Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[Zn][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].FC(F)(F)S(O[C:22]1[C:27]([CH3:29])([CH3:28])[CH2:26][CH2:25][CH2:24][C:23]=1[CH3:30])(=O)=O.C(OCC)C>CC(N(C)C)=O.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>[CH3:30][C:23]1[CH2:24][CH2:25][CH2:26][C:27]([CH3:29])([CH3:28])[C:22]=1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CC1=C(OS(=O)(=O)C(F)(F)F)C(C)(C)CCC1
Reactant: CCOC(=O)CCCCCCCC[Zn]Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)N(C)C
Solvent: CCOCC
Product: CCOC(=O)CCCCCCCCC1=C(C)CCCC1(C)C
Temperature: 95 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
To freshly prepared ethyl 9-(bromozincio)nonanoate (37.7 mmol) in dimethylacetamide under nitrogen in a reaction tube was added 2,6,6-trimethylcyclohex-1-en-1-yl trifluoromethanesulfonate (10.8 g, 39.6 mmol) followed by tetrakis(triphenylphosphine)palladium(0) (872 mg, 0.754 mmol). The tube was sealed and the mixture was stirred at 95° C. for 2 h. The reaction mixture was allowed to cool and was then poured into diethyl ether (100 mL). The upper layer was decanted and the lower layer was washed twice with diethyl ether (2×25 mL). The combined ether layers were washed with sat NH4Cl and brine, dried (MgSO4) and concentrated to give crude material (˜12 g). The material was purified by flash chromatography (silica, 0 to 1.5% EtOAc in hexane). The obtained oil was stirred under vacuum for 8 h in order to remove most of the side-product, ethyl nonanoate, and was then purified by a second flash chromatography (silica, 0 to 15% toluene in hexane). The fractions were analyzed by LCMS and GCMS. The purest fractions were collected and concentrated at a temperature below 25° C. to give ethyl 9-(2,6,6-trimethylcyclohex-1-en-1-yl)nonanoate as a colorless oil (6.16 g, 53% yield over two steps). LCMS ESI+m/z 309 [M+H]+; GCMS m/z 308 [M]+.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:19][C:20]([CH3:29])([O:22][CH2:23][CH2:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH3:21])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:18]=1)[CH3:2].[H][H].[OH-].[Na+]>FC(F)(F)C(O)=O.O.[Pt](=O)=O>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:19][C:20]([CH3:21])([O:22][CH2:23][CH2:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH3:29])[C:7]2[C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:18]=1)[CH3:2]
Reactant: [H][H]
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)OCCS(C)(=O)=O
Agent: O=[Pt]=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCOCc1nc2c(N)nc3c(c2n1CC(C)(C)OCCS(C)(=O)=O)CCCC3
Yield: 75.8 %

Procedure:
A mixture of 2-(ethoxymethyl)-1-{2-methyl-2-[2-(methylsulfonyl)ethoxy]propyl}-1H-imidazo[4,5-c]quinolin-4-amine (prepared as described in Example 9, 1.70 g, 4.04 mmol) and platinum(IV) oxide (1.0 g) in trifluoroacetic acid (20 mL) was hydrogenated on a Parr apparatus at 50 psi (3.5×105 Pa) hydrogen pressure for 40 hours. The mixture was filtered through CELITE filter agent, which was washed afterwards with dichloromethane. The filtrate was concentrated under reduced pressure to afford an oil that was suspended in water (20 mL) and adjusted to pH 13 with 50% aqueous sodium hydroxide. The mixture was extracted with dichloromethane (3×50 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield a white solid. The solid was recrystallized from toluene to afford 1.3 g of 2-(ethoxymethyl)-1-{2-methyl-2-[2-(methylsulfonyl)ethoxy]propyl}-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine as a white, fluffy powder, mp 150-153° C.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:19]2[CH2:18][CH2:17][C@@:16]2([CH3:24])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:15])[CH2:13]Br)[CH2:3]1.[OH:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[OH:1][C@@H:2]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:19]2[CH2:18][CH2:17][C@@:16]2([CH3:24])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:15])[CH2:13][O:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH2:3]1
Reactant: Oc1cccnc1
Reactant: C[C@]12CC[C@@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C(=O)CBr)CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@]12CC[C@@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C(=O)COc3cccnc3)CC[C@@H]12
Reaction time: 0.5 h
Yield: 16 %

Procedure:
To a solution of 3α-hydroxy-21-bromo-5β-pregnan-20-one (300 mg, 0.76 mmol) in DMF (5 mL) was added 3-hydroxypyridine (215 mg, 2.27 mmol) and K2CO3 (313 mg, 2.27 mmol) and the mixture obtained was sired at 25° C. for 0.5 h. The reaction mixture was then poured into a separatory funnel containing water (30 mL) and the mixture was extracted with EtOAc (3×35 mL). The combined extracts were washed with water (2×25 mL) and then dried over Na2SO4. Removal of the solvent in vacuo resulted in the crude product which was purified by flash chromatography over silica gel to yield the pure 3α-hydroxy-21-(pyrid-3-yl)oxy-5β-pregnan-20-one (50 mg); mp 63-66° C.; TLC Rf (MeOH:CH2Cl2 5:95)=0.15.
Reaction SMILES: C(N(CC)CC)C.[CH:8]1([NH:14][C:15](=[O:33])[C@H:16]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)[NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.C(Cl)(=O)[O:35][CH2:36][CH3:37].S([C:44]1[CH:50]=[CH:49][C:47](N)=[CH:46][CH:45]=1)(=O)(=O)N>O1CCCC1>[CH:8]1([NH:14][C:15](=[O:33])[C@H:16]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:37][C:36]([C:44]3[CH:50]=[CH:49][CH:47]=[CH:46][CH:45]=3)=[O:35])=[CH:28][CH:27]=2)[NH:17][C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CCOC(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)NC1CCCCC1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCC(=O)c2ccccc2)cc1)C(=O)NC1CCCCC1
Reaction time: 0.5 h
Yield: 71.7 %

Procedure:
Triethylamine (1.5 ml) was added to a solution of N-(t-butyloxycarbonyl)-4-benzyloxy-L-phenylalanine (I) (2 g) dissolved in dry tetrahydrofuran (30 ml) and ethyl chlorocarbonate (0.65 g) was added under ice-cooling, followed by stirring for 30 minutes. To this solution was added 4-sulfamoylaniline (0.65 g) and the mixture was stirred at room temperature for 10 hours. Post-treatment was carried out in the same manner as in Example 1 to give 1.3 g of N-(t-butyloxycarbonyl)-4-benzyloxy-L-phenylalanine 4-sulfamoylanilide (II). To the above compound (II) (0.5 g) was added under ice-cooling 4N-hydrogen chloride/dioxane solution (3 ml) and the mixture was stirred at room temperature for 30 minutes. Post-treatment conducted in the same manner as in Example 1 gave quantitatively 4-benzyloxy-L-phenylalanine 4-sulfamoylanilide hydrochloride (III). On the other hand, trans-4-(t-butyloxycarbonyl)aminomethylcyclohexylcarboxylic acid (0.25 g) and triethylamine (0.2 ml) were added, and ethyl chlorocarbonate (0.1 g) was added under ice-cooling, followed by stirring for 30 minutes. To this solution were added the above compound (III) (0.42 g) and triethylamine (1 ml), and the mixture was stirred at room temperature for 3 hours. After extraction with chloroform, according to the same post-treatment as in Example 1, 0.28 g of N-[trans-4-(t-butyloxycarbonyl)aminomethylcyclohexylcarbonyl]-4-benzyloxy-L-phenylalanine 4-sulfamoylanilide (IV) was obtained. To the above compound (IV) (0.28 g) was added 4N-hydrogen chloride/dioxane solution (2 ml) and, after stirring at room temperature for 30 minutes, following the same procedure as in Example 1, 0.15 g of N-(trans-4-aminomethylcyclohexylcarbonyl)-4-benzyloxy-L-phenylalanine 4-sulfamoylanilide hydrochloride was obtained.
Reaction SMILES: [F:1][C:2](=[C:10]([F:12])[F:11])[CH2:3][CH2:4][CH:5]([C:8]#[N:9])[C:6]#[N:7].[H-].[Na+].Br[CH2:16][C:17]1[CH:18]=[N:19][C:20]([Cl:23])=[CH:21][CH:22]=1>CN(C)C=O>[Cl:23][C:20]1[N:19]=[CH:18][C:17]([CH2:16][C:5]([CH2:4][CH2:3][C:2]([F:1])=[C:10]([F:11])[F:12])([C:6]#[N:7])[C:8]#[N:9])=[CH:22][CH:21]=1
Reactant: Clc1ccc(CBr)cn1
Reactant: N#CC(C#N)CCC(F)=C(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)=C(F)F)Cc1ccc(Cl)nc1
Yield: 60.9 %

Procedure:
By using (3,4,4-trifluoro-3-butenyl)malononitrile (0.21 g), N,N-dimethylformamide (5 ml), sodium hydride (60% in oil, 0.05 g) and 3-bromomethyl-6-chloropyridine (0.28 g) according to the similar method described in Production Example 1 was obtained 0.22 g of 2-((6-Chloro-3-pyridyl)methyl)-2-(3,4,4-trifluoro-3-butenyl)malononitrile represented by the following formula (the present invention compound (3)).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:11]([O:15][C:16]([N:18]1[C@H:22]([CH:23]=O)[CH2:21][CH2:20][C@H:19]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[O:17])([CH3:14])([CH3:13])[CH3:12].[C@H:32](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+].O>C1(C)C=CC=CC=1.C1COCC1>[C:11]([O:15][C:16]([N:18]1[C@H:22]([CH:23]=[CH2:32])[CH2:21][CH2:20][C@H:19]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)[C@@H]1CC[C@@H](C=O)N1C(=O)OC(C)(C)C
Reactant: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: C=C[C@@H]1CC[C@@H](C(=O)OC(C)(C)C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 88 %

Procedure:
93.5 ml (61.69 mmol, 2.0 eq) of a solution of KHMDS in toluene (15 w %, ABCR) was added under argon at RT to a suspension of 22.037 g (61.69 mmol, 2.0 eq) Ph3PMeBr in 220 ml THF, and the substance was stirred for 1 h. Then, a solution of 9.234 g (30.88 mmol, 1.0 eq) of the aldehyde 111 in 70 ml THF was dropped in at −78° C., and the resulting solution was stirred for 2.5 h at RT. 160 ml saturated Rochelle salt solution and 100 ml water was added to the reaction mixture, then extracted 3× with 260 ml MTBE each, the combined organic phases were washed with saturated NaCl solution and dried over magnesium sulfate. The solvent was removed at reduced pressure and, after purification by means of column chromatography on silica gel with EtOAc/CyHex (1:9) as eluent, 8.091 g (27.21 mmol, 88%) of the vinyl proline 112 was obtained as an isomeric mixture (d.r.: 1.7:1 cis:trans).
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:24])[CH2:6][CH:7]([C:11]2[S:12][CH:13]=[CH:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[N:17]=2)[CH2:8][C:9]=1O)(=O)[CH3:2].N1CCCC1.Cl.[NH2:31][C:32]([NH2:34])=[NH:33]>CCO>[NH2:34][C:32]1[N:33]=[C:1]([CH3:2])[C:4]2[C:5](=[O:24])[CH2:6][CH:7]([C:11]3[S:12][CH:13]=[CH:14][C:15]=3[C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[N:17]=3)[CH2:8][C:9]=2[N:31]=1
Reactant: N=C(N)N
Reactant: COc1cccc(-c2ccsc2C2CC(=O)C(C(C)=O)=C(O)C2)n1
Agent: Cl
Solvent: CCO
Solvent: C1CCNC1
Product: COc1cccc(-c2ccsc2C2CC(=O)c3c(C)nc(N)nc3C2)n1
Temperature: 100 °C
Yield: 14.7 %

Procedure:
To a 150 mL pressure vessel was added 2-acetyl-3-hydroxy-5-(3-(6-methoxypyridin-2-yl)thiophen-2-yl)cyclohex-2-enone (30G, 1.72 g, 5.01 mmol, 1.0 eq.), EtOH (50 mL), pyrrolidine (2.13 g, 30.1 mmol, 6.0 eq.), guanidine hydrochloride (1.44 g, 15 mmol, 3.0 eq.). The vessel was sealed and heated overnight at 100° C. LC/MS analysis showed the reaction to be complete whereupon the reaction mixture was concentrated and the residue was taken up in 20% EtOAc/CH2Cl2. An insoluble solid proving not to be product was filtered off. The remaining filtrate was purified via column chromatography (20% EtOAc/CH2Cl2 to 70% EtOAc/CH2Cl2) to yield the product 30H as a light gray solid (270 mg, 15%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.55 (s, 3H) 2.76-2.95 (m, 2H) 3.02-3.22 (m, 2H) 3.70 (s, 3H) 4.62-4.77 (m, 1H) 6.72 (d, J=8.34 Hz, 1H) 7.31 (d, J=7.58 Hz, 1H) 7.41-7.54 (m, 4H) 7.75 (t, J=7.83 Hz, 1H). ESI-MS: m/z 367.3 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[CH:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][C:47]([O:49][CH2:50]C)=[O:48])=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[CH:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][C:47]([O:49][CH3:50])=[O:48])=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CN1CCCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOCc4ccccc4OC)cc3)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)CN1CCCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOCc4ccccc4OC)cc3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
A solution of 0.133 g (0.189 mmol) of (3RS,4RS)-3-(1-ethoxycarbonylmethyl-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester [example 2(d)] in 5 ml of methanol was treated with 0.10 g (0.72 mmol) of anhydrous potassium carbonate. The suspension was stirred for 1 h at 25° C. The salts were filtered off, the filtrate was concentrated. The thus-obtained crude product was purified by chromatography on silica gel using a 2:1 mixture of hexane and ethyl acetate as the eluent, and yielded 0.060 g (0.087 mmol, 46.1% of theory) of (3RS,4RS)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-3-(1-methoxycarbonylmethyl-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester as yellow oil; MS: 689 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:10]([NH:11][S:12]([CH2:15][CH2:16][CH3:17])(=[O:14])=[O:13])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:18]N(C)C=O.C(Cl)(=O)C(Cl)=O.CO>ClCCl>[CH3:18][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([NH:11][S:12]([CH2:15][CH2:16][CH3:17])(=[O:14])=[O:13])[C:2]=1[F:1]
Reactant: CN(C)C=O
Reactant: CCCS(=O)(=O)Nc1cccc(C(=O)O)c1F
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CO
Product: CCCS(=O)(=O)Nc1cccc(C(=O)OC)c1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a 2-fluoro-3-(propane-1-sulfonylamino)-benzoic acid (15, 5.05 g, 19.3 mmol) in 100 mL of dichloromethane, N,N-dimethylformamide (0.075 mL, 0.97 mmol) was added under an atmosphere of nitrogen. The reaction was cooled with ice water bath, followed by slow addition of oxalyl chloride (10.8 mL, 2.00 M in dichloromethane, 21.6 mmol). The reaction mixture was stirred at room temperature for 3.0 hours, then cooled with ice water bath, followed by slowly adding 36.0 mL of methanol. The reaction was stirred at room temperature overnight, then concentrated under vacuum. The resulting material was purified by silica gel column chromatography eluting with 30% ethyl acetate in hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound as a crude white solid (16, 4.0 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]([NH2:15])[CH:11]=[CH:12][C:13]=1[CH3:14].CCO/[C:19](/[CH3:26])=[CH:20]/[C:21](OCC)=[O:22].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]2[N:15]=[C:19]([CH3:26])[CH:20]=[C:21]([OH:22])[C:11]2=[CH:12][C:13]=1[CH3:14]
Reactant: Cc1ccn(N)c1-c1ccc(Cl)cc1Cl
Reactant: CCOC(=O)/C=C(\C)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Product: Cc1cc(O)c2cc(C)c(-c3ccc(Cl)cc3Cl)n2n1
Temperature: 25 °C

Procedure:
A mixture of 2-(2,4-dichlorophenyl)-3-methyl-1H-pyrrol-1-amine (2.34 g, 9.69 mmol), ethyl trans-3-ethoxycrotonate (1.58 g, 10.0 mmol) and p-toluenesulfonic acid (0.095 g, 0.50 mmol) in CHCl3 (100 mL) is refluxed with a Dean-Stark tube charged with molecular sieves for 24 h. After cooling down to room temperature, the mixture is concentrated in vacuo to dryness and the residue is subjected to column chromatography (silica gel, 1/4 EtOAc/heptane) to give 1.88 g (63%) of light yellow solid as the title compound: mp 234–237° C.; 1H NMR (400 MHz, DMSO-d6) δ 7.76 (d, J=2.1 Hz, 1H), 7.52 (dd, J=2.1, 8.3 Hz, 1H), 7.44 (d, J=8.3 Hz, 1H), 6.49 (s, 1H), 5.94 (s, 1H), 2.20 (s, 3H), 2.10 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 153.0, 149.0, 134.2, 135.2, 132.0, 128.2, 127.6, 125.7, 121.2, 119.0, 118.8, 96.0, 92.5, 20.0, 10.5; IR (diffuse reflectance) 3075, 3008, 2997, 2989, 2353, 2327, 2216, 2190, 2105, 1555, 1367, 1314, 1185, 828, 814 cm−1; MS (EI) m/z 308 (M+), 306 (M+); HRMS (FAB) calcd for C15H12Cl2N2O+H 307.0405, found 307.0414; Anal. Calcd for C15H12Cl2N2O: C, 58.65; H, 3.94; N, 9.12. Found: C, 58.68; H, 3.91; N, 8.96.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH2:13])[CH:11]=2)[N:6]=[CH:5][N:4]=1.C(N(CCC)CCC)CC.N1C=CC=CC=1.[CH3:30][C:31]([CH3:37])([CH3:36])[CH2:32][C:33](Cl)=[O:34]>C(Cl)(Cl)Cl.CO.CO.C(Cl)(Cl)Cl>[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:33](=[O:34])[CH2:32][C:31]([CH3:37])([CH3:36])[CH3:30])[CH:11]=2)[N:6]=[CH:5][N:4]=1
Reactant: Nc1ccc2ncnc(N)c2c1
Reactant: CC(C)(C)CC(=O)Cl
Agent: CCCN(CCC)CCC
Agent: Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)(C)CC(=O)Nc1ccc2ncnc(N)c2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 64.7 %

Procedure:
To a mixture of 4,6-diaminoquinazoline hydrochloride (10.0 g), tripropylamine (17.61 g) and dry pyridine (100 ml) was added dropwise during 35 minutes 3,3-dimethylbutyryl chloride (10.34 g) under ice-cooling. The reaction mixture was stirred for 2 hours at the same temperature. To the resultant mixture was added ice-water. The mixture was stirred for 5 minutes and then concentrated under reduced pressure. To the residue was added water and sodium hydrogen carbonate (13.0 g) little by little to give precipitates, which were separated by filtration, washed with water and dried. Thus obtained crude crystals were dissolved in a mixture of chloroform and methanol under heating. After insoluble materials were removed by filtration, the filtrate was concentrated under reduced pressure to give a residue, which was suspended in 5% methanol-chloroform solution (70 ml). After stirring under heating, the suspension was filtered to give crystalline 4-amino-6-(3,3-dimethylbutyramido)quinazoline (8.5 g).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[CH2:10](Cl)/[CH:11]=C/CCl.[OH-].[K+].[CH2:18](Cl)Cl>>[C:1]([C:2]1([CH3:18])[C:3](=[O:4])[CH:5]1[CH:10]=[CH2:11])([O:7][CH2:8][CH3:9])=[O:6]
Reactant: ClC/C=C/CCl
Reactant: CCOC(=O)CC(C)=O
Reactant: ClCCl
Agent: *OCC(*)C
Agent: [K+]
Agent: [OH-]
Product: C=CC1C(=O)C1(C)C(=O)OCC
Temperature: 35 °C

Procedure:
Ethyl acetoacetate was reacted with 1,4-dichlorobutene-2 in a manner similar to that described in Example III using a poly(oxypropylene) catalyst. For the reaction, 5.6 g potassium hydroxide and 50 mls. methylene dichloride were combined in the reaction vessel and ethyl acetoacetate (6.5 g), the poly(propylene glycol) catalyst (1.06 g) and 20 mls. methylene dichloride rapidly added with vigorous stirring. 1,4-Dibromobutene-2 (10.7 g) was then added via a solids addition funnel while maintaining the temperature at about 35° C. Seventy-four percent yield 1-carboethoxy-1-methylketo-2-vinylcyclopropane was obtained. The product had a boiling point of 58° C. at 0.85 mm Hg, refractive index (nD25) of 1.4707, and the structure was confirmed by infrared and proton nmr spectroscopy. When the process is repeated reacting 1,4-dichlorobutene-2 with phenylacetonitrile, ethyl phenylacetate and acetoacetanilide, 1-cyano-1-phenyl-2-vinylcyclopropane, 1-carboethoxy-1-phenyl-2-vinylcyclopropane, and 1-carboxanilido-1-methylketo-2-vinylcyclopropane are respectively obtained.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH:11]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[N+:8]([C:3]1[CH:4]=[CH:5][C:6]([N:11]2[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]2)=[CH:7][CH:2]=1)([O-:10])=[O:9]
Reactant: OC1CCNCC1
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(N2CCC(O)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 145.2 %

Procedure:
A 100 mL round bottom flask was dried in an oven overnight and cooled to room temperature under Ar(g). The flask was charged with fluoronitrobenzene (0.500 mL, 4.71 mmol), Piperidin-4-ol (0.619 g, 2.30 mmol) and dioxane (9.0 mL). To the resulting solution, diisopropyl ethyl amine (0.463 mL, 6.12 mmol) was added dropwise, and the reaction was allowed to stir at 105° C. for 48 h. The mixture was extracted with EtOAc (3×˜50 mL), and brine (2×˜50 mL). The combined organic layers were then dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude mixture was then purified over silica (10% MeOH/90% CHCl3) affording a yellow solid (0.742 g, 3.34 mmol, 71% yield).
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.[OH:6][C:7]1[CH:12]=[C:11]([OH:13])[CH:10]=[CH:9][C:8]=1[C:14]12[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2.[OH-].[Na+].C[CH2:27][C:28]([CH3:30])=[O:29]>CC(CC(C)=O)C.CS(C)=O>[CH2:1]([O:6][C:7]1[CH:12]=[C:11]([O:13][CH2:27][CH:28]2[O:29][CH2:30]2)[CH:10]=[CH:9][C:8]=1[C:14]12[CH2:15][CH:16]3[CH2:22][CH:20]([CH2:19][CH:18]([CH2:17]3)[CH2:23]1)[CH2:21]2)[CH:3]1[O:5][CH2:4]1
Reactant: CCC(C)=O
Reactant: Oc1ccc(C23CC4CC(CC(C4)C2)C3)c(O)c1
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CC(=O)CC(C)C
Product: c1cc(C23CC4CC(CC(C4)C2)C3)c(OCC2CO2)cc1OCC1CO1
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
Into a separable flask having an inner volume of 300 ml and equipped with a reflux condenser, a stiffer, a thermometer, and a nitrogen inlet were charged 30 ml of MIBK, 60 ml of DMSO, and 65 g (0.70 mol) of epichlorohydrin. After the atmosphere was displaced with nitrogen, 20.6 g (0.09 mol) of 1-(2,4-dihydroxyphenyl)adamantane synthesized in the above (1) was added and the mixture was heated to 45° C. with agitation. Into this solution, 7.6 g (0.19 mol) of sodium hydroxide was added over 0.5 hour, and the agitation was continued for another 0.5 hour. Then the temperature was raised to 65° C. and the agitation was continued for 2 hours. The reaction solution was cooled to room temperature, added with 25 ml of MIBK, and washed by water until the aqueous phase became neutral, and then the organic layer was concentrated to obtain yellowish viscous solution. The yellowish viscous solution was dissolved into 285 g of MEK, added with 3.4 g of 25% by mass of aqueous sodium hydroxide solution, and then heated under reflux with agitation for 2 hours. The solution was cooled to room temperature, washed with water until the aqueous phase became neutral from alkaline, and then the washing was done for two more times. The organic layer was concentrated to obtain the target compound (yield 94%). The LC (liquid chromatography) of this compound showed the purity of 95% (monomer content was 95% and the rests were oligomers of the target compound).