Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:7])[NH:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20](Cl)=[O:21]>C1COCC1>[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20]([N:6]1[CH2:5][CH2:4][CH2:3][CH2:2][C:1]1=[O:7])=[O:21]
Reactant: O=C(Cl)c1ccco1
Reactant: O=C1CCCCN1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1CCCCN1C(=O)c1ccco1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
All glassware is dried thoroughly, and the reaction is kept under an inert atmosphere (argon) at all times. With stirring, 20.0 g (0.18 mol) of 2-furoic acid (Aldrich) and 40.0 mL (0.53 mol) of thionyl chloride (Aldrich, d=1.631 g/mol) are added to 300 mL THF (Aldrich, HPLC grade) in a single-neck round bottom flask equipped with a reflux condenser and magnetic stirrer. The resulting reaction mixture is heated to reflux and stirred for 16 h. After cooling to room temperature, the solvent and excess thionyl chloride are removed by evaporation under reduced pressure to yield 2-furoyl chloride. In a subsequent reaction, 9.2 g (92 mmol) of valerolactam (Aldrich) and 14.1 mL (101 mmol) of triethylamine (Aldrich, d=0.726 g/mol) are added to 150 mL THF (Aldrich, HPLC grade) in a 3-neck round bottom flask equipped with a reflux condenser, addition funnel, and magnetic stirrer. Addition of a solution of 12.0 g (92 mmol) of the 2-furoyl chloride in 150 mL THF proceeds dropwise over a period of 30 min, and the resulting reaction mixture is heated to reflux and stirred for 16 h. Upon cooling to room temperature, the THF is removed by evaporation under reduced pressure. The solid residue is redissolved in methylene chloride, and extracted several times with 5% aqueous hydrochloric and then deionized water. The organic layer is dried over Na2SO4, filtered, concentrated by removal of solvent, and poured into hexane to precipitate the product. The precipitate is collected by suction filtration, rinsed with hexane, and dried under vacuum to yield N-(2-furoyl)valerolactam as a white, crystalline solid.
Reaction SMILES: [OH:1][CH:2]([CH3:39])[CH2:3][CH:4]([CH:11]1[CH:15]([OH:16])[CH2:14][CH:13]([CH:17]=[CH:18][CH:19]([O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:12]1[O:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1)[CH:5]1[O:10][CH2:9][CH2:8][CH2:7][O:6]1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>CC(C)=O>[O:1]=[C:2]([CH3:39])[CH2:3][CH:4]([CH:11]1[C:15](=[O:16])[CH2:14][CH:13]([CH:17]=[CH:18][CH:19]([O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:12]1[O:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1)[CH:5]1[O:10][CH2:9][CH2:8][CH2:7][O:6]1
Reactant: CCCCCC(C=CC1CC(O)C(C(CC(C)O)C2OCCCO2)C1OC1CCCCO1)OC1CCCCO1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: CC(C)=O
Product: CCCCCC(C=CC1CC(=O)C(C(CC(C)=O)C2OCCCO2)C1OC1CCCCO1)OC1CCCCO1
Reaction time: 0.5 h

Procedure:
0.45 g of 1[4(3-hydroxy-1(1,3-dioxa-2-cyclohexyl)butyl]-2(3-tetrahydropyranyloxy-1-octenyl)-3(tetrahydropyranyloxy)-5-hydroxy-cyclopentane (IV) (Example 3) were dissolved in 30 ml of acetone. At -20° to -25° C., 2 ml of Jones reagent (2.1 g of chromic acid, 6 ml of water, 1.7 ml of concentrated sulfuric acid) were added under argon. The mixture was stirred for 30 minutes, 3 ml of isopropanol were added and stirring was continued for a further 10 minutes to destroy the oxidation reagent in excess. Next, 100 ml of methylene chloride and 100 ml of water were added, the mixture was shaken and the phases were separated. The organic phase was dried with MgSO4 and the solvent was removed under reduced pressure at a temperature of at most +5° C. 0.32 g of compound VIII in the form of an almost colorless clear oil was obtained.
Reaction SMILES: [Na:1].COC1OCC([CH2:10][O:11][C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH2:18][S:19]([C:21]3[NH:25][C:24]4[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=4[N:22]=3)=[O:20])[C:13]=2[CH3:30])CO1.[CH3:31][C:32]1(CO)[O:37][CH2:36][CH2:35][CH2:34][O:33]1>>[Na:1].[CH3:30][C:13]1[C:14]([CH2:18][S:19]([C:21]2[NH:22][C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=3[N:25]=2)=[O:20])=[N:15][CH:16]=[CH:17][C:12]=1[O:11][CH2:10][C:32]1([CH3:31])[O:37][CH2:36][CH2:35][CH2:34][O:33]1
Reactant: COC1OCC(COc2ccnc(CS(=O)c3nc4ccccc4[nH]3)c2C)CO1
Reactant: CC1(CO)OCCCO1
Agent: [Na]
Product: Cc1c(OCC2(C)OCCCO2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Yield: 8.6 %

Procedure:
The same procedure as in the steps (6b) to (6f) of Example 6 was repeated using (2-methyl-1,3-dioxan-2-yl)methanol obtained in the step (33a) to obtain the title compound (220 mg, total yield: 8.6%) as a light yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15](Br)=[CH:16][CH:17]=2)[CH:12]=[C:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]([Cu])#[N:26].O>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([C:25]#[N:26])=[CH:16][CH:17]=2)[CH:12]=[C:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(OCc2ccccc2)c2ccc(Br)cc2c1
Reactant: N#C[Cu]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(OCc2ccccc2)c2ccc(C#N)cc2c1
Temperature: 25 °C
Yield: 74.3 %

Procedure:
A solution of 12 (9.46 g, 27.2 mmol) in anhydrous DMF (12.6 mL) under Ar was treated with CuCN (2.92 g, 32.6 mmol, 1.2 equiv) and the mixture was warmed at reflux for 20 h. The reaction mixture was cooled to 25° C. and poured into 250 mL of H2O to which FeCl3 (5.29 g, 32.6 mmol, 1.2 equiv) was added with swirling. The solution was extracted with EtOAc (3×200 mL) and the combined organic layers were washed with saturated aqueous NaCl, dried (MgSO4) and concentrated. Recrystallization from 20% EtOAc-hexane provided 13 (6.70 g, 9.00 g theoretical, 74%) as a white solid. Chromatography (SiO2, 4×20 cm, 10% EtOAc-hexane) of the crystallization mother liquors afforded additional 13 (2.00 g, 22%, 96% combined) as white solid: mp 125° C. (needles, EtOH); 1H NMR (CDCl3, 250 MHz) δ8.43 (d, 1H, J=8.7 Hz), 8.29 (s, 1H), 8.25 (s, 1H), 7.69 (dd, 1H, J=1.6, 8.7 Hz), 7.66 (s, 1H), 7.56-7.39 (m, 5H), 5.32 (s, 2H), 4.46 (q, 2H, J=7.2 Hz), 1.46 (t, 3H, J=7.1 Hz); 13C NMR (CDCl3, 62.5 MHz) δ165.9, 154.3, 135.9, 134.6, 132.3, 129.8, 128.6, 128.3, 128.2, 127.8, 127.5, 123.8, 123.2, 118.6, 110.7, 106.9, 70.5, 61.5, 14.3; IR (KBr) vmax 2994, 2226, 1711, 1577, 1502, 1284, 1252, 1093, 1029, 916, 827 cm-1 ; FABHRMS (NBA) m/z 332.1276 (M+ +H, C21H17NO3 requires 332.1287).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH3:20].[C:21]1([N:27]=[C:28]=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH3:20])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:28]([NH:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:29])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: Cc1nc2c(N)nc3ccccc3c2n1CCCCN
Reactant: O=C=Nc1ccccc1
Product: Cc1nc2c(N)nc3ccccc3c2n1CCCCNC(=O)Nc1ccccc1

Procedure:
Using the general method of Example 143, 1-(4-aminobutyl)-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (500 mg, 1.9 mmol) was reacted with phenyl isocyanate to provide 123 mg of N-[4-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N′-phenylurea as a light brown solid, m.p. 171.5-172.5° C. Analysis: Calculated for C22H24N6O.0.60 H2O: %C 66.18; %H, 6.36; %N, 21.05; Found: %C, 66.05; %H, 6.43; %N, 20.61.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([CH2:7]P(OC)(OC)=O)=[O:6].[OH:14][C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][CH2:23][CH:24]=O)[O:18][C:17](=[O:26])[C:16]=1[C:27](=[O:30])[CH2:28][CH3:29]>C1COCC1>[OH:14][C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:7]/[C:5]([O:4][CH3:3])=[O:6])[O:18][C:17](=[O:26])[C:16]=1[C:27](=[O:30])[CH2:28][CH3:29]
Reactant: CCC(=O)c1c(O)cc(CCCC=O)oc1=O
Reactant: COC(=O)CP(=O)(OC)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(=O)c1c(O)cc(CCC/C=C/C(=O)OC)oc1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
NaH (0.4 g; 10 mmol; 60% dispersion in mineral oil; Aldrich) was added to trimethyl phosphonoacetate (1.90 g; 10 mmol; Aldrich) in 25 ml THF. The reaction was stirred at 25° C. for 15 min, after which 4-(4-hydroxy-2-oxo-3-propionyl-2H-pyran-6-yl)butanal (XVI; 1.01 g; 4.3 mmol) in 40 ml THF was added. The reaction mixture was stirred at 25° C. for 2 h, quenched with saturated NH4Cl, extracted with 3×30 ml EtOAc, dried with anhydrous Na2SO4, and evaporated. The product was purified via silica flash chromatography (EtOAc gradient in hexanes).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]2[CH:13]=[CH:12][NH:11][N:10]=2)[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CC(C)=O>[CH2:20]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[C:9]1[CH:13]=[CH:12][NH:11][N:10]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Oc1ccc(Cl)cc1-c1cc[nH]n1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Clc1ccc(OCc2ccccc2)c(-c2cc[nH]n2)c1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
To a stirred solution of 4-chloro-2-(1H-pyrazol-3-yl)-phenol (1 g, CAS 18704-67-1) at r.t. in acetone (20 ml) under an argon atmosphere were added K2CO3 (746 mg) and benzylbromid (0.61 ml). The reaction mixture was stirred at r.t. for 21 h. The solids were filtered off and washed with acetone. The filtrate was concentrated to leave a light orange oil. The crude product was purified by chromatography (silica gel, cyclohexane/ethyl acetate 2:1) to give 3-(2-benzyloxy-5-chloro-phenyl)-1H-pyrazole as off-white solid. MS 284.8 ([M+H]+)
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)[C:10]2[C:5](=[CH:6][C:7]([O:30][CH3:31])=[C:8]([O:28][CH3:29])[CH:9]=2)[N:4]=1.[CH3:32][NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH3:27][O:26][C:20]1[CH:19]=[C:18]([C:11]2[C:10]3[C:5](=[CH:6][C:7]([O:30][CH3:31])=[C:8]([O:28][CH3:29])[CH:9]=3)[N:4]=[C:3]([CH2:2][N:33]([CH3:32])[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:23]=[CH:22][C:21]=1[O:24][CH3:25]
Reactant: CCOC(=O)c1c(CCl)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Reactant: CNc1ccccc1
Product: CCOC(=O)c1c(CN(C)c2ccccc2)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1

Procedure:
According to the same manner as that described in Example 34, ethyl 2-chloromethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline-3-carboxylate was reacted with N-methylaniline to give ethyl 4-(3,4-dimethoxyphenyl)-2-(N-methyl-N-phenylaminomethyl)-6,7-dimethoxyquinoline-3-carboxylate. This compound was recrystallized from dichloromethane-hexane. Colorless prisms, mp. 194°-196° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[C:8]2[CH2:17][CH:16]([CH3:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=O)=[CH:3][CH:2]=1.[NH2:20][NH2:21].C(Cl)(Cl)Cl>C(O)C>[CH3:18][CH:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]2=[N:20][NH:21][CH:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH:8]2[CH2:17]1
Reactant: NN
Reactant: CC1CC(=Cc2ccncc2)C(=O)c2ccccc21
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CC1CC2C(=NNC2c2ccncc2)c2ccccc21

Procedure:
To a mixture of 25 grams of 2-(4-pyridylmethylene)-3,4-dihydro-4-methyl-1 (2H)-naphthalenone and 5 grams of hydrazine in 150 ml of ethanol is added sufficient chlorform to dissolve all the reactants. The solution is refluxed overnight under anhydrous conditions. After cooling, the reaction mixture is filtered and the solvent removed by evaporation to yield 5-methyl-3-(4-pyridyl)-3,3a,4,5-tetrahydro-2H-naphtho[1,2-c]Pyrazole. This is chromatographed on silica using benzene as the eluant to yield 4,5-dihydro-5-methyl-3l -(4-pyridyl)-2H-naphtho[1,2c]pyrazole.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][C:8]1[CH:13]=[C:12]([F:14])[C:11](OB(O)O)=[C:10]([F:19])[CH:9]=1.[F:20][C:21]1[CH:28]=[C:27](Br)[CH:26]=[CH:25][C:22]=1[C:23]#[N:24].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([C:27]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([F:20])[CH:28]=2)=[C:10]([F:19])[CH:9]=1
Reactant: OB(O)Oc1c(F)cc(CCC2OCCO2)cc1F
Reactant: N#Cc1ccc(Br)cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2c(F)cc(CCC3OCCO3)cc2F)cc1F
Yield: 66 %

Procedure:
To 300 ml of DMF were added 14 g (54 mmol) of 4-(1,3-dioxolan-2-ylethyl)-2,6-difluorophenylboric acid obtained in Step 2 of Example 1, 10 g (50 mmol) of 2-floro-4-bromobenzonitrile, 20 g (198 mol) of triethyl amine, 0.50 g (2.2 mmol) of palladium acetate, and 0.50 g (3.8 mmol) of triphenylphosphine, and the mixture was refluxed for 7 hours. The solvent was distilled off under reduced pressure. To the residue were added 700 ml of methylene chloride and 300 ml of a 10% aqueous ammonia, and the mixture was stirred. The organic layer was dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by column chromatography on silica gel (eluting solvent: toluene/ethyl acetate=5/1). The solvent was distilled under reduced pressure and the residue was washed with ethanol and then dried under reduced pressure to afford 11 g (33 mmol) of 1-(1,3-dioxolan-2-ylethyl)-3,5-difluoro-4-(3-fluoro-4-cyanophenyl)benzene.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[S:16])[NH2:15])[CH2:10][CH2:9]1)=O)(C)(C)C.Br[CH2:18][C:19](=O)[C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(O)C>[CH2:23]([O:22][C:20]([C:19]1[N:15]=[C:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[S:16][CH:18]=1)=[O:21])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=S)CC1
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Product: CCOC(=O)c1csc(C2CCNCC2)n1
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
A mixture of 10 g (41 mmol) 4-thiocarbamoyl-piperidine-1-carboxylic acid tert-butyl ester (commercially available) and 7.98 g (41 mmol) ethyl bromopyruvate (commercially available) in 120 ml ethanol was stirred at 70° C. for 90 min. The mixture was evaporated to dryness, Na2CO3 aq. was added and the residue was extracted with ethyl acetate. The organic phases were washed with NaCl aq., dried with MgSO4 and evaporated to dryness. The residue was purified on silica eluting with DCM/MeOH/25% NH3 in water 100/20/1 to yield after evaporation of the product fractions 7.28 g (74%) of the title compound as light brown solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]=[C:11]=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:13]12([CH2:23][N:24]3[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[N:28]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:27](=[O:41])[CH:26]([NH2:42])[C:25]3=[O:43])[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2>C(#N)C.ClCCl>[C:13]12([CH2:23][N:24]3[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[N:28]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:27](=[O:41])[CH:26]([NH:42][C:11]([NH:10][C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=4)=[O:12])[C:25]3=[O:43])[CH2:22][CH:17]3[CH2:16][CH:15]([CH2:21][CH:19]([CH2:18]3)[CH2:20]1)[CH2:14]2
Reactant: O=C=Nc1cccc([N+](=O)[O-])c1
Reactant: NC1C(=O)N(CC23CC4CC(CC(C4)C2)C3)c2ccccc2N(c2ccccc2)C1=O
Solvent: ClCCl
Solvent: CC#N
Product: O=C(Nc1cccc([N+](=O)[O-])c1)NC1C(=O)N(CC23CC4CC(CC(C4)C2)C3)c2ccccc2N(c2ccccc2)C1=O
Reaction time: 2 h
Yield: 82.1 %

Procedure:
A solution of 3-nitrophenyl isocyanate (0.082 g) in dry acetonitrile (8 ml) was added to a solution of the 1-(1-Adamantylmethyl-3-amino-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (0.2 g) in dry acetonitrile (10 ml) under a nitrogen atmosphere. The mixture was stirred at 23° for 2 h, then diluted with dichloromethane (15 ml) and washed with brine (15 ml). The organic solution was dried, concentrated in vacuo and the residue was triturated with diethyl ether to give the title compound as a white solid (0.229 g). M.p. 213°-5°. T.I.c. CH-EA (2:1), Rf0.33.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[CH:6][CH:7]=1.[O:10]1[CH2:14][CH2:13][O:12][CH:11]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=[O:25].O1CCOC1CCCCCCCCOC1C=C(C=CC=1)C=O>>[O:10]1[CH2:14][CH2:13][O:12][CH:11]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:22]=[C:23]([CH:24]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[OH:25])[CH:26]=[CH:27][CH:28]=1
Reactant: Fc1cccc([Mg]Br)c1
Reactant: O=Cc1cccc(OCCCCCC2OCCO2)c1
Agent: O=Cc1cccc(OCCCCCCCCC2OCCO2)c1
Product: OC(c1cccc(F)c1)c1cccc(OCCCCCC2OCCO2)c1

Procedure:
The title compound was prepared as described in Example 10 Step 2 with 3-fluorophenylmagnesium bromide and 3-((5-(1,3-dioxolan-2-yl)pentyl)oxy)benzaldehyde replacing 2-thienylmagnesium bromide and 3-(8-(1,3-dioxolan-2-yl)octyloxy)benzaldehyde respectively.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)[N:14]=[CH:13][NH:12][C:11]2=O.CN(C)C1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:3][C:11]1[C:10]2[C:15](=[CH:16][C:17]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[C:8]([O:7][CH3:6])[CH:9]=2)[N:14]=[CH:13][N:12]=1
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCc1ccncc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)c1ccccc1
Product: COc1cc2c(Cl)ncnc2cc1OCc1ccncc1
Yield: 41 %

Procedure:
Phosphorus oxytrichloride (0.1 ml) was added to a mixture of 6-methoxy-7-(4-pyridylmethoxy)-3,4-dihydroquinazolin-4-one (81 mg, 0.29 mmol) and N,N-dimethylaniline (0.1 ml) in toluene (5 ml), and the mixture heated at reflux for 1 hour. The volatiles were removed by evaporation and the residue partitioned between methylene chloride and aqueous ammonia. The organic extract was separated, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by chromatography on silica eluting with ethyl acetate progressing through increasingly polar mixtures to methanol/methylene chloride (1/9) to give 4-chloro-6-methoxy-7-(4-pyridylmethoxy)quinazoline (40 mg, 41%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O.Cl>[CH2:22]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH3:11]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCCCCCCCCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCOc1ccc(C=O)cc1
Temperature: 105 °C
Reaction time: 21.5 h

Procedure:
4-Hydroxybenzaldehyde (8.00 g, 6.55×10−2 mol), 1-bromododecane (16.50 ml, 6.87×10−2 mol), K2CO3 (9.05 g, 6.55×10−2 mol) and dry DMF (100 ml) were added to a two-neck round-bottom flask. The reaction mixture was stirred at 105° C. for 21.5 h under Ar. After cooling, the solution was diluted with H2O, 2M HCl and extracted three times with CH2Cl2. The combined organic layers were washed with aqueous NaHCO3, H2O and dried over Na2SO4. The product was chromatographed on silica gel with 1:1 hexane:CH2Cl2 as the eluent. Yield=19.02 g (100% based on 8.00 g of 4-hydroxybenzaldehyde). 1H NMR (250 MHz, CDCl3): δ 9.88 (s, 1H, —CHO), 7.83 (d, 2H, J=8.8 Hz, Ph), 6.99 (d, 2H, J=8.7 Hz, Ph), 4.04 (t, 2H, J=6.5 Hz, OCH2), 1.82 (quint, 2H, J=6.9 Hz, OCH2CH2), 1.40-1.54 (m, 2H, —CH2—), 1.16-1.40 (m, 16H, —CH2—), 0.88 (t, 3H, J=6.5 Hz, —CH3). CI MS m/z: 291.232 ((M+H)+) (calcd 291.232).
Reaction SMILES: [CH:1](=O)/[CH:2]=[CH:3]/[CH3:4].[C:6]1([S:12]([C:15]#[N:16])(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.B(OCCCC)(OCCCC)OCCCC>C1(C)C=CC=CC=1>[C:6]1([S:12]([C:15]2[CH:4]=[CH:3][CH:2]=[CH:1][N:16]=2)(=[O:13])=[O:14])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: C/C=C/C=O
Reactant: N#CS(=O)(=O)c1ccccc1
Agent: CCCCOB(OCCCC)OCCCC
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccccc1)c1ccccn1
Temperature: 110 °C
Yield: 86.9 %

Procedure:
First, 8.20 g (115 mmol) of crotonaldehyde and 9.55 g (57.2 mmol) of benzenesulfonyl cyanide were introduced to the same reaction vessel as in Example 1. Toluene (15 ml) was added as the solvent, and 1.33 g (5.78 mmol) of tributyl borate was added. Then the mixture was heated under reflux for 3 hours while agitating at an internal temperature of 110° C. in a nitrogen atmosphere, separating and removing water that was produced. After this solution was cooled to room temperature, the low-boiling components, such as solvent, etc., were removed under reduced pressure and the resulting concentrate was cooled in an ice bath to precipitate crystals. The crystals were filtered with a glass filter and washed with 10 ml of toluene that had been cooled to 5° C. or lower. Then the crystals were dried for 2 hours in vacuo to give 10.9 g of 2-benzenesulfonylpyridine as colorless crystals (purity of 98%, yield of 85% based on benzenesulfonyl cyanide).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)(=O)=O)[N:3]=1.[OH:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[N:3]=1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: OCCN1CCCCC1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(OCCN2CCCCC2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile, hydroxyethylpiperidine and DBU in DME. ES-MS m/e (%:314 (M+H+, 100).
Reaction SMILES: [CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][C:29]([O:31]CC)=[O:30]>CC(C)=O>[CH3:1][C@:2]12[CH2:3][CH2:4][C@H:5]3[C@@H:14]([CH2:13][CH2:12][C:11]4[CH:10]=[C:9]([O:20][CH2:28][C:29]([OH:31])=[O:30])[CH:8]=[CH:7][C:6]=43)[C@@H:15]1[CH2:16][CH2:17][C:18]2=[O:19]
Reactant: CCOC(=O)CBr
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C[C@]12CC[C@@H]3c4ccc(OCC(=O)O)cc4CC[C@H]3[C@@H]1CCC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.5 %

Procedure:
The mixture of estrone (540 mg, 2.0 mmol), potassium carbonate (910 mg, 6.6 mmol), ethyl bromoacetate (500 mg, 3.0 mmol), and acetone (25 ml) was refluxed for 6 h. After cooling, the mixture was filtered to remove potassium carbonate. The filtrate was concentrated under reduced pressure. To this residue, 10 ml dioxane and 14 ml 5% sodium hydroxide solution were added. After the mixture was stirred at room temperature overnight, it was acidified with concentrated hydrochloric acid to pH 2, and then extracted three times with ethyl acetate (15 ml each). The organic phases were combined, washed with water and brine, dried over magnesium sulfate, filtered, and then evaporated in vacuo. The residue was recrystallized from ethanol to give 246 mg estra-1,3,5(10)-trien-17-one-3-oxyacetic acid as white crystals, mp 205-208° C.