Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([OH:15])=O.[NH2:20][C:21]1[S:22][CH:23]=[CH:24][N:25]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CN(C=O)C>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([NH:20][C:21]1[S:22][CH:23]=[CH:24][N:25]=1)=[O:15]
Reactant: CC(C)CC(C(=O)O)N1C(=O)c2ccccc2C1=O
Reactant: Nc1nccs1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)CC(C(=O)Nc1nccs1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Referring to Scheme 3, a mixture of 2-(1,3-dioxoisoindolin-2-yl)-4-methylpentanoic acid (78 mg, 0.3 mmol), 2-aminothiazole (30 mg, 0.3 mmol), HBTU (114 mg, 0.3 mmol) and 0.1 mL of Et3N in DMF (2 mL) was stirred at room temperature for 2 hours to provide the title compound, which was then purified by HPLC. 1H NMR (400 MHz, MeOH-d4) δ: 7.83-7.86 (m, 2H), 7.89-7.92 (m, 2H), 7.41 (d, J=3.2 Hz, 1H), 7.12 (d, J=3.2 Hz, 1H), 5.15 (dd, J=4.8, 11.6 Hz, 2H), 2.35-2.45 (m, 1H), 1.96-2.05 (m, 1H), 1.51 (m, 1H), 0.99 (d, J=6.4 Hz, 3H), 0.95 (d, J=6.4 Hz, 3H). [M+H] calc'd for C17H17N3O3S, 344; found, 344.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14](O)=[O:15])=[CH:11][CH:12]=2)[CH:7]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2].[NH2:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44]>>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([NH:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[O:15])=[CH:11][CH:12]=2)[C@H:7]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)=[CH:20][CH:19]=2)[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CCOCCOCCOCCN
Reactant: CC(=O)N1c2ccc(C(=O)O)cc2C(Nc2ccc(N3CCOCC3)cc2)C[C@@H]1C
Product: CC(=O)N1c2ccc(C(=O)NCCOCCOCCOCCC(=O)OC(C)(C)C)cc2[C@H](Nc2ccc(N3CCOCC3)cc2)C[C@@H]1C
Yield: 69.7 %

Procedure:
Reactions and treatments were carried out in the same manner as in Example 110, using 29 mg of (2S)-1-acetyl-2-methyl-4-[(4-morpholinophenyl)amino]-1,2,3, 4-tetrahydroquinoline-6-carboxylic acid and 40 mg of tert-butyl 12-amino-4,7,10-trioxadodecanoate. Thus, 33 mg (69%) of the title compound was obtained as a colorless oily substance.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].Cl[C:39]([O:41][CH2:42][CH2:43][CH2:44][CH3:45])=[O:40]>ClCCl.CO>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:39]([O:41][CH2:42][CH2:43][CH2:44][CH3:45])=[O:40])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: COC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Reactant: CCCCOC(=O)Cl
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CCCCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OC)c4ccccn4)ccc3n2C)cc1
Yield: 30 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide-hydrochloride and n-butyl chloroformate. Yield: 30% of theory, C31H35N7O5 (585.7) Rf value: 0.62 (silica gel; dichloromethane/methanol=9:1) ##EQU75##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.Cl.[CH3:13]O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: CO
Agent: Cl
Product: COC(=O)Cc1ccc(Cl)cc1

Procedure:
4-Chlorophenylacetic acid (5.0 g) was dissolved in 10% hydrogen chloride-methanol solution (50 ml) and heated under reflex for 14 hours. The solvent then was removed under reduced pressure and saturated sodium hydrogencarbonate solution was added to the residue, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and condensed under reduced pressure to provide methyl 2-(4-chlorophenyl)acetate (5.35 g) as a colorless, oily substance.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C@@H:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[N+:27]([C:30]1[CH:68]=[CH:67][C:33]([CH2:34][O:35][C:36]([NH:38][S:39]([NH:42][CH2:43][CH2:44][S:45][C:46]2[N:47]=[CH:48][N:49]3[CH:53]=[C:52]([Sn](CCCC)(CCCC)CCCC)[S:51][C:50]=23)(=[O:41])=[O:40])=[O:37])=[CH:32][CH:31]=1)([O-:29])=[O:28]>>[OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])=[C:8]([C:52]3[S:51][C:50]4=[C:46]([S:45][CH2:44][CH2:43][NH:42][S:39]([NH:38][C:36]([O:35][CH2:34][C:33]5[CH:67]=[CH:68][C:30]([N+:27]([O-:29])=[O:28])=[CH:31][CH:32]=5)=[O:37])(=[O:40])=[O:41])[N:47]=[CH:48][N:49]4[CH:53]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(SCCNS(=O)(=O)NC(=O)OCc3ccc([N+](=O)[O-])cc3)c2s1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(SCCNS(=O)(=O)NC(=O)OCc5ccc([N+](=O)[O-])cc5)c4s3)[C@H](C)[C@H]12
Yield: 26.6 %

Procedure:
The procedure of Example 1a) was repeated, except that 54 mg of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 116 mg of 7-[2-(4-nitrobenzyloxycarbonyl)aminosulfonylaminoethyl]thio-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds. Thus, 31.8 mg of 4-nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-[2-(4-nitrobenzyloxycarbonyl)aminosulfonylaminoethyl]thioimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate was prepared.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=O)[C:11]3[CH2:14][CH2:15][CH2:16][C:10]=3[NH:9]2)=[C:4]([F:17])[CH:3]=1.P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:12]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[F:17])[N:9]=[C:10]2[CH2:16][CH2:15][CH2:14][C:11]=12
Reactant: O=c1c2c([nH]n1-c1ccc(Cl)cc1F)CCC2
Reactant: O=P(Cl)(Cl)Cl
Product: Fc1cc(Cl)ccc1-n1nc2c(c1Cl)CCC2

Procedure:
By reacting 2-(4-chloro-2-fluorophenyl)-1,4,5,6-tetrahydrocyclopentapyrazol-3(2H)-one with phosphorous oxychloride according to the procedure of Example 1(d), 3-chloro-2-(4-chloro-2-fluorophenyl)-2,4,5,6-tetrahydrocyclopentapyrazole (m.p. 102°-104°) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][C:10](=O)[CH2:9][CH2:8]2.[N+:14]([CH3:17])([O-:16])=[O:15]>C(N)CN>[CH3:1][O:2][C:3]1[C:12]2[CH:11]=[C:10]([CH2:17][N+:14]([O-:16])=[O:15])[CH2:9][CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c1CC(=O)CC2
Reactant: C[N+](=O)[O-]
Solvent: NCCN
Product: COc1cccc2c1C=C(C[N+](=O)[O-])CC2
Temperature: 25 °C

Procedure:
44.1 g of 8-methoxy-2-tetralone (0.25 mol) are stirred at 70° C. under argon for 3 h in 402 ml of nitromethane (7.50 mol) and 2.5 ml of ethylenediamine. After the mixture has cooled to room temperature, a yellow crystallisate is filtered off with suction. The nitromethane is distilled off from the solution in vacuo. The residue is dissolved in 500 ml of toluene. The solvent is again distilled off in vacuo in order to remove nitromethane residues. The residue is then dissolved in 200 ml of toluene again. An insoluble component is filtered off and the solution is concentrated to 50 ml. The concentrated solution is then chromatographed on 500 g of silica gel using toluene. After concentrating the main fraction, the final product is obtained as a yellow oil.
Reaction SMILES: [N+:1]([CH3:4])([O-:3])=[O:2].N12CCCN=C1CCCCC2.[C:16]([O:23][CH3:24])(=[O:22])/[CH:17]=[CH:18]/[CH2:19][CH2:20][CH3:21].Cl>C(#N)C>[N+:1]([CH2:4][CH:18]([CH2:19][CH2:20][CH3:21])[CH2:17][C:16]([O:23][CH3:24])=[O:22])([O-:3])=[O:2]
Reactant: CCC/C=C/C(=O)OC
Reactant: C[N+](=O)[O-]
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCCC(CC(=O)OC)C[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 14 h
Yield: 53.4 %

Procedure:
Nitromethane (2.54 ml, 46 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (5.4 ml, 36 mmol) were added to a solution of methyl (E)-2-hexenoate (4.62 g, 36 mmol) in acetonitrile (20 ml) and the reaction mixture was stirred at room temperature for 14 hours. The reaction mixture was acidified by addition of a 1N HCl aqueous solution and then extracted with ethyl acetate. After washing the organic layer with brine and drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (3.64 g) as a light yellow oil. 1H-NMR (CDCl3) δ(ppm) 0.92 (3H, t, J=0.8 Hz), 1.29-1.48 (4H, m), 2.45 (2H, d, J=6.4 Hz), 2.57-2.68 (1H, m), 3.69 (3H, s), 4.43 (1H, dd, J=14.0 Hz, 6.0 Hz), 4.50 (1H, dd, J=14.0, 6.8 Hz)
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[CH:20]([CH2:22][CH2:23][CH2:24][C:25]1[N:26]=[CH:27][N:28]([Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:29]=1)=[O:21].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[C:1]([NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH:20]([OH:21])[CH2:22][CH2:23][CH2:24][C:25]2[N:26]=[CH:27][N:28]([Si:30]([CH3:31])([CH3:32])[CH3:33])[CH:29]=2)=[CH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)n1cnc(CCCC=O)c1
Reactant: CC(C)(C)NC(=O)c1ccc(Br)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)NC(=O)c1ccc(C(O)CCCc2cn([Si](C)(C)C)cn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 6.95 g of p-(tert-butylaminocarbonyl)-bromobenzene is dissolved in 175 ml of tetrahydrofuran at -70° under nitrogen and 20.1 ml of a solution of n-butyllithium (2.7M) in hexane is added dropwise. After reacting 30 min, a solution of 5.69 g of 4-(3-formyl-n-propyl)-1-trimethylsilylimidazole in 10 ml of tetrahydrofuran is added slowly. The reaction mixture is allowed to warm slowly to room temperature and 20 ml of ammonium chloride is added. The organic layer is separated, dried over sodium sulfate and evaporated to yield the title compound (b).
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[Br:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15]>C(Cl)Cl.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[Br:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][O:1]1
Reactant: C1=COCCC1
Reactant: OCCCCCCCBr
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: BrCCCCCCCOC1CCCCO1
Reaction time: 8 h
Yield: 114.3 %

Procedure:
Dihydropyran (1 mL, 11.0 mmol) and pyridinium p-toluenesulfonate (148 mg, 0.59 mmol) were added to a solution of 7-Bromo-1-heptanol (1.1 g, 5.64 mmol) in CH2Cl2 (22 mL). After stirring overnight, the solution was washed with 1 M HCl (20 mL), saturated NaHCO3 solution (20 mL) and brine (20 mL). The solution was dried (Na2SO4), filtered and evaporated. The residue was purified by flash chromatography on silica gel (0%→50% ethyl acetate/hexanes) to give the title compound (1.8 g, >100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[NH:5][CH:6]=1.[H-].[Na+].[Br:13][CH2:14][CH2:15]Br>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[N:5]([CH2:15][CH2:14][Br:13])[CH:6]=1
Reactant: BrCCBr
Reactant: COC(=O)c1cc(Br)c[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)cn1CCBr
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 46 %

Procedure:
To a solution of methyl 4-bromo-1H-pyrrole-2-carboxylate (Combi-Blocks, San Diego, Calif.; 5.15 g, 25.2 mmol) in DMF (25 mL) at 0° C. was added NaH (60% wt. in mineral oil, 1.81 g, 45.4 mmol) and the resulting mixture was stirred at 0° C. for 15 min. 1,2dibromoethane (4.79 ml, 55.5 mmol) was added and the reaction was stirred at RT for 10 min, then heated in an oil bath at 70° C. for 2 h. After cooling to RT, it was treated with ice cold NH4Cl solution (10 mL), extracted with 2×75 mL of EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. Purification on a silica gel column (15-35% EtOAc in hexanes) furnished methyl 4-bromo-1-(2-bromoethyl)-1H-pyrrole-2-carboxylate (3.60 g, 11.58 mmol, 46% yield) as an off-white amorphous solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.41 (1H, d, J=2.0 Hz), 6.92 (1H, d, J=1.8 Hz), 4.65 (2H, t, J=6.5 Hz), 3.75 (5H, m). m/z (ESI, +ve) 311.9 (M+H)+.
Reaction SMILES: C([N:3](CC)CC)C.[Al+3].[Cl-].[Cl-].[Cl-].[C:12]1([C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][O:14]1)=[O:13].CCOC(C)=O>ClCCCl>[OH:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=1[C:12]([NH2:3])=[O:13]
Reactant: O=C1OCc2ccccc21
Reactant: CCN(CC)CC
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: NC(=O)c1ccccc1CO
Temperature: 17.5 °C
Yield: 97.5 %

Procedure:
A solution of triethylamine (TEA, 0.824 g, 1.13 ml, 8.14 mmol, 1.5 equiv.) in 1,2-dichloroethane (3 ml) was added dropwise under stirring and cooling with ice to a suspension of AlCl3 (0.796 g, 5.97 mmol, 1.1 equiv.) in 1,2-dichloroethane (7 ml). The temperature was maintained at 15-20° C. during the addition and the mixture was then allowed to warm up at room temperature. A solution of 1-dimethoxytrityl-6-amino-hexan-1-ol (16) (2.505 g, 5.97 mmol, 1.1 equiv., prepared as described by Woo and Fung (1996), International Pat. App. Pub. No. WO 96/05215, which is incorporated herein by reference in its entirety) and phthalide (17) (0.728 g, 5.43 mmol, 1.0 equiv.) in 1,2-dichloroethane (3 ml) was added over a period of 20 min and the mixture was stirred at room temperature overnight. The completion of the reaction was confirmed by TLC analysis (EtOAc containing 1% TEA). The reaction mixture was then quenched with an ice-water mixture (30 ml) and stirred for further 30 min. The resulting suspension was filtered through a bed of Celite® and the filter cake was washed with 1,2-dichloroethane (10 ml). The organic phase of the combined filtrates was separated, washed with water (30 ml) and brine (20 ml), dried over MgSO4 and concentrated. The crude product was purified by flash chromatography (15-70% EtOAc in hexanes containing 1% of TEA, gradient elution) yielding 0.80 g (27%) of compound (19) as a pale yellow oil. Rf=0.68 (EtOAc containing 1% TEA). 1H NMR (400 MHz, CD3CN) δ 7.61-7.19 (m, 14H), 6.85 (d, J=8.9 Hz, 4H), 5.33 (s, 1H), 4.50 (s, 2H), 3.75 (s, 6H), 3.32 (q, J=6.6 Hz, 2H), 3.01 (t, J=6.6 Hz, 2H), 1.63-1.53 (m, 4H), 1.44-1.28 (m, 4H).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]3[S:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)=[CH:21][CH:22]=3)(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:29][CH2:30][CH:31]([C:33]1[CH:34]=[CH:35][C:36]([OH:44])=[C:37]([NH:39][S:40]([CH3:43])(=[O:42])=[O:41])[CH:38]=1)[OH:32]>>[OH:32][CH:31]([C:33]1[CH:34]=[CH:35][C:36]([OH:44])=[C:37]([NH:39][S:40]([CH3:43])(=[O:42])=[O:41])[CH:38]=1)[CH2:30][NH:29][CH:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][S:15]([C:18]3[S:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)=[CH:21][CH:22]=3)(=[O:17])=[O:16])=[CH:12][CH:13]=2)[CH2:6][CH2:7]1
Reactant: O=C1CCN(c2ccc(NS(=O)(=O)c3ccc(-c4ccccn4)s3)cc2)CC1
Reactant: CS(=O)(=O)Nc1cc(C(O)CN)ccc1O
Product: CS(=O)(=O)Nc1cc(C(O)CNC2CCN(c3ccc(NS(=O)(=O)c4ccc(-c5ccccn5)s4)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from 5-pyridin-2-yl-thiophene-2-sulfonic acid [4-(4-oxo-piperidine-1-yl)-phenyl]-amide (which was obtained in Example 227) and N-[5-(2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 9) according to the procedure of Example 278 as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.40 (m, 2H), 1.80-1.90 (m, 2H), 2.45-2.75 (m, 5H), 2.91 (s, 3H), 3.40-3.60 (m, 2H), 4.47 (dd, J=8.0, 4.1 Hz, 1H), 6.80 (d, J=8.3 Hz, 1H), 6.82 (d, J=8.0 Hz, 2H), 6.95 (d, J=8.0 Hz, 2H), 7.00 (dd, J=8.3, 2.0 Hz, 1H), 7.17 (d, J=2.0 Hz, 1H), 7.37 (dd, J=4.8, 1.7 Hz, 1H), 7.40 (d, J=3.9 Hz, 1H), 7.75 (d, J=3.9 Hz, 1H), 7.88 (dd, J=8.0, 1.7 Hz, 1H), 7.98 (d, J=8.0 Hz, 1H), 8.54 (brd, J=4.8 Hz, 1H); MS (ES) m/z: 644.1 (MH+); HRMS Calcd. for C29H34N5O6S3 (MH+): 644.1671. Found: 644.1663.
Reaction SMILES: Cl[CH:2]([C:13]#[N:14])[CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1>[Zn].C(O)(=O)C>[C:13]([CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)#[N:14]
Reactant: N#CC(Cl)Cc1ccc(C(=O)O)cc1
Agent: [Zn]
Solvent: CC(=O)O
Product: N#CCCc1ccc(C(=O)O)cc1

Procedure:
100 parts of zinc powder are gradually added to a solution of 209.5 parts of 4-(2-chloro-2-cyanoethyl) benzoic acid in 500 parts of glacial acetic acid. The temperature rises quickly up to reflux and is maintained for approximately 1 hour. The solution is filtered when hot so a to eliminate the insoluble matter, then the filtrate is diluted with 1000 parts of water and the precipitate formed is isolated. Thus 122 parts of 4-(2-cyanoethyl) benzoic acid are obtained. M.P.: 182° C.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:14][CH2:15][CH2:16][C:17]#[N:18].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(O)CCC.O1CCOCC1>[C:1]1([CH:7]2[CH2:8][CH2:9][N:10]([CH2:14][CH2:15][CH2:16][C:17]#[N:18])[CH2:11][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: N#CCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCCCO
Product: N#CCCCN1CCC(c2ccccc2)CC1
Temperature: 25 °C
Yield: 53.7 %

Procedure:
A suspension of 4-phenylpiperidine (5.20 g, 32.2 mmol, 1.00 equiv), 4-bromobutyronitrile (4.81 mL, 48.4 mmol, 1.50 equiv), potassium carbonate (11.14 g, 80.6 mmol, 2.50 equiv), and potassium iodide (266 mg, 12.9 mmol, 0.4 equiv) in n-butanol (60 mL) and 1,4-dioxane (60 mL) was stirred at reflux under argon for 48 hours. The mixture was cooled to room temperature and concentrated. The residue was purified by flash chromatography (SiO2, MeOH-EtOAc 1:19) to afford 3.95 g of 4-(4-phenylpiperidin-1-yl)butyronitrile (white solid, 53%), which was characterized spectroscopically.
Reaction SMILES: BrC([C:4]1[C:9]2=[N:10][O:11][N:12]=[C:8]2[CH:7]=[CH:6][CH:5]=1)Br.C[CH2:14][OH:15]>O.[N+]([O-])([O-])=O.[Ag+]>[CH:14]([C:6]1[CH:5]=[CH:4][C:9]2[C:8]([CH:7]=1)=[N:12][O:11][N:10]=2)=[O:15]
Reactant: CCO
Reactant: BrC(Br)c1cccc2nonc12
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Product: O=Cc1ccc2nonc2c1
Reaction time: 2 h
Yield: 78 %

Procedure:
AgNO3 (163 g) in 2 L of water was added to a refluxing mixture of dibromomethylbenzofurazan (122 g, 418 mmol) in EtOH (1 L). Heating at reflux temperature was continued for 2 h. The mixture was cooled, the precipitated AgBr was removed by filtration through Celite, and the solvent was concentrated. The resulting solution was extracted with toluene (10×100 mL), dried over magnesium sulfate, and the solvent was removed in vacuo. The residue was chromatograghed (EtOAc/hexane, 1/125), giving the title aldehyde (48.2 g, 78%) as a white solid: 1H NMR δ 7.92 (m, 2H), 8.39 (s, 1 H), 10.10 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([C:21]#[C:22][CH2:23][OH:24])=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]#[C:22][CH2:23][OH:24])[CH:17]=3)[N:12]([CH2:35][CH2:36][N:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)[CH:11]=2)=[O:9])=[CH:25][CH:26]=1
Reactant: ClCCN1CCCCC1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(C#CCO)cc2c1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCc1ccc(Cl)cc1)c1cn(CCN2CCCCC2)c2ccc(C#CCO)cc2c1=O
Temperature: 90 °C
Reaction time: 48 h

Procedure:
A solution of N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinecarboxamide from Preparation No. 5 (0.367 g) is dissolved in DMF (10 mL), and K2CO3 (0.55 g, 4.0 mmol) and 1-(2-chloroethyl)piperidine hydrochloride (0.375 g, 2.0 mmol) are added. The reaction mixture is heated to 90° C. for 3 h, and then allowed to stir at room temperature for 48 h. Water is added and a precipitate formed. The precipitate is filtered and allowed to dry at room temperature and then under reduced pressure to give 0.171 g of a solid. The solid is dissolved in CHCl3 and filtered. The filtrate is concentrated in vacuo and crystallized from ethyl acetate to give 0.066 g of the title compound as a solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[OH-:14].[K+].O.Cl>CS(C)=O>[OH:14][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1cc(O)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-Chloro-2-nitrobenzoic acid (100 g) in 800 ml dimethylsulfoxide was treated with 112 g powdered KOH with cooling, 170 ml anhydrous alcohol added and the mixture stirred 2 hours at 25° and then left overnight. The mixture was kept at 28° for about 8 hours, then overnight at 0°, warmed to room temperature and 3.5 liters of water added. The mixture was acidified with HCl, 1 kg NcCl added and extracted with ethyl acetate. The extract was washed with water, dried, 50 g KHCO3 in 500 ml water added, diluted to 2 liters, and the ethyl acetate blown off with a stream of nitrogen. The solution was acidified and filtered to give 56 g product, m.128-30°.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:17](Cl)=[O:18].[NH2:20][C:21]1[CH:22]=[C:23]([C:28]#[N:29])[C:24]([Cl:27])=[N:25][CH:26]=1.O>N1C=CC=CC=1>[Cl:27][C:24]1[N:25]=[CH:26][C:21]([NH:20][C:17]([C:3]2[CH:4]=[N:5][N:6]([C:7]3[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][N:8]=3)[C:2]=2[CH3:1])=[O:18])=[CH:22][C:23]=1[C:28]#[N:29]
Reactant: Cc1c(C(=O)Cl)cnn1-c1ccc(C(F)(F)F)cn1
Reactant: N#Cc1cc(N)cnc1Cl
Solvent: c1ccncc1
Solvent: O
Product: Cc1c(C(=O)Nc2cnc(Cl)c(C#N)c2)cnn1-c1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Yield: 195.8 %

Procedure:
5-Methyl-1-(5-(trifluoro methyl)pyridin-2-yl)-1H-pyrazole-4-carboxylic acid chloride (200 mg) and 5-amino-2-chloro-3-cyanopyridine (228 mg) were dissolved in pyridine (10 ml) and stirred at room temperature. After completion of the reaction, water was added to the reaction solution, the precipitated solid was collected by filtration and dried under heating and blow to give N-(6-chloro-5-cyanopyridin-3-yl)-5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (550 mg) as a light brown solid.