Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][C:4](O)=[O:5].[CH3:8][NH:9][OH:10]>C(Cl)(Cl)Cl>[CH3:8][N:9]([C:4](=[O:5])[CH2:3][N:2]([CH3:7])[CH3:1])[OH:10]
Reactant: CNO
Reactant: CN(C)CC(=O)O
Solvent: ClC(Cl)Cl
Product: CN(C)CC(=O)N(C)O
Yield: 25.6 %

Procedure:
To the solution of 131 g of sodium hydroxide dissolved in 400 ml of water, 400 ml of an aqueous solution containing 273 g of N-methylhydroxylamine hydrochloride was added, with ice-cooling. Subsequently, 384 g of N,N-dimethylglycine methyl ester was added thereto. The resultant reaction mixture was stirred at room temperature for 3 days. The results of gas chromatography demonstrated a rate of residual raw materials: 2.3%, a rate of formation of N-methyl-α-dimethylaminoacetohydroxamic acid: 51.5%, and a rate of secondary production of N,N-dimethylglycine: 45.1%. After a large portion of the solvent was distilled off under a reduced pressure, chloroform and then anhydrous magnesium sulfate were added to the residue; thereafter, they were fully shaked, followed by filtration, to remove insoluble substances. After the resultant filtrate was concentrated, the residue was recrystallized from aceton/methanol (50/1), to give 186 g of crystals. As a result of analysis of the crystals using gas chromatography and 1H-NMR, it was found that each several percents of each of N,N-dimethylglycine and N-methylhydroxylamine were mixed therein, and therefore the crystals were dissolved again in 3 liters of chloroform, to remove insoluble substances by filtration. After the filtrate was concentrated, the residue was recrystallized from aceton/methanol (12/1), to give 111 g (yield 25.6%) of pure N-methyl-α-dimethylaminoacetohydroxamic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=2)[NH2:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:18]([C:20]1([C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=2)[C:26](O)=[O:27])[CH2:22][CH2:21]1)#[N:19].Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:18]([C:20]1([C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=2)[C:26]([NH:12][C:11]2[CH:13]=[CH:14][CH:15]=[C:9]([O:8][C:7]3[CH:16]=[CH:17][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[CH:10]=2)=[O:27])[CH2:21][CH2:22]1)#[N:19]
Reactant: N#CC1(c2cccc(C(=O)O)c2)CC1
Reactant: Nc1cccc(Oc2ccc([N+](=O)[O-])cc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc([N+](=O)[O-])cc4)c3)c2)CC1
Yield: 91.9 %

Procedure:
Using 3-(4-nitrophenoxy)aniline (3.21 g, 13.9 mmol) produced in Example A12(i), 3-(1-cyanocyclopropyl)benzoic acid (2.70 g, 14.4 mmol) produced in Example A1(iii), pyridine (100 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (3.20 g, 16.7 mmol) and N,N-dimethylpyridine-4-amine (122 mg, 997 μmol) as starting materials, and in the same manner as in Example A12(ii), the title compound (5.1 g, 91%) was obtained as a yellow amorphous substance.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([Cl:14])=[C:6]([CH:13]=1)[C:7](N(OC)C)=[O:8].[CH3:15][Mg]Br>C1COCC1>[Br:1][C:2]1[CH:13]=[C:6]([C:7](=[O:8])[CH3:15])[C:5]([Cl:14])=[N:4][CH:3]=1
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1cc(Br)cnc1Cl
Solvent: C1CCOC1
Product: CC(=O)c1cc(Br)cnc1Cl
Temperature: -78 °C
Reaction time: 3 h

Procedure:
Starting material 5-bromo-2-chloro-N-methoxy-N-methylnicotinamide (5.0 g, 17.89 mmol) was charged into a 250 ml round bottom flask and the flask was chilled to −78° C. Methyl magnesium bromide 96.5 ml, 19.68 mmol) in 5 ml THF was added dropwise via addition funnel. The resulting mixture was allowed to stir for 3 hours at −78° C. After removing the THF solvent via rotatory evaporation under reduced pressure, the reaction mixture was partitioned between ethylacetate and saturated aqueous sodium bicarbonate. After removing the ethylacetate, the resulting crude product was subject to a silica gel column with 20% ethylacetate in hexane. The resulting product (2.28 g, y=54.3%) was used for the following step.
Reaction SMILES: [ClH:1].Cl.[C:3]([C:6]1[CH:7]=[C:8](/[CH:12]=[CH:13]/[CH2:14][N:15]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[CH:22][CH:21]=2)[C:16](=[O:19])[CH2:17][OH:18])[CH:9]=[CH:10][CH:11]=1)(=[NH:5])[NH2:4].Cl.[C:34](=[NH:39])(OCC)[CH3:35].C(N(CC)CC)C.Cl>CO.O1CCOCC1>[ClH:1].[ClH:1].[C:34]([N:30]1[CH2:29][CH2:28][CH:27]([O:26][C:23]2[CH:22]=[CH:21][C:20]([N:15]([CH2:14]/[CH:13]=[CH:12]/[C:8]3[CH:9]=[CH:10][CH:11]=[C:6]([C:3](=[NH:4])[NH2:5])[CH:7]=3)[C:16](=[O:19])[CH2:17][OH:18])=[CH:25][CH:24]=2)[CH2:32][CH2:31]1)(=[NH:39])[CH3:35]
Reactant: N=C(N)c1cccc(/C=C/CN(C(=O)CO)c2ccc(OC3CCNCC3)cc2)c1
Reactant: CCOC(C)=N
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(=N)N1CCC(Oc2ccc(N(C/C=C/c3cccc(C(=N)N)c3)C(=O)CO)cc2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 160.8 %

Procedure:
To a solution of N-[3-(3-amidinophenyl)-2-(E)-propenyl]-N-[4-(piperidin-4-yloxy)phenyl]-2-hydroxyacetamide dihydrochloride (385 mg) in methanol (20 ml) were added ethyl acetimidate hydrochloride (300 mg) and triethylamine (0.56 ml) at room temperature. The resulting mixture was stirred at room temperature for 12 hours. To the reaction mixture was added a 4M solution of hydrogen chloride in dioxane (1 ml) and the solution was concentrated in vacuo. The residue was purified by preparative HPLC (YMC-Pack ODS YMC) using 14% aqueous acetonitrile as an eluant to afford an amorphous solid. To a solution of the solid in methanol (10 ml) was added a 4M solution of hydrogen chloride in dioxane (0.5 ml) and the mixture was concentrated to dryness in vacuo. A solution of the residual solid in water (about 10 ml) was lyophilized to give the title compound (336 mg, yield 80%) as a colorless amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([O:16][CH2:17][C:18]([OH:20])=[O:19])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH2:21][CH2:22][OH:23])([CH2:10]2)[CH2:8][CH2:7][C:6](=[O:24])[CH:5]=1.C(=O)(O)[O-].[Na+:29]>O>[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([O:16][CH2:17][C:18]([O-:20])=[O:19])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH2:21][CH2:22][OH:23])([CH2:10]2)[CH2:8][CH2:7][C:6](=[O:24])[CH:5]=1.[Na+:29]
Reactant: O=C(O)COc1cc2c(c(Cl)c1Cl)C1=CC(=O)CCC1(CCO)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=C([O-])COc1cc2c(c(Cl)c1Cl)C1=CC(=O)CCC1(CCO)C2

Procedure:
{[5,6-Dichloro-9a-(2-hydroxyethyl)-3-oxo-2,3,9,9a-tetrahydro-1H-fluoren-7-yl]oxy}acetic acid (500 mg) is dissolved by stirring and warming with 0.25N sodium bicarbonate solution (5.4 ml). The solution is diluted to 10 ml and sterilized by filtration. All the water that is used in the preparation is pyrogen-free. The concentration of the active agent in the final solution is 5%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]#[C:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:9]=1[NH2:10])=[O:4].[N:17]1([CH:22]2[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]2)[CH:21]=[N:20][CH:19]=[N:18]1.C([Sn](Cl)(Cl)CCCC)CCC.C1([SiH3])C=CC=CC=1>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]#[C:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:9]=1[NH:10][CH:25]1[CH2:26][CH2:27][CH:22]([N:17]2[CH:21]=[N:20][CH:19]=[N:18]2)[CH2:23][CH2:24]1)=[O:4]
Reactant: O=C1CCC(n2cncn2)CC1
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1NC1CCC(n2cncn2)CC1

Procedure:
Reductive amination of 3-amino-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (0.237 g, 1.0 mmol) and 4-[1,2,4]triazol-1-yl-cyclohexanone (0.170 g, 1.0 mmol) is performed under the same conditions previously described using dibutyltin dichloride and phenylsilane to give 5-(3,3-dimethyl-but-1-ynyl)-3-(4-[1,2,4]triazol-1-yl-cyclohexylamino)-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:9]1[C:20](O)=[O:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>CN(C=O)C.CCOC(C)=O>[CH2:23]([NH:30][C:20]([CH:9]1[CH:10]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:11][CH2:12][CH2:13][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2ccccc2)C1C(=O)O
Reactant: NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC(c2ccccc2)C1C(=O)NCc1ccccc1
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-3-phenylpiperidine-2-carboxylic acid (1.03 g, 3.36 mmol) in DMF (5 ml) were added benzyl amine (0.4 ml, 3.70 mmol), 1-hydroxybenzotriazole (567 mg, 3.70 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (949 mg, 4.70 mmol). The reaction was adjusted to pH 7 with the addition of diisopropylethylamine and allowed to stir for 1 h. The reaction mixture was diluted with EtOAc, washed with saturated sodium bicarbonate (3×) and brine (2×), dried over sodium sulfate, filtered, and concentrated in vacuo to yield tert-butyl 2-[(benzylamino)carbonyl]-3-phenylpiperidine-1-carboxylate (100%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.Cl.Cl[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]Cl.C(=O)([O-])[O-].[K+].[K+].Cl>C(O)CCC>[N:1]1([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH:4]=[CH:5][NH:6]3)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: Nc1cccc2[nH]ccc12
Reactant: ClCCNCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: c1cc(N2CCNCC2)c2cc[nH]c2c1
Yield: 22.4 %

Procedure:
A suspension of 4-aminoindole (2.30 g, 0.017 moles), bischloroethylamine hydrochloride (3.49 g, 0.02 moles) and potassium carbonate (5.41 g, 0.02 moles) in butanol (50 ml) was heated at reflux under argon for 7 h. Further bischloroethylamine hydrochloride (0.70 g, 0.04 moles) and potassium carbonate (1.1 g 0.04 moles) was added, then the suspension was heated at reflux for 18 h. The solvent was evaporated in vacuo to give a brown gummy residue which was taken up into dilute hydrochloric acid (200 ml), washed with ethyl acetate (2×100 ml), made basic with potassium carbonate, extracted into dichloromethane (3×50 ml), dried (MgSO4) then evaporated in vacuo to give a white solid which was triturated with ethyl acetate and dried to give 4-(1-piperazinyl)indole (0.78 g, 0.0038 moles) as white crystals.
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[C:10]([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)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:27][OH:28].[OH-].[Na+]>C(O)C>[C:1]1([C:7]2[S:8][CH:9]=[C:10](/[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)=[N:27]\[OH:28])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1cc(C(=O)c2csc(-c3ccccc3)n2)cc(OC)c1OC
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(/C(=N/O)c2csc(-c3ccccc3)n2)cc(OC)c1OC
Temperature: 55 °C
Reaction time: 3 h

Procedure:
To a suspension of 1h (210 mg, 0.59 mmol) in 10 mL ethanol was added an aqueous solution (2 mL) of hydroxylamine hydrochloride (127 mg, 1.83 mmol). Then 2 mL 1 N NaOH was added dropwise to the reaction mixture and the mixture was stirred at 55° C. for 3 h. After completion of the reaction, the residue was absorbed on silica gel and purified by column chromatography to give compounds 2e-cis (85 mg) and 2e-trans (50 mg). 1H NMR (300 MHz, DMSO-d6) δ 11.95 (s, 1H), 8.35 (s, 1H), 7.91-7.89 (m, 2H), 7.50-7.44 (br, 3H), 6.85 (s, 2H), 3.73 (s, 6H), 3.70 (s, 3H). MS (ESI) m/z 393.1 (M+Na)+; 368.9 (M−H)−.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:14]2[C:19]3[CH:20]=[CH:21][C:22]([O:24][CH2:25][O:26][CH3:27])=[CH:23][C:18]=3[O:17][CH2:16][CH:15]2[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][O:36][CH3:37])=[CH:30][CH:29]=2)[CH:11]=[CH:12][CH:13]=1.[I-:38].[Na+].O>C(C(C)=O)C>[I:38][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:14]2[C:19]3[CH:20]=[CH:21][C:22]([O:24][CH2:25][O:26][CH3:27])=[CH:23][C:18]=3[O:17][CH2:16][CH:15]2[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][O:36][CH3:37])=[CH:30][CH:29]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: COCOc1ccc(C2COc3cc(OCOC)ccc3C2c2cccc(OCCCCCCl)c2)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: O
Product: COCOc1ccc(C2COc3cc(OCOC)ccc3C2c2cccc(OCCCCCI)c2)cc1
Temperature: 25 °C
Yield: 94.7 %

Procedure:
4-[3-(5-Chloropentyloxy)phenyl]-7-methoxymethyloxy-3-[4-(methoxymethyloxy)phenyl]-2,3-dihydro-4H-benzopyran (283 mg, 0.5 mmol) and sodium iodide (24 mg, 1.6 mmol) were dissolved in methyl ethyl ketone (5 ml) and then refluxed for 12 hours. The reaction mixture was cooled to room temperature and then water was added thereto. The reaction solution was extracted with ethyl acetate and the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to remove the organic solvent. The concentrate was separated by column chromatography (n-hexane:ethyl acetate=8:1) to obtain 293 mg (yield: 94%) of the title compound as a yellow oil.
Reaction SMILES: [O:1]([CH:9]1[CH2:13][C:12](=[O:14])[CH:11]=[CH:10]1)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>[Cl-].[Cl-].[Zn+2]>[Si:2]([O:1][C@@H:9]1[CH2:13][C@H:12]([OH:14])[CH:11]=[CH:10]1)([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OC1C=CC(=O)C1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Product: CC(C)(C)[Si](C)(C)O[C@H]1C=C[C@@H](O)C1
Temperature: -20 °C
Reaction time: 2 h
Yield: 64.4 %

Procedure:
A stirred solution of ZnCl2 (19 mL, 19 mmol, 1M in ether) is treated with 4-tert-butyldimethylsiloxy-2-cyclopentenone (2.0 g, 9.42 mmol) under an atmosphere of argon. The solution is cooled to -20° C. and treated dropwise with lithium aluminum hydride (9.0 mL, 9.0 mmol, 1M in ether) at such a rate as to keep the reaction temperature at or below -15° C. After stirring for about 2 hours at -20° C., approximately 5 mL of 1N NaOH was added. The reaction is filtered through diatomaceous earth, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide the title compound (1.3 g); cis/trans/l-2+l-4 addition, 81/3/16.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH:11]([F:13])[F:12])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH:14]([Mg]Br)=[CH2:15]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH:11]([F:12])[F:13])=[C:6]([CH:7]([OH:8])[CH:14]=[CH2:15])[CH:9]=1
Reactant: O=Cc1cc(Cl)ccc1OC(F)F
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: C=CC(O)c1cc(Cl)ccc1OC(F)F
Temperature: -78 °C
Reaction time: 2 h
Yield: 102.9 %

Procedure:
5-Chloro-2-(difluoromethoxy)benzaldehyde (0.480 g, 2.324 mmol) was dissolved in dry THF (11.62 mL) and the reaction was cooled to −78° C. under argon. Vinyl magnesium bromide (3.49 mL, 3.49 mmol) was then added dropwise. After the reaction was complete, the ice bath was removed and reaction was allowed to warm to rt and stirred for an additional 2 h. The reaction was cooled to 0° C. and then carefully quenched with saturated ammonium chloride. The mixture was then diluted with water and extracted with EtOAc (3×). The combined organic phases were dried over Na2SO4, filtered and concentrated to yield 1-(5-chloro-2-(difluoromethoxy)phenyl)prop-2-en-1-ol (561 mg, 103%) as a clear oil. MS (ESI) m/z: 236.9 (M+H, Chlorine isotope peak)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9]2[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:12](=[O:21])[C:11](=[C:22]3[N:26]([CH3:27])[C:25]4[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=4[S:23]3)[S:10]2)[CH:5]=[CH:6][CH:7]=1.C(Cl)Cl.[C:35]1(=[O:41])[O:40][C:38](=[O:39])[CH2:37][CH2:36]1>C(Cl)(Cl)Cl>[CH2:14]([N:13]1[C:12](=[O:21])[C:11](=[C:22]2[N:26]([CH3:27])[C:25]3[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=3[S:23]2)[S:10][C:9]1=[N:8][C:4]1[CH:3]=[C:2]([NH:1][C:35](=[O:41])[CH2:36][CH2:37][C:38]([OH:40])=[O:39])[CH:7]=[CH:6][CH:5]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C1CCC(=O)O1
Reactant: CN1C(=C2SC(=Nc3cccc(N)c3)N(Cc3ccccc3)C2=O)Sc2ccccc21
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CN1C(=C2SC(=Nc3cccc(NC(=O)CCC(=O)O)c3)N(Cc3ccccc3)C2=O)Sc2ccccc21
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 61.2 %

Procedure:
To a 25 mL flask was added 2-(3-aminophenylimino)-3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one (100 mg, 225 μmol), anhydrous DCM (5 mL) and CHCl3 (3 mL). To the solution was added succinic anhydride (23 mg, 239 μmol). The reaction solution was allowed to stir at 50° C. for 1.5 h. The white precipitates were collected by filtration under reduced pressure, washed with DCM (10 mL) and hexanes (20 mL), and then dried under vacuum to give the title compound (75 mg, 61%). MS(ESI): 545 (MH+).
Reaction SMILES: [CH3:1][CH:2]([CH3:33])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)=O)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].Cl.[C:35]1([NH:45]N)[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=[CH:37][CH:36]=1>>[CH3:1][CH:2]([CH3:33])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21]3[C:36]4[C:35](=[C:44]5[CH:43]=[CH:42][CH:41]=[CH:40][C:39]5=[CH:38][CH:37]=4)[NH:45][C:22]=3[C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4]
Reactant: NNc1cccc2ccccc12
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc([N+](=O)[O-])cc3)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccc([N+](=O)[O-])cc4)[nH]c4c3ccc3ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-(3-{1-[5-(4-nitrophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)propanamide and 1-naphthylhydrazine hydrochloride: ESMS m/e: 574.7 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[CH:17][CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].Cl[C:21]1[C:26]([I:27])=[CH:25][N:24]=[CH:23][N:22]=1.[F-].[Cs+].C(N(CC)C(C)C)(C)C>>[I:27][C:26]1[C:21]([NH:1][C@H:2]([C:4]2[N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:8](=[O:16])[C:7]3=[CH:17][CH:18]=[CH:19][N:6]3[N:5]=2)[CH3:3])=[N:22][CH:23]=[N:24][CH:25]=1
Reactant: C[C@H](N)c1nn2cccc2c(=O)n1-c1ccccc1
Reactant: Clc1ncncc1I
Agent: [Cs+]
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncncc1I)c1nn2cccc2c(=O)n1-c1ccccc1
Yield: 15.2 %

Procedure:
(S)-2-(1-Aminoethyl)-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (110 mg, 0.43 mmol) was treated with 4-chloro-5-iodopyrimidine (166 mg, 0.69 mmol), cesium fluoride (131 mg, 0.86 mmol) and N,N-diisopropylethylamine (377 μL, 2.16 mmol) according to Preparation 13. The residue was purified by reverse phase using SP1® Purification System to give 30 mg (13% yield) of the title compound as a solid. Purity 86%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([O:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=2)[CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]([OH:20])=O)=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C[N:34](C)CCCN=C=NCC.[NH4+].ON1C2C=CC=CC=2N=N1.CN(C)C=O>O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([O:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:29])=[O:30])=[CH:24][CH:23]=2)[CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]([NH2:34])=[O:20])=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(Oc2cc(OCc3ccccc3)c3[nH]c(C(=O)O)cc3c2)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(Oc2cc(OCc3ccccc3)c3[nH]c(C(N)=O)cc3c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.9 %

Procedure:
A mixture of 7-(benzyloxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylic acid (1.59 g), 1-[3-(dimethylamino)propyl-3-ethylcarbodiimide hydrochloride (1.4 g), 1-hydroxybenzotriazole ammonium salt (1.1 g) and N,N-dimethylformamide (40 mL) was stirred at room temperature for 16 hr. Water was added to the reaction solution, and the precipitated solid was collected by filtration, and washed successively with water, ethanol and diethyl ether to give the title compound (1.6 g, yield 100%) as a pale-yellow solid. The pale-yellow solid was recrystallized from N,N-dimethylformamide-water to give pale-yellow crystals. melting point 251-252° C.
Reaction SMILES: [OH:1][C:2]1[S:3][C:4]2[CH2:14][CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[O:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:5]=2[N:6]=1.[H-].[Na+].[C:24]1([CH:30]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:31][CH2:32]I)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CN(C)C=O>O>[C:24]1([CH:30]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:31][CH2:32][O:1][C:2]2[S:3][C:4]3[CH2:14][CH2:13][C:12]4[C:7](=[CH:8][CH:9]=[CH:10][C:11]=4[O:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:5]=3[N:6]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: ICCC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)COc1cccc2c1CCc1sc(O)nc1-2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc2c1CCc1sc(OCCC(c3ccccc3)c3ccccc3)nc1-2
Temperature: 70 °C
Reaction time: 2 h
Yield: 35.4 %

Procedure:
A mixture of ethyl [(2-hydroxy-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acetate (1.40 g, 4.58 mmol), sodium hydride (60% dispersion in liquid paraffin, 200 mg, 5.00 mmol), 3,3-diphenylpropyl iodide (1.60 g, 5.04 mmol), and N,N-dimethylformamide (30 ml) was stirred at 70° C. for 2 hours. This reaction mixture was poured into water (50 mL) and extracted with 2 portions of ethyl acetate. The pooled organic solution was washed with water, dried over MgSO4, and filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate=8:1) to provide 810 mg of ethyl [[2-(3,3-diphenylpropyl)oxy-4,5-dihydronaphtho[1,2-d]thiazol-6-yl]oxy]acetate. To a solution of this compound (700 mg, 1.40 mmol) in a mixture of tetrahydrofuran (8 mL) and methanol (2 mL) was added 1N-aqueous sodium hydroxide solution (1.4 mL) dropwise and the mixture was stirred at room temperature for 5 minutes. To this reaction mixture was added 1N-hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure and the residue was recrystallized from ethyl acetate-hexane to provide 500 mg of the title compound. Yield 24%.