0.05 g) and anhydrous potassium carbonate (0.092 g, 0.67 mmole) were added the mixture. After stirring at reflux for 16 hours it was checked using HPLC whether all the starting material was consumed. The mixture was washed with water dried with magnesium sulfate and evaporated. Purification of the crude product with preparative HPLC (Kromasil C8, 7 μm, 50×250 mm) using actonitrile(40-80%) in ammonium acetate buffer (pH 7) as mobile phase gave 0.048 g (22% yield) of the desired product
Reaction SMILES: [C:1]([N:8]1[CH2:16][CH2:15][CH:11]([C:12](O)=[O:13])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:17](N1C=CN=C1)([N:19]1C=CN=[CH:20]1)=O.Cl.CNC.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[C:4]([O:3][C:1]([N:8]1[CH2:16][CH2:15][CH:11]([C:12](=[O:13])[N:19]([CH3:20])[CH3:17])[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CNC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 8 h

Procedure:
To a stirring solution of BOC-isonipecotic acid (400 mg) in N,N-dimethylformamide (4 mL) was added 1,1′-carbonyldiimidazole (560 mg). The reaction mixture was stirred overnight and then dimethylamine hydrochloride (280 mg) and triethylamine (0.48 mL) were added. After 5 hours the reaction mixture was diluted with ethyl acetate, washed with water, dried (MgSO4) and the solvent removed in vacuo to yield 4-dimethylcarbamoyl-piperidine-1-carboxylic acid tert-butyl ester. Removal of the BOC group with HCl yielded piperidine-4-carboxylic acid dimethylamide, which was isolated as the hydrochloride salt.
Reaction SMILES: CN(C)N=[C:4]([CH2:6][CH:7]([OH:28])[CH:8]([O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)=[CH:13][CH:12]=1)[CH3:9])[CH3:5].I([O-])(=O)(=O)=[O:31].[Na+]>CO.P([O-])([O-])([O-])=O.O>[OH:28][CH:7]([CH:8]([O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)=[CH:13][CH:12]=1)[CH3:9])[CH2:6][C:4](=[O:31])[CH3:5]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CC(CC(O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)=NN(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(=O)CC(O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reaction time: 3 h

Procedure:
4-Hydroxy-5-[4-(4-trifluoromethylphenoxy)phenoxy]-2-hexanone N,N-dimethylhydrazone (1 mmol) is dissolved in methanol (15 ml) and 1.0 N pH 7 phosphate buffer (3 ml), and a solution of sodium periodate (2.2 mmol) in water (5 ml) is added at 25° with stirring. After about 3 hours, the reaction mixture is filtered, poured into water and extracted with methylene chloride. The extract is dried and concentrated in vacuo to give 4-hydroxy-5-[4-(4-trifluoromethylphenoxy)phenoxy]-2-hexanone (cpd. 1, Table B).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:12]=[C:13]([NH:26][C:27](=[O:29])[CH3:28])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:5][CH:4]=1.[Na].O.C(O)C.C[N:36](C)C=O>Cl.CO>[NH2:36][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:12]=[C:13]([NH:26][C:27](=[O:29])[CH3:28])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:5][CH:4]=1
Reactant: CC(=O)Nc1nc(CCc2ccc(CBr)cc2)c(-c2ccc(S(C)(=O)=O)cc2)s1
Reactant: CN(C)C=O
Agent: Cl
Agent: [Na]
Solvent: CO
Solvent: CCO
Solvent: O
Product: CC(=O)Nc1nc(CCc2ccc(CN)cc2)c(-c2ccc(S(C)(=O)=O)cc2)s1
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
To a solution of N-{4-{2-[4-(bromomethyl)phenyl]ethyl}-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}acetamide (70 mg) in N,N-dimethylformamide (1 ml) was added diformimide sodium salt (13.5 mg), and the mixture was stirred for 10 min at 20° C. To the reaction mixture was added water, the mixture was extracted with ethyl acetate, washed with water twice, dried over magnesium sulfate, and evaporated to give a crude diformimide compound. The diformimide compound was suspended in conc. hydrocloric acid (200 μl), ethanol (2 ml) and methanol (0.5 ml). The reaction mixture was stirred at 20° C. for 3 hrs., then at 50° C. for 3 hrs. The volatails were evaporated. To the residue was added saturated sodium hydrogen carbonate aqueous solution, the mixture was extracted with chloroform, dried over maganesium sulfate and evaporated to give crude N-{4-(2-{4-[aminomethyl]phenyl}ethyl)-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}acetamide, that was used as crude in the next reaction.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:20])[CH2:10][CH2:11][C:12]([N:14]([CH2:16][C:17]([OH:19])=O)[CH3:15])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:21]1[CH2:27][CH2:26][CH2:25][C@H:22]1[CH2:23][OH:24].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:20])[CH2:10][CH2:11][C:12]([N:14]([CH2:16][C:17]([N:21]1[CH2:27][CH2:26][CH2:25][C@H:22]1[CH2:23][OH:24])=[O:19])[CH3:15])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(CC(=O)O)C(=O)CCC(=O)OCc1ccccc1
Reactant: OC[C@@H]1CCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CC(=O)N1CCC[C@H]1CO)C(=O)CCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.8 %

Procedure:
N-(benzyloxysuccinyl)sarcosine (139.5 g, 0.5 mol), L-prolinol (50.5 g, 0.5 mol) and triethylamine (200 ml) are dissolved in methylene chloride (2 l), and a solution of DMC (127 g, 0.75 mol) in methylene chloride (500 ml) is added dropwise thereto under water-cooling over a period of thirty minutes. The mixture is stirred at room temperature for a further three hours, and the reaction liquid is washed successively with water (1 l), a saturated aqueous solution of sodium hydrogen carbonate (1 l), 1N hydrochloric acid (1 l) and water (1 l). The organic layer is dried over anhydrous magnesium sulfate and filtered. The filtrate is then concentrated to dryness under reduced pressure, and the residue is purified by column chromatography on silica gel (chloroform:methanol) to give N-(benzyloxysuccinyl)sarcosyl-L-prolinol (88.4 g, 48.8%).
Reaction SMILES: C([Li])CCC.[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][CH:16]([N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25](Br)[CH:26]=3)[CH2:21][CH2:20]2)[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].CN(C)[CH:31]=[O:32].[Cl-].[NH4+]>CCCCCC.O1CCCC1.C(OCC)(=O)C>[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][CH:16]([N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([CH2:31][OH:32])[CH:26]=3)[CH2:21][CH2:20]2)[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCc3ccc(Br)cc32)CC1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(N2CCc3ccc(CO)cc32)CC1
Temperature: 25 °C
Yield: 91 %

Procedure:
A 2.5 M solution (16 ml) of n-butyllithium in hexane was added dropwise at ±78° C. into a solution of 1-[1-(t-butoxycarbonyl)piperidin-4-yl]-6-bromoindoline (10 g) in tetrahydrofuran (250 ml) over 5 mm. After 10 mm, dimethylformamide (3.0 ml) was added and the resultant mixture was allowed to warm to room temperature. Next, a saturated aqueous solution of ammonium chloride and ethyl acetate were added thereto and the layers were separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To the residue were added ethanol (50 ml) and sodium borohydride (1.0 g) and the resultant mixture was stirred at room temperature for 30 mm. Then ice water and ethyl acetate were added to the reaction solution and the layers were separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate system) to give the title compound (7.9 g) (yield: 91%).
Reaction SMILES: [NH:1]1[C:5](B(O)O)=[CH:4][CH:3]=[N:2]1.Br[C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][CH:16]=1)[NH2:13].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:2]1[NH:1][C:5]([C:10]2[CH:11]=[C:12]([NH2:13])[CH:14]=[CH:15][CH:16]=2)=[CH:4][CH:3]=1
Reactant: Nc1cccc(Br)c1
Reactant: OB(O)c1ccn[nH]1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Nc1cccc(-c2ccn[nH]2)c1
Temperature: 25 °C
Yield: 20 %

Procedure:
1H-pyrazole-5-boronic acid (0.072 g, 0.639 mmol) and 3-bromoaniline (0.063 mL, 0.581 mmol) were combined in dioxane (2 mL) in a flame-dried, round-bottom flask. K3PO4 (1.27M, 0.778 mL, 0.99 mmol), PCy3 (0.004 g, 0.014 mmol), and Pd2(dba)3 (0.005 g, 0.006 mmol) were added to the stirred solution. The reaction was refluxed overnight under argon flow, and subsequently cooled to room temperature. The solvent was removed under vacuum and the resulting residue was resuspended in CH2Cl2. The organic phase was dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by flash silica column chromatography (70-100% EtOAc/hexanes). The purification was monitored by TLC. The solvent was removed under vacuum from fractions containing product, resulting in 0.018 g in 20% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][CH:7]([C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.[C:21]1([SH:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][CH:7]([C:12]2[CH:17]=[CH:16][C:15]([S:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:14][CH:13]=2)[C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1
Reactant: Sc1ccccc1
Reactant: COC(=O)C(Oc1ccc(Cl)cc1)c1ccc(I)cc1
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)C(Oc1ccc(Cl)cc1)c1ccc(Sc2ccccc2)cc1

Procedure:
A mixture of 6.04 g of methyl α-(p-chlorophenoxy)(p-iodophenyl)acetate, 3.36 g of cuprous phenylmercaptide, and 800 mg of thiophenol in 150 ml of pyridine is heated under Argon overnight. The mixture is poured into 300 ml of water and extracted with two 100 ml portions of chloroform. The combined organic layers are washed with two 50 ml portions of 5% NaOH, two 50 ml portions of water, 50 ml of saturated brine and dried over MgSO4. Evaporation of the solvent at reduced pressure yields an oil. After column chromatography (benzene) and bulb-to-bulb distillation (173° C. @ 0.01 mm) there is obtained the product as a yellow oil.