Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]([C:20]1[C:24]([CH3:25])=[C:23]([CH3:26])[O:22][N:21]=1)[CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])(=[O:12])=[O:11])(O)O.Br[C:28]1[CH:35]=[CH:34][C:33]([C:36]2[O:37][CH:38]=[CH:39][N:40]=2)=[CH:32][C:29]=1[CH:30]=[O:31]>C1(C)C=CC=CC=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:25][C:24]1[C:20]([N:13]([CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])[S:10]([C:5]2[C:4]([C:28]3[CH:35]=[CH:34][C:33]([C:36]4[O:37][CH:38]=[CH:39][N:40]=4)=[CH:32][C:29]=3[CH:30]=[O:31])=[CH:9][CH:8]=[CH:7][CH:6]=2)(=[O:12])=[O:11])=[N:21][O:22][C:23]=1[CH3:26]
Reactant: COCCOCN(c1noc(C)c1C)S(=O)(=O)c1ccccc1B(O)O
Reactant: O=Cc1cc(-c2ncco2)ccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: COCCOCN(c1noc(C)c1C)S(=O)(=O)c1ccccc1-c1ccc(-c2ncco2)cc1C=O
Temperature: 85 °C

Procedure:
To the 2-borono-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]benzenesulfonamide and 2-bromo-5-(2-oxazolyl)benzaldehyde (13.32 g, 58.14 mmol, prepared as described in Example 21 of European Patent Application No. 702,012) in 264 ml of toluene and 132 ml of 95% ethanol ("EtOH"), 106 ml 2M aqueous sodium carbonate and tetrakis(triphenylphosphine)palladium(0) (6.11 g, 5.29 mmol) were added and the reaction mixture heated under argon at 85° C. for 4 hrs, cooled and diluted with 250 ml of EtOAc. The organic layer was separated and washed with 100 ml H2O and 50 ml brine, dried and concentrated. The residue was chromatographed on silica gel using 1:1 hexane/EtOAc to afford the title product of this step (16.95 g, 62.7% for two steps) as a colorless gum.
Reaction SMILES: C(N(CC)CC)C.N1C=CC(CN)=CC=1.Cl[C:17]1[C:26]2[C:21](=[CH:22][C:23]([NH:30][CH2:31][CH3:32])=[C:24]([N+:27]([O-:29])=[O:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1.[O:33]1CCCC1>>[CH2:31]([NH:30][C:23]1[CH:22]=[C:21]2[C:26]([C:17](=[O:33])[NH:18][CH:19]=[N:20]2)=[CH:25][C:24]=1[N+:27]([O-:29])=[O:28])[CH3:32]
Reactant: CCNc1cc2ncnc(Cl)c2cc1[N+](=O)[O-]
Reactant: C1CCOC1
Agent: NCc1ccncc1
Solvent: CCN(CC)CC
Product: CCNc1cc2nc[nH]c(=O)c2cc1[N+](=O)[O-]

Procedure:
Triethylamine (10 ml, 72.1 mmol) and 4-picolylamine (4 ml, 39.4 mmol) were added to a tetrahydrofuran solution (20 ml) of 4-chloro-7-ethylamino-6-nitroquinazoline obtained from 7-ethylamino-6-nitro-4(3H)-quinazolone (737.9 mg, 3.15 mmol) according to the procedures in Reference Example 13 under ice-cooling. The mixture was stirred at room temperature for 13 hours and at 55° C. for 4 hours. After a solvent was distilled off, the residue was purified by silica gel column chromatography (eluted with ethyl acetate:hexane=9:1) to give the title compound (780 mg, 76%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[NH:7][C:8](=[O:18])[N:9]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH2:10][CH2:11][C:5]=2[CH:4]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([O:28][C:29]2[CH:38]=[C:37]([CH3:39])[C:32]3[NH:33][C:34](=[O:36])[S:35][C:31]=3[CH:30]=2)[CH:23]=1.CCN(C(C)C)C(C)C.O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[NH:7][C:8](=[O:18])[N:9]([CH:12]3[CH2:13][CH2:14][N:15]([C:22]4[N:27]=[CH:26][N:25]=[C:24]([O:28][C:29]5[CH:38]=[C:37]([CH3:39])[C:32]6[NH:33][C:34](=[O:36])[S:35][C:31]=6[CH:30]=5)[CH:23]=4)[CH2:16][CH2:17]3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: Cc1cc(Oc2cc(Cl)ncn2)cc2sc(=O)[nH]c12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4cc(C)c5[nH]c(=O)sc5c4)ncn3)CC1)C(=O)N2
Reaction time: 0.5 h

Procedure:
100 mg (0.36 mmol) 7-methoxy-3-(piperidin-4-yl)-4,5-dihydro-1H-benzo[d][1,3]diazepin-2(3H)-one, 110 mg (0.36 mmol) 6-(6-chloropyrimidin-4-yloxy)-4-methylbenzo[d]thiazol-2(3H)-one and 140 μL (0.81 mmol) DIPEA in 2.0 mL DMF were stirred for 14 h at 60° C. The reaction mixture was cooled, mixed with water and stirred for 30 min. The precipitate formed was suction filtered and dried.
Reaction SMILES: C(NC(=O)[C@H](C)NC(OCC1C=CC=CC=1)=O)C.[CH2:19]([O:26][C:27]([NH:29][C@H:30]([C:32]([OH:34])=O)[CH3:31])=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[CH2:35]([NH:38][C:39](=[O:50])[C@@H:40]1[CH2:44][CH2:43][CH2:42][N:41]1[C:45](=[O:49])[C@H:46]([CH3:48])[NH2:47])[CH2:36][CH3:37]>CN(C)C=O>[CH2:35]([NH:38][C:39](=[O:50])[C@@H:40]1[CH2:44][CH2:43][CH2:42][N:41]1[C:45](=[O:49])[C@H:46]([CH3:48])[NH:47][C:32](=[O:34])[C@H:30]([CH3:31])[NH:29][C:27]([O:26][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:28])[CH2:36][CH3:37]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCCNC(=O)[C@@H]1CCCN1C(=O)[C@H](C)N
Agent: CCNC(=O)[C@H](C)NC(=O)OCc1ccccc1
Solvent: CN(C)C=O
Product: CCCNC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)OCc1ccccc1
Yield: 71 %

Procedure:
This compound was prepared by a process analogous to that employed in preparing benzyloxycarbonyl alanine ethylamide from benzyloxycarbonyl alanine and alanyl proline propylamide in a 71% yield with a melting point of 101 to 103 degrees C. [α]D20 -47.7 degrees (c 0.3; dimethylformamide).
Reaction SMILES: [Br:1][C:2]([Br:9])([Br:8])[CH2:3][CH2:4][C:5](O)=[O:6].S(Cl)([Cl:12])=O>CN(C)C=O>[Br:1][C:2]([Br:9])([Br:8])[CH2:3][CH2:4][C:5]([Cl:12])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCC(Br)(Br)Br
Solvent: CN(C)C=O
Product: O=C(Cl)CCC(Br)(Br)Br
Temperature: 40 °C
Reaction time: 3 h
Yield: 104.9 %

Procedure:
324.8 g (1 mole) of 4,4,4-tribromobutyric acid is added to 600 g of thionylchloride and 1 ml of dimethylformamide and the whole is heated at first for 2 hours at 40° C. and subsequently for 3 hours at 75° C. Then the excess of thionyl chloride is evaporated and the residue is distilled in vacuo. 360 g (95% of theory) of 4,4,4-tribromobutyric acid chloride, b.p. 71°-73° C./0.05 torr, is obtained.
Reaction SMILES: [OH:1][C:2]1[C:10]2[O:9][C:8]([CH3:11])=[C:7]([C:12]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)=[O:13])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:26][CH3:27].C(Br)(Br)(Br)Br.[CH2:33]([O:40][P:41]([O-:50])[O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(N(CC)CC)C>C(#N)C.C(OCC)(=O)C>[P:41]([O:1][C:2]1[C:10]2[O:9][C:8]([CH3:11])=[C:7]([C:12](=[O:13])[C:14]3[CH:15]=[C:16]([O:24][CH3:25])[C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[O:26][CH3:27])([O:40][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:50]
Reactant: COc1cc(C(=O)c2c(C)oc3c(O)c(OC)ccc23)cc(OC)c1OC
Reactant: [O-]P(OCc1ccccc1)OCc1ccccc1
Agent: BrC(Br)(Br)Br
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)c2c(C)oc3c(OP(=O)(OCc4ccccc4)OCc4ccccc4)c(OC)ccc23)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.4 %

Procedure:
To a mixture of 0.081 g (0.22 mmol) of (7-hydroxy-6-methoxy-2-methylbenzofuran-3-yl)(3,4,5-trimethoxyphenyl)methanone, 0.086 g (0.261 mmol) of carbon tetrabromide and 0.063 ml (0.283 mmol) of dibenzylphosphite in 2.5 ml of anhydrous acetonitrile 0.046 ml of anhydrous triethylamine was added dropwise at 0° C. under nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature, then diluted to 20 ml with ethyl acetate, washed with water brine, dried over anhydrous magnesium sulfate, filtered off and evaporated to dryness under reduced pressure. The residue was purified by flash column chromatography (dichloromethane/ ethyl acetate, 9:1) to give the title compound as a colorless foam (0.13 g, 94%); 1H NMR (CDCl3) δ 2.42 (s, 3H, Me-2); 3.83 (s, 1H, OMe); 3.93 (s, 3H, OMe); 5.33 (m, 4H, CH2Ph); 6.89 (d, CH aromatic, J=8.7 Hz); 7.21 (dd, 1H, CH aromatic, J=8.72 Hz; J=1.2 Hz); 7.08 (s, 2H, CH aromatic); 7.29-7.43 (m, 10H, CH aromatic).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:14])=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[CH3:13].C1C=C(O[C:22](OC2N=CC=CC=2)=[S:23])N=CC=1.CN(C1C=CC=CN=1)C>C(Cl)Cl>[N:1]([C:2]1[C:3]([CH3:14])=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[CH3:13])=[C:22]=[S:23]
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Reactant: Cc1cc(N)c(C)c2c(C)ccnc12
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: Cc1cc(N=C=S)c(C)c2c(C)ccnc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 6-amino-4,5,8-trimethylquinoline (0.37 g), di-2-pyridyl thionocarbonate (0.494 g) (DPT) (Aldrich), dimethylaminopyridine (0.052 g) and methylene chloride (4 mL) is stirred at room temperature for 2 hours. An additional 100 mg of DPT is added, and stirring is continued for one hour. Another 100 mg portion of DPT is added, and the reaction is stirred at room temperature for one more hour. The mixture is concentrated by evaporation and purified by chromatography through a short column consisting of layers of sand/flash silica gel/sand, using 20% ethyl acetate in hexane as the eluting solvent, providing 6-isothiocyanato-4,5,8-trimethylquinoline.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=3)=[N:10][NH:9][CH:8]([CH3:21])[CH2:7][C:6]=2[CH:22]=1.[CH3:23][N:24]=[C:25]=[O:26]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([C:12]3[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=3)=[N:10][N:9]([C:25](=[O:26])[NH:24][CH3:23])[CH:8]([CH3:21])[CH2:7][C:6]=2[CH:22]=1
Reactant: CN=C=O
Reactant: CC1Cc2cc(Cl)ccc2C(c2ccc([N+](=O)[O-])cc2)=NN1
Solvent: ClCCl
Product: CNC(=O)N1N=C(c2ccc([N+](=O)[O-])cc2)c2ccc(Cl)cc2CC1C
Reaction time: 240 h
Yield: 95.1 %

Procedure:
0.72 g (2.2 mmoles) of 7-chloro-4-methyl-1-(4-nitrophenyl)-4,5-dihydro-3H-2,3-benzodiazepine prepared in Example 1, Step D are dissolved in 15 ml of anhydrous dichloromethane, and to the solution obtained, 1.3 ml (22.0 moles) of methyl isocyanate are added, and the reaction mixture is left to stand at 25° C. for 10 days. The mixture is evaporated, and the residue is recrystallized from 3 ml of hot ethanol. The crystals are filtered, washed 3 times using 1 ml of ethanol each time, then dried. Thus, 0.78 g (95%) of the title compound are obtained. M.p.: 224°-226° C.
Reaction SMILES: C([S-])=S.[Na+].[C:5]([S-:8])(=[S:7])[CH3:6].[Na+].C(S[CH:13]([CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])=[CH:23][CH:22]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])=S>>[C:5]([S:8][CH:13]([CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])=[CH:23][CH:22]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])(=[S:7])[CH3:6]
Reactant: CC(=S)[S-]
Reactant: CCOC(=O)C(CCc1ccc(-c2ccccc2Cl)cc1)SC=S
Agent: S=C[S-]
Agent: [Na+]
Product: CCOC(=O)C(CCc1ccc(-c2ccccc2Cl)cc1)SC(C)=S

Procedure:
When sodium dithioformate is used in the above procedure in place of sodium dithioactate then the product prepared is ethyl α-thioformylthio-γ-(2'-chloro-4-biphenylyl)butyrate.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]=[C:34]=[O:35]>O1CCCC1>[CH3:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][C:34]([N:15]1[CH2:16][CH2:17][N:12]([C:10]2[S:9][N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:11]=2)[CH2:13][CH2:14]1)=[O:35]
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: COc1ccccc1N=C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccccc1NC(=O)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.2 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 2-methoxyphenyl isocyanate (0.162 ml, 1.22 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of hexane and ethyl acetate to give 219 mg (68.2%) of the desired product as a solid.
Reaction SMILES: [C:1]([C:4]1[CH:20]=[CH:19][C:7]([CH2:8][CH2:9][C:10]2[CH:11]=[C:12](Cl)[C:13]([C:16]#[N:17])=[N:14][CH:15]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:21][C:22]1[CH:23]=[CH:24][C:25](B2OC(C)(C)C(C)(C)O2)=[C:26]([NH:28]C(=O)OC(C)(C)C)[CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C(O)C.O>[NH2:17][C:16]1[C:13]2[N:14]=[CH:15][C:10]([CH2:9][CH2:8][C:7]3[CH:19]=[CH:20][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=3)=[CH:11][C:12]=2[C:25]2[CH:24]=[CH:23][C:22]([CH3:21])=[CH:27][C:26]=2[N:28]=1
Reactant: CC(=O)c1ccc(CCc2cnc(C#N)c(Cl)c2)cc1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(NC(=O)OC(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)c1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)cc1
Temperature: 25 °C

Procedure:
To a solution of 5-(4-acetylphenethyl)-3-chloropicolinonitrile (from the previous step) (1 eq) and tert-butyl 5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (1.0 eq.), tetrakis(triphenyl-phosphine)palladium (10 mol %), and 2N aqueous sodium carbonate solution (2.0 eq.) in toluene/ethanol (1:1, 0.09 M) was heated under microwave condition using a BIOTAGE INITIATOR 2.0 at 150° C. for 20 minutes. After cooling to ambient temperature, the reaction mixture was diluted with ethanol/water. The insoluble solids were filtered off, and the filtrate was concentrated en vaccuo to obtain a crude residue. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-80% ethyl acetate in hexane to give 1-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenyl)ethanone as a yellow solid. 1H NMR (Methanol-d4) TFA Salt: δ 8.69 (d, 2H), 8.30 (d, 1H), 7.80 (d, 2H), 7.38 (s, 1H), 7.36 (d, 1H), 7.28 (d, 2H), 3.25 (t, 2H), 3.13 (t, 2H), 2.47 (s, 3H), 2.45 (s, 3H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[Cl:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](Cl)=[O:31]>>[Cl:26][C:27]1[CH:28]=[C:29]([C:30]([N:20]2[CH2:21][CH2:22][CH:17]([N:15]3[C:14](=[O:23])[C:13]([CH3:25])([CH3:24])[C:12]([C:6]4[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=4)=[N:16]3)[CH2:18][CH2:19]2)=[O:31])[CH:33]=[CH:34][CH:35]=1
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cccc(Cl)c4)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and 3-chlorobenzoyl chloride as starting compounds. The crude product is purified by crystallization from EA to yield the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:16]1[CH2:21][CH2:20]O[CH2:18][CH2:17]1.[C:22](=O)(O)[O-].[Na+]>O1CCCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][CH2:12][C:13]([N:16]2[CH2:21][CH2:20][CH2:22][CH2:18][CH2:17]2)=[O:15])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C([O-])O
Reactant: C1COCCN1
Reactant: O=C(O)CCCc1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(CCCc1ccc([N+](=O)[O-])cc1)N1CCCCC1
Temperature: 35 °C

Procedure:
A room temperature solution of 1.1220 gms. 4-(4-nitro-phenyl)-butyric acid in tetrahydrofuran (3 mL) is treated with 0.8978 gms. 1′,1′-carbonyl-diimidizole using an ice bath to attenuate the intensity of the reaction. The reaction mixture is stirred for 30 minutes in the ice bath and 30 minutes at room temperature. The reaction mixture is then treated with 0.5 mL morpholine. The reaction was heated overnight at 35° C. The reaction is then allowed to cool to room temperature, and is made basic with the addition of saturated aqueous sodium bicarbonate. The resulting mixture is extracted with ethyl acetate. The organics are dried over anhydrous sodium sulfate, filtered and evaporated to dryness in vacuo. The crude product residue is then purified by filtering it through a plug of silica gel using 50% ethyl acetate in hexanes as the eluant. Following evaporation of solvent, 4-(4-nitro-phenyl)-1-piperidin-1-yl-butan-1-one is isolated as a yellow oil in the amount of 1.47 gms.
Reaction SMILES: [CH3:1][O:2][N:3]1[CH2:8][CH2:7][C:6]([S:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)([C:9](O)=[O:10])[CH2:5][CH2:4]1.S(Cl)([Cl:24])=O>C1(C)C=CC=CC=1.CN(C)C=O>[CH3:1][O:2][N:3]1[CH2:8][CH2:7][C:6]([S:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)([C:9]([Cl:24])=[O:10])[CH2:5][CH2:4]1
Reactant: COc1ccc(CSC2(C(=O)O)CCN(OC)CC2)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc(CSC2(C(=O)Cl)CCN(OC)CC2)cc1
Temperature: 100 °C

Procedure:
700 mg 1-Methoxy-4-(4-methoxy-benzylsulfanyl)-piperidine-4-carboxylic acid (from Step 5) was dissolved in 10 ml toluene, 1 drop N,N-dimethylformamide was added, followed by 400 mg thionyl chloride. The mixture was heated to 100° C. for 1 hour, at which time the evolution of gas has ceased. The solvent was evaporated, to yield crude 1-methoxy-4-(4-methoxy-benzylsulfanyl)-piperidine-4-carbonyl chloride.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH2:7]O)[S:5][CH:6]=1.S(Cl)([Cl:11])=O>C1(C)C=CC=CC=1>[ClH:11].[Cl:11][CH2:7][C:4]1[S:5][CH:6]=[C:2]([CH3:1])[N:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1csc(CO)n1
Solvent: Cc1ccccc1
Product: Cc1csc(CCl)n1
Product: Cl
Temperature: 65 °C
Reaction time: 1 h
Yield: 70.9 %

Procedure:
To a solution of (4-methylthiazol-2-yl)methanol (0.423 g, 3.27 mmol) in toluene (7 mL) was added thionyl chloride (0.478 mL, 6.55 mmol) dropwise. The mixture was heated to 65° C. and stirred for 1 hour. The mixture was concentrated under reduced pressure and the residue was triturated with ether. The solids were collected by filtration to afford 2-(chloromethyl)-4-methylthiazole hydrochloride (0.427 g, 71% yield) as pale yellow solids.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([F:18])=[CH:15][CH:16]=2)[C:11](Cl)=[C:10]([C:20]#[N:21])[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>ClCCl>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([F:18])=[CH:15][CH:16]=2)[C:11]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[C:10]([C:20]#[N:21])[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1c(Cl)c2cc(F)ccc2n(Cc2ccccc2)c1=O
Reactant: C1CNCCN1
Solvent: ClCCl
Product: N#Cc1c(N2CCNCC2)c2cc(F)ccc2n(Cc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.9 %

Procedure:
A solution of Compound 45 (1.0 g, 3.2 mmol) in dichloromethane was added slowly to a stirred solution of piperazin (826 mg g, 9.59 mmol) in dichloromethane at room temperature. The solution was stirred overnight at room temperature. The solvent was removed under reduced pressure. The residue was taken in water sonicated briefly and filtered. The solid was dissolved in ethyl acetate and washed by water. The organic layer was dried over Na2SO4 and concentrated to yield 1.1 g (96%) yellow solids. M.P. 162° C. 1H NMR (DMSO-d6): δ 2.70 (s, 1H), 2.94 (m, 4H), 3.53 (m, 4H), 5.47 (s, 2H), 7.19-7.25 (m, 3H), 7.42 (m, 2H), 7.51 (dd, J=4.3, 9.3 Hz, 1H), 7.54 (td, J=2.4, 8.0 Hz, 1H), 7.58 (dd, J=2.9, 8.9 Hz, 1H). EIMS m/z 363 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[C:11](F)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[C:11]([S:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(OCc2ccccc2)cc1F
Reactant: Oc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)cc1Sc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
The product of Example 237A (0.301 g, 1.22 mmol), 4-mercaptophenol (0.184 g, 1.46 mmol, 1.2 eq) and cesium carbonate (0.952 g, 2.92 mmol, 2.4 eq) in dimethylformamide (10 mL) was heated in a 100° C. oil bath for 3 hours and then cooled to room temperature. Water (20 mL) was added and the mixture was stirred at room temperature for 2 hours, and the resulting solid was isolated by vacuum filtration and dried to provide the title compound (0.405 g, 94%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[C:12]([CH3:14])[C:11]([CH:15]=[O:16])=[N:10]2)=[CH:5][CH:4]=1.[CH:17]1([Mg]Br)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>O1CCCC1>[CH:17]1([CH:15]([C:11]2[C:12]([CH3:14])=[CH:13][N:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[N:10]=2)[OH:16])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Br[Mg]C1CCCCC1
Reactant: COc1ccc(-n2cc(C)c(C=O)n2)cc1
Solvent: C1CCOC1
Product: COc1ccc(-n2cc(C)c(C(O)C3CCCCC3)n2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 53 %

Procedure:
To a solution (10 mL) of 1-(4-methoxyphenyl)-4-methyl-1H-pyrazole-3-carbaldehyde (0.96 g) synthesized in the above-mentioned (2) in tetrahydrofuran was added dropwise under ice-cooling cyclohexylmagnesium bromide (6.0 mL, 1M tetrahydrofuran solution). After the completion of the dropwise addition, the ice bath was removed, and the mixture was stirred at room temperature for 15 min. To the reaction mixture was added aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2, volume ratio) to give the title object compound (0.70 g, 53%) as a pale-yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12]N(C2C=CC(Br)=CC=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:21][CH:22]1CCNCC1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:22]([OH:21])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Br)cc2)CC1
Reactant: OC1CCNCC1
Product: CC(C)(C)OC(=O)N1CCC(O)CC1

Procedure:
Prepared according to the method for the preparation of 4-(4-bromophenyl)-piperazine-1-carboxylic acid tert-butyl ester, from 4-hydroxypiperidine (18.4 g), to give the title compound as a light orange oil that crystalised from hexane (25.6 g, 71%).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].[CH2:10]1[O:12][CH:11]1[CH2:13][CH2:14][CH:15]1[O:17][CH2:16]1>O>[C:2]1([CH2:1][O:8][CH2:16][CH:15]2[O:17][CH:11]([CH2:10][OH:12])[CH2:13][CH2:14]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C(CC1CO1)C1CO1
Reactant: OCc1ccccc1
Agent: [Na]
Solvent: O
Product: OCC1CCC(COCc2ccccc2)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.6 %

Procedure:
100 ml of benzyl alcohol (0.97 mol) is cooled to 5° in an ice-bath and under a nitrogen atmosphere. 0.32 g of sodium (0.0139 mole; washed with hexane to remove the mineral oil) is slowly added to the rapidly stirred benzyl alcohol. The addition of the sodium is made at such a rate that the temperature remains below 20°. After the addition of the sodium has been completed the mixture is allowed to stir for 1/2 hour and slowly warmed to room temperature. Slowly, and with stirring 20 g of 1,5-hexadiene diepoxide (0.175 mole) is added to the mixture. After the addition of the diepoxide has been completed, the reaction mixture is heated at 150° for 16 hours. The mixture is then cooled to room temperature and with stirring is poured into 350 ml of water. The aqueous mixture is extracted with 2×250 ml portions of chloroform, the CHCl3 extracts are combined and dried over anhydrous sodium sulfate. The CHCl3 is removed in vacuo and the colorless oil vacuum distilled through a 10 cm vigreux distilling column. The fraction distilling at 151°-155° @0.5 mm is collected yielding 18.52 g (48%) of the above compound.