Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:19]([N:21]=[N+]=[N-])=[O:20])[CH2:13][C:14]1[N:18]=[CH:17][NH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(N[C@H](C(NN)=O)CC1N=CNC=1)=O)C1C=CC=CC=1.[C:46]1([NH:52][C:53]([C@@H:55]2[CH2:59][CH2:58][CH2:57]N2)=[O:54])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:19]([N:21]1[CH2:57][CH2:58][CH2:59][C@H:55]1[C:53]([NH:52][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:54])=[O:20])[CH2:13][C:14]1[N:18]=[CH:17][NH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccccc1)[C@@H]1CCCN1
Reactant: [N-]=[N+]=NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)OCc1ccccc1
Agent: NNC(=O)[C@H](Cc1c[nH]cn1)NC(=O)OCc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(N[C@@H](Cc1c[nH]cn1)C(=O)N1CCC[C@H]1C(=O)Nc1ccccc1)OCc1ccccc1

Procedure:
To 45 ml of an ethyl acetate solution of Nα -benzyloxycarbonyl-L-histidine azide (4) prepared from 3.03 g of Nα -benzyloxycarbonyl-L-histidine hydrazide (3) by a known method was added 1.52 g of compound (94) under ice-cooling and the reaction was maintained overnight in a refrigerator. The reaction mixture was concentrated and the residue thus formed was subjected to silica gel column chromatography. By eluting the product with chloroform-methanol (95:5), 2.49 g of Nα -benzyloxycarbonyl-L-histidyl-N-phenyl-L-prolinamide (95) was obtained.
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH2:16][CH3:17])[N:5]=[C:4]([C:18]([NH2:20])=O)[CH:3]=1.C(O)(=O)C>P(Cl)(Cl)(Cl)=O>[C:18]([C:4]1[CH:3]=[C:2]([OH:1])[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH2:16][CH3:17])[N:5]=1)#[N:20]
Reactant: CCCOc1ccccc1-c1nc(O)cc(C(N)=O)n1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC(=O)O
Product: CCCOc1ccccc1-c1nc(O)cc(C#N)n1

Procedure:
A stirred solution of 6-hydroxy-2-(2-propoxyphenyl)pyrimidine-4-carboxamide (0.50 g) in phosphoryl chloride (16 ml) was heated under reflux for 4 hours and then the reaction mixture was evaporated under reduced pressure to remove excess phosphoryl chloride. Water was added to the residue, which was extracted with chloroform (3×20 ml). The combined extracts were washed with water, dried (magnesium sulfate) and evaporated under reduced pressure to yield an oil which was heated on a steam bath with glacial acetic acid (15 ml) for 4 hours. The cooled reaction mixture was evaporated under reduced pressure to yield a crude product which was combined with further product similarly prepared from 6-hydroxy-2-(2-propoxyphenyl)-pyrimidine-4-carboxamide (0.82 g) and phosphoryl chloride (25 ml). The combined products were eluted from silica with ether:chloroform (9:1) and fractions containing product were combined and evaporated under reduced pressure to yield the title compound, 0.31 g, m.p. 135°-6° C. (from isopropanol/ether).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12]Br.[C-:14]#[N:15].[K+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(Cl)Cl.O>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][C:14]#[N:15]
Reactant: [C-]#N
Reactant: BrCc1ccc2ccccc2c1Br
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: N#CCc1ccc2ccccc2c1Br
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 99 parts of 1-bromo-2-(bromomethyl)naphthalene, 103 parts of potassium cyanide and 1 part of benzyl triethylammonium chloride in 150 parts by volume of methylene chloride and 30 parts by volume of water is stirred at room temperature for about 72 hours. The mixture is then diluted with additional quantities of methylene chloride and water, the organic layer separated, dried over calcium sulfate, and concentrated to give α-(1-bromo-2-naphthyl)acetonitrile, as a solid.
Reaction SMILES: [CH3:1]CN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.[CH:19]1([CH2:25][N:26]2[C:30]([CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][N:36]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=4[O:45][CH3:46])[CH2:35][CH2:34]3)=[N:29][NH:28][C:27]2=[O:47])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.CI>CC#N.C(Cl)Cl>[CH:19]1([CH2:25][N:26]2[C:30]([CH2:31][CH2:32][N:33]3[CH2:34][CH2:35][N:36]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=4[O:45][CH3:46])[CH2:37][CH2:38]3)=[N:29][N:28]([CH3:1])[C:27]2=[O:47])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: COc1ccccc1N1CCN(CCc2n[nH]c(=O)n2CC2CCCCC2)CC1
Reactant: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: ClCCl
Solvent: CI
Solvent: CC#N
Product: COc1ccccc1N1CCN(CCc2nn(C)c(=O)n2CC2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 82.3 %

Procedure:
To a slurry of PS-BEMP (0.95 g, 2.08 mmol, 2.2 mmol/g) and 4-(cyclohexylmethyl)-5-{2-[4-(2-methoxyphenyl)piperazino]ethyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (E17; 415 mg, 1.028 mmol) in MeCN (20 mL), methyl iodide (0.13 mL, 2.08 mmol) was added and the reaction mixture was stirred at room temperature for 2 days. The resin was filtered, washed with MeOH (25 mL) and the solvent was evaporated in vacuo to afford 560 mg crude yellow glassy solid. This was dissolved in DCM (3 mL) and purified by flash chromatography (Flash Master, Biotage Isolute SI, 20 g column, gradient 0-10% MeOH in DCM over 30 min) to afford 350 mg of a light yellow oil. Further purification by preparative LC-MS afforded 190 mg (44%) of the title compound as a glassy solid.
Reaction SMILES: [CH:1]([C:3]1[C:4](=[O:18])[NH:5][C:6](=[O:17])[N:7]([CH:16]=1)[C@@H]1O[C@H](CO)[C@@H](O)C1)=[O:2]>COS(C)(=O)=O.[O-2].[O-2].[Mn+4]>[CH:1]([C:3]1[C:4](=[O:18])[NH:5][C:6](=[O:17])[NH:7][CH:16]=1)=[O:2]
Reactant: O=Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: [Mn+4]
Agent: COS(C)(=O)=O
Agent: [O-2]
Product: O=Cc1c[nH]c(=O)[nH]c1=O

Procedure:
5-formyl-2′-deoxyuridine prepared according to Mertes and Shipchandler, J. Heterocyclic Chem. 1, 751 (1970). 5-hydroxymethyluricil (1 mmol) dissolved in 20 ml dimethylsulfonate was heated at 100° C. with manganese dioxide (2.5 mmol) for 15 minutes. The solvent was evaporated at reduced pressure. The residue was taken up in hot ethanol and recrystallized from ethanol to yield 5-formyluracil, 5-formyluracil (0.10 g) was silylated and dissolved in dry acetonitrile (2.5 ml). 2-deoxy-3,5-di-O-p-toluoyl-D-ribofuranosyl chloride (Bhat, Syn. Proc. in Nucleic Acid Chem., Vol. I, p. 521 (1968) (0.22 g) and molecular sieves (0.2 g) were added, and the mixture stirred at 25° C. for 40 hours under anhydrous conditions. The mixture was filtered and evaporated. The resulting oil was treated with anhydrous ethanol (2 ml) and chromatographed on silica gel to obtain the partially pure anomer which was recrystallized from ethanol (M.P. 195-196° C.) The toluoyl groups were removed by reaction of the product in methanol benzene, with sodium methoxide. The mixture was neutralized with Dowex 50 (H+). 5-formyl-2′-deoxyuridine was recrystallized from ethanol M.P. 175-176° C.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:34])=[C:23]([CH3:35])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[NH2:38][CH2:39][C:40]1[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=1.CS(C)=O.C(N(CC)CC)C>C(#N)C>[N:42]1[CH:43]=[CH:44][CH:45]=[C:40]([CH2:39][NH:38][C:3]([C:5]2[N:14]3[C:8]([CH2:9][N:10]([C:19]([C:21]4[CH:26]=[CH:25][C:24]([C:27]5[C:28]([CH3:34])=[CH:29][CH:30]=[CH:31][C:32]=5[CH3:33])=[C:23]([CH3:35])[CH:22]=4)=[O:20])[C:11]4[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=4[CH2:13]3)=[CH:7][CH:6]=2)=[O:4])[CH:41]=1
Reactant: Cc1cc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)ccc1-c1c(C)cccc1C
Reactant: NCc1cccnc1
Solvent: CC#N
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)ccc1-c1c(C)cccc1C
Temperature: 80 °C
Yield: 50.9 %

Procedure:
A suspension of 2,2,2-trichloro-1-{10-[(2,2′,6′-trimethyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Step D (0.610 g, 1.1 mmol) and 3-(aminomethyl)pyridine (0.119 g, 1.0 mmol) in acetonitrile (15 mL), was treated with dimethylsulfoxide (0.432 g, 5.5 mmol) and triethylamine (0.246 g, 2.4 mmol). The mixture was heated under nitrogen at 80° C. overnight, and then concentrated. The residue was taken up in dichloromethane (25 mL), washed with brine and water, dried over anhydrous magnesium sulfate and concentrated. Flash chromatography of the residue on silica gel Merck-60 eluting with 85:10:5 ethylacetate:hexane:dichloromethane provided the title compound (0.275 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]([CH2:22][N:23](C)[C:24](=O)OC(C)(C)C)[S:11][C:12]=1[S:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1.[C:32]([O:35]CC)(=[O:34])[CH3:33].Cl.[C:39]([O:42]CC)(=[O:41])[CH3:40]>C(O)C>[C:39]([OH:42])(=[O:41])/[CH:40]=[CH:33]/[C:32]([OH:35])=[O:34].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]([CH2:22][NH:23][CH3:24])[S:11][C:12]=1[S:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1
Reactant: CCOC(C)=O
Reactant: COc1cccc(Sc2sc(CN(C)C(=O)OC(C)(C)C)cc2-c2ccccc2F)c1
Agent: Cl
Solvent: CCO
Product: CNCc1cc(-c2ccccc2F)c(Sc2cccc(OC)c2)s1
Product: O=C(O)/C=C/C(=O)O
Reaction time: 6 h

Procedure:
tert-Butyl ({4-(2-fluorophenyl)-5-[(3-methoxyphenyl)thio]-2-thienyl}methyl)methylcarbamate (182 mg) was dissolved in ethyl acetate (3 mL) and ethanol (1 mL), and a 4 mol/L hydrogen chloride-ethyl acetate solution (2 mL) was added at room temperature. After stirring for 6 hr, the reaction mixture was concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a free base of the title compound (149 mg). To a solution of fumaric acid (48 mg) in ethanol (10 mL) was added a solution of the obtained free base in ethyl acetate (5 mL), and the solvent was evaporated under reduced pressure. The obtained crude crystals were recrystallized from a mixed solvent of ethyl acetate and 2-propanol to give the title compound as colorless crystals (yield 118 mg, yield 63%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[C:9]1([S:15][CH:16]=[CH:17][C:18](Cl)=[O:19])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl>C(#N)C>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:18](=[O:19])[CH:17]=[CH:16][S:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:3][CH:4]=1
Reactant: Cc1ccc(N)cc1
Reactant: O=C(Cl)C=CSc1ccccc1
Agent: Cl
Solvent: CC#N
Product: Cc1ccc(NC(=O)C=CSc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96.6 %

Procedure:
p-Toluidine (2.46 g) was dissolved to acetonitrile (20 ml), then acetonitrile (3 ml) solution of 3-(phenylthio)acryloyl chloride (2.0 g) was added dropwise thereto under ice-cooling. The mixture was stirred at room temperature for 1.5 hours. The reaction mixture was poured into 50 ml of ice-water, and adjusted to pH 4 with concentrated hydrochloric acid. The precipitated crystal was collected by filtration, washed with water and dried to obtain N-(4-methylphenyl)-3-(phenylthio)acrylamide (2.62 g) as light brown crystal.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH3:9].[O:10]=[C:11]1[NH:19][CH:18]=[N:17][C:16]2[N:15]([CH2:20][CH2:21][C:22](OCC)=[O:23])[CH:14]=[N:13][C:12]1=2>C(#N)C>[O:10]=[C:11]1[NH:19][CH:18]=[N:17][C:16]2[N:15]([CH2:20][CH2:21][C:22]([NH:1][CH2:2][CH2:3][CH:4]3[CH2:8][CH2:7][CH2:6][N:5]3[CH3:9])=[O:23])[CH:14]=[N:13][C:12]1=2
Reactant: CN1CCCC1CCN
Reactant: CCOC(=O)CCn1cnc2c(=O)[nH]cnc21
Solvent: CC#N
Product: CN1CCCC1CCNC(=O)CCn1cnc2c(=O)[nH]cnc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
0.565 g (4.41 mmol) of 2-(2-aminoethyl)-1-methylpyrrolidine was added to a 10 ml round bottom flask equipped with a magnetic stirring bar. The solution was heated and 0.250 g (1.06 mmol) of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propionic acid, ethyl ester (AIT-0027) was added and the solution was heated at 110°-120° C. for two hours. The orange solution was allowed to cool to room temperature and 8 ml acetonitrile was added and the solution was stirred for 20 minutes to wash the solid. The solution was filtered by Buchner vacuum filtration and the solid was washed with acetonitrile and then with ether. Upon drying 265 mg of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]propanamide (AIT-0045) as a white solid was obtained.
Reaction SMILES: CS(C)=O.[CH3:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[N+:22]([O-:24])=[O:23])=[CH:16][CH:15]=2)=[N:10][CH:11]=1.C(O)(=O)C.[BH4-].[Na+]>O>[CH3:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][N+:22]([O-:24])=[O:23])=[CH:16][CH:15]=2)=[N:10][CH:11]=1
Reactant: Cc1ccc(OCc2ccc(/C=C/[N+](=O)[O-])cc2)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(OCc2ccc(CC[N+](=O)[O-])cc2)nc1
Reaction time: 0.17 h
Yield: 54.4 %

Procedure:
To a dimethyl sulfoxide (40.0 mL) solution of 5-methyl-2-(4-((E)-2-nitro-vinyl)-benzyloxy)-pyridine (3.50 g, 12.9 mmol) described in Manufacturing Example 44-1-3 and acetic acid (3.50 mL) was added sodium borohydride (822 mg, 20.6 mmol) at room temperature while cooling appropriately under nitrogen atmosphere, which was stirred for 10 minutes. Water was then added dropwise at room temperature while cooling appropriately. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:4) to obtain the title compound (1.91 g, 54.3%).
Reaction SMILES: Cl[CH2:2][CH:3]1[CH2:7][O:6][C:5]([CH3:17])([C:8]([CH3:16])=[CH:9][C:10]2[S:11][CH:12]=[CH:13][C:14]=2[CH3:15])[O:4]1.[CH3:18][CH:19]1[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]1>>[CH3:17][C:5]1([C:8]([CH3:16])=[CH:9][C:10]2[S:11][CH:12]=[CH:13][C:14]=2[CH3:15])[O:4][CH:3]([CH2:2][N:21]2[CH2:22][CH2:23][CH2:24][CH:19]([CH3:18])[CH2:20]2)[CH2:7][O:6]1
Reactant: CC(=Cc1sccc1C)C1(C)OCC(CCl)O1
Reactant: CC1CCCNC1
Product: CC(=Cc1sccc1C)C1(C)OCC(CN2CCCC(C)C2)O1
Temperature: 120 °C
Yield: 80.9 %

Procedure:
A mixture of 19 g (0.07 mol) of 4-chloromethyl-2-methyl-2-[1-(3-methylthien-2-yl)-propen-2-yl]-dioxolane and 18 g (0.18 mol) of 3-methylpiperidine is heated at 120° C. for 16 hours, with stirring. For working up, the cooled reaction mixture is partitioned between water, and diethyl ether and the organic phase is separated off, dried over magnesium sulphate and evaporated in vacuo. 19 g (81% of theory) of 2-methyl-4-(3-methylpiperidin-1-yl-methyl)-2-[1-(3-methylthien-2-yl]-propen-2-yl]-dioxolane of refractive index nD20 1.5402 are obtained.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]1[CH:9](O)[CH2:8][CH2:7][O:6][P:5]1(=[O:15])[NH:11][CH2:12][CH2:13][Cl:14].[CH:16]1([NH3+:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.[SH:23][CH2:24][CH2:25][S:26]([O-:29])(=[O:28])=[O:27].ClC(Cl)(Cl)C(O)=O>O>[CH:16]1([NH3+:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.[Cl:1][CH2:2][CH2:3][N:4]1[CH:9]([S:23][CH2:24][CH2:25][S:26]([O-:29])(=[O:28])=[O:27])[CH2:8][CH2:7][O:6][P:5]1([NH:11][CH2:12][CH2:13][Cl:14])=[O:15]
Reactant: O=S(=O)([O-])CCS
Reactant: O=P1(NCCCl)OCCC(O)N1CCCl
Agent: O=C(O)C(Cl)(Cl)Cl
Agent: [NH3+]C1CCCCC1
Solvent: O
Product: O=P1(NCCCl)OCCC(SCCS(=O)(=O)[O-])N1CCCl
Reaction time: 20 h

Procedure:
277 mg (1 mmol) of 3-(2-chloroethyl)-2-(2-chloroethylamino)-hydroxy-tetrahydro-2H-1,3,2-oxazaphosphorin-2-oxide and 240 mg (1 mmol) of cyclohexylammonium-2-mercaptoethanesulphonate were dissolved in 4 ml of water, mixed with a trace of trichloroacetic acid and stored for 20 hours at 0° C. The reaction mixture which was concentrated under vacuum was dissolved twice in ethanol and re-concentrated. It was then taken up in ethanol and precipitated with ether.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)=[CH:4][CH:3]=1.Cl.[CH3:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[NH:40]N>>[I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:40][C:35]3[C:36]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:37][CH:38]=[CH:39][C:34]=3[CH3:33])=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(I)cc3)CC2)c1
Reactant: Cc1ccccc1NN
Agent: Cl
Product: Cc1cccc2c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c(-c3ccc(I)cc3)[nH]c12

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(4-iodophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-(2-methylphenyl)hydrazine hydrochloride: ESMS m/e: 620.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([O:9]CC)=O.[C:12](#[N:14])[CH3:13].Cl>O1CCOCC1>[CH3:13][C:12]1[NH:14][C:7](=[O:9])[C:6]2[CH:5]=[CH:4][S:3][C:2]=2[N:1]=1
Reactant: CCOC(=O)c1ccsc1N
Reactant: CC#N
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nc2sccc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.5 %

Procedure:
To a solution of ethyl 2-aminothiophene-3-carboxylate (0.1 g, 0.64 mmol) and acetonitrile (50 μl, 0.95 mmol) in dioxane (3 ml) was added 4M HCl in dioxane (3 ml). The mixture was stirred at room temperature overnight. The solvents were removed under reduced pressure. The residue was diluted with water and made alcaline with a saturated aqueous sodium bicarbonate solution. The precipitate was filtered off, washed with water and dried. The crude residue was purified by flash chromatography on silica gel (CH2Cl2/MeOH 50:1) to yield the title compound as a white solid (42 mg, 40%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH3:11])=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[CH2:18](Br)[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH3:11])=[C:9]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:8]=[C:5]2[N:6]([CH2:18][C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:20])[CH:7]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: Cc1c(-c2ccccc2)[nH]c2ncc(Br)cc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC#N
Product: Cc1c2cc(Br)cn(CC(=O)c3ccccc3)c-2nc1-c1ccccc1
Yield: 72 %

Procedure:
5-Bromo-3-methyl-2-phenylpyrrolo[2,3-b]pyridine (0.34 g, 1.2 mmol) and phenacyl bromide (0.49 g, 2.4 mmol) in acetonitrile (20 ml) was refluxed over night to give a clear solution. The cooled solution was alkalized with sodium carbonate solution (10%) and extracted with methylene chloride. Drying over MgSO4, filtration and evaporation of solvents gave a residue which was dissolved in the minimum amount of ethanol. Crystallization was driven to completeness by keeping crystals and mother liquor in the fridge for a few days. Recrystallization by dissolving in hot ethanol and cooling in the fridge over night gave 0.35 g (73%) of yellow crystals.
Reaction SMILES: [O:1]=[C:2]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)[CH2:3][N:4]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[S:5]1.Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[O:9]=[C:8]1[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[S:5][N:4]1[CH2:3][C:2]([N:14]1[CH2:19][CH2:18][N:17]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH2:16][CH2:15]1)=[O:1]
Reactant: O=C(Cn1sc2ccccc2c1=O)N1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cn1sc2ccccc2c1=O)N1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
Compound 10 (100 mg, 0.36 mmol) was treated with benzyl chloroformate (75 mg, 0.44 mmol) and DIEA (140 mg, 1.10 mmol) in anhydrous CH2Cl2 (5 mL) and DMF (1 mL) at room temperature for 4 h. CH2Cl2 and DMF were removed in reduced pressure. The mixture was washed successively with 1 M HCl(aq) and saturated NaHCO3(aq.). The organic phase was dried over MgSO4, filtered, concentrated, and the title compound was obtained after purification on a thin-layer silica-gel plate (20 cm×20 cm×2 mm) using CH2Cl2/MeOH (9:1) as the developing solution. C21H21N3O4S; white solid; mp 138-142° C.; IR vmax (neat) 2923, 2854, 1700, 1655, 1428, 1354, 1286, 1227, 1125, 1075, 1027, 984, 861, 741 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.01 (1H, d, J=8.0 Hz), 7.60 (1H, t, J=7.2 Hz), 7.53 (1H, d, J=8.0 Hz), 7.36 (6H, m), 5.12 (2H, s), 4.69 (2H, s), 3.62 (8H, m); 13C NMR (100 MHz, CDCl3) δ 165.1, 154.8, 141.1, 136.1, 132.1, 128.5, 128.1, 127.9, 126.7 (2×), 126.3 (2×), 125.4, 123.2, 120.2, 67.6, 45.2, 44.9, 43.6 (2×), 42.0; ESI-HRMS calcd for C21H21N3O4NaS: 434.1150. found: m/z 434.1149 [M+H]+.
Reaction SMILES: C(N1C=CN=C1)([N:3]1C=CN=C1)=O.[CH:13]1([NH:19][C:20]2[CH:29]=[C:28]3[C:23]([C:24](=[O:38])[C:25]([C:35]([OH:37])=O)=[CH:26][N:27]3[CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[CH:22][C:21]=2[F:39])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.N>CN(C=O)C>[CH:13]1([NH:19][C:20]2[CH:29]=[C:28]3[C:23]([C:24](=[O:38])[C:25]([C:35]([NH2:3])=[O:37])=[CH:26][N:27]3[CH:30]3[CH2:31][CH2:32][CH2:33][CH2:34]3)=[CH:22][C:21]=2[F:39])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: O=C(O)c1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: CN(C)C=O
Product: NC(=O)c1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O
Temperature: 100 °C
Reaction time: 13.5 h
Yield: 92.7 %

Procedure:
2.6 g of 1,1′-carbonyldiimidazole was added to a 30 ml DMF suspension of 4.0 g 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, followed by stirring at 100° C. for 13.5 hours. 10 ml of 28% aqueous ammonia was added thereto under ice-cooling, followed by stirring under ice-cooling for 75 minutes and at room temperature for 5 hours. After evaporation of the solvent under a reduced pressure, ethanol was added, and heating under reflux was carried out. After cooling to room temperature, the insoluble materials were collected by filtration and dried to obtain 3.7 g of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxamide.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[OH:12].[Cl-].[Al+3].[Cl-].[Cl-].[C:17](Cl)(=[O:19])[CH3:18]>ClCCl>[CH3:1][C:2]1[CH:11]=[C:10]([C:17](=[O:19])[CH3:18])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[OH:12]
Reactant: CC(=O)Cl
Reactant: Cc1ccc2ccccc2c1O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1cc(C)c(O)c2ccccc12
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To an ice-cooled solution of 2-methyl-l-naphthol (7.9 g, 0.05 mmol) in dichloromethane, anhydrous aluminum chloride (7.2 g) was slowly added with stirring, followed by slow addition of acetyl chloride (4.7 g) to start reaction. The reaction mixture was stirred at 10° C. or below for 1 h, then at room temperature for 3 h. Thereafter, the mixture was poured into ice water. Then, the reaction product was extracted with dichloromethane and the extracted layer was washed with water. Further, the extracted layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was recrystallized with benzene, giving the desired compound, 2-methyl-4-acetyl-1-naphthol, in an amount of 3.9 g .