Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4](Cl)=[O:5].Cl.[CH2:13]([O:15][C:16](=[O:24])[CH:17]([NH2:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:14].C(N(CC)CC)C.O>ClCCl>[CH2:21]([O:20][C:18](=[O:19])[CH:17]([NH:23][C:4](=[O:5])[C:3]1[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:2]=1[Cl:1])[C:16]([O:15][CH2:13][CH3:14])=[O:24])[CH3:22]
Reactant: O=C(Cl)c1cc(F)ccc1Cl
Reactant: CCOC(=O)C(N)C(=O)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C(NC(=O)c1cc(F)ccc1Cl)C(=O)OCC
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
A solution of 24.4 g of 2-chloro-5-fluoro-benzoyl chloride in 100 ml of dichloromethane was added dropwise to a solution of 26.8 g of aminomalonic acid diethyl ester hydrochloride and 38.6 ml of triethylamine in 50 ml of dichloromethane with cooling in an ice bath. The reaction mixture was stirred for 2 h while the temperature was maintained at 0-5° C. Then 100 ml of water were added slowly. The phases were separated, and the aqueous phase was extracted twice with 100 ml of dichloromethane. The combined organic phases were dried with sodium sulfate, filtered and evaporated to give 39.3 g of the crude title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH:16]2[CH2:25][CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]2O)[CH2:11][CH2:10]1.C(=O)(O)[O-].[Na+].CCOCC>S(=O)(=O)(O)O.C(O)(=O)C.O>[CH:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:24][CH2:25][C:16]=1[CH2:15][N:12]1[CH2:11][CH2:10][N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:14][CH2:13]1
Reactant: COc1ccccc1N1CCN(CC2CCc3ccccc3C2O)CC1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOCC
Product: COc1ccccc1N1CCN(CC2=Cc3ccccc3CC2)CC1
Temperature: 25 °C
Yield: 98.4 %

Procedure:
6.0 g of 1,2,3,4-tetrahydro-2-[[4-(2-methoxyphenyl)-1-piperazinyl]methyl]-1-naphthalenol (prepared as described in Example 1) is suspended in 24 ml of 20% sulfuric acid/acetic acid and the mixture is heated on a steam bath for 15 minutes. The reaction mixture is then cooled room temperature, diluted with water (200 ml) and then made alkaline to pH 8 using sodium bicarbonate solution. The alkaline suspension is extracted with two 250 ml portions of methylene chloride and the organic phase is back-washed with water (250 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The syrup obtained solidifies upon addition of a minimal amount of ether to yield 5.6 g of the title compound, melting point 84°-85° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15]Cl)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[F:24])[C:6]=2[CH:25]=1.[I-].[K+].[CH2:28]([CH:31]=[CH:32][CH2:33][NH2:34])[CH2:29][CH3:30]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][NH:34][CH2:33][CH2:32][CH2:31][CH2:28][CH:29]=[CH2:30])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[F:24])[C:6]=2[CH:25]=1
Reactant: CCCC=CCN
Reactant: Fc1cccc(F)c1C1=NCc2nnc(CCl)n2-c2ccc(Cl)cc21
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCCCCNCc1nnc2n1-c1ccc(Cl)cc1C(c1c(F)cccc1F)=NC2

Procedure:
In the manner given in Preparation 39, 8-chloro-1-(chloromethyl)-6-(2,6-difluorophenyl)-4H-s-triazolo-[4,3-a][1,4]benzodiazepine, potassium iodide and propylallylamine in tetrahydrofuran are reacted to give 8-chloro-1-[(allylpropylamino)methyl]-6-(2,6-difluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine. Preparation 45 8-Nitro-1-[(allylpropylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine
Reaction SMILES: [CH3:1][C:2]([O:7][CH3:8])([CH3:6])[C:3](O)=O.[NH2:9][NH:10][C:11]([NH2:13])=[S:12].P(Cl)(Cl)(Cl)=O.[OH-].[Na+]>C(OCC)C.O.O1CCOCC1>[CH3:8][O:7][C:2]([C:3]1[S:12][C:11]([NH2:13])=[N:10][N:9]=1)([CH3:6])[CH3:1]
Reactant: NNC(N)=S
Reactant: COC(C)(C)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: C1COCCO1
Product: COC(C)(C)c1nnc(N)s1
Temperature: 85 °C

Procedure:
Into a 150 milliliter, 3-neck flask equipped with a Claisen adaptor, paddle stirrer, thermometer, addition funnel and condenser were charged 7.1 grams (0.060 mole) of 2-methyl-2-methoxypropanoic acid, prepared above, (5.5 grams, 0.060 mole) of thiosemicarbazide and 50 milliliters of dry dioxane. The slurry was heated to 85° C. and the addition funnel was charged with phosphorous oxychloride (POCl3). The POCl3 (10.1 grams, 0.066 mole) was slowly added (for 20 minutes) while maintaining the temperature within 85°-95° C. The resulting suspension was refluxed for 1 hour and topped slightly with a water aspirator and then cooled. Fifty (50) milliliters of water was added and 50% solution of NaOH was also added until the pH of the solution was 10; an aqueous phase formed. The mixture was placed in a continuous diethylether extractor and extracted for 16 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9](I)[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH2:12].[CH3:13][O:14][CH2:15][CH2:16][O:17][CH2:18][C:19]#[CH:20].C(NC(C)C)(C)C>C(OCC)(=O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:10]=[C:9]([C:20]#[C:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH3:13])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH2:12]
Reactant: Nc1c(Cl)cc(I)c2c1OCO2
Reactant: C#CCOCCOC
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: COCCOCC#Cc1cc(Cl)c(N)c2c1OCO2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 85.6 %

Procedure:
5-Chloro-7-iodo-1,3-benzodioxol-4-amine (1.0 g, 3.36 mmol) and 3-(2-methoxyethoxy)prop-1-yne (766 mg, 6.72 mmol) in ethyl acetate (12 ml) were cooled in ice-methanol, under an atmosphere of nitrogen, and then treated with bis(triphenylphosphine) palladium(II) dichloride (236 mg, 10 mol %) followed by copper(I) iodide (64 mg, 10 mol %) and diisopropylamine (681 mg, 6.74 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 2.5 hours and then filtered through Celite. The filtrate was purified by column chromatography on silica using a 1:1 mixture of methyl tert-butyl ether and iso-hexane as eluent to give 5-chloro-7-[3-(2-methoxyethoxy)prop-1-yn-1-yl]-1,3-benzodioxol-4-amine (816 mg, 86%) as a dark orange oil; solidified on standing; NMR Spectrum: (CDCl3) 3.40 (s, 3H), 3.58 (m, 2H), 3.74 (m, 2H), 4.06 (s, 2H), 4.42 (s, 2H), 6.01 (s, 2H), 6.88 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[CH3:11].S(Cl)(Cl)=O.[CH2:16](N(CC)CC)[CH3:17].Cl.CNOC.C([Mg]Br)C>C(Cl)Cl.C1COCC1.CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](=[O:8])[CH2:16][CH3:17])=[CH:4][C:3]=1[CH3:11]
Reactant: CCN(CC)CC
Reactant: Cc1cc(C(=O)O)ccc1Cl
Agent: CC[Mg]Br
Agent: CNOC
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCC(=O)c1ccc(Cl)c(C)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 4-chloro-3-methylbenzoic acid (8.31 g, 48.7 mmol) in CH2Cl2 (50 mL) was added DMF (175 μm) and thionyl chloride (35.5 mL, 487 mmol) and the resulting mixture was refluxed for 1 hour. After cooling down, the mixture was evaporated to dryness and taken up in THF (50 mL). The resulting solution was cooled to 0° C. and triethylamine (13.5 mL, 97 mmol) was added followed by N,O-dimethylhydroxyl-amine hydrochloride (5.7 g, 58.4 mmol) and the resulting mixture was stirred at room temperature overnight. The mixture was diluted with CH2Cl2 and washed with 1 M KHSO4, saturated aqueous NaHCO3 and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The resulting crude Weinreb amide (10.4 g, 48.7 mmol) was taken up in THF (440 mL) and cooled to 0° C. under an argon atmosphere. Ethylmagnesium bromide (1 M in TBME, 97 ml, 97 mmol) was then slowly added and the resulting mixture was stirred for 2 hours at 0° C. The mixture was quenched with a saturated aqueous ammonium chloride solution. The THF was evaporated and the product was extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel (cyclohexane/EtOAc) to give INT 5.
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([NH2:18])=[O:17])=[CH:13][CH:14]=2)[C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][C:26]([C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)=[O:27])[CH:20]=2)=[N:8]1.OO.[OH-].[Na+].O>C(O)C>[N:30]1[CH:31]=[CH:32][CH:33]=[C:28]([C:26]([NH:25][C:21]2[CH:20]=[C:19]([C:9]3[C:10]4[C:15](=[CH:14][CH:13]=[C:12]([C:16]([NH2:18])=[O:17])[CH:11]=4)[NH:7][N:8]=3)[CH:24]=[CH:23][CH:22]=2)=[O:27])[CH:29]=1
Reactant: NC(=O)c1ccc2c(c1)c(-c1cccc(NC(=O)c3cccnc3)c1)nn2C1CCCCO1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: NC(=O)c1ccc2[nH]nc(-c3cccc(NC(=O)c4cccnc4)c3)c2c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 30 %

Procedure:
Precursor, 1-perhydro-2H-pyran-2-yl-3-[3-(3-pyridylcarbonylamino) phenyl]-1H-indazole-5-carboxamide, was dissolved in ethanol (4 mL). Hydrogen peroxide (4 mL, 30% wt) was added to the solution followed by 0.200 mL of 6.0 N NaOH aqueous solution. The suspension turned white upon heating to 60° C. for 3.5 h. The reaction could not be driven to completion even after addition of excess reagent. The reaction mixture was neutralized. A white precipitate formed upon addition of water. The solid was collected by filtration and dried in a vacuum oven at 40° C. overnight. A suspension of this solid in 10 mL of toluene was cooled to 0° C. HCl gas was bubbled through the suspension for 10 min before stirring the flask content at room temperature for 2 hours. The desired product was purified using preparatory HPLC (0.049 g, 30% yield over 3 steps): 1H NMR (CD3OD) 9.2 (d, 1H), 8.77 (dd, 1H), 8.7 (s, 1H), 8.4 (s, 1H), 8.39 (dt, 1H), 7.9–7.8 (m, 3H), 7.6–7.5 (m, 4H); ES-MS (m/z) 358 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:15]=[CH:14][C:13]([N:16]4[C:20]([CH2:21][C@@H:22]5[CH2:26][CH2:25][N:24]([C:27]([CH:29]6[CH2:31][CH2:30]6)=[O:28])[CH2:23]5)=[N:19][NH:18][C:17]4=[O:32])=[CH:12][CH:11]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:40][C:41]([O:43][CH3:44])=[O:42]>CN(C)C=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:11]=[CH:12][C:13]([N:16]4[C:17](=[O:32])[N:18]([CH2:40][C:41]([O:43][CH3:44])=[O:42])[N:19]=[C:20]4[CH2:21][C@@H:22]4[CH2:26][CH2:25][N:24]([C:27]([CH:29]5[CH2:30][CH2:31]5)=[O:28])[CH2:23]4)=[CH:14][CH:15]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: COC(=O)CCl
Reactant: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(-c3ccc4occc4c3)cc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)Cn1nc(C[C@@H]2CCN(C(=O)C3CC3)C2)n(-c2ccc(-c3ccc4occc4c3)cc2)c1=O
Temperature: 80 °C
Reaction time: 16 h
Yield: 57.7 %

Procedure:
To a solution of 4-[4-(1-benzofuran-5-yl)phenyl]-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (55 mg, 0.128 mmol) in N,N-dimethylformamide (1 mL) in a 5 mL microwaveable vial was added potassium carbonate (60 mg, 0.434 mmol, 3.3 eq) and methyl chloroacetate (25 mg, 0.227 mmol, 1.7 eq). The vial was capped and purged with nitrogen gas, and the reaction mixture was stirred for 16 h at 80° C. Analysis by LC/MS displayed the reaction had gone to completion. The reaction mixture was cooled to room temperature and poured into a mixture of dichloromethane and water. The organic layer was separated. The aqueous layer was washed with dichloromethane. The organic extracts were combined and washed 3× with a dilute brine solution. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by reverse phase HPLC (LUNA C-18: 30×50 mm column; 20-55% acetonitrile w/0.1% TFA/water w/0.1% TFA). The product fractions were neutralized with the addition of saturated aq sodium bicarbonate, combined, and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound (37 mg, 57%). MS(ES)+ m/e 501.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([C:12]([Cl:15])([F:14])[F:13])[N:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].C([N:27]([CH2:30][CH3:31])[CH2:28]C)C.N1CCC1>CN(C=O)C>[N:27]1([C:2]2[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([C:12]([Cl:15])([F:14])[F:13])[N:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[C:3]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:28][CH2:31][CH2:30]1
Reactant: CCN(CC)CC
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1Cl
Agent: C1CNC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1N1CCC1
Yield: 86.9 %

Procedure:
This compound was prepared as described in Example 37: 5.0 g (0.013 mol) of product of Example 28, 1.32 g (0.013 mol) of triethylamine, 0.75 g (0.013 mol) of azetidine in 30 ml of DMF were reacted at room temperature for 16 hours affording 4.71 g of solid which was recrystallized in hot hexane to give 3.93 g (72.5%) of white solid. A portion of this solid, 1.93 g, was recrystallized a second time in hot hexane to give 1.43 g of product as a white solid; mp 74.5°-75.5° C.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:9]([O:10][CH2:11][CH2:12][CH3:13])=[CH:8][S:7][CH:6]=1)CC.C(O)C(O)CC[CH2:18][CH2:19][OH:20].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[O:10]1[CH:11]([CH2:12][CH2:13][CH2:18][CH2:19][OH:20])[CH2:1][O:4][C:5]2=[CH:6][S:7][CH:8]=[C:9]12
Reactant: OCCCCC(O)CO
Reactant: CCCOc1cscc1OCCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: OCCCCC1COc2cscc2O1

Procedure:
9.06 g (45.2 mmol) of 3,4-di-n-propoxythiophene, 30.3 g (226 mmol) of 1,2,6-hexanetriol and 0.09 g (0.5 mmol) of p-toluenesulphonic acid are heated to 150 to 165° C. (bath temperature) under N2 for 3 h. During this time, 5.8 g of distillate (substantially n-propanol) were collected. The cooled liquid was diluted with 50 ml of methylene chloride, washed to neutrality and to free it of hexanetriol with water and the organic phase was dried over Na2SO4. After filtering and evaporating the methylene chloride, the residue (6.73 g=74.8% of theory) was identified by 1H NMR spectroscopy (in CDCl3 against TMS) using δ=6.30 ppm (2H, thiophene H) and 2.85 ppm (1H, OH) as being substantially 4-(2,3-dihydrothieno[3,4-b][1,4]dioxin-2-yl)-1-butanol.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[CH:9][CH:10]=2)[C:5]([CH3:21])=[N:4][C:3]=1[C:22](OC)=[O:23].[NH2:26][CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+]>CO>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[CH:9][CH:10]=2)[C:5]([CH3:21])=[N:4][C:3]=1[C:22]([NH:26][CH2:27][C:28]([OH:30])=[O:29])=[O:23]
Reactant: NCC(=O)O
Reactant: COC(=O)c1nc(C)c2cc(Oc3ccc(OC)cc3)ccc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(Oc2ccc3c(O)c(C(=O)NCC(=O)O)nc(C)c3c2)cc1
Temperature: 110 °C

Procedure:
A pressure glass reaction flask which included top threads for a screw cap lid can be fitted with a magnetic stirrer, charged with 5e, glycine (about 3 molar equivalents), methanol, and a sodium methoxide solution (with 1.2 molar eqivalents NaOCH3) and sealed. The reaction can then be heated to 110° C. for at least 6 h during which time the reaction forms a yellow suspension. The reaction can then be cooled to 20-25° C. and evaluated by HPLC. The reaction can be continued until less than 1% 5e remains as determined by HPLC, filtered, washed with methanol, dried under vacuum, dissolved in water and extracted with ethyl acetate to remove impurities to below 0.1%. The ethyl acetate can be removed and an acetic acid solution (with 3 molar eqivalents acetic acid) can be added over one hour. The suspension can be stirred at room temperature for at least 3 hours, filtered, and the solid washed with water (3×), cold acetone (5-10° C., 2×) and evaluated for impurities by HPLC. If acetone removable impurities are present, the flask can be charged with acetone and refluxed for at least 8 h, slowly cooled to 5-10° C., stirred for at least 2-3 h, filtered, washed with cold acetone (5-10° C., 3×) and dried under vacuum to obtain 2-[4-hydroxy-1-methyl-7-(4-methoxy-phenoxy)-isoquinoline-3-carboxamido]acetic acid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[C:15]([C:17]([CH3:25])([CH3:24])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:14]=[CH:13][C:10]=1[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:33][C:34](=[O:36])[CH3:35])C=CC=CC=1>ClCCl>[CH2:1]([O:8][C:9]1[CH:16]=[C:15]([C:17]([CH3:25])([CH3:24])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:14]=[CH:13][C:10]=1/[CH:11]=[CH:33]/[C:34](=[O:36])[CH3:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCCC(C)(C)c1ccc(C=O)c(OCc2ccccc2)c1
Solvent: ClCCl
Product: CCCCCCC(C)(C)c1ccc(/C=C/C(C)=O)c(OCc2ccccc2)c1
Reaction time: 24 h
Yield: 73.8 %

Procedure:
A solution of 2-benzyloxy-4-(1,1-dimethylheptyl)benzaldehyde (65.2 g, 0.193 mole) and of 1-triphenylphosphoranylidene-2-propanone (62.0 g, 0.195 mole) in dichloromethane (195 ml) was heated at reflux for 20 hous. Another portion of 15.5 g yield (15.5 g, 0.047 mole) was added and heating at reflux continued for 24 hours. The reaction mixture was cooled, evaporated and diluted with ether. The resulting precipitate of triphenylphosphine oxide was removed by filtration. The crude oil was purified via column chromatography on 1.5 kg of silica gel eluted with 20% etherhexane to yield 53.9 g (74%) of the title compound as an oil.
Reaction SMILES: C([O:8][C@H:9]1[C@H:25]([O:26]CC2C=CC=CC=2)[C@@H:24]([CH2:34][O:35]CC2C=CC=CC=2)[O:23][CH:10]1OC(=O)C1C=CC([N+]([O-])=O)=CC=1)C1C=CC=CC=1.[N:43]([C:46]1[N:54]=[C:53]([F:55])[N:52]=[C:51]2[C:47]=1[NH:48][CH:49]=[N:50]2)=[N+]=[N-]>C(#N)C>[C@@H:10]1([N:50]2[CH:49]=[N:48][C:47]3[C:51]2=[N:52][C:53]([F:55])=[N:54][C:46]=3[NH2:43])[O:23][C@H:24]([CH2:34][OH:35])[C@@H:25]([OH:26])[C@@H:9]1[OH:8]
Reactant: O=C(OC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1)c1ccc([N+](=O)[O-])cc1
Reactant: [N-]=[N+]=Nc1nc(F)nc2nc[nH]c12
Solvent: CC#N
Product: Nc1nc(F)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.6 %

Procedure:
A solution of 2,3,5-tri-O-benzyl-1-α-D-arabinofuranosylchloride (freshly prepared from 1.9 g of 2,3,5-tri-O-benzyl-1-O-p-nitrobenzoyl-D-arabinofuranose) and 6-azido-2-fluoropurine (0.50 g) in anhydrous acetonitrile (30 mL) was stirred for 1 hour at room temperature and then 3 Å molecular sieve (1.26 g, pellets) was added. The mixture was stirred under an inert atmosphere for 3 days and then filtered. The filtrate was concentrated under reduced pressure and the residue was dissolved in 2-propanol and methanol, and then sodium borohydride (0.13 g) was added. After stirring overnight at room temperature the resulting precipitate was collected by filtration. The precipitate was washed with 2-propanol followed by boiling water and then dried to obtain 0.14 g of the title compound. The organic filtrates were concentrated under reduced pressure and the residue was partitioned between dichloromethane and water. The dichloromethane solution was dried over MgSO4 and then filtered and placed on a silica gel column. Elution with 1% methanol in dichloromethane provided an additional 0.10 g of the title compound. Both samples were identical by IR and TLC to an authentic sample of the title compound.
Reaction SMILES: S(=O)(=O)(O)O.C(OC[O:10][C:11]1[CH:12]=[C:13]([CH:22]=[CH:23][C:24]2[CH:25]=[C:26]([CH:30]=[CH:31][CH2:32][CH2:33][CH2:34][C:35]([CH3:38])([OH:37])[CH3:36])[CH:27]=[CH:28][CH:29]=2)[CH:14]=[C:15]([O:17]COCC)[CH:16]=1)C>CO.C1COCC1>[OH:37][C:35]([CH3:38])([CH3:36])[CH2:34][CH2:33][CH2:32][CH:31]=[CH:30][C:26]1[CH:25]=[C:24]([CH:23]=[CH:22][C:13]2[CH:12]=[C:11]([OH:10])[CH:16]=[C:15]([OH:17])[CH:14]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: CCOCOc1cc(C=Cc2cccc(C=CCCCC(C)(C)O)c2)cc(OCOCC)c1
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(O)CCCC=Cc1cccc(C=Cc2cc(O)cc(O)c2)c1

Procedure:
In a manner similar to Example 1(j), by reacting 0.15 ml of concentrated sulphuric acid in 3 ml of methanol with 314 mg (0.67 mmol) of 7-{3-[2-(3,5-bis-ethoxymethoxyphenyl)vinyl]phenyl}-2-methylhept-6-en-2-ol in 3 ml of methanol and 3 ml of THF, after purification on a silica column (ethyl acetate 50-heptane 50), white crystals (m=206 mg; Y=91%) are obtained. m.p.=60-4° C.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][S:5]([OH:8])(=[O:7])=[O:6].[C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH2:21][NH:22][C:23](=[O:37])[C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][N:33]=[C:32](Cl)[N:31]=4)=[CH:26][CH:25]=3)[CH:18]=2)[NH:13][CH:12]=1)#[N:10]>>[C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH2:21][NH:22][C:23]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][N:33]=[C:32]([N:2]([CH3:1])[CH2:3][CH2:4][S:5]([OH:8])(=[O:7])=[O:6])[N:31]=4)=[CH:26][CH:25]=3)=[O:37])[CH:18]=2)[NH:13][CH:12]=1)#[N:10]
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Reactant: CNCCS(=O)(=O)O
Product: CN(CCS(=O)(=O)O)c1nccc(-c2ccc(C(=O)NCCc3ccc4[nH]cc(C#N)c4c3)cc2)n1

Procedure:
Using 2-(N-methyl-amino)-ethanesulfonic acid and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:11]=[CH:12][C:13]([Cl:17])=[C:14]([OH:16])[CH:15]=1>CCO>[Cl:17][C:13]1[CH:12]=[CH:11][C:10]([NH:9][C:2]2[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=2)=[CH:15][C:14]=1[OH:16]
Reactant: Cc1ccnc(Cl)n1
Reactant: Nc1ccc(Cl)c(O)c1
Solvent: CCO
Product: Cc1ccnc(Nc2ccc(Cl)c(O)c2)n1
Temperature: 90 °C
Yield: 74 %

Procedure:
Following the general procedure for the synthesis of 2-R-5-(heteroaryl-2-ylamino)phenol, 2-chloro-4-methylpyrimidine (69 mg, 0.54 mmol) and 5-amino-2-chlorophenol (77 mg, 0.54 mmol) in 10% aqueous EtOH (3 mL) was heated at 90° C. for 18 h. The title compound was obtained in 74% yield a (94 mg) and used for the next step without additional purification.
Reaction SMILES: I[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2I)[CH:5]=[CH:4][CH:3]=1.[CH3:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.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>[CH3:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[C:15]2[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:14]=2[CH3:13])[CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(B(O)O)c(C)c1
Reactant: Ic1cccc2cccc(I)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cccc3cccc(-c4ccc(OC)cc4C)c23)c(C)c1
Yield: 99 %

Procedure:
A solution of 1,8-diiodonaphthalene, (1.70 g, 4.5 mmol), 2-methyl-4-methoxyphenylboronic acid, 2, (2.20 g, 13.4 mmol), Pd(PPh3)4 (0.78 g, 0.67 mmol) and K3PO4, (4.30 g, 20.1 mmol) in 50 mL toluene was stirred at 100° C. for 18 hours. The resulting mixture was allowed to come to room temperature, quenched with water and extracted with CH2Cl2. The combined organic layers were dried over MgSO4 and concentrated in vacuo. Purification by flash chromatography on silica gel (CH2Cl2:hexanes 2:3) afforded 1.65 g (4.5 mmol, >99%) of off-white crystals containing syn- and anti-isomers of 7 in a ratio of 1:3.