Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7](Cl)[C:6]([N+:10]([O-:12])=[O:11])=[C:5]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([N:22]([CH3:24])[CH3:23])=[O:21])[CH:15]=2)[N:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:31]([NH2:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(#N)C>[CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:38][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:6]([N+:10]([O-:12])=[O:11])=[C:5]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([N:22]([CH3:24])[CH3:23])=[O:21])[CH:15]=2)[N:4]=1
Reactant: CSc1nc(Cl)c([N+](=O)[O-])c(Oc2cccc(C(=O)N(C)C)c2)n1
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CSc1nc(NCc2ccccc2)c([N+](=O)[O-])c(Oc2cccc(C(=O)N(C)C)c2)n1
Temperature: 75 °C
Yield: 46.3 %

Procedure:
In a similar manner, to 2-methylthio-4-chloro-5-nitro-6-(3-dimethylaminocarbonylphenoxy)pyrimidine (3.19 g, 8.65 mmol), a compound of formula (M), in 90 mL acetonitrile at 0° C. was added cesium carbonate (3.66 g, 11.2 mmol), followed by the addition of benzylamine (0.95 mL, 8.65 mmol). The reaction mixture was heated at 75° C. for 4 hours. The reaction mixture was filtered, the filtrate evaporated and the residue chromatographed on silica gel (ethyl acetate:methanol, 10:1) to afford 1.76 g (48%) of 2-methylthio-4-(benzyl)amino-5-nitro-6-(3-dimethylaminocarbonylphenoxy)pyrimidine, a compound of formula (N).
Reaction SMILES: Cl[C:2]1[C:3](=[O:19])[N:4]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:20][O-:21].[Na+].O>CO>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([N:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:11]=[C:2]([O:21][CH3:20])[C:3]2=[O:19])=[CH:13][CH:14]=1
Reactant: C[O-]
Reactant: O=c1c(Cl)nc2ccccc2n1-c1ccc(Cl)cc1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1nc2ccccc2n(-c2ccc(Cl)cc2)c1=O
Yield: 67.3 %

Procedure:
A solution of 3-chloro-1-(4-chlorophenyl)-1,2-dihydroquinoxalin-2-one (7.7 g) and sodium methoxide (2.0 g) in methanol (70 ml) was refluxed for 4 hours. Water was added and the product was extracted into chloroform. Evaporation of the solvent followed by crystallization from ethanol gave the title compound (5.1 g) mp 245°-247° C.
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=2[F:21])[CH:3]=1.[CH2:22]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)[C:23]#[CH:24].C(N(CC)CC)C>C1COCC1.[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:21][C:13]1[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=1[O:11][C:8]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:3]=[C:2]([C:24]#[C:23][CH2:22][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[S:10][C:9]=12
Reactant: C#CCN1CCOCC1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(Br)sc23)c(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(Oc2ccnc3cc(C#CCN4CCOCC4)sc23)c(F)c1
Temperature: 25 °C
Yield: 78.8 %

Procedure:
To a solution of bromide 42 (100 mg, 0.27 mmol) in THF (5 ml) was added 4-(prop-2-ynyl)morpholine (68 mg, 0.54 mmol) [H-W. Tsou, et. al. J. Med. Chem., 2001, 44, 2719-2734], triethylamine (68 mg, 0.67 mmol), CuI (5 mg, 0.03 mmol) and Pd(PPh3)2Cl2 (5.3 mg, 7.56 μmol). The reaction mixture was degassed with nitrogen and refluxed for 2 hrs, cooled to room temperature and adsorbed onto silica. Purification by column chromatography (eluent EtOAc) afforded the title compound 56 as a beige solid (88 mg, 79%). MS (m/z): 397.1 (M+H).
Reaction SMILES: [OH:1][B:2]1[C:6]2[C:7]([O:11][CH2:12][CH2:13][CH2:14][C:15]([NH2:17])=[O:16])=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]([CH2:18][N+:19]([O-])=O)[O:3]1.N.CC[OH:25]>[Ni]>[C:15]([OH:16])(=[O:25])[CH3:14].[NH2:19][CH2:18][CH:4]1[O:3][B:2]([OH:1])[C:6]2[C:7]([O:11][CH2:12][CH2:13][CH2:14][C:15]([NH2:17])=[O:16])=[CH:8][CH:9]=[CH:10][C:5]1=2
Reactant: NC(=O)CCCOc1cccc2c1B(O)OC2C[N+](=O)[O-]
Reactant: CCO
Agent: [Ni]
Agent: N
Product: CC(=O)O
Product: NCC1OB(O)c2c(OCCCC(N)=O)cccc21
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
A mixture of 4-(1-hydroxy-3-nitromethyl-1,3-dihydro-benzo[c][1,2]oxaborol-7-yloxy)-butyramide (50 mg, 0.17 mmol), Raney Ni (˜20 mg), 2 M NH3 in EtOH (1 mL), and EtOH (100 mL) was shaken under an atmosphere of H2 (42 psi) for 4.5 h at rt. The mixture was filtered through a bed of Celite and the filtrate was concentrated in vacuo. 3 N HCl in MeOH (1 mL) was added immediately to the residue and the resulting mixture was concentrated in vacuo. The residue was then purified by preparative HPLC (AcOH). The title compound was isolated as a white lyophilizate: yield 5 mg (111%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:20]I.O>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([O:17][CH3:20])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCC(O)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
To a solution of 1-benzyloxycarbonyl-4-hydroxypiperidine (1.3 g) in dimethylformamide (10 mL) was added sodium hydride (360 mL) under ice cooling and the mixture was stirred at room temperature under nitrogen-gas atmosphere for 1 hours. To the reaction mixture was added methyl iodide (374 μL) under ice-cooling and the mixture was stirred at the same temperature for 1 hour and at room temperature for 2 hours. To the reaction mixture was added water and ethyl acetate and the mixture was stirred. The organic layer washed with a brine, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the resultant crude product was purified by column chromatography on silica gel (solvent: hexane/ethyl acetate=88/12 to 70/30) to obtain 1-benzyloxycarbonyl-4-methoxypiperidine (622 mg, yield: 45%) as a pale yellow oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:18]=2[N:19]=1.[CH3:28][O:29][CH2:30][CH2:31][NH2:32].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:28][O:29][CH2:30][CH2:31][NH:32][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:13]
Reactant: COCCN
Reactant: Cn1c(Nc2nc3ccc(C(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COCCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(C(F)(F)F)cc3s1)n2C
Yield: 68.1 %

Procedure:
1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2-methoxy-ethyl)-amide (78 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100 mg), 2-methoxy-ethylamine (21 mg), HBTU (116 mg), and DIEA (67 uL). LC/MS: m/z 450.9. 1H NMR (DMSO-d6, 400 MHz): δ 12.45 (bs, 1H), 8.47 (s, 1H), 8.24 (s, 1H), 8.09 (s, 1H), 7.78 (s, 2H), 7.67 (d, 1H), 7.48 (d, 1H), 3.66 (bs, 3H), 3.51-3.39 (m, 4H), 3.27 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[CH3:9][C:10]1[CH:11]=[C:12]([S:17]([C:19]2[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[CH:20]=2)=O)[CH:13]=[C:14]([CH3:16])[CH:15]=1.C[Si](Cl)(C)C.Cl>C(Cl)Cl>[Br-:1].[CH3:26][C:21]1[CH:20]=[C:19]([S+:17]([C:12]2[CH:11]=[C:10]([CH3:9])[CH:15]=[C:14]([CH3:16])[CH:13]=2)[C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=2)[CH:24]=[C:23]([CH3:25])[CH:22]=1
Reactant: Cc1cc(C)cc(S(=O)c2cc(C)cc(C)c2)c1
Reactant: Fc1ccc(Br)cc1
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: ClCCl
Product: Cc1cc(C)cc([S+](c2ccc(F)cc2)c2cc(C)cc(C)c2)c1
Product: [Br-]
Reaction time: 0.5 h

Procedure:
To a Grignard reagent prepared from 79 g of 1-bromo-4-fluorobenzene, 13 g of bis(3,5-dimethylphenyl) sulfoxide obtained in Synthesis Example 1-46 and 50 g of methylene chloride were added. Under ice cooling, 16 g of trimethylsilyl chloride was added dropwise to the solution, which was aged for 30 minutes. To the reaction solution, 50 g of 3 wt % dilute hydrochloric acid was added to quench the reaction. The organic layer was separated. Without further purification, it was ready for use in the subsequent reaction.
Reaction SMILES: C([Li])CCC.[S:6]1[CH:10]=[CH:9][N:8]=[C:7]1[NH:11][C:12](=[O:14])[CH3:13].[O:15]=[C:16]1[C:21]2[CH:22]=[CH:23][CH:24]=[C:25]([C:26]([F:29])([F:28])[F:27])[C:20]=2[N:19]=[C:18]([CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[O:17]1.Cl>CCCCCC.O1CCCC1.O>[O:15]=[C:16]([C:21]1[CH:22]=[CH:23][CH:24]=[C:25]([C:26]([F:29])([F:28])[F:27])[C:20]=1[NH:19][C:18](=[O:17])[CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:35])([CH3:37])[CH3:36])[CH2:13][C:12](=[O:14])[NH:11][C:7]1[S:6][CH:10]=[CH:9][N:8]=1
Reactant: CC(=O)Nc1nccs1
Reactant: CC(C)(C)OC(=O)NCc1nc2c(C(F)(F)F)cccc2c(=O)o1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CC(C)(C)OC(=O)NCC(=O)Nc1c(C(=O)CC(=O)Nc2nccs2)cccc1C(F)(F)F
Temperature: -75 °C
Yield: 52.8 %

Procedure:
A solution of 85.6 ml of n-butyllithium in hexane was introduced into 8.5 g of N-2-thiazolyl acetamide suspended in 260 ml of tetrahydrofuran. After cooling to -75° C., a solution of 10.33 g of the product of Step A in 75 ml of tetrahydrofuran was added at this temperature. The reaction mixture was poured into 400 ml of water and 100 ml of 2N hydrochloric acid, and was extracted with ether. The organic phase was washed with N hydrochloric acid, then with water, dried, and concentrated to dryness under reduced pressure. The orange oil residue crystallized and the residue was triturated in ether, separated, washed with ether, and dried under reduced pressure to obtain 7.7 g of 1,1-dimethylethyl N-[2-[[2-[1,3-dioxo-3-(2-thiazolylamino)-propyl]-6-trifluoromethylphenyl]-amino]-2-oxo-ethyl]-carbamate melting at 166° C.
Reaction SMILES: [CH2:1]([Sn:5]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:19][CH2:20][CH2:21][CH3:22])[C:6]1[CH:7]=[C:8]([C:12]2[O:16][C:15]([CH:17]=O)=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4].[CH2:27]([O:29][C:30](=[O:39])[CH2:31][N:32]1[C:36](=[O:37])[CH2:35][S:34][C:33]1=[S:38])[CH3:28].N1CCCCC1>ClCCl>[CH2:27]([O:29][C:30](=[O:39])[CH2:31][N:32]1[C:36](=[O:37])/[C:35](=[CH:17]/[C:15]2[O:16][C:12]([C:8]3[CH:9]=[CH:10][CH:11]=[C:6]([Sn:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])[CH:7]=3)=[CH:13][CH:14]=2)/[S:34][C:33]1=[S:38])[CH3:28]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(-c2ccc(C=O)o2)c1
Reactant: CCOC(=O)CN1C(=O)CSC1=S
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CCCC[Sn](CCCC)(CCCC)c1cccc(-c2ccc(/C=C3\SC(=S)N(CC(=O)OCC)C3=O)o2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-(3-(Tributylstannyl)phenyl)furan-2-carbaldehyde (7 mg, 0.015 mmol) and ethyl-2-(4-oxo-2-thioxothiazolidin-3-yl)acetate (3.5 mg, 0.016 mmol) synthesized by the same method as in Example 1 were dissolved in dichloromethane (2 mL), piperidine (5 μL) was added thereto, and the mixture was stirred at room temperature (25° C.) overnight. After the reaction was completed the solvent was removed by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography using ethyl acetate/hexane (3/7 (volume ratio)) as an eluent, to give labeling precursor 1 in a yield of 6 mg (yield 56.6%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=O.[CH3:13][N:14]1[CH:18]=[C:17](C=O)[N:16]=[CH:15]1.[C:21]([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>O>[CH3:13][N:14]1[CH:18]=[CH:17][N:16]=[C:15]1[CH:21]=[C:9]1[C:10](=[O:11])[O:12][C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[N:8]1
Reactant: CC(=O)[O-]
Reactant: Cn1cnc(C=O)c1
Reactant: O=C(O)CNC(=O)c1cccs1
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: Cn1ccnc1C=C1N=C(c2cccs2)OC1=O
Temperature: 90 °C
Yield: 20.6 %

Procedure:
To a screw-capped test tube, N-(2-thienylcarbonyl)glycine (56 mg, 0.3 mmol), 1-methylimidazol-4-carboxaldehyde (36 mg, 0.3 mmol), sodium acetate (25 mg, 0.3 mmol) and acetic anhydride (0.3 mL) were added. The test tube was sealed, and it was then stirred at an external temperature of 90° C. Three hours later, the temperature of the reaction solution was returned to room temperature, and water (1.5 mL) was then added thereto. The obtained mixture was stirred at the same temperature as described above for 1.5 hours. Thereafter, the precipitated crystal was collected by filtration, and it was washed with water (5 mL) and was then dried under reduced pressure, so as to obtain 16 mg of the above-captioned compound.
Reaction SMILES: [SH:1][C:2]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10](=[O:18])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[O:25]1[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][S:1][C:2]2[N:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:10](=[O:18])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:23][CH2:24]1
Reactant: ClCCN1CCOCC1
Reactant: O=c1c2ccccc2nc(S)n1-c1ccccc1
Product: O=c1c2ccccc2nc(SCCN2CCOCC2)n1-c1ccccc1
Yield: 49.8 %

Procedure:
The title compound was prepared in a yield of 49.8%, using 2-mercapto-3-phenyl-4(3H)-quinazolinone in place of 3-isobutyl-2-mercapto-4(3H)-quinazolinone and N-(2chloroethyl)morpholine in place of 2-chloromethylpyridine hydrochloride.
Reaction SMILES: Cl.Cl.Cl.[N:4]1([C:10]2[CH:15]=[CH:14][C:13]([C@H:16]3[NH:21][CH2:20][CH2:19][NH:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.C(N(CC)CC)C.Cl[C:30]1[N:35]([CH3:36])[C:34](=[O:37])[CH:33]=[C:32]([C:38]2[CH:43]=[CH:42][N:41]=[CH:40][C:39]=2[F:44])[N:31]=1>O1CCCC1>[F:44][C:39]1[CH:40]=[N:41][CH:42]=[CH:43][C:38]=1[C:32]1[N:31]=[C:30]([N:18]2[CH2:19][CH2:20][NH:21][C@@H:16]([C:13]3[CH:12]=[CH:11][C:10]([N:4]4[CH2:5][CH2:6][O:7][CH2:8][CH2:9]4)=[CH:15][CH:14]=3)[CH2:17]2)[N:35]([CH3:36])[C:34](=[O:37])[CH:33]=1
Reactant: c1cc(N2CCOCC2)ccc1[C@@H]1CNCCN1
Reactant: Cn1c(Cl)nc(-c2ccncc2F)cc1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1c(N2CCN[C@@H](c3ccc(N4CCOCC4)cc3)C2)nc(-c2ccncc2F)cc1=O
Reaction time: 12 h
Yield: 72.8 %

Procedure:
To a solution of the above prepared (3R)-3-(4-(morpholin-4-yl)phenyl)piperazine trihydrochloride (0.5 g, 1.40 mmol) and triethylamine (0.8 g, 7.91 mmol) in tetrahydrofuran (10 ml) was added 2-chloro-6-(3-fluoropyridin-4-yl)-3-methyl-(3H)-pyrimidin-4-one (0.3 g, 1.25 mmol) which was prepared by Reference Example 2 portionwise. After stirring for 12 hours, the resulting suspension was partitioned between chloroform and 1N sodium hydroxide and the aqueous layer was extracted with chloroform. The combined organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting 5-10% methanol in chloroform to furnish 6-(3-fluoro-pyridin-4-yl)-3-methyl-2-((3S)-3-(4-morpholin-4-yl-phenyl)-piperazin-l-yl)-3H-pyrimidin-4-one (0.41 g, 0.91 mmol, 73%) as white crystals.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[C:5]([C:7]([OH:9])=O)[N:6]=1.[NH:17]1[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23][C:24]([C:26]2[N:33]3[C:29]([S:30][CH:31]=[CH:32]3)=[N:28][C:27]=2[CH3:34])=[O:25])[CH2:18]1>>[CH3:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[C:5]([C:7]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23][C:24]([C:26]3[N:33]4[C:29]([S:30][CH:31]=[CH:32]4)=[N:28][C:27]=3[CH3:34])=[O:25])[CH2:18]2)=[O:9])[N:6]=1
Reactant: Cc1nc2sccn2c1C(=O)N[C@@H]1CCCNC1
Reactant: Cc1ccc(-c2sc(C)nc2C(=O)O)cc1
Product: Cc1ccc(-c2sc(C)nc2C(=O)N2CCC[C@@H](NC(=O)c3c(C)nc4sccn34)C2)cc1

Procedure:
prepared by reaction of 2-methyl-5-p-tolyl-thiazole-4-carboxylic acid with (R)-6-methyl-imidazo[2,1-b]-thiazole-5-carboxylic acid-piperidin-3-ylamide.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:34]1([CH2:40][S:41][CH:42]([C:46](O)=[O:47])[C:43](O)=[O:44])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C1COCC1>[OH:47][C:46]1[CH:17]=[C:16]([C:13]2[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)=[CH:11][CH:12]=2)[O:18][C:43](=[O:44])[C:42]=1[S:41][CH2:40][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(O)C(SCc1ccccc1)C(=O)O
Reactant: CC(=O)c1ccc(OCCN2CCOCC2)cc1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1oc(-c2ccc(OCCN3CCOCC3)cc2)cc(O)c1SCc1ccccc1

Procedure:
The title compound was prepared by Method A using 4'-[2-(4-morpholinyl)ethoxy]acetophenone (1.31 g, 5.29 mmol), lithium bis(trimethylsilyl)amide (0.972 g, 5.81 mmol), chlorotrimethylsilane (0.738 mL, 5.81 mmol), THF (58 mL), and diethyl ester of [(phenylmethyl)thio]propanedioic acid (1.35 g, 4.80 mmol). m.p. dec. 207° C.; 1H NMR (250 MHz, DMSO-d6) δ 2.54 (s, 2 H), 6.89 (m, 4 H), 2.83 (t, 2 H), 3.55 (m, 4 H), 3.96 (s, 2 H), 4.22 (t, 2 H), 6.58 (s, 1 H), 7.08 (d, 2 H), 7.23 (m, 5 H), 7.73 (d, 2 H).
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6]([CH:8]1[C:13](=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7].Cl[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([CH3:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:19][CH:18]=1>CN(C)C=O>[CH2:4]([O:5][C:6]([C:8]1([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([CH:23]([CH3:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:21][CH:22]=2)[CH2:9][CH2:10][CH2:11][CH2:12][C:13]1=[O:14])=[O:7])[CH3:3]
Reactant: CCOC(=O)C(C)c1ccc(CCl)cc1
Reactant: CCOC(=O)C1CCCCC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)c1ccc(CC2(C(=O)OCC)CCCCC2=O)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 79.2 %

Procedure:
To a mixture of 9.6 g of 50% sodium hydride and 200 ml of dimethyl formamide was added dropwise 34 g of ethyl 2-cyclohexanone carboxylate under ice-cooling, the mixture was stirred at 50° C. for 30 minutes, thereafter again under ice-cooling 45.3 g of ethyl 2-(p-chloromethylphenyl)propionate was added dropwise, and the mixture was heated at 50°-60° C. with stirring for 1 hour. After the reaction was completed, the reaction mixture was poured into an ice-water, extracted with ether, the extract washed with water, dried over anhydrous sodium sulfate, and the solvent removed by distillation to give 69.5 g of an oily substance, which was subjected to a vacuum distillation affording 57 g of the dsired compound as a colorless oily substance, b.p. 200°-205° C. at 0.4 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[Cl:17][CH2:18][CH2:19][S:20][S:21][CH2:22][CH2:23]Cl.[OH-].[K+]>CS(C)=O>[ClH:1].[ClH:17].[ClH:1].[ClH:1].[CH2:23]([N:14]1[CH2:13][CH2:12][N:11]([CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:16][CH2:15]1)[CH2:22][S:21][S:20][CH2:19][CH2:18][N:14]1[CH2:13][CH2:12][N:11]([CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:16][CH2:15]1
Reactant: Clc1ccc(CCCN2CCNCC2)cc1
Reactant: ClCCSSCCCl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Cl
Product: Clc1ccc(CCCN2CCN(CCSSCCN3CCN(CCCc4ccc(Cl)cc4)CC3)CC2)cc1

Procedure:
The procedure described in Example 12 is followed using 1[3-(4-chlorophenyl)propyl]-piperazine (4.8 g), bis(2-chloroethyl) disulfide (1.9 g), potassium hydroxide (5.0 g), and dimethylsulfoxide (50 ml). Workup as described in Example 12 provides an oil which is purified on a silica gel column (methylene chloride:methanol, 9:1). The resulting oil (1.5 g) is precipitated with ethereal hydrochloric acid and recrystallized from water/ethanol to give 1,1'-(dithiodi-2, 1-ethanediyl)bis{4-[3-(4-chlorophenyl)propyl]piperazine} tetrahydrochloride as a white crystalline solid, m.p. 284°-286° C.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[C:5](O)(=[O:15])[C:6]1[CH:14]=[C:12]([OH:13])[C:10]([OH:11])=[C:8]([OH:9])[CH:7]=1.[Na+].[Cl-]>OS(O)(=O)=O>[OH:3][CH2:2][CH2:1][O:4][C:5](=[O:15])[C:6]1[CH:14]=[C:12]([OH:13])[C:10]([OH:11])=[C:8]([OH:9])[CH:7]=1
Reactant: O=C(O)c1cc(O)c(O)c(O)c1
Reactant: OCCO
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Product: O=C(OCCO)c1cc(O)c(O)c(O)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 27.7 %

Procedure:
A mixture consisting of ethylene glycol (105 g, 1.11 mol), gallic acid (28.5 g, 168 mmol), and concentrated H2SO4 (10 drops) was stirred at 90° C. overnight before mixing with ice water (1500 ml). Upon adding NaCl (100 g), the solution was extracted with ethyl acetate (150 ml×4). The combined organic portion was evaporated to dryness to obtain (m) (9.98 g, 28%). Proton-NMR spectral data (DMSO-d6), δ (ppm): 3.64 (t, HOCH2CH2, 2H), 4.15 (t, ArOCH2CH2, 2H), 6.93 (s, aromatic, 2H)
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[CH:7][NH:6][C:5](=[O:9])[C:4]=1[C:10]1[NH:21][C:20]2[CH:19]=[C:18]3[C:14]([CH:15]=[N:16][NH:17]3)=[CH:13][C:12]=2[N:11]=1.Cl.[NH2:23][CH2:24][C@H:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=1)[OH:26].CN1CCOCC1>C(#N)C>[Cl:33][C:29]1[CH:28]=[C:27]([C@H:25]([OH:26])[CH2:24][NH:23][C:3]2[CH:8]=[CH:7][NH:6][C:5](=[O:9])[C:4]=2[C:10]2[NH:21][C:20]3[CH:19]=[C:18]4[C:14]([CH:15]=[N:16][NH:17]4)=[CH:13][C:12]=3[N:11]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: NC[C@@H](O)c1cccc(Cl)c1
Reactant: O=c1[nH]ccc(Cl)c1-c1nc2cc3cn[nH]c3cc2[nH]1
Agent: Cl
Solvent: CC#N
Solvent: CN1CCOCC1
Product: O=c1[nH]ccc(NC[C@@H](O)c2cccc(Cl)c2)c1-c1nc2cc3cn[nH]c3cc2[nH]1
Temperature: 80 °C
Yield: 60.8 %

Procedure:
The mixture of crude 4-chloro-3-(1,7-dihydro-1,2,5,7-tetraaza-s-indacen-6-yl)-1H-pyridin-2-one hydrochloric acid salt (80 mg, 0.25 mmol), (S)-2-amino-1-(3-chloro-phenyl)-ethanol hydrochloric acid salt (80 mg, 0.38 mmol), N-methyl morpholine (0.5 ml, excess), and acetonitrile (15 mL) was heated to 80° C. overnight and cooled to room temperature. After concentration in vacuo, the residue was purified by prep. HPLC to yield the titled compound (64 mg, 61%). 1H NMR (400 MHz, CD3OD) δ 8.16 (s, 1H), 7.90 (s, 1H), 7.62 (s, 1H), 7.59 (s, 1H), 7.54 (s, 1H), 7.27–7.41 (m, 4H), 6.21 (d, J=7.6 Hz, 1H), 4.99 (m, 1H), 3.60–3.71 (m, 2H). LCMS (t=1.44 min), [M+H]+421.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[C:7]1(B(O)O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.I[C:17]1[CH:39]=[CH:38][C:20]([CH2:21][N:22]([S:34]([CH3:37])(=[O:36])=[O:35])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:19][CH:18]=1>C1(C)C=CC=CC=1.CCO.CCOC(C)=O>[C:17]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:39]=[CH:38][C:20]([CH2:21][N:22]([S:34]([CH3:37])(=[O:36])=[O:35])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:19][CH:18]=1
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)CCCCCCN(Cc1ccc(I)cc1)S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)CCCCCCN(Cc1ccc(-c2ccccc2)cc1)S(C)(=O)=O
Yield: 80.2 %

Procedure:
Tetrakis(trphenylphosphine)palladium(0) (102 mg, 0.09 mmol), aqueous Na2CO3 (0.9 mL, 1 M), and phenyl boronic acid (216 mg, 1.77 mmol) were added to a solution of ethyl 7-{[4-iodobenzyl]-methanesulfonyl-amino}-heptanoate (415 mg, 0.89 mmol) in toluene (37 mL) and EtOH (7 mL). The reaction mixture was heated at reflux for 3 h. The solution was diluted with EtOAc and was washed with water (2×) followed by brine (1×). The organic solution was dried over MgSO4, filtered, and concentrated in vacuo. Purification by radial chromatography (10% EtOAc-hexanes to 30% EtOAC/hexanes) provided the title compound of Step A (298 mg). 1H NMR (400 MHz, CDCl3) δ 7.62-7.30 (m, 4H), 4.41 (s, 2H), 4.12 (q, 2H), 3.20 (t, 2H), 2.82 (s, 3H), 2.23 (t, 3H), 1.58 (m, 4H), 1.35 (m, 7H); MS 418.3 (M+).