Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=C1CCC(=O)N1[O:8][C:9](=O)[CH2:10][CH2:11][CH:12]([NH:20][C:21](=[O:47])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[NH2:49][CH2:50][CH2:51][O:52][CH2:53][CH2:54][O:55][CH2:56][C:57]([NH:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][O:65][CH2:66][C:67]([OH:69])=[O:68])=[O:58].NCCOCCOCC(O)=O.CCN(C(C)C)C(C)C>C(O)C>[C:43]([O:42][C:40](=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][C:21](=[O:47])[NH:20][C@H:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:10][C:9](=[O:8])[NH:49][CH2:50][CH2:51][O:52][CH2:53][CH2:54][O:55][CH2:56][C:57](=[O:58])[NH:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][O:65][CH2:66][C:67]([OH:69])=[O:68])([CH3:46])([CH3:44])[CH3:45]
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCCCC(=O)NC(CCC(=O)ON1C(=O)CCC1=O)C(=O)OC(C)(C)C
Reactant: NCCOCCOCC(=O)NCCOCCOCC(=O)O
Agent: NCCOCCOCC(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCCCC(=O)N[C@@H](CCC(=O)NCCOCCOCC(=O)NCCOCCOCC(=O)O)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 96 %

Procedure:
To a solution of 2-(19-tert-Butoxycarbonylnonadecanoylamino)pentanedioic acid 1-tert-butyl ester 5-(2,5-dioxopyrrolidin-1-yl) ester (2.50 g, (prepared similarly as described in WO 2005/012347) and [2-(2-{2-[2-(2-Aminoethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetic acid (1.47 g, alternative name: 8-amino-3,6-dioxaoctanoic acid dimer, IRIS Biotech GmbH, Cat. No. PEG1221) in ethanol (40 ml) was added DIPEA (1.26 ml). The mixture was stirred at room temperature over night and then concentrated in vacuo. To the residue was added aqueous 0.1 N HCl (150 ml) and ethyl acetate (200 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate (100 ml). The combined organic layers were washed with water and brine, dried (magnesium sulphate) and concentrated in vacuo to give an oil, which crystalised on standing. Yield 96% (3.1 g). LC-MS (electrospray): m/z=874.49.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][C:8]1[S:9][C:10]([CH:31]=[O:32])=[CH:11][C:12]=1[S:13](=[O:30])(=[O:29])[N:14]([CH2:16][CH:17]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)[O:18][CH2:19][O:20][CH3:21])[CH3:15])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)[C:44]2C=CC=[CH:40][C:39]1=2)=O.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[C:1]([O:5][C:6](=[O:33])[NH:7][C:8]1[S:9][C:10]([C:31](=[O:32])[CH:39]([CH3:40])[CH3:44])=[CH:11][C:12]=1[S:13](=[O:30])(=[O:29])[N:14]([CH2:16][CH:17]([C:22]1[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=1)[O:18][CH2:19][O:20][CH3:21])[CH3:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCOC(CN(C)S(=O)(=O)c1cc(C=O)sc1NC(=O)OC(C)(C)C)c1ccc(F)cc1
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: COCOC(CN(C)S(=O)(=O)c1cc(C(=O)C(C)C)sc1NC(=O)OC(C)(C)C)c1ccc(F)cc1
Reaction time: 1 h
Yield: 83 %

Procedure:
Using (3-{[2-(4-fluorophenyl)-2-methoxymethoxyethyl]methylsulfamoyl}-5-formylthiophene-2-yl)carbamic acid t-butyl ester (200 mg), isopropyl group was introduced in the same way as Preparation Example 87, and a crude alcohol was obtained. Dess-Martin reagent (204 mg) was added to a solution of this compound in dichloromethane (2 mL). After stirring for 1 hour, an aqueous solution of saturated sodium bicarbonate and an aqueous solution of sodium thiosulfate were added, and the solution was extracted with ethyl acetate. After washing with saturated sodium chloride water, the solution was dried with anhydrous sodium sulfate. The solution was filtered through a small amount of silica gel, and the title compound (180 mg) was obtained as an orange oily substance.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([NH:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])[C:14]([O:16]C1C=CC([N+]([O-])=O)=CC=1)=O)=[O:7])([CH3:4])[CH3:3].[NH2:37][C@H:38]([C:46]([O:48][CH3:49])=[O:47])[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.Cl.C(N(CC)CC)C>CN(C)C=O>[NH:26]([C:27]([O:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:28])[C@H:13]([C:14]([NH:37][C@H:38]([C:46]([O:48][CH3:49])=[O:47])[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7]
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1

Procedure:
25.0 g of Z-Lys(BOC)-ONP and 10.7 g of H-Phe-OMe.HCl in 70 ml of dimethylformamide are mixed with 6.9 ml of triethylamine at room temperature whilst stirring and the mixture stirred for a further 18 hours. After dilution with ethyl acetate the mixture is washed with potassium carbonate solution until free of nitrophenol, extracted by shaking with 0.1 M citric acid and water, dried over sodium sulphate and evaporated to dryness in vacuo. The protected dipeptide of melting point 78°-80° C. crystalises from ethyl acetate-hexane. Rf = 0.45 in a thin layer chromatogram on silica gel in the system chloroform-acetone (8:2).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29]([O:31]CC)=O)[C:15](=[O:28])[N:16]3[CH2:19][C:20]([N:22]([CH3:27])[CH2:23][CH2:24][O:25][CH3:26])=[O:21])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[F:35][C:36]([F:40])([F:39])[CH2:37][NH2:38]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29]([NH:38][CH2:37][C:36]([F:40])([F:39])[F:35])=[O:31])[C:15](=[O:28])[N:16]3[CH2:19][C:20]([N:22]([CH3:27])[CH2:23][CH2:24][O:25][CH3:26])=[O:21])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N(C)CCOC)c1=O
Reactant: NCC(F)(F)F
Product: COCCN(C)C(=O)Cn1c(=O)c(C(=O)NCC(F)(F)F)c(O)c2ncc(Cc3ccc(F)cc3)cc21

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-(2-{methyl[2-(methyloxy)ethyl]amino}-2-oxoethyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2,2,2-trifluoroethylamine employing methods similar to those described in Example 9 and was recrystallized from a mixture of DMSO and EtOH. The product was obtained as a white solid: 1H NMR (d6-DMSO) mixture of rotamers δ 10.53 (1H, m), 8.55 (1H, s), 7.77 and 7.59 (1H, s), 7.29 (2H, m), 7.12 (2H, br t, J=8 Hz), 5.20 and 5.16 (2H, s), 4.27 (2H, br), 4.12 (2H, s), 3.63 and 3.57 (2H, br m), 3.40-3.20 (2H, m), 3.33 and 3.22 (3H, s), 3.16 and 2.81 (3H, s); AP+ MS: 525 (M+H+, 100).
Reaction SMILES: Cl.[NH2:2][CH:3]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=1)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:19]1([CH:25]([CH2:29][CH3:30])[C:26](Cl)=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[N+:16]([C:12]1[CH:11]=[C:10]([CH:3]([NH:2][C:26](=[O:27])[CH:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:29][CH3:30])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:15]=[CH:14][CH:13]=1)([O-:18])=[O:17]
Reactant: CCC(C(=O)Cl)c1ccccc1
Reactant: CCOC(=O)CC(N)c1cccc([N+](=O)[O-])c1
Agent: Cl
Product: CCOC(=O)CC(NC(=O)C(CC)c1ccccc1)c1cccc([N+](=O)[O-])c1

Procedure:
Corresponding to Example 3a, 5.0 g of (1b) were acetylated with addition of 2-phenylbutyryl chloride. A white solid was obtained (yield: 6.3 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([C:20]([C:22]1[N:23]=[CH:24][N:25](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:26]=1)=[O:21])[CH:14]=[CH:13]2>>[NH:25]1[CH:26]=[C:22]([C:20]([C:15]2[CH:14]=[CH:13][C:12]3[C:17](=[CH:18][CH:19]=[C:10]([O:9][CH3:8])[CH:11]=3)[CH:16]=2)([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[OH:21])[N:23]=[CH:24]1
Reactant: Brc1ccccc1
Reactant: COc1ccc2cc(C(=O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Product: COc1ccc2cc(C(O)(c3ccccc3)c3c[nH]cn3)ccc2c1

Procedure:
In a similar manner to that described in Example 6-(i), the reaction of bromo benzene (0.85 ml) with (6-methoxynaphthalen-2-yl)-(1-trityl-1H-imidazol-4-yl)ketone (1.0 g) was carried out. The reaction mixture was purified by silica gel column chromatography (eluent, hexane:ethyl acetate=3:1→2:1) to give the titled compound (0.98 g) as a pale yellow powder.
Reaction SMILES: Br.[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[OH:12])[CH2:8][CH:7]([N:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])[CH2:6]2.Br[CH2:21][CH2:22]Br.Cl>>[CH2:21]1[CH2:22][O:2][C:3]2[CH:4]=[C:5]3[C:9]([CH2:8][CH:7]([N:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])[CH2:6]3)=[CH:10][C:11]=2[O:12]1
Reactant: CCCN(CCC)C1Cc2cc(O)c(O)cc2C1
Reactant: BrCCBr
Agent: Br
Agent: Cl
Product: CCCN(CCC)C1Cc2cc3c(cc2C1)OCCO3

Procedure:
5,6-Dihydroxy-2-(di-n-propylamino)indan hydrobromide (200 mg, 0.6 mmol) was reacted with 1,2-dibromoethane (0.05 mL, 0.66 mmol) under the same reaction conditions as Example 4. The crude material was chromatographed (200 g silica gel) eluting with methylene chloride/methanol (9:1) to yield an oil. The oil was converted into the HCl salt and recrystallized using methanol/ethyl acetate/ether: mp 210°-215° C.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][CH2:23][C:24]1[N:25]=[CH:26][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH:28]=1.ON1C2C=CC=CC=2N=N1>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][CH2:23][C:24]1[N:25]=[CH:26][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH:28]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)n1cnc(CON)c1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1cnc(CONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.7 %

Procedure:
To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.250 g, 0.905 mmol) in DCM (10.0 mL) was added tert-butyl 4-[(aminooxy)methyl]-1H-imidazole-1-carboxylate 122 (0.289 g, 1.358 mmol), 1-hydroxybenzotriazole (0.183 g, 1.358 mmol) and 1-ethyl-(3-dimethylaminapropyl) carbodiimide hydrochloride (0.260 g, 1.358 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to provide a residue which was subjected to chromatography to give 123 (0.40 g, 94%) as a colorless oil.
Reaction SMILES: [C@@H:1]1([N:8]2[CH:15]=[CH:14][C:12](=O)[NH:11][C:9]2=[O:10])[O:7][C@H:4]([CH2:5][OH:6])[CH2:3][CH2:2]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:17].O>N1C=CC=CC=1>[C@@H:1]1([N:8]2[CH:15]=[CH:14][C:12](=[S:17])[NH:11][C:9]2=[O:10])[O:7][C@H:4]([CH2:5][OH:6])[CH2:3][CH2:2]1
Reactant: O=c1ccn([C@H]2CC[C@@H](CO)O2)c(=O)[nH]1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Solvent: O
Product: O=c1[nH]c(=S)ccn1[C@H]1CC[C@@H](CO)O1
Yield: 95 %

Procedure:
When the 2',3'-dideoxy-uridine derivatives being raw materials in the invention are allowed to react with phosphorus pentasulfide in pyridine solvent, the amount of phosphorus pentasulfide is desirable to be not less than 0.5 times mol, preferably 1 to 2 times mol to 2',3'-dideoxy-uridine derivatives. In order to raise the yield of reaction further, it is preferable to add water to the reaction system and the amount of water to be added therefor is preferable to be 0.5 times mol to equivalent mol to phosphorus pentasulfide. Although the reaction proceeds without the addition of water, the reaction liquor becomes blackish brown and tarry substances are produced at this time resulting in the lowering in yield by several steps. The reaction completes by refluxing for 2 to 5 hours. After the completion of reaction, the pyridine solution is concentrated to distill off pyridine and the residue is extracted with chloroform. Thus, aimed 2',3'-dideoxy-4-thiouridine derivatives can be obtained easily in a yield of not less than 95 %. Following this, by eliminating the protecting groups with alkali or acid according to usual method, 2',3'-dideoxy-4-thio-uridine being the compound of the invention can be prepared in high yield and yet with ease.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[N+]([O-])([O-])=O.[Ag+:14]>C(OCCCC)(=O)C.O>[Ag:14].[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: c1ccc2[nH]nnc2c1
Solvent: CCCCOC(C)=O
Solvent: O
Product: [Ag]

Procedure:
Benzotriazole (17.9 g) was dissolved in n-butyl acetate (300 ml), followed by the addition of water (300 ml). Silver nitrate (25.5 g) was dissolved in water (150 ml). The resulting solution was added to the previously prepared butyl acetate solution of benzotriazole under vigorous agitation. After 30-minute agitation, the aqueous phase was removed from the mixture, and the n-butyl acetate phase was washed with water. It was then washed with methanol and finally centrifuged to give benzotriazole silver (33.2 g). A portion (22.6 g) of the benzotriazole was added to a mixture of a 6% aqueous polyvinyl alcohol solution (600 ml) and a 6% aqueous gelatin solution (200 ml), and the reactants were mixed under agitatioh for 48 hrs. in a ball mill until a silver salt dispersion formed. An 8% aqueous polyvinyl alcohol solution was prepared in an amount of 150 ml, and in this solution, a 1% methanol solution of 3-amino-4-allyl-5-mercapto-1,2,4-triazole (14 ml), phthalazine (0.80 g), phthalic acid (1.0 g) and t-butylhydroquinone (2.1 g or 0.0125 mol) were dissolved. To the resultion solution, an 8% aqueous gelatin solution (50 ml) and 200 ml of the separately prepared silver salt dispersion were added. To the mixture, 25 ml of a silver iodobromide emulsion (particle size: 0.06 μm, silver iodide content: 4 mol %, gelatin content: 60 g per kg of the emulsion) was added, and the resulting coating solution was applied to photographic baryta paper to give a wet thickness of 55 μm, and the web was dried. Subsequently, a 3% acetone solution of diacetyl cellulose was applied to the emulsion layer to give a wet thickness of 55 μm, and the applied layer was dried to form a protective film.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:10]OC(OC)N(C)C>>[N:1]12[CH:10]3[N:4]([CH2:5][CH2:6][N:7]3[CH2:8][CH2:9]1)[CH2:3][CH2:2]2
Reactant: COC(OC)N(C)C
Reactant: C1CNCCNCCN1
Product: C1CN2CCN3CCN1C23

Procedure:
In a manner similar to that of Example 1 (C), 4.55 g (35.5 mmol) of 1,4,7-triazacyclononane and 4.20 g of dimethylformamide dimethyl acetal were reacted to give 4.33 g (88%) clear, colorless liquid, bp 79°-80° (2.6mm).
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:25]([CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=1)=O.CCCCCC>C(Cl)Cl>[Br:2][C:1]([Br:5])=[CH:25][CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=1
Reactant: BrC(Br)(Br)Br
Reactant: COc1cccc(CCCC=O)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCCCCC
Product: COc1cccc(CCCC=C(Br)Br)c1
Reaction time: 0.17 h
Yield: 94.8 %

Procedure:
To a solution of carbon tetrabromide (16.7 g) in methylene chloride (35 ml) was added triphenylphosphine (26.0 g) in methylene chloride (35 ml) at 0° C., and the mixture was stirred for 10 min. To the mixture was added a solution of 1-(3-formylpropyl)-3-methoxybenzene (3.00 g) in methylene chloride (20 ml) at 0° C. The mixture was stirred for 30 min at 0° C. To the mixture was added gradually n-hexane and to remove triphenylphosphineoxide. The mixture was filtered was washed with water and a saturated aqueous solution of sodium chloride, successively, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=24:1) to give the title compound (5.33 g) having the following physical data.
Reaction SMILES: [C:1]([C:11]1[O:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:14][N:15]=1)(=O)[C:2]1[CH:7]=[CH:6][C:5](OC)=[CH:4]C=1.I.[OH2:23]>>[C:16]1([C:13]2[O:12][C:11]([C:1]3[CH:2]=[CH:7][C:6]([OH:23])=[CH:5][CH:4]=3)=[N:15][N:14]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O
Reactant: COc1ccc(C(=O)c2nnc(-c3ccccc3)o2)cc1
Agent: I
Product: Oc1ccc(-c2nnc(-c3ccccc3)o2)cc1
Temperature: 130 °C

Procedure:
3.5 g (13.89 mmol) of 2-(p-anisoyl) 5-phenyl 1,3,4-oxadiazole and 100 mL of concentrated HI aqueous solution was mixed under nitrogen and refluxed at 130° C. for 12 hours. The mixture was cooled down to room temperature and 100 mL of deionized water was added. The precipitate was collected by filtration and dried under vacuum, p-(5-phenyl-1,3,4-oxadiazole-2-yl)phenol was obtained. 1H-NMR (acetone-d6, ppm): δ 9.26 (s, 1H), δ 8.15 (m, 2H), δ 8.06 (d, 2H), δ 7.62 (m, 3H), δ 7.07 (d, 2H); mp 256.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][O:7][C:8]2=[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]2=[O:20])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[CH:30]1([C:33](Cl)=[O:34])[CH2:32][CH2:31]1>C1COCC1>[O:20]=[C:12]1[C:11](=[C:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([NH:1][C:33]([CH:30]4[CH2:32][CH2:31]4)=[O:34])[CH:10]=3)[CH2:6][O:7]2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13]1
Reactant: Nc1ccc2c(c1)C(=C1C(=O)Nc3ccccc31)OC2
Reactant: O=C(Cl)C1CC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1Nc2ccccc2C1=C1OCc2ccc(NC(=O)C3CC3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.2 %

Procedure:
To a solution of 3-(6-Amino-3H-isobenzofuran-1-ylidene)-1,3-dihydro-indol-2-one (50.0 mg, 0.189 mmol) and N,N-diisopropylethylamine (98.8 μL, 0.567 mmol) in 2.0 mL THF was added cyclopropane carbonyl chloride (17.2 μL, 0.189 mmol). After stirring at room temperature for 1 h, the slurry was warmed briefly, stirred 10 min at room temperature, filtered and rinsed with MeOH and EtOAc/hexanes (1:1) to afford the title compound (44.7 mg, 71%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([N:13]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH2:14][CH2:15][CH3:16])[CH2:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[N:30]1([C:36](Cl)=[O:37])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([N:13]([CH2:14][CH2:15][CH3:16])[CH:17]3[CH2:18][CH2:19][N:20]([C:36]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[O:37])[CH2:21][CH2:22]3)[CH2:10]2)=[CH:5][CH:4]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: CCCN(C1CCNCC1)C1CCc2ccc(OC)cc2C1
Solvent: CCN(CC)CC
Product: CCCN(C1CCN(C(=O)N2CCOCC2)CC1)C1CCc2ccc(OC)cc2C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.6 %

Procedure:
To an ice-cold solution of (7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-piperidin-4-yl-propyl-amine (1.0 g, 3.3 mmol) and triethylamine (0.5 ml, 3.6 mmol) under an inert atmosphere was added morpholine-4-carbonyl chloride (0.4 mL, 3.5 mmol) dropwise. The ice bath was removed and the reaction stirred at room temperature for 4 h. The methylene chloride was washed 2 times with water (30 mL), dried (MgSO4), filtered, and concentrated to afford {4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-morpholin-4-yl-methanone as an oil (1.16 g).
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6](=[O:12])[CH2:7][NH:8][CH2:9][CH2:10][NH2:11])[CH3:4].[C:13]1([C:19]2[S:23][C:22]([S:24](Cl)(=[O:26])=[O:25])=[N:21][N:20]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:3]([O:5][C:6](=[O:12])[CH2:7][NH:8][CH2:9][CH2:10][NH:11][S:24]([C:22]1[S:23][C:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:20][N:21]=1)(=[O:25])=[O:26])[CH3:4]
Reactant: O=S(=O)(Cl)c1nnc(-c2ccccc2)s1
Reactant: CCOC(=O)CNCCN
Agent: Cl
Product: CCOC(=O)CNCCNS(=O)(=O)c1nnc(-c2ccccc2)s1

Procedure:
The title compound was synthesized by the reaction of N-(2-aminoethyl)-glycine ethyl ester 2HCl with 5-phenyl-1,3,4-thiadiazole-2-sulfonyl chloride as per the procedure of example 1. 1H NMR (500 MHz; DMSO-d6) δ 8.05 (d, 2H), 7.60–7.56 (m, 3H), 4.02 (q, 2H), 3.26 (s, 2H), 3.16 (t, 2H), 2.64 (t, 2H), 1.14 (t, 3H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:12][N:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14](Cl)=[O:15]>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:14](=[O:15])[N:13]([CH3:12])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: CS(=O)(=O)c1ccc(O)cc1
Product: CN(C(=O)Oc1ccc(S(C)(=O)=O)cc1)c1ccccc1

Procedure:
The title product was prepared from 4-methylsulfonylphenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (50%, white solid). HPLC-MS: m/z=306.1 (M+1); Rt: 3.22 min.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([NH2:14])=[O:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C(OC([NH:22][CH:23]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:24](O)=[O:25])=O)(C)(C)C>>[NH2:22][CH:23]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:24]([NH:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([NH2:14])=[O:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2)=[O:25]
Reactant: NC(=O)c1ccc(N)c2cccnc12
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1ccccc1
Product: NC(=O)c1ccc(NC(=O)C(N)c2ccccc2)c2cccnc12

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 27 by using 5-aminoquinoline-8-carboxamide coupled with 2-((tert-butoxycarbonyl)amino)-2-phenylacetic acid, followed by removal of the protecting group to afford Example 29. LC-MS (M+H=321, obsd=321).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:8]2[C:12](=[O:13])[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:10][N:9]2CC)[CH:5]=[CH:6][CH:7]=1.Cl.[F:23][C:24]([F:34])([F:33])C1C=C(NN)C=CC=1.C1C=CC=CC=1>C(N(CC)CC)C>[C:14]1([C:11]2[C:12](=[O:13])[N:8]([C:4]3[CH:3]=[C:2]([C:24]([F:34])([F:33])[F:23])[CH:7]=[CH:6][CH:5]=3)[NH:9][CH:10]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: NNc1cccc(C(F)(F)F)c1
Reactant: CCn1cc(-c2ccccc2)c(=O)n1-c1cccc(Cl)c1
Agent: Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=c1c(-c2ccccc2)c[nH]n1-c1cccc(C(F)(F)F)c1

Procedure:
A mixture of 8.2 grams of the atropic acid, methyl ester, (prepared in Example 11), 8.5 grams 3-(trifluoromethyl)-phenyl-hydrazine hydrochloride, 100 ml. benzene and 4 grams triethylamine, was refluxed overnight and worked up to yield 6.5 grams of 4-phenyl-1-(α,α, α-trifluoro-3-tolyl)-3-pyrazolin-5-one having a melting point of about 210°-213° C.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1>>[Br:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]2[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:14]=2)=[CH:18][CH:17]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: Nc1ccccc1Nc1ccccc1
Product: Brc1ccc(-c2nc3ccccc3n2-c2ccccc2)cc1

Procedure:
To a flask containing N-phenyl-o-phenylenediamine (9.21 g, 50 mmol) and 4-bromobenzaldehyde (9.25 g, 50 mmol) was added 50 mL of 20-methoxyethanol. After the mixture was refluxed for 48 h, the volatile was removed under vacuum and the residue was extracted with CH2Cl2. The organic extract was washed with brine, dried over anhydrous MgSO4, filtered and pumped dry. The crude product was purified by column chromatography using a mixture of CH2Cl2 and n-hexane (1:1 by vol.) as the eluent. Analytically pure 2-(4-bromophenyl)-1-phenyl-1H-benzo[d]imidazole was isolated as a white solid in 72% (9.77 g) yield. 1H NMR (400 MHz, CDCl3): δ 7.68 (d, 1 H, J=8.0 Hz), 7.35-7.29 (m, 4 H), 7.24-7.20 (m, 1 H), 7.15-7.02 (m, 7 H). MS (FAB): m/z 348.9 (M+). Anal. calcd. for C19H13BrN2: C, 65.35; H, 3.75; N, 8.02. Found: C, 65.22; H, 3.78; N, 8.01.