Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].N1C=CC=CC=1.[C:26](Cl)(=[O:28])[CH3:27].C.[CH2:31]([O:33]CC)[CH3:32]>C(Cl)Cl.O>[Cl:13][C:12]1[C:7]([N:6]2[C:2]([N:1]([C:31]([CH3:32])=[O:33])[C:26]([CH3:27])=[O:28])=[C:3]([C:18]#[N:19])[CH:4]=[N:5]2)=[N:8][CH:9]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:11]=1
Reactant: N#Cc1cnn(-c2ncc(C(F)(F)F)cc2Cl)c1N
Reactant: CCOCC
Reactant: CC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N(C(C)=O)c1c(C#N)cnn1-c1ncc(C(F)(F)F)cc1Cl
Temperature: 5 °C

Procedure:
Under a dry nitrogen atmosphere, a stirred mixture of 5.02 grams (0.0175 mole) of 5-amino-1-(3-chloro-5-trifluoromethylpyridin-2-yl)-4-cyanopyrazole and 12.7 grams (0.161 mole) of pyridine in 470 mL of methylene chloride was cooled to 5° C. Acetyl chloride (12.5 grams, 0.159 mole) was added dropwise. After the addition was complete, the reaction mixture was heated at reflux for approximately 20 hours. The mixture was then cooled, treated with decolorizing charcoal, and filtered through a pad of Celite® filter aid. The filtrate was evaporated under reduced pressure, leaving a residue. This residue was stirred vigorously with a mixture of water and diethyl ether. The diethyl ether was allowed to evaporate at room temperature and pressure, leaving an aqueous slurry, which was cooled in an ice bath and then filtered. The filter cake was washed with water and air dried to yield 6.6 grams of 1(3-chloro-5-trifluoromethylpyridin-2-yl)-4-cyano-5-bis(methylcarbonyl)aminopyrazole, m.p. 129.5°-132° C. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][C:2]([S:21]([CH3:24])(=[O:23])=[O:22])([CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:12]=[CH:11]1)[C:3]([O:5]CC)=[O:4].O.[OH-].[Li+]>C1COCC1.CO.O.Cl>[CH3:1][C:2]([S:21]([CH3:24])(=[O:22])=[O:23])([CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:12]=[CH:11]1)[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)(CCn1cnc(-c2ccccc2)c1)S(C)(=O)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(CCn1cnc(-c2ccccc2)c1)(C(=O)O)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
To a solution of ethyl 2-methyl-2-(methylsulfonyl)-4-(4-phenyl-1H-imidazol-1-yl)butanoate (335 mg, 0.956 mmol, 1 eq) in THF/MeOH/Water (4:1:1) was added lithium hydroxide monohydrate (160 mg, 3.82 mmol, 4 eq) and the mixture was allowed to stir at RT overnight. The reaction was diluted with 1 N HCl and loaded onto a 6 g MCX column. The column was washed with 1 column volume water and 2 column volumes MeOH. The washes were discarded. The column was then eluted with 0.5 N NH3 in Methanol. The eluant was concentrated to give 2-methyl-2-(methylsulfonyl)-4-(4-phenyl-1H-imidazol-1-yl)butanoic acid (304 mg, 98% yield). LC-MS M+H+323.4.
Reaction SMILES: [OH:1][CH:2]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[N:20]=1)[CH2:3][O:4][C:5]1[CH:18]=[CH:17][C:8]([CH2:9][CH:10]2[S:14][C:13](=[O:15])[NH:12][C:11]2=[O:16])=[CH:7][CH:6]=1.N1C=CC=CC=1.[C:32](OC(=O)C)(=[O:34])[CH3:33]>O>[C:32]([O:1][CH:2]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[N:20]=1)[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][CH:10]2[S:14][C:13](=[O:15])[NH:12][C:11]2=[O:16])=[CH:17][CH:18]=1)(=[O:34])[CH3:33]
Reactant: Cc1cccc(C(O)COc2ccc(CC3SC(=O)NC3=O)cc2)n1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)OC(COc1ccc(CC2SC(=O)NC2=O)cc1)c1cccc(C)n1
Reaction time: 48 h

Procedure:
A mixed solution of 5-{4-[2-hydroxy-2-(6-methyl-2-pyridyl)ethoxy]benzyl}-2,4-thiazolidinedione (350 mg), pyridine (5 ml) and acetic anhydride (0.2 ml) was allowed to stand at room temperature for 2 days, and then poured in water, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and freed of the solvent. The residue was chromatographed on a silica gel (20 g) column, and elution was effected with benzene-acetone (15:1, V/V) to give 5-{4-[2-acetoxy-2-(6-methyl-2-pyridyl)ethoxy]benzyl}-2,4-thiazolidinedione in the form of an oily substance. Yield of 360 mg (89.8%). IR (neat): 1740, 1690, 1230 cm-1. NMR (CDCl3)δ: 211(3H,s), 2.51(3H,s), 3.02 (1H,dd,J=14 and 9 Hz), 3.41(1H,dd,J=14 and 4 Hz), 4.37(2H,d, J=5 Hz), 4.44(1H,dd,J=9 and 4 Hz), 6.13(1H,t,J=5 Hz), 6.83(2H, d,J=9 Hz), 7.09(2H,d,J=9 Hz), 7.0-7.7(3H,m).
Reaction SMILES: Cl.[CH2:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH:4]([C:12]([OH:14])=[O:13])[NH:3]1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.C(N(CC)CC)C>ClCCl>[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([S:23]([N:3]2[CH:4]([C:12]([OH:14])=[O:13])[CH2:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:2]2)(=[O:25])=[O:24])=[CH:21][CH:22]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(O)C1Cc2ccccc2CN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N2Cc3ccccc3CC2C(=O)O)cc1

Procedure:
1,2,3,4-Tetrahydro-3-isoquinolinecarboxylic acid hydrochloride is reacted with 4-methoxybenzenesulfonyl chloride in dichloromethane in the presence of triethylamine, to give 2-[(4-methoxyphenyl)sulfonyl]-1,2,3,4-tetrahydro-3-isoquinoline carboxylic acid.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[CH:20][C:6]1=2)=[O:4].[NH:21]1[CH2:26][CH:25]([CH:27]2[CH2:32][CH2:31][CH2:30][N:28]2[CH3:29])[CH2:24][CH2:23][CH2:22]1>C(OCC)(=O)C>[CH3:29][N:28]1[CH2:30][CH2:31][CH2:32][CH:27]1[CH:25]1[CH2:24][CH2:23][CH2:22][N:21]([CH2:2][C:3]([N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[NH:8][C:7]3[CH:17]=[CH:18][CH:19]=[CH:20][C:6]2=3)=[O:4])[CH2:26]1
Reactant: CN1CCCC1C1CCCNC1
Reactant: O=C1Nc2ccccc2N(C(=O)CCl)c2ccccc21
Solvent: CCOC(C)=O
Product: CN1CCCC1C1CCCN(CC(=O)N2c3ccccc3NC(=O)c3ccccc32)C1

Procedure:
The title compound is prepared analogously to Example 35 from 5-(chloroacetyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one and hexahydronicotine to give colorless crystals, mp. 161°-163° C. (ethyl acetate).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([O:19]CC)=[O:18])=[CH:5]2.[C:22](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1.C(OCC)(=O)C>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:22][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2
Reactant: CCOC(=O)C1=Cc2cc(Br)c(F)cc2OC1C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc2c(cc1F)OC(C(F)(F)F)C(C(=O)O)=C2
Temperature: 110 °C

Procedure:
To the mixture of ethyl 6-bromo-7-fluoro-2-(trifluoromethyl)-2H-chromene-3-carboxylate (2.2g, 6 mmol), potassium carbonate(3.22g, 23.4mmol), and tetrakis(triphenylphosphine)palladium (0) (700 mg, 0.6 mmol) in 18 ml of anhydrous DMF was added trimethylboroxine(2.5 mL, 9 mmol). The resulting mixture was heated to 110° C. under nitrogen atmosphere for 15 hrs. After cooling to room temperature, to the reaction was added 200 mL of ethyl acetate, the resulting organic phase was washed with brine, and dried over anhydrous magnesium sulfate. After removing the solvents, the residue was purified on a short silica gel column with hexane/EtOAc mixture. The collected fraction was then evaporated to dryness. 300 mg of the purified intermediate was then dissolved in 9 mL of 1:1:1 THF/EtOH/Water, followed by addition of lithium hydroxide hydrate (102 mg). The resulting solution was heated to 80° C. for 1.5 hrs. The volatiles were then removed, the residue was diluted with water, and acidified at 0° C. with dilute hydrochloric acid. Plenty of precipitates were formed. The product was then extracted with ethyl acetate. After removing the solvents, the crude product was purified on reverse phase HPLC. Light yellow solid. 1H NMR (CDCl3/CD3OD/300 MHz) 7.76(s, 1H), 7.07(d, J=8.1 Hz, 1H), 6.68(d, J=9.9 Hz, 1H), 5.65(q, J=6.9 Hz, 1H), 2.20(s, 3H). 19F NMR(CDCl3/CD3OD/300 MHz) −78.93(d, J=6.9 Hz), −107.11(t, J=7.9 Hz). 13C NMR(CDCl3/CD3OD/300 MHz) 168.0, 165.8, 162.3, 153.2(d, J=12.8 Hz), 138.4, 132.2, 123.6(q, J=287.5 Hz), 119.8(d, J=18.5 Hz), 115.0(d, J=43.2 Hz), 104.1(d, J=27.1 hz), 70.7(q, J=33.3 Hz), 14.0(d, J=3.2 Hz). LC-MS(ES+): 277.2(M+1, 100). Hight resolution mass(ES−): m/z calc. For C12H8F4O3: 275.0337(M−H), found: 275.0341.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH2:15])[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1.Cl[C:17](=[O:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH:15][C:17](=[O:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1
Reactant: Nc1nc2cccc(-c3ccoc3)n2n1
Reactant: CCOC(=O)CC(=O)Cl
Product: CCOC(=O)CC(=O)Nc1nc2cccc(-c3ccoc3)n2n1

Procedure:
The title compound was prepared following procedure described for intermediate B1, but starting from 5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 660 mg; 0.30 mmol; 1.0 eq.) and ethyl 3-chloro-3-oxopropionate (90 mg, 0.60 mmol; 2.0 eq.) as a white powder (42 mg, 45%). HPLC, Rt: 2.72 min. (purity 90.8%). LC/MS, M+(ESI): 315.3, M−(ESI): 313.3.
Reaction SMILES: C([O:3][P:4](Cl)[O:5]CC)C.[CH2:9]([Mg]Br)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O.Cl.[CH2:21](OCC)C>>[C:11]1([CH2:10][CH2:9][CH2:21][PH:4](=[O:3])[OH:5])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOP(Cl)OCC
Reactant: Br[Mg]CCc1ccccc1
Reactant: CCOCC
Agent: Cl
Solvent: O
Product: O=[PH](O)CCCc1ccccc1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
Diethylchlorophosphite (15.7 g, 0.1 mol) in 50 mL of dry diethyl ether was cooled to 5° C. under an atmosphere of nitrogen. Phenethylmagnesium bromide (100 mL, 0.1 mol, 1.0 M solution of in Et2O) was added dropwise over 2 hours while maintaining a temperature between 0-10° C. A thick white slurry formed and was stirred for an additional 30 minutes. The mixture was filtered under a nitrogen atmosphere and the filtrate evaporated under reduced pressure to give a clear and colorless liquid. To the liquid was added 20 mL of water followed by 0.5 ml of concentrated hydrochloric acid. An exothermic reaction was observed and stirring continued for 20 minutes followed by extraction with ethyl acetate. The organics were combined, washed with brine, dried (MgSO4) and evaporated. To the clear liquid was added sodium hydroxide (40 mL, 2.0 M NaOH), the resulting solution stirred for 1 hour and then washed with diethyl ether. The aqueous layer was acidified to pH 1.0 with concentrated hydrochloric acid and extracted twice with ethyl acetate. The organics were combined, dried (MgSO4) and evaporated to give 3-phenylpropylphosphinic acid (1, R=CH2CH2CH2Ph, R1 =H) (9.8 g, 53%) as a clear and colorless oil.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][N:5]([CH2:7][CH2:8][OH:9])[CH:6]=1.N1C=CN=C1.[C:15]([Si:19](Cl)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:18])([CH3:17])[CH3:16]>CN(C=O)C.CCOC(C)=O>[Si:19]([O:9][CH2:8][CH2:7][N:5]1[CH:6]=[C:2]([I:1])[CH:3]=[N:4]1)([C:15]([CH3:18])([CH3:17])[CH3:16])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCCn1cc(I)cn1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](OCCn1cc(I)cn1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 111.4 %

Procedure:
A solution of 2-(4-iodo-1H-pyrazol-1-yl)ethanol (Preparation 57) (1.01 g, 4.24 mmol) in DMF (21 mL) was treated with imidazole (410 mg, 6.03 mmol) followed by tert-butylchlorodiphenylsilane (1.321 mL, 5.09 mmol) and the mixture was stirred to room temperature for 18 hours. The mixture was diluted with EtOAc and quenched with brine. The aqueous layer was extracted with EtOAc three times. The combined organic layers were washed with water and brine, dried and concentrated. The residue was purified by silica gel column chromatography eluting with 0 to 10% EtOAc in cyclohexane to give the title compound (2.25 g, quant).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[S:12])[NH:10][NH2:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[Cl:13][C:14]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:15]=1[C:16](=O)[CH2:17]Cl>>[ClH:13].[Cl:13][C:14]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:15]=1[C:16]1[CH2:17][S:12][C:9]([NH:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[N:10][N:11]=1
Reactant: CCCCCCCNC(=S)NN
Reactant: O=C(CCl)c1ccc(Cl)cc1Cl
Product: CCCCCCCNC1=NN=C(c2ccc(Cl)cc2Cl)CS1
Product: Cl

Procedure:
3.78 g (0.02 mole) of 4-n-heptyl-thiosemicarbazide and 4.67 g (0.02 mole) of 2,4-dichlorophenacyl chloride are reacted analogously to Example 1. After recrystallization from methanol/methyl acetate, 5.2 g of 5-(2,4-dichlorophenyl)-N-heptyl-6H-1,3,4-thiadiazin-2-amine monohydrochloride are produced. m.p. 175°-177° C.
Reaction SMILES: [Na].[NH2:2][C:3]([NH2:5])=[O:4].C([O:8][C:9]([C:11]1([C:40](OCC)=[O:41])[CH2:15][CH2:14][CH2:13][N:12]1[C:16]1[CH:17]=[N:18][C:19]([O:22][C:23]2[CH:24]=[C:25]3[C:29](=[CH:30][CH:31]=2)[N:28]([C:32]2[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=2)[N:27]=[CH:26]3)=[CH:20][CH:21]=1)=O)C>C(O)C>[C:38]([C:35]1[CH:36]=[CH:37][C:32]([N:28]2[C:29]3[C:25](=[CH:24][C:23]([O:22][C:19]4[N:18]=[CH:17][C:16]([N:12]5[C:11]6([C:40](=[O:41])[NH:5][C:3](=[O:4])[NH:2][C:9]6=[O:8])[CH2:15][CH2:14][CH2:13]5)=[CH:21][CH:20]=4)=[CH:31][CH:30]=3)[CH:26]=[N:27]2)=[CH:33][CH:34]=1)#[N:39]
Reactant: CCOC(=O)C1(C(=O)OCC)CCCN1c1ccc(Oc2ccc3c(cnn3-c3ccc(C#N)cc3)c2)nc1
Reactant: NC(N)=O
Agent: [Na]
Solvent: CCO
Product: N#Cc1ccc(-n2ncc3cc(Oc4ccc(N5CCCC56C(=O)NC(=O)NC6=O)cn4)ccc32)cc1
Temperature: 80 °C

Procedure:
To a flame dried flask is added ethanol (6 mL) and freshly cut sodium metal (62.4 mg, 2.71 mmol). The solution is stirred until homogenous. Recrystallized urea (98 mg, 1.63 mmol) is added and the solution is stirred at room temperature for 5 minutes. 1-{6-[1-(4-Cyano-phenyl)-1H-indazol-5-yloxy]-pyridin-3-yl}-pyrrolidine-2,2-dicarboxylic acid diethyl ester (0.54 mmol) is added, and the solution is heated to 80° C. for 30 minutes, then cooled to 50° C. and stirred for 16 hours. The reaction is then quenched by the addition of 10 mL water, and 1N hydrochloric acid is added to adjust the pH to 5. The aqueous layer is extracted with ethyl acetate (3×20 mL). The combined ethyl acetate layers are washed with saturated sodium chloride, dried with magnesium sulfate, filtered, and concentrated under vacuum to produce crude product. This material is chromatographed on silica gel (ISCO MPLC purification, 30 minutes, 50-100% ethyl acetate gradient, Biotage flash 40s column) to provide 1-{6-[1-(4-Cyano-phenyl)-1H-indazol-5-yloxy]-pyridin-3-yl}-1,7,9-triaza-spiro[4.5]decane-6,8,10-trione.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:24])[C:5]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23])=[C:6]([CH3:12])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[C:25](Cl)(=[O:27])[CH3:26].S(S([O-])=O)([O-])=O.[Na+].[Na+].[C:37]([Si:41](Cl)([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([CH3:40])([CH3:39])[CH3:38].N1C=CN=C1>ClCCl.O.N1C=CC=CC=1>[C:25]([O:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:5]1[C:4]([OH:24])=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][Si:41]([C:37]([CH3:40])([CH3:39])[CH3:38])([C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:6]=1[CH3:12])(=[O:27])[CH3:26]
Reactant: COC1=C(OC)C(=O)C(CCCCCCCCCCO)=C(C)C1=O
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC(=O)Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: COc1c(O)c(CCCCCCCCCCOC(C)=O)c(C)c(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1OC

Procedure:
2,3-Dimethoxy-6-(10-hydroxydecyl)-5-methylbenzoquinone (3.38 g, 10 mmol) was dissolved in dichloromethane (50 ml). Pyridine (1 ml) followed by acetyl chloride (0.8 ml) was added with stirring under ice-cooling, and the mixture was stirred for 1 hour. Water (5 ml) was added to the reaction mixture which was then stirred for 20 minutes. Then sodium hydrosulfite (4 g) was added, and the mixture was stirred at room temperature for 2 hours. The dichloromethane layer was separated, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in dichloromethane (50 ml), and tert-butylchlorodiphenylsilane (5.5 g, 20 mmol) and imidazole (1.36 g, 20 mmol) were added. The mixture was stirred at 43° C. for 16 hours under a stream of nitrogen. The reaction mixture was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain crude 6-(10-acetoxydecyl)-4-tert-butyldiphenylsilyloxy-2,3-dimethoxy-5-methylphenol. The concentrate was dissolved in dimethylformamide (15 ml). Sulfur trioxide-pyridine complex (3.2 g, 20 mmol) was added, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in methanol (40 ml), and 1N sodium hydroxide solution (60 ml) was added. The mixture was allowed to react for 16 hours. Methanol was distilled off under reduced pressure, and the residue was extracted with ether. The aqueous layer was subjected to Amberlite (trade mark) XAD-II column chromatography and eluted with water followed by 50% ethanol/water. The desired fraction was concentrated and lyophilized to obtain the desired compound (2.8 g).
Reaction SMILES: Br[C:2]1[CH:22]=[C:21]([CH3:23])[C:5]([O:6][C:7]2[C:12]([CH3:13])=[C:11]([NH:14][CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH:10]=[C:9]([CH3:20])[N:8]=2)=[C:4]([CH3:24])[CH:3]=1.[CH2:25]([Li])[CH2:26]CC.C(I)C>C1COCC1>[CH2:25]([C:2]1[CH:22]=[C:21]([CH3:23])[C:5]([O:6][C:7]2[C:12]([CH3:13])=[C:11]([NH:14][CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH:10]=[C:9]([CH3:20])[N:8]=2)=[C:4]([CH3:24])[CH:3]=1)[CH3:26]
Reactant: [Li]CCCC
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(Br)cc2C)c1C
Solvent: C1CCOC1
Solvent: CCI
Product: CCc1cc(C)c(Oc2nc(C)cc(NC(CC)CC)c2C)c(C)c1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of [2-(4-bromo-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-(1-ethyl-propyl)-amine in dry THF was added n-butyllithium at −78° C. After stirring at −78° C. for 10 min, ethyl iodide was added and the resulting mixture was stirred at −78° C. for 30 min, the dry-ice bath was removed. After stirring for 5 min, the mixture was quenched with brine and extracted with ethyl acetate. The organic layer was separated, dried, and concentrated to dryness. The residue was purified through silica gel chromatography to give the title compound. 1H NMR(CDCl3) d 6.89(s,2H), 6.07(s,1H), 3.72(d,1H), 3.34(m,1H), 2.58(q,2H), 2.16(s,3H), 2.12(s,3H), 2.09(s,6H), 1.4-1.7(m,4H), 1.25(t,3H), 0.96(t,6H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([N:8]([C@H:10]2[C@H:14]([OH:15])[CH2:13][N:12]([CH2:16][CH3:17])[CH2:11]2)[CH3:9])=[O:7])=[CH:4][CH:3]=1.[H][H]>C(O)C.[Pd]>[ClH:1].[CH2:16]([N:12]1[CH2:13][C@@H:14]([OH:15])[C@H:10]([N:8]([CH3:9])[C:6](=[O:7])[C:5]2[CH:18]=[CH:19][CH:2]=[CH:3][CH:4]=2)[CH2:11]1)[CH3:17]
Reactant: CCN1C[C@@H](O)[C@H](N(C)C(=O)c2ccc(Cl)cc2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCN1C[C@@H](O)[C@H](N(C)C(=O)c2ccccc2)C1
Product: Cl
Yield: 97.2 %

Procedure:
A solution of 14 g (49.5 mmoles) of trans-4-chloro-N-(1-ethyl-4-hydroxy-3-pyrrolidinyl)-N-methylbenzamide in 150 ml of absolute ethanol was treated with ca. 0.5 g of palladium-on-charcoal catalyst and was shaken with hydrogen at 60° C. in the Parr reduction apparatus for 3 hr. The mixture was cooled and filtered and the filtrate was concentrated. The residue crystallized when it was stirred with 3:1 diethyl ether-acetone. Separation of the precipitate gave 13.7 g (97%) of white powder; m.p. 160°-163° C.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=O)[C:4]=2[CH:3]=[CH:2]1.[CH3:12][CH:13]([CH3:29])[C:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:18]=1)=[O:15]>CC(O)=O>[NH:1]1[C:9]2[C:4](=[C:5]([CH2:10][N:26]3[CH2:27][CH2:28][CH:23]([C:19]4[CH:18]=[C:17]([NH:16][C:14](=[O:15])[CH:13]([CH3:12])[CH3:29])[CH:22]=[CH:21][CH:20]=4)[CH2:24][CH2:25]3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=Cc1cccc2[nH]ccc12
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Solvent: CC(=O)O
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4[nH]ccc34)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R, without HOAc, using 1H-indole-4-carbaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 376.2 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O.C(OCC)(=O)C>[CH3:16][N:8]1[CH:9]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[N:11]=[C:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1c[nH]c(-c2ccccc2)n1
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cn(C)c(-c2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59.6 %

Procedure:
The compound prepared in Example 130 (0.204 g) was suspended in N,N-dimethyl formamide (4 mL) and cooled to 0° C. Potassium carbonate (0.279 g) was added and then iodomethane (0.069 mL). The reaction mixture was stirred at 0° C. for 30 minutes and then warmed to room temperature and stirred at room temperature for further 1 hour. The reaction mixture was diluted with ethyl acetate and washed sequentially with sodium bicarbonate aqueous solution and brine. The organics were dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford the crude material, which was purified by flash column chromatography to furnish the title compound (0.130 g) having the following physical data.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:23]=[C:22]3[C:17]([CH:18]=[C:19]([C:24]([O:26]CC)=[O:25])[CH:20]=[N:21]3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CCO.C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:23]=[C:22]3[C:17]([CH:18]=[C:19]([C:24]([OH:26])=[O:25])[CH:20]=[N:21]3)=[CH:16][CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cnc2cc(N3CCN(C(=O)OC(C)(C)C)CC3)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3cc(C(=O)O)cnc3c2)CC1
Temperature: 60 °C
Reaction time: 5 h
Yield: 80 %

Procedure:
A mixture of ethyl 7-(4-(tert-butoxycarbonyl)piperazin-1-yl)quinoline-3-carboxylate (385 mg, 1 mmol), NaOH (2M, 5 mL) in EtOH (15 mL) and THF (15 mL) was stirred at 60° C. for 5 h. The mixture was concentrated to a residue, to which was added aq.sat. citric acid (10 mL). The solution was extracted with EA(25 mL×2), separated, dried, filtered and concentrated to give the compound 7-(4-(tert-butoxycarbonyl)-piperazin-1-yl)quinoline-3-carboxylic acid (286 mg, 80%) as light yellow solid.