Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)=[O:4].[B-](F)(F)(F)F.C1C=CN=CC=1.C1C=CN=CC=1.[IH2+:34].C(S(O)(=O)=O)(F)(F)F>ClCCl>[F:16][C:2]([F:1])([F:15])[C:3]([NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[I:34])=[O:4]
Reactant: [IH2+]
Reactant: O=C(NCCc1ccc(Cl)cc1)C(F)(F)F
Agent: F[B-](F)(F)F
Agent: O=S(=O)(O)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(NCCc1ccc(Cl)cc1I)C(F)(F)F
Reaction time: 8 h
Yield: 38.9 %

Procedure:
A solution of N-trifluoroacetyl-4-chlorophenethylamine (1.6 g, 6.4 mmol) in dichloromethane (20 mL) was treated with bis(pyridine)iodonium(I)tetrafluoroborate (2.6 g, 7.0 mmol), CF3SO3H (2.1 g, 14.1 mmol) and stirred overnight at 20 C. The product mixture was concentrated, dissolved in EtOAc (100 mL), washed twice with 5% aqueous sodium bisulfite (50 mL), twice with saturated aqueous NaHCO3, (50 mL) once to with brine (50 mL), dried with Na2SO4 and concentrated to give 0.94 g of a clear oil. MS calculated for C10H8ClF3INO+H: 378, observed: 378.
Reaction SMILES: C(OC1C=C(CCCC(=O)[CH2:15][CH2:16][C:17]2([CH3:24])[C:21](=O)[CH2:20][CH2:19][C:18]2=[O:23])C=CC=1)(=O)C.C([O:29][C:30]1[CH:31]=[C:32]([CH2:36][CH2:37][CH2:38][C:39](=O)CCN(CC)CC)[CH:33]=[CH:34][CH:35]=1)(=O)C.C(OC1C=C(CCCC(=O)C=C)C=CC=1)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1.CCOCC>[CH3:24][C@:17]12[CH2:16][CH2:15][C:39]3[C:33]4[CH:34]=[CH:35][C:30]([OH:29])=[CH:31][C:32]=4[CH2:36][CH2:37][C:38]=3[C:21]1=[CH:20][CH2:19][C:18]2=[O:23]
Reactant: CC(=O)Oc1cccc(CCCC(=O)CCC2(C)C(=O)CCC2=O)c1
Reactant: CCN(CC)CCC(=O)CCCc1cccc(OC(C)=O)c1
Agent: C=CC(=O)CCCc1cccc(OC(C)=O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: c1ccccc1
Product: C[C@]12CCC3=C(CCc4cc(O)ccc43)C1=CCC2=O

Procedure:
Reflux 2-(6-m-acetoxyphenyl-3-oxohexyl)-2-methylcyclopentane-1,3-dione (0.8 g, the product of Michael condensation of 2-methylcyclopentanedione and a mixture of 6-m-acetoxyphenyl-1-diethylaminohexan-3-one and 6-m-acetoxyphenylhex-1-en-3-one, and containing some of the corresponding free phenolic compound) in benzene (25 cc) with toluene-p-sulfonic acid (0.3 g) for 50 minutes. On cooling add ether (50 cc) and wash the mixture in turn with water, saturated aqueous potassium bicarbonate, and brine; dry over anhydrous magnesium sulfate. The residue after removal of solvent is a purple gum (0.6 g), part of which can be induced to crystallize. Dissolve a portion (0.45 g) of this gum in benzene and adsorb on an activated Fuller's earth (40 g); elute with benzene to obtain 13β-methyl-3-hydroxygona-1,3,5(10),8,14-pentaen-17-one, which one recrystallizes from diisopropyl ether, m.p. 225°-226°; ultraviolet absorption peak at 312.5 mμ (ε23,000); infrared absorption peaks at 2.99 μ, 5.81 μ, and 8.00μ. This compound has estrogenic activity, lowers the blood lipid level, and is useful as an intermediate for preparing the hormonal compounds of this invention.
Reaction SMILES: [CH2:1]([C:5]1[O:9][N:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:6]=1)[CH:2]([CH3:4])[CH3:3].[I:14]N1C(=O)CCC1=O>C(O)(C(F)(F)F)=O>[I:14][C:6]1[C:7]([C:10]([O:12][CH3:13])=[O:11])=[N:8][O:9][C:5]=1[CH2:1][CH:2]([CH3:4])[CH3:3]
Reactant: COC(=O)c1cc(CC(C)C)on1
Reactant: O=C1CCC(=O)N1I
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1noc(CC(C)C)c1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.6 %

Procedure:
A mixture of methyl 5-isobutylisoxazole-3-carboxylate (Preparation 5A, 0.923 g, 5.04 mmol) and N-iodosuccinimide (1.247 g, 5.54 mmol) in TFA (25 mL) was stirred at room temperature overnight. The TFA was removed under reduced pressure, and the residue was diluted with dichloromethane (100 mL), washed with a saturated aqueous solution of sodium bicarbonate (2×25 mL), 2.5% aqueous solution of sodium bisulfate (25 mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure followed by purification by flash silica gel chromatography using a 5% mixture of ethyl acetate in hexane afforded methyl 4-iodo-5-isobutylisoxazole-3-carboxylate (1.21 g, 3.91 mmol, 78% yield) as a pale yellow oil. The product had an HPLC ret. time=2.40 min. (condition A); LC/MS M+1=310.1.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=[O:21])=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:50][CH2:51][CH2:52][NH:53][C:54](=[O:60])[O:55][C:56]([CH3:59])([CH3:58])[CH3:57].CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1>C1COCC1>[C:56]([O:55][C:54]([NH:53][CH2:52][CH2:51][CH2:50][O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=[O:21])=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29])=[O:60])([CH3:59])([CH3:58])[CH3:57]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Reactant: CC(C)(C)OC(=O)NCCCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCCCOc1ccc(-c2cc3cc(C=O)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Yield: 99.1 %

Procedure:
In a similar manner to Step 1 of Example 149, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (150 mg, 0.382 mmol) was dissolved in THF (7.5 mL), and the solution was treated with triphenylphosphine (200 mg, 0.764 mmol), tert-butyl N-(3-hydroxypropyl)carbamate (134 mg, 0.764 mmol) and 40% DEAD-toluene solution (0.348 mL), followed by purification by flash column chromatography (chloroform/methanol=100/0 to 95/5) to obtain 4-[3-(tert-butoxycarbonylamino)propoxy]-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (208 mg, yield 99%).
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][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1I.C(N(CC)CC)C.[CH:29]#[C:30][CH3:31]>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[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][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:29]#[C:30][CH3:31]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1I
Reactant: C#CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC#Cc1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Temperature: -78 °C
Reaction time: 48 h

Procedure:
To a stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)4-iodopyrazole (0.904 g, the compound of Example A1) in dimethylformamide(2 ml) and triethylamine (10 ml) contained in a stainless steel bomb was added cuprous iodide (60 mg) and bis(triphenylphosphine)palladium(II) chloride (120 mg). The reaction vessel was cooled to −78° C. and propyne (2 g) condensed into it. The vessel was sealed and then heated at 70° C. for 18 hours and then left at room temperature for 2 days. The reaction mixture was partitioned between ether and water. The organic layer was separated, washed with brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography on silica gel eluted with dichloromethane : hexane (1:1) to provide the title compound as a white solid m.p. 226-8° C.
Reaction SMILES: S1CCS[CH:2]1[CH2:6][C:7]1[C:8]([Cl:14])=[N:9][CH:10]=[N:11][C:12]=1[Cl:13].C(#N)C.C(=O)([O-])[O-:19].[Ca+2]>[Hg](Cl)Cl.O>[Cl:14][C:8]1[C:7]([CH2:6][CH:2]=[O:19])=[C:12]([Cl:13])[N:11]=[CH:10][N:9]=1
Reactant: Clc1ncnc(Cl)c1CC1SCCS1
Reactant: O=C([O-])[O-]
Agent: Cl[Hg]Cl
Agent: [Ca+2]
Solvent: O
Solvent: CC#N
Product: O=CCc1c(Cl)ncnc1Cl
Yield: 87 %

Procedure:
5-[(1,3-dithiolan-2-yl)methyl]-4,6-dichloropyrimidine (compound of the formula IV-1, 13.4 g, 0.05 mol) was added to 200 mL of a 4:1 mixture of acetonitrile and water, and mercury dichloride (27.1 g, 0.1 mol) and calcium carbonate (10 g, 0.1 mol) were then further added with stirring. After 6 hours of reaction at the room temperature, suction filtration was carried out. The solid was washed with acetonitrile and then the combined filtrate was subjected to solvent removal, followed by the addition of 200 mL of dichloromethane. The organic phase was then washed with an aqueous solution saturated with sodium bicarbonate, dried and subjected to solvent removal, resulting in a yellow solid. The solid was then recrystallized in ethyl acetate and petroleum ether (1:1) in order to obtain a yellowish solid of 8.3 g with a yield of 87%. 1HNMR (400 MHz, CDCl3) δ: 9.80 (s, 1H), 8.74 (s, 1H), 4.14 (s, 2H).
Reaction SMILES: [CH3:1][C:2]([OH:6])([C:4]#[CH:5])[CH3:3].C(N(CC)CC)C.[N+:14](=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N-:15]>FC(F)(F)S([O-])(=O)=O.[Zn+2].FC(F)(F)S([O-])(=O)=O.O>[OH:6][C:2]([C:4]1[NH:15][N:14]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:5]=1)([CH3:3])[CH3:1]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C#CC(C)(C)O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Zn+2]
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)c1cc(C(C)(C)O)[nH]n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 27.9 %

Procedure:
Zinc trifluoromethanesulfonate (2.378 mmol, 0.864 g), 2-methyl-3-butyn-2-ol (11.89 mmol, 1 g) and triethylamine (17.83 mmol, 1.804 g) were added into a flask under nitrogen atmosphere. Ethyl diazoacetate (14.27 mmol, 1.628 g) was added slowly and the temperature was carefully raised to 100° C. and stirred for 8 h. Water was added and the mixture was extracted twice with DCM. The combined DCM phases were dried, filtered and evaporated. The crude product was purified by flash chromatography. 0.658 g of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.28 (t, 3H), 1.45 (s, 6H), 4.24 (q, 2H), 5.34 (s, 1H), 6.52 (s, 1H), 13.22 (bs, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]2[C:13](=[O:15])[O:12][CH2:11][C:10]3[CH:16]=[C:17]([CH3:22])[CH:18]=[C:19]([O:20][CH3:21])[C:9]=3[O:8][C:7]=2[CH:6]=[CH:5][C:4]=1[C:23](=[O:28])[CH2:24][CH:25]([CH3:27])[CH3:26].[CH3:29][Mg]Br.[Cl-].[NH4+]>O1CCCC1.C(OCC)C>[OH:28][C:23]([C:4]1[CH:5]=[CH:6][C:7]2[O:8][C:9]3[C:19]([O:20][CH3:21])=[CH:18][C:17]([CH3:22])=[CH:16][C:10]=3[CH2:11][O:12][C:13](=[O:15])[C:14]=2[C:3]=1[O:2][CH3:1])([CH3:29])[CH2:24][CH:25]([CH3:26])[CH3:27]
Reactant: C[Mg]Br
Reactant: COc1cc(C)cc2c1Oc1ccc(C(=O)CC(C)C)c(OC)c1C(=O)OC2
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cc(C)cc2c1Oc1ccc(C(C)(O)CC(C)C)c(OC)c1C(=O)OC2
Reaction time: 4 h

Procedure:
100 mg (0.26 mmol) of 4,11-dimethoxy-9-methyl-3-(3-methylbutan-1-onyl)-7H-dibenzo[b,g][1,5]dioxocin-5-one are dissolved in 5 ml of absolute tetrahydrofuran under argon and 0.2 ml (0.6 mmol) of a 3M methylmagnesium bromide solution in diethyl ether are added at room temperature. After 4 h, the reaction is discontinued by addition of 0.2 ml of ammonium chloride solution. The mixture is concentrated in vacuo, the residue is taken up in dichloromethane and the solution is washed with water. After drying the organic phase over magnesium sulphate, it is concentrated and the residue is purified by column chromatography on silica gel using petroleum ether/ethyl acetate 10:1.
Reaction SMILES: Cl.[C:2]([O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH2:11][CH:10]([NH2:15])[CH2:9]2)(=[O:4])[CH3:3].Cl[C:17]1[C:18]2[C:25]([CH3:26])=[CH:24][S:23][C:19]=2[N:20]=[CH:21][N:22]=1.C(N(CC)CC)C>C(O)C>[C:2]([O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH2:11][CH:10]([NH:15][C:17]1[C:18]3[C:25]([CH3:26])=[CH:24][S:23][C:19]=3[N:20]=[CH:21][N:22]=1)[CH2:9]2)(=[O:4])[CH3:3]
Reactant: CC(=O)Oc1ccc2c(c1)CC(N)C2
Reactant: Cc1csc2ncnc(Cl)c12
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc2c(c1)CC(Nc1ncnc3scc(C)c13)C2
Yield: 26.3 %

Procedure:
Using 5-acetoxy-2-aminoindan hydrochloride (86 mg, 0.38 mmol), 4-chloro-5-methylthieno[2,3-d]pyrimidine (76 mg, 0.41 mmol), triethylamine (0.23 ml, 1.6 mmol), and ethanol (6 ml), a similar procedure to b) in Production Example 208 was carried out. The product obtained was purified by silica gel chromatography (hexane:ethyl acetate=2:1) to obtain the title compound (34 mg, 0.10 mmol) having the following physical properties:
Reaction SMILES: Cl.Cl[C:3]1[N:12]=[C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[F-].[NH4+].[CH3:27][N:28](C=O)[CH3:29]>>[CH3:24][O:23][C:17]1[CH:16]=[C:15]([N:13]([CH3:14])[C:11]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]=[C:3]([N:28]([CH3:29])[CH3:27])[N:12]=2)[CH:20]=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: CN(C)C=O
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1OC
Agent: Cl
Agent: [F-]
Agent: [NH4+]
Product: COc1ccc(N(C)c2nc(N(C)C)nc3ccccc23)cc1OC

Procedure:
A solution of (2-chloro-quinazolin-4-yl)-(3,4-dimethoxy-phenyl)-methyl-amine hydrochloride (105 mg; 0.287 mmol) and ammonium fluoride (73 mg; 1.97 mmol) in DMF (2 mL) was heated at 90° C. After 4 days the reaction was concentrated on a rotary evaporator then saturated NaHCO3 (5 mL) and water (3 mL) were added. Product was extracted into chloroform (4×2 mL) and the combined extracts washed with water (4×2 mL) and brine (3×3 mL). This solution was dried (MgSO4), filtered through silica and washed with 100:10:1 CHCl3:MeOH:concentrated NH4OH, concentrated then purified by MPLC (12 g SiO2/0-10% (20:1 MeOH:concentrated NH4OH) in CHCl3 gradient). Product was obtained as an oil, which solidified to a tan solid under high vacuum (68 mg; 70%). 1H NMR (CDCl3) δ 7.45 (m, 1H), 7.35 (m, 1H), 6.89 (m, 1H), 6.83 (m, 1H), 6.75-6.68 (m, 2H), 6.64 (m, 1H), 3.90 (s, 3H), 3.77 (s, 3H), 3.54 (s, 3H), 3.31 (s, 6H); LC-MS (ESI+; 339 ([M+H]+).
Reaction SMILES: N[C:2]1[CH:3]=[N:4][C:5]([Cl:9])=[C:6]([Cl:8])[CH:7]=1.[CH2:10]([S:12]SCC)[CH3:11].N(OC(C)(C)C)=O>C(Cl)Cl>[Cl:9][C:5]1[C:6]([Cl:8])=[CH:7][C:2]([S:12][CH2:10][CH3:11])=[CH:3][N:4]=1
Reactant: CCSSCC
Reactant: Nc1cnc(Cl)c(Cl)c1
Agent: CC(C)(C)ON=O
Solvent: ClCCl
Product: CCSc1cnc(Cl)c(Cl)c1

Procedure:
24.45 g (0.15 mol) of 3-amino-5,6-dichloropyridine in 280 ml of methylene chloride were reacted with 36.6 g (0.3 mol) of diethyl disulfide and 23.2 g (0.225 mol) of tert-butyl nitrite in 130 ml of methylene chloride by a method similar to Example 1, Precursor α. After working up and subsequently washing the crude product with ethanol, 13.3 g of product of value were obtained.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.N1C=CC=CC=1.[CH2:17]([O:19][P:20]([CH2:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1)([O:22][CH2:23][CH3:24])=[O:21])[CH3:18]>ClCCl.C(=O)([O-])O.[Na+]>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:1][C:30]([C:29]1[CH:33]=[CH:34][C:26]([CH2:25][P:20](=[O:21])([O:19][CH2:17][CH3:18])[O:22][CH2:23][CH3:24])=[CH:27][CH:28]=1)=[O:31]
Reactant: CCOP(=O)(Cc1ccc(C(=O)Cl)cc1)OCC
Reactant: Nc1nc2ccccc2s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOP(=O)(Cc1ccc(C(=O)Nc2nc3ccccc3s2)cc1)OCC
Reaction time: 10 h
Yield: 84.3 %

Procedure:
In 30 ml of dry dichloromethane were dissolved 3.0 g of 2-aminobenzothiazole and 10 ml of pyridine and while the resulting solution was stirred under ice-cooling, a solution of 5.8 g 4-[(diethoxyphosphoryl)methyl]benzoyl chloride in 10 ml dry dichloromethane was slowly added dropwise. The stirring was continued at room temperature for 10 hours, after which the reaction mixture was diluted with 30 ml of 10% aqueous sodium hydrogen carbonate solution and extracted with chloroform. The chloroform layer was washed serially with 30 ml of 10% hydrochloric acid and 30 ml of water and dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: chloroform-ethyl acetate=1:1) and the resulting crude crystals were recrystallized from ethanol to provide 6.8 g of the title compound as colorless crystals. The structure and melting point of the compound thus obtained are shown in Table 1.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[C:12]([NH:14][C@H:15]1[CH2:19][CH2:18][NH:17][CH2:16]1)=[N:11][C:10]([C:20]1[NH:24][C:23](=[O:25])[NH:22][N:21]=1)=[CH:9]2.CC1C=CC=C(C)N=1.[C:34](Cl)(=[O:37])[CH:35]=[CH2:36]>C(Cl)Cl>[C:34]([N:17]1[CH2:18][CH2:19][C@H:15]([NH:14][C:12]2[C:13]3[C:8](=[CH:7][CH:6]=[CH:5][C:4]=3[O:3][CH3:2])[CH:9]=[C:10]([C:20]3[NH:24][C:23](=[O:25])[NH:22][N:21]=3)[N:11]=2)[CH2:16]1)(=[O:37])[CH:35]=[CH2:36]
Reactant: COc1cccc2cc(-c3n[nH]c(=O)[nH]3)nc(N[C@H]3CCNC3)c12
Reactant: C=CC(=O)Cl
Agent: Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: C=CC(=O)N1CC[C@H](Nc2nc(-c3n[nH]c(=O)[nH]3)cc3cccc(OC)c23)C1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 27.1 %

Procedure:
To a mixture of (S)-3-(8-methoxy-1-(pyrrolidin-3-ylamino)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one hydrochloride (120 mg, 0.33 mmol) in DCM (8 mL) was added 2,6-dimethylpyridine (106 mg, 0.99 mmol). The resulting mixture was cooled to −78° C. Acryloyl chloride (120 mg, 1.20 mmol, 10 mg/mL in dry DCM) was added dropwise and the reaction mixture was stirred at −78° C. for 1.5 hours. The reaction was quenched with MeOH (5 mL) and the mixture was concentrated in vacuo. The crude product was purified by preparative HPLC to give the title compound (34 mg, 27%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.81 (s, 1H), 11.69 (s, 1H), 7.85 (dd, J=7.1, 14.5 Hz, 1H), 7.57-7.51 (m, 1H), 7.43 (d, J=3.3 Hz, 1H), 7.36 (d, J=8.0 Hz, 1H), 7.02 (d, J=8.0 Hz, 1H), 6.72-6.54 (m, 1H), 6.16 (m, 1H), 5.73-5.61 (m, 1H), 5.21-5.03 (m, 1H), 4.16 (m, 1H), 4.04-3.89 (m, 3H), 3.79 (m, 1H), 3.71-3.61 (m, 1H), 3.44 (m, 1H), 3.24 (m, 1H), 2.42-2.21 (m, 1H), 2.09-1.90 (m, 1H); ESI-MS m/z [M+H]+ 381.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:6][CH2:5][O:4][C:3]1=[CH:7][N:8]1[CH:12]=[N:11][CH:10]=[N:9]1.Cl.C[OH:16]>>[CH3:1][C:2]1([CH3:13])[CH2:6][CH2:5][O:4][C:3]1([OH:16])[CH2:7][N:8]1[CH:12]=[N:11][CH:10]=[N:9]1
Reactant: CC1(C)CCOC1=Cn1cncn1
Reactant: CO
Agent: Cl
Product: CC1(C)CCOC1(O)Cn1cncn1
Yield: 93 %

Procedure:
30 g (0.17 mole) of (3,3-dimethyl-tetrahydrofuran-2-ylidene)-(1,2,4-triazol-1-yl)-methane and 100 g of concentrated hydrochloric acid are stirred in 300 ml of methanol at room temperature for 4 hours. The reaction mixture is concentrated in vacuo, the residue is taken up in water, the pH value is adjusted to 7 to 8 with dilute sodium hydroxide solution and the mixture is extracted with methylene chloride. The organic phase is washed with water, dried over sodium sulphate and concentrated in vacuo. 30.7 g (93% of theory) of 3,3-dimethyl-2-hydroxy-2-(1,2,4-triazol-1-yl-methyl)-tetrahydrofuran of melting point 93°-95° C. are obtained. ##STR99##
Reaction SMILES: [C:1]([C:3]1[C:8](Br)=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].[C:10]1([CH3:19])[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(O)C>[C:1]([C:3]1[C:8]([C:13]2[CH:14]=[CH:15][C:10]([CH3:19])=[CH:11][CH:12]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: N#Cc1ncccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc(-c2cccnc2C#N)cc1
Yield: 34 %

Procedure:
Under nitrogen, 13.91 g (76 mmol) of 2-cyano-3-bromopyridine from step 2 and 11.41 g (84 mmol) of 4-tolylboronic acid from step 3 were treated with 2.65 g (2.3 mmol) of tetrakis (triphenylphosphine)palladium zero, 155 mL of toluene, 60 mL of ethanol, and 77 mL of 2M aqueous sodium carbonate. The reaction mixture was heated to reflux and vigorously stirred overnight. The product crystallized from the reaction mixture after several days at ambient temperature. Filtration provided 5.02 g (34%) of 2-cyano-3-(4-tolyl)pyridine as a colorless solid: mp 136°-138° C.; NMR (CDCl3) δ2.44 (s, 3H), 7.34 (d, J=8 Hz, 2H), 7.47 (d, J=8 Hz, 2H), 7.56 (dd, J=8 and 5 Hz, 1H), 7.85 (dd, J=8 and 2 Hz, 1H), 8.68 (dd, J=5 and 2 Hz, 1H); MS (70 eV) m/e (rel intensity) 194 (100).
Reaction SMILES: [C:1]1([N:7]2[N:11]3[C:12](=[O:19])[C:13]([C:16]([OH:18])=[O:17])=[CH:14][N:15]=[C:10]3[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.O1[CH2:29][CH2:28]OCC1>>[C:1]1([N:7]2[N:11]3[C:12](=[O:19])[C:13]([C:16]([O:18][CH2:2][CH2:1][N:7]([CH2:28][CH3:29])[CH2:8][CH3:9])=[O:17])=[CH:14][N:15]=[C:10]3[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1COCCO1
Reactant: O=C(O)c1cnc2ccn(-c3ccccc3)n2c1=O
Solvent: O=S(Cl)Cl
Product: CCN(CC)CCOC(=O)c1cnc2ccn(-c3ccccc3)n2c1=O

Procedure:
1-phenyl-7-oxo-1H,7H-pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (1.2 g) was reacted with thionyl chloride (0.8 ml) in dioxane (30 ml) at the reflux temperature for 3 hours, then the mixture was evaporated in vacuo to dryness. The residue was dissolved in dioxane (30 ml) and reacted with 2-(diethylamino)-ethanol (1.2 g) at room temperature for 24 hours. After dilution with water and alkalinization with Na2CO3 the precipitate was extracted with ethyl acetate: evaporation to dryness and crystallization from chloroformethanol gave 0.7 g of 1-phenyl-7-oxo-1H,7H-pyrazolo[1,5-a]pyrimidine-6-carboxylic acid, 2-(diethylamino)-ethyl ester, m.p. 127°-130° C.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([NH2:18])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].C(O[CH:22](OCC)[CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])C>C(#N)C.C(O)(=O)C>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([N:18]=[CH:22][CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2]
Reactant: CCOCc1nc2cnc3ccccc3c2n1N
Reactant: CCOC(CCNC(=O)OC(C)(C)C)OCC
Solvent: CC(=O)O
Solvent: CC#N
Product: CCOCc1nc2cnc3ccccc3c2n1N=CCCNC(=O)OC(C)(C)C
Reaction time: 15 h
Yield: 99.9 %

Procedure:
A solution of 2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-amine (1.00 g, 4.13 mmol) in 20 mL of acetonitrile and 5 mL of glacial acetic acid was treated with tert-butyl (3,3-diethoxypropyl)carbamate (2.55 g, 10.3 mmol) and heated to reflux under an atmosphere of nitrogen. After 15 h, the reaction mixture was concentrated under reduced pressure to yield a brown oil. The oil was partitioned between CHCl3 and saturated NaHCO3 solution and the phases were separated. The organic portion was washed with water (2×) and brine, dried over Na2SO4, filtered and concentrated under reduced pressure to yield tert-butyl {3-[(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)imino]propyl}carbamate (1.64 g) as a dark red/orange oil.
Reaction SMILES: N[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:8]([O:12][CH2:13][O:14][CH3:15])[CH:7]([CH2:16][CH2:17][CH:18](N(CCC)CCC)[CH3:19])[CH2:6]2.C(=O)([O-])[O-].[K+].[K+].C([C:38]1[CH:48]=[CH:47][CH:46]=[C:40]2[C:41]([NH:43][C:44](=[O:45])[C:39]=12)=[O:42])(OCC)=O.O>CN(C=O)C>[CH2:41]([N:43]([CH2:44][CH2:39][CH3:38])[CH2:19][CH2:18][CH2:17][CH2:16][CH:7]1[CH2:6][C:5]2[C:9](=[CH:10][CH:11]=[C:3]([CH2:2][N:43]3[C:44](=[O:45])[C:39]4[C:40](=[CH:46][CH:47]=[CH:48][CH:38]=4)[C:41]3=[O:42])[CH:4]=2)[CH:8]1[O:12][CH2:13][O:14][CH3:15])[CH2:40][CH3:46]
Reactant: CCOC(=O)c1cccc2c1C(=O)NC2=O
Reactant: CCCN(CCC)C(C)CCC1Cc2cc(CN)ccc2C1OCOC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCN(CCC)CCCCC1Cc2cc(CN3C(=O)c4ccccc4C3=O)ccc2C1OCOC
Temperature: 25 °C
Reaction time: 3 h
Yield: 130.9 %

Procedure:
The compound (189 mg) obtained in Example 11-10 was dissolved in DMF (5.6 ml) and added with potassium carbonate (108.5 mg) and carbethoxyphthalimide (172.0 mg) and the whole was stirred at room temperature for 3 hours. The reaction solution was added with water and subjected to extraction with chloroform. The extract was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (253 mg) as a yellow oily substance.