Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][O:13][Si](C(C)(C)C)(C)C)=[CH:8][C:7]=1[NH:21][C:22](=[O:40])[CH2:23][CH:24]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][C:31]=1[O:38][CH3:39])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])([CH3:5])([CH3:4])[CH3:3]>CO.C(Cl)Cl.C(OCC)C>[C:2]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][OH:13])=[CH:8][C:7]=1[NH:21][C:22](=[O:40])[CH2:23][CH:24]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][C:31]=1[O:38][CH3:39])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])([CH3:3])([CH3:4])[CH3:5]
Reactant: CCCCCC(CC(=O)Nc1cc(CO[Si](C)(C)C(C)(C)C)ccc1C(C)(C)C)c1ccc(OC)cc1OC
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCCC(CC(=O)Nc1cc(CO)ccc1C(C)(C)C)c1ccc(OC)cc1OC
Reaction time: 0.67 h
Yield: 96.5 %

Procedure:
0.1 ml of concentrated aqueous hydrochloric acid was added, with stirring and ice-cooling, to a solution of 460 mg (0.828 mmol) of N-[2-t-butyl-5-(t-butyldimethylsilyloxymethyl)phenyl]-3-(2,4-dimethoxyphenyl)octanamide (prepared as described in Preparation 8) in a mixture of 9 ml of methanol and 1 ml of methylene chloride, and the resulting mixture was allowed to stand at the same temperature for 40 minutes, after which it was diluted with diethyl ether. The diluted solution was washed twice with water and once with a saturated aqueous solution of sodium chloride, after which it was dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was recrystallized from a mixture of hexane and ethyl acetate to give 353 mg (yield 96%) of the title compound as crystals, melting at 125°-126° C.
Reaction SMILES: [CH3:1]/[C:2](/[C:5]([CH3:7])=[O:6])=[N:3]\[OH:4].[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1.Cl>C(O)(=O)C>[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]2[O:6][C:5]([CH3:7])=[C:2]([CH3:1])[N+:3]=2[O-:4])=[CH:12][CH:11]=1
Reactant: CC(=O)/C(C)=N/O
Reactant: COc1ccc(C=O)cc1
Agent: Cl
Solvent: CC(=O)O
Product: COc1ccc(-c2oc(C)c(C)[n+]2[O-])cc1

Procedure:
50.6 g of Diacetylmonoxime and 66.7 ml of 4-methoxy-benzaldehyde are added to 100 ml of glacial acetic acid, and HCl gas is introduced for 30 minutes, with ice-cooling. The product is precipitated as the hydrochloride by addition of methyl tert-butyl ether and filtered off with suction, and the precipitate is washed with methyl tert-butyl ether. The precipitate is suspended in water and the pH is made alkaline using ammonia. The mixture is extracted three times with in each case 200 ml of dichloromethane, the combined organic phases are dried over MgSO4 and the solvent is then removed under reduced pressure. This gives 82.1 g of 2-(4-methoxy-phenyl)-4,5-dimethyl-oxazole 3-oxide as a white solid. C12H13NO3 (219.24), MS (ESI)=220 (M+H+).
Reaction SMILES: [C:1]([NH:4][CH:5]([C:9]#[N:10])[C:6]([O-:8])=[O:7])(=O)[CH3:2].[C:11]1([CH3:17])C=CC=CC=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:27])=CC=1.Cl>CO>[CH2:11]([O:8][C:6]([C:5]1[N:4]=[C:1]([CH3:2])[S:27][C:9]=1[NH2:10])=[O:7])[CH3:17]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1ccccc1
Reactant: CC(=O)NC(C#N)C(=O)[O-]
Agent: Cl
Solvent: CO
Product: CCOC(=O)c1nc(C)sc1N
Temperature: 70 °C
Reaction time: 16 h

Procedure:
Add acetoamidocyanoacetate (1000 g, 5.88 mol) to a 22 L 3-necked RB flask equipped with reflux condenser, thermometer, mechanical stirrer then add toluene (12L). Add to this suspension at RT Lawesson's reagent (1187 g, 2.93 mol). Stir the resulting yellow slurry at 70° C. for 16 h, cool to RT. Pour the top yellow solution away from the gummy material on the bottom of the flask into a separation funnel. Add 1N HCl solution (2.5L) and TBEA (2.5L) and stir the mixture. After 15 min., combine the bi-phase solution was into the toluene solution in the funnel. Gummy material maybe left in the flask. Repeat the above procedure again. Separate the aqueous and wash the combine organic solution with 1N HCl (2×2.5L). Separate the organic layer and combine the aqueous and basify with 2N KOH solution. Add ethyl acetate (3×4L) and extract the product. Combine the organic layer, dry over anhydrous sodium sulfate, and evaporate to give 552 g as a pale yellow solid. Dissolve the remaining gummy in methanol (1L) and evaporate to dryness. Add MTBE (2.5L) and 1N HCl (4 L) and stir the mixture. After 15 min., separate the organic layer and basify the aqueous with 2N KOH solution Extract the product with ethyl acetate (2×2L). Combine the organic layers and dry over anhydrous sodium sulfate and evaporate to give 165 g as a pale yellow solid. (Total: 717 g, 65%). Mass spectrum (m/e): 187(M+1); 1HNMR(300 MHz, DMSO-d6, ppm): δ 1.21(t, 3H), 2.38(s, 3H), 4.21(q, 2H), 7.21(bs, 2H). 13CNMR(75 MHz, DMSO, ppm): δ 15.1, 19.2, 59.8, 119.3, 145.6, 161.7, 164.1. Formula: C7H10N2O2S.
Reaction SMILES: [CH:1]([N:3]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11])=O.P(Cl)(Cl)(Cl)=O.[S:29](=[O:33])(=[O:32])([OH:31])[OH:30]>C1(C)C=CC=CC=1.C(O)(C)C>[S:29]([O-:33])([OH:32])(=[O:31])=[O:30].[Cl:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH2:4][N+:3]1[CH2:12][CH2:13][C:14]2[C:19](=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=2)[CH:1]=1
Reactant: O=S(=O)(O)O
Reactant: COc1ccc(CCN(C=O)Cc2ccccc2Cl)cc1OC
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: COc1cc2c(cc1OC)CC[N+](Cc1ccccc1Cl)=C2
Product: O=S(=O)([O-])O

Procedure:
N-Formyl-N(2-chlorobenzyl)-2(3,4-dimethoxyphenyl)-ethylamine (12.1 g) are dissolved in toluene (50 ml), combined with phosphorus oxychloride (15.2 g=9 ml) and heated under reflux for 1.5 hours. The mixture is concentrated, the residue is mixed with ice, made alkaline with potassium carbonate and extracted with ethyl acetate. The ethyl acetate extract is concentrated by evaporation. The residue obtained is dissolved in isopropanol and mixed with conc. sulphuric acid (2 ml). After cooling, the mixture is suction filtered, washed with isopropanol and ether and dried. Yield: 8.6 g. Melting point: 226°-228° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:11]=[N:12][C:13]([NH2:16])=[CH:14][CH:15]=2)=[C:6]([CH3:17])[N:5]=[C:4]([NH2:18])[N:3]=1.[C:19]([O:23][C:24](=[O:32])[NH:25][CH:26]1[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]1)([CH3:22])([CH3:21])[CH3:20].C(OCC)(=O)C.C([O-])([O-])=O.[Na+].[Na+]>CN1C(=O)CCC1.CS(C)=O>[C:19]([O:23][C:24](=[O:32])[NH:25][CH:26]1[CH2:31][CH2:30][CH2:29][N:28]([C:2]2[C:7]([C:8]#[C:9][C:10]3[CH:11]=[N:12][C:13]([NH2:16])=[CH:14][CH:15]=3)=[C:6]([CH3:17])[N:5]=[C:4]([NH2:18])[N:3]=2)[CH2:27]1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Reactant: Cc1nc(N)nc(Cl)c1C#Cc1ccc(N)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1nc(N)nc(N2CCCC(NC(=O)OC(C)(C)C)C2)c1C#Cc1ccc(N)nc1

Procedure:
The title compound is synthesized according to general procedure GP7 starting from 2.0 g (7.7 mmol) 4-chloro-6-methyl-5-(6-amino-pyridin-3-ylethynyl)-pyrimidin-2-ylamine and 2.0 g (10.0 mmol) piperidin-3-yl-carbamic acid tert-butyl ester using 1.29 mL (9.2 mmol) triethylamine in 5 mL NMP and 5 mL DMSO. 200 mL ethyl acetate and 100 mL half concentrated aqueous Na2CO3 solution are added and the phases are separated. The aqueous phase is extracted 2 times with ethyl acetate (100 mL each). The combined organic layers are dried over sodium sulfate and the solvent is removed under reduced pressure. The crude product is used without further purification in the next step.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[NH:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1.[C:13]1([CH3:28])[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]2[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=2)[CH:14]=1.O>CN(C)C=O>[CH3:3][C:4]1[N:8]([CH2:24][C:23]2[CH:22]=[CH:21][C:20]([O:19][C:15]3[CH:14]=[C:13]([CH3:28])[CH:18]=[CH:17][CH:16]=3)=[CH:27][CH:26]=2)[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]=1
Reactant: Cc1nc2ccccc2[nH]1
Reactant: Cc1cccc(Oc2ccc(CBr)cc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc(Oc2ccc(Cn3c(C)nc4ccccc43)cc2)c1
Reaction time: 1 h
Yield: 71.1 %

Procedure:
To a suspension of sodium hydride (0.14 g, 3.6 mmole; 62% in oil) in anhydrous dimethylformamide (10 ml), 2-methylbenzimidazole (0.48 g, 3.6 mmole) was added while stirring, and stirring was continued at room temperature for 1 hour. The resultant mixture was cooled to 5°-10° C., and a solution of 4-(3-tolyloxy)benzyl bromide (1.00 g, 3.6 mmole) in anhydrous dimethylformamide (5 ml) was dropwise added thereto in 30 minutes, followed by stirring at room temperature overnight. After completion of the reaction, the reaction mixture was poured into water (100 ml) and extracted with toluene (30 ml) two times. The toluene layer was washed with water, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove toluene. The residue was purified by silica gel column chromatography to give 2-methyl-1-[4-(3-tolyloxy)benzyl]benzimidazole (0.84 g) as colorless liquid. nD27.0 1.6112.
Reaction SMILES: [CH3:1][O:2][N:3]1[C:8]([CH3:10])([CH3:9])[CH2:7][C:6](=[O:11])[CH2:5][C:4]1([CH3:13])[CH3:12].CC(O)([C:17]#[N:18])C.S(=O)(=O)(O)O.[C:25]([O-:28])(O)=O.[Na+]>C(O)(=O)C>[CH3:1][O:2][N:3]1[C:8]([CH3:9])([CH3:10])[CH2:7][C:6]2([O:11][CH2:17][NH:18][C:25]2=[O:28])[CH2:5][C:4]1([CH3:13])[CH3:12]
Reactant: O=C([O-])O
Reactant: CON1C(C)(C)CC(=O)CC1(C)C
Reactant: CC(C)(O)C#N
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: CON1C(C)(C)CC2(CC1(C)C)OCNC2=O
Temperature: 70 °C
Reaction time: 18 h

Procedure:
0.61 g of 1-Methoxy-2,2,6,6-tetramethyl-piperidin-4-one and 299 mg acetone cyanhydrine are dissolved in 1.76 g acetic acid and 0.7 g conc. sulfuric acid is added. The reaction mixture is stirred at 70° C. for 18 h. The reaction mixture is added to 40 ml saturated NaHCO3 solution, and extracted with 40 ml ethyl acetate. The organic phase is washed with H2O and subsequently dried over sodium sulfate. The solvent is removed in vacuo to leave 0.61 g of a tan residue. The residue is recrystallized from hexane to yield 0.29 g product. White solid, mp. 130° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([F:11])[CH:3]=1.S(=O)(=O)(O)O.[Br:17]Br>S([O-])([O-])(=O)=O.[Ag+2]>[Br:17][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([F:11])=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Reactant: BrBr
Agent: [Ag+2]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Product: O=[N+]([O-])c1cc(Br)c(Cl)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a mixture of 4-chloro-2-fluoronitrobenzene (1.00 g), silver sulfate (1.95 g) and concentrated sulfuric acid (5 ml), bromine (0.32 ml) was added under ice cooling and the resulting mixture was stirred at 0° C. for 30 min, then at room temperature for 1 h. The reaction mixture was put into ice water and subjected to extraction with ether. The organic layer was washed with water, a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution sequentially, dried with anhydrous sodium sulfate and concentrated under reduced pressure to give 1.38 g of the titled compound (yield, 95%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[O:6][C:7]1[C:12](/[C:13](=[CH:18]\[O:19][CH3:20])/[C:14]([O:16][CH3:17])=[O:15])=[CH:11][CH:10]=[CH:9][N:8]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.O>ClCCl>[CH:2]([C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[O:6][C:7]1[C:12](/[C:13](=[CH:18]\[O:19][CH3:20])/[C:14]([O:16][CH3:17])=[O:15])=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:1]
Reactant: CO/C=C(/C(=O)OC)c1cccnc1Oc1cccc(CO)c1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: O
Product: CO/C=C(/C(=O)OC)c1cccnc1Oc1cccc(C=O)c1
Reaction time: 3 h
Yield: 54.8 %

Procedure:
To a stirred solution of (E)-methyl 2-[2-(3-hydroxymethylphenoxy)pyridin-3-yl]-3-methoxypropenoate (0.250 g) in dichloromethane (5 ml) at room temperature was added pyridinium dichromate (0.414 g). After stirring for 3 hours, GC analysis of an aliquot indicated the absence of starting material. Water was added and stirring continued for 10 minutes. The reaction mixture was filtered (filter washed through with water (5 ml) and dichloromethane (5 ml)) and then further diluted with dichloromethane (5 ml). The organic layer was separated and the aqueous phase further extracted with dichloromethane (× 3). The combined organic layers were dried, filtered and evaporated to give a dark yellow oil. Chromatography on silica gel (eluent ether-petroleum ether, 7:3) afforded (E)-methyl 2-[2-(3-formylphenoxy)pyridin-3-yl]-3-methoxypropenoate (0.136 g, 55%) as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([CH3:15])[CH:9]=1.[CH3:16][O:17][CH:18]([O:21][CH3:22])[CH2:19]Br.O>CN(C=O)C.CCOC(C)=O>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:19][CH:18]([O:21][CH3:22])[O:17][CH3:16])=[C:10]([CH3:15])[CH:9]=1
Reactant: COC(CBr)OC
Reactant: Cc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(COc1ccc(Br)cc1C)OC
Temperature: 25 °C
Yield: 39.9 %

Procedure:
Powdered potassium carbonate (3.36 g, 24.3 mmol) is added to a stirred solution of 4-bromo-2-methylphenol (3.03 g, 16.2 mmol) and bromoacetaldehyde dimethyl acetal (3.56 g, 21.1 mmol) in anhydrous DMF (20 mL). The resultant mixture is stirred at 85° C. under nitrogen for 24 hours. The mixture is cooled to ambient temperature; then water (100 mL) and EtOAc (100 mL) are added to the mixture. The organic layer is separated, dried over MgSO4, filtered and concentrated. The oil is chromatographed on silica (gradient 5-20% EtOAc in hexane) to give 1.78 g (6.47 mmol, 40% yield) of the title compound. EIMS: m/z 274 (M+, 79Br), 276 (M+, 81Br). Analysis for C11H15BrO3: calcd: C, 48.02; H, 5.50; found: C, 48.32; H, 5.53.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:19])=[CH:4][C:5]2[C:14]3[C:9](=[C:10]([CH3:15])[N:11]=[CH:12][CH:13]=3)[C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[CH:18]=1.[H-].[Na+].[CH3:22]I>CN(C=O)C.O>[Cl:1][C:2]1[C:3]([O:19][CH3:22])=[CH:4][C:5]2[C:14]3[C:9](=[C:10]([CH3:15])[N:11]=[CH:12][CH:13]=3)[C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[CH:18]=1
Reactant: CI
Reactant: Cc1nccc2c1c(=O)n(C)c1cc(Cl)c(O)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c3ccnc(C)c3c(=O)n(C)c2cc1Cl
Temperature: 25 °C
Reaction time: 10 h
Yield: 38.1 %

Procedure:
To the stirred solution of 8-chloro-9-hydroxy-4,6-dimethylbenzo[c][2,7]naphthyridin-5(6H)-one (0.3 g, 1.092 mmol) in DMF (10 mL) cooled to 0° C., was added NaH (0.052 g, 2.184 mmol) followed by methyl iodide (0.205 mL, 3.28 mmol). The resultant mixture was allowed to stir at ambient temperature for 10 h. The reaction mixture was then diluted with water (50 mL) and extracted with ethyl acetate (2×80 mL). The combined organic layers were separated, washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 70% ethyl acetate in petroleum ether to afford 8-chloro-9-methoxy-4,6-dimethylbenzo[c][2,7]naphthyridin-5(6H)-one (0.12 g, 0.416 mmol, 38% yield) as a semi-solid. LC/MS (ESI) m/e 288.4 [(M)+, calcd for C15H13ClN2O2 288.1]; LC/MS retention time (Method A): tR=1.9 min.
Reaction SMILES: [CH:1]12[C:11]3([Cl:15])[C:12]([Cl:14])([Cl:13])[C:8]([Cl:18])([C:9]([Cl:17])=[C:10]3[Cl:16])[CH:2]1[C:3]([O:5][C:6]2=[O:7])=O.C1(C)C=CC=CC=1.[SH:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1>O.O1CCOCC1>[SH:26][C:27]1[CH:33]=[CH:32][C:30]([N:31]2[C:6](=[O:7])[CH:1]3[CH:2]([C:8]4([Cl:18])[C:12]([Cl:13])([Cl:14])[C:11]3([Cl:15])[C:10]([Cl:16])=[C:9]4[Cl:17])[C:3]2=[O:5])=[CH:29][CH:28]=1
Reactant: Nc1ccc(S)cc1
Reactant: O=C1OC(=O)C2C1C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: O=C1C2C(C(=O)N1c1ccc(S)cc1)C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl
Temperature: 25 °C

Procedure:
A 1000 ml 3-neck flask, equipped with a Dean-Stark water trap and a mechanical stirrer, was charged with 102 g (10% molar excess) of chlorendic anhydride, 400 ml toluene and 300 ml of dry dioxane. Thirty-one grams of 4-mercaptoaniline were then added to the resultant solution, whereupon a pale yellow solid formed instantly. The reaction mixture was heated gradually until the solvent began to reflux, at which point the evolution of water commenced and the solid disappeared. About 4.5 ml of water were collected in about 3 hours. Solvent was then distilled to reduce the volume to about one-half its original volume. The resultant solution, when cooled to room temperature, deposited white crystals of the carboximide. The crystals were separated by filtration and dried overnight at room temperature. The melting point of the carboximide was 237°-240° C.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([CH3:12])[C:3]=1[CH2:13][CH2:14]Cl.[NH2:16][CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19]>>[CH2:18]([CH:17]([N:16]1[C:2]2[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=[C:4]([CH3:12])[C:3]=2[CH2:13][CH2:14]1)[CH2:20][CH3:21])[CH3:19]
Reactant: Cc1cc2nc(C)c(CCCl)c(Cl)n2n1
Reactant: CCC(N)CC
Product: CCC(CC)N1CCc2c(C)nc3cc(C)nn3c21
Reaction time: 8 h

Procedure:
A solution of 7-chloro-6-(2-chloroethyl)-2,5-dimethylpyrazolo[1,5-a]pyrimidine (4.0 g, 16 mmol), 3-aminopentane (40 mL) in acetonitryl (120 mL) was heated under reflux for nine hours. After overnight, the residue was purified by silica gel column chromatography (20% ethyl acetate/hexane), to give the title compound (3.7 g) as white crystals.
Reaction SMILES: CCC(OO)=[O:4].[C:7]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:9])[CH3:8]>CC(C)=O>[C:7]([C:15]1[CH:20]=[C:19]([OH:4])[C:18](=[CH:17][CH:16]=1)[OH:21])([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:8])[CH3:9]
Reactant: CC(C)(C)CC(C)(C)c1ccc(O)cc1
Reactant: CCC(=O)OO
Solvent: CC(C)=O
Product: CC(C)(C)CC(C)(C)c1ccc(O)c(O)c1
Yield: 58 %

Procedure:
The procedure of Example 9 was repeated, except 10.4g (0.1 mol) of perisobutyric acid in the form of about 20 weight% acetone solution was added over 30 minutes in place of perpropionic acid. Consequently, the conversion of para-tert.-octyl phenol was 13.2%, 4-tert.-octyl pyrocatechol was formed in a yield of 58% based on the converted octyl phenol and the conversion of perisobutyric acid was 100%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH:5]=[CH:4][C:3]=1[C:20](=[O:22])[CH3:21].Br[CH2:24][C:25]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[C:26]=1[O:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(#N)C>[C:20]([C:3]1[CH:4]=[CH:5][C:6]([O:8][CH2:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[CH:7][C:2]=1[O:1][CH2:24][C:25]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[C:26]=1[O:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])(=[O:22])[CH3:21]
Reactant: CCOC(=O)COc1c(C)cccc1CBr
Reactant: CC(=O)c1ccc(OCc2ccc3ccccc3n2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCOC(=O)COc1c(C)cccc1COc1cc(OCc2ccc3ccccc3n2)ccc1C(C)=O
Temperature: 50 °C

Procedure:
1-[2-Hydroxy-4-(quinolin-2-ylmethoxy)-phenyl]-ethanone (185 mg, 0.63 mmol, example 58) is dissolved in 2:1 DMF/acetonitrile (6 mL). Ethyl (2-bromomethyl-6-methyl-phenoxy)-acetate (272 mg, 0.95 mmol, example 43b) and K2CO3 (177 mg, 1.26 mmol) are added and the contents are heated to 50° C. for 2 days. The reaction is cooled to r.t. and the volume reduced under a nitrogen stream at 40° C. The contents are partitioned between ethyl acetate (50 mL) and water (50 mL). The aqueous layer is further extracted with ethyl acetate (2×50 mL). The organic fractions are combined and washed with brine (3×75 mL), dried over MgSO4 and concentrated. The crude material is dissolved in 1:1 dichloromethane/methanol, preadsorbed onto silica gel, and purified by flash chromatography (silica, 20% ethyl acetate in hexanes) to give the title compound. MS (ion spray) 500 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1>>[F:9][C:7]1[CH:8]=[C:2]([C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([O:11][CH3:10])[CH:17]=2)[CH:3]=[CH:4][C:5]=1[NH2:6]
Reactant: COc1cccc(B(O)O)c1
Reactant: Nc1ccc(Br)cc1F
Product: COc1cccc(-c2ccc(N)c(F)c2)c1
Yield: 75.3 %

Procedure:
The title compound (430 mg) was prepared from 4-bromo-6-fluoroaniline (500 mg, 2.63 mmol) and 3-Methoxyphenylboronic acid (519 mg, 3.42 mmol) as a red liquid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 7.34 (dd, J 2, 13.1, 1H), 7.27 (t, J 7.9, 1H), 7.22 (dd, J 2, 8.3, 1H), 7.12 (d, J 7.9, 1H), 7.09-7.07 (m, 1H), 6.84-6.78 (m, 2H), 5.29 (s, 2H), 3.78 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7](CBr)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:12][NH:13][CH3:14].CO.[C:17](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:12][N:13]([CH2:17][C:4]1([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][CH:7]=[CH:10][CH2:11]1)[CH3:14]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CNC
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: CN(C)CC1([N+](=O)[O-])C=CC=CC1
Yield: 72 %

Procedure:
A mixture of 4-nitrobenzyl bromide (2.16 g, 10 mmol), a solution of dimethylamine in methanol (2 M, 50 ml, 100 mmol), N,N-dimethylformamide (20 ml), and potassium carbonate (2.07 g, 15 mmol) was stirred for 12 hours. The methanol was removed by concentrating under reduced pressure and the mixture was treated with ethyl acetate (200 ml). The mixture was washed with water (100 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to yield 4-(N,N-dimethylaminomethyl)-4-nitrobenzene (0.98 g, 72% yield).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].[CH3:18][O:19][C:20](=[O:38])[CH2:21][C:22]1[C:23]([CH3:37])=[N:24][N:25]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([CH2:35]Cl)=[CH:31][CH:30]=2)[C:26]=1[CH3:27].C(OCC)(=O)C>CN(C)C=O.O>[CH3:18][O:19][C:20](=[O:38])[CH2:21][C:22]1[C:23]([CH3:37])=[N:24][N:25]([CH2:28][C:29]2[CH:30]=[CH:31][C:32]([CH2:35][S:9][C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:10])[F:11])=[CH:8][CH:7]=3)=[CH:33][CH:34]=2)[C:26]=1[CH3:27]
Reactant: FC(F)(F)c1ccc(S)cc1
Reactant: COC(=O)Cc1c(C)nn(Cc2ccc(CCl)cc2)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1c(C)nn(Cc2ccc(CSc3ccc(C(F)(F)F)cc3)cc2)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-(Trifluoromethyl)thiophenol (0.25 ml, 1.8 mmol) was dissolved in 5 ml dimethylformamide, and K2CO3 (337 mg, 2.4 mmol) was added to the solution. A solution of [1-(4-chloromethyl-benzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-acetic acid methyl ester (intermediate 16.1.2, 1 g, 1.6 mmol) in dimethylformamide was added to the mixture within 5 min, and the mixture was stirred for 1 h at room temperature. Ethyl acetate and water were added, the mixture was washed with aqueous NaOH solution (1 M) and with water. The organic layer was dried over MgSO4 and the solvent was evaporated under reduced pressure. The residue was purified by MPLC (silica gel, CH2Cl2/methanol 99:1) and preparative reversed phase HPLC (gradient of methanol in water+0.1% NH3).