Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:18][CH2:19][CH2:20][NH:21][S:22]([C:25]3[N:26]=[CH:27][N:28]([CH3:30])[CH:29]=3)(=[O:24])=[O:23])[CH:8]=2)[CH2:3]1.C(NC(C)C)(C)C.[Cl:38][CH2:39][C:40]([CH3:45])([CH3:44])[C:41](Cl)=[O:42].Cl>ClCCl>[CH2:11]([CH:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:18][CH2:19][CH2:20][NH:21][S:22]([C:25]3[N:26]=[CH:27][N:28]([CH3:30])[CH:29]=3)(=[O:24])=[O:23])[CH:8]=2)[CH2:3][CH:2]1[NH:1][C:41](=[O:42])[C:40]([CH3:45])([CH3:44])[CH2:39][Cl:38])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Cn1cnc(S(=O)(=O)NCCOc2ccc3c(c2)C(Cc2ccccc2)C(N)C3)c1
Reactant: CC(C)(CCl)C(=O)Cl
Agent: Cl
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: Cn1cnc(S(=O)(=O)NCCOc2ccc3c(c2)C(Cc2ccccc2)C(NC(=O)C(C)(C)CCl)C3)c1
Temperature: 25 °C

Procedure:
To a solution of N-(2-(2-amino-3-benzyl-2,3-dihydro-1H-inden-5-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide (40.5 mg, 0.095 mmol; see example 193) in dry dichloromethane (2 ml) containing diisopropylamine (0.025 ml, 0.142 mmol) and under argon was added a solution of 3-chloropivaloyl chloride (0.019 ml, 0.142 mmol) in dichloromethane and stirred at room temperature over night. Added 0.5M hydrochloric acid and extracted with dichloromethane, co extracted aqueous layer with dichloromethane and the combined organic layers were washed with sodium bicarbonate and brine, dried over sodium bicarbonate, filtered and evaporated to obtain the desired N-(1-benzyl-6-(2-(1-methyl-1H-imidazole-4-sulfonamido)ethoxy)-2,3-dihydro-1H-inden-2-yl)-3-chloro-2,2-dimethylpropanamide as yellow oil. m=51 mg (quant.) that was used without further purification for the next steps.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=4[CH3:30])[C:24](O)=[O:25])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[CH3:31][N:32]1[CH:36]=[CH:35][C:34]([C:37]2([NH2:40])[CH2:39][CH2:38]2)=[N:33]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([C:24](=[O:25])[NH:40][C:37]5([C:34]6[CH:35]=[CH:36][N:32]([CH3:31])[N:33]=6)[CH2:39][CH2:38]5)[CH:27]=[CH:28][C:29]=4[CH3:30])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)cc12
Reactant: Cn1ccc(C2(N)CC2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ccn(C)n5)CC4)ccc3C)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.15 g, 0.37 mmol, 1 eq), 1-(1-methyl-1H-pyrazol-3-yl)cyclopropanamine (0.061 g, 0.44 mmol, 1.2 eq), HOBT (0.057 g, 0.42 mmol, 1.7 eq), EDC.HCl (0.086 g, 0.44 mmol, 1.8 eq) in DCM at ambient temperature under nitrogen was added diisopropylethylamine (0.16 g, 1.2 mmol, 5.0 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was further purified by column chromatography (neutral alumina) using 0.5% Methanol/DCM and finally by preparative HPLC. Yield: 0.06 g (40%) 1H NMR (400 MHz, DMSO-d6): δ 1.12-1.16 (m, 2H), 1.20-1.23 (m, 2H), 2.29 (s, 3H), 2.82-2.83 (d, 3H, J=4.64 Hz), 3.37 (s, 3H), 5.9-6.0 (d, 1H, J=2.12 Hz), 7.39-7.48 (m, 5H), 7.58 (d, 1H, J=1.68 Hz), 7.75-7.77 (d, 1H, J=9.7 Hz), 7.81-7.83 (t, 2H, J=2.87 Hz), 7.98-8.46 (m, 2H), 8.47-8.48 (d, 1H, J=4.52 Hz), 9.14 (s, 1H). LCMS: (ES+) m/z=523.2 (M+H). LCMS Method: Column-Ascentis Express C18 (5×2.1 mm-2.7 μm) Mphase A: 2% MeCN-98% H2O-10 mM NH4COOH Mphase B: 98% MeCN-2% H2O-10 mM NH4COOH Flow: 1 mL/Min
Reaction SMILES: CCOCC.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.[CH3:15][N:16]([CH3:29])[C:17]1(C#N)[CH2:26][CH2:25][C:20]2([O:24][CH2:23][CH2:22][O:21]2)[CH2:19][CH2:18]1>C1COCC1>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([C:17]2([N:16]([CH3:29])[CH3:15])[CH2:26][CH2:25][C:20]3([O:24][CH2:23][CH2:22][O:21]3)[CH2:19][CH2:18]2)=[CH:8][CH:9]=1
Reactant: COc1ccc(Br)cc1
Reactant: CN(C)C1(C#N)CCC2(CC1)OCCO2
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(C2(N(C)C)CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Magnesium (3.65 g, 150 mmol) and an iodine crystal were provided in a nitrogen atmosphere and heated. Abs. ether (10 mL) was then added and a solution of 4-bromoanisole (18.8 mL, 150 mmol) in abs. ether (150 mL) was added in drops so that the ether lightly boiled. The solution formed was subsequently stirred for 1 h at RT and then mixed in drops with a solution of 8-dimethylamino-1,4-dioxa-spiro[4.5]decane-8-carbonitrile (10.5 g, 50.0 mmol) in abs. THF (100 mL), and the solution heated to 37-40° C. until boiling during the addition. A precipitate separated out and the batch was stirred overnight at RT. The solution was mixed with NH4Cl solution with ice cooling, the phases were separated, the aqueous phase extracted three times with ether, the combined organic phases washed with saturated NaCl solution and water, dried over Na2SO4 and concentrated to low volume in a vacuum. Flash chromatography of the residue with ethyl acetate/methanol (20:1→9:1→4:1→1:4→MeOH) gave the desired product.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][C:13]1[N:18]=[CH:17][C:16]([C:19]2([CH2:25][NH2:26])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[CH:15][N:14]=1>>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:26][CH2:25][C:19]1([C:16]2[CH:17]=[N:18][C:13]([CH3:12])=[N:14][CH:15]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[O:6]
Reactant: O=C(O)c1cccc(F)c1Cl
Reactant: Cc1ncc(C2(CN)CCOCC2)cn1
Product: Cc1ncc(C2(CNC(=O)c3cccc(F)c3Cl)CCOCC2)cn1

Procedure:
From 2-chloro-3-fluorobenzoic acid and (4-(2-methylpyrimidin-5-yl)tetrahydro-2H-pyran-4-yl)methanamine. LCMS (MH+): m/z=364.1, tR (minutes, Method F)=1.95
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)=[O:10])=[CH:4][CH:3]=1.[CH2:20]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)[CH3:21].C([O-])([O-])=O.[Na+].[Na+]>COCOC.O>[CH2:20]([C:22]1[CH:27]=[CH:26][C:25]([C:2]2[N:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)=[O:10])=[CH:4][CH:3]=2)=[CH:24][CH:23]=1)[CH3:21]
Reactant: O=C(Cc1ccc(Cl)nc1)NCc1cccc(F)c1
Reactant: CCc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCOC
Product: CCc1ccc(-c2ccc(CC(=O)NCc3cccc(F)c3)cn2)cc1
Temperature: 25 °C

Procedure:
2-(6-Chloro-pyridin-3-yl)-N-(3-fluoro-benzyl)-acetamide and (0.125 gm, 0.5 mmole), 4-ethylbenzeneboronic acid (0.083 gm, 0.55 mmole) was dissolved in dimethoxymethane (DME), Na2CO3 (0.11 gm, 1 mmole) in 5 ml of water was added to the DME solution, the solution was then degassed for 30 min (Ar through the solution and vacuum applied for the first 5 min), Palladiumtetrakistriphenylphosphine (0.029 gm, 0.025 mmole) was added, degassed for additional 15 min, refluxed for 24 hr. The reaction was allowed to cool to room temperature, filtered, solid washed with ethyl acetate; the organic layer was dried, evaporated. The residue was chromatographed using ethyl acetate/hexane 3:2. The product is white solid (0.08 gm, 47%). H1NMR INOVA-500 (DMSO d6) δ 1.228 (t, J=7.5 Hz, 3H), 2.669 (q, J=7.5 Hz, 2H), 3.590 (s, 2H), 4.321 (d, J=6 Hz, 2H), 7.053-7.113 (m, 3H), 7.324-7.375 (m, 3H), 7.766 (dd, J=9.0, 2.0 Hz, 1H), 7.887 (d, J=8.5 Hz, 1H), 7.994 (d, J=8.0 Hz, 2H), 8.548 (s, 1H), 8.696 (t, J=5.5 Hz, 1H). MS (m/z) 349.3 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[NH:5][C:6]2[C:11]([C:12]=1[CH2:13][C:14]([OH:16])=[O:15])=[C:10]([N+:17]([O-:19])=[O:18])[CH:9]=[CH:8][CH:7]=2)([CH3:3])[CH3:2].OS(O)(=O)=O.[CH3:25][CH2:26]O>>[CH:1]([C:4]1[NH:5][C:6]2[C:11]([C:12]=1[CH2:13][C:14]([O:16][CH2:25][CH3:26])=[O:15])=[C:10]([N+:17]([O-:19])=[O:18])[CH:9]=[CH:8][CH:7]=2)([CH3:3])[CH3:2]
Reactant: CC(C)c1[nH]c2cccc([N+](=O)[O-])c2c1CC(=O)O
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1c(C(C)C)[nH]c2cccc([N+](=O)[O-])c12

Procedure:
A solution of (2-isopropyl-4-nitro-1H-indol-3-yl)acetic acid from Step D (500 mg, 1.91 mmol) and conc. H2SO4 (0.5 mL) in EtOH (100 mL) was heated at reflux for 1 h. The cooled mixture was partially concentrated in vacuo, made basic by addition of saturated aqueous NaHCO3 and washed with CHCl3 (4×30 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound, which was of sufficient purity for use in the next step. MS: m/z=291 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([CH:15]1[CH2:17][CH2:16]1)[O:5][C:6]1[C:7](Cl)=[N:8][C:9]([Cl:13])=[N:10][C:11]=1[Cl:12].C(N(CC)CC)C.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[CH3:1][O:2][C:3](=[O:18])[CH:4]([CH:15]1[CH2:17][CH2:16]1)[O:5][C:6]1[C:11]([Cl:12])=[N:10][C:9]([Cl:13])=[N:8][C:7]=1[N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: C1COCCN1
Reactant: COC(=O)C(Oc1c(Cl)nc(Cl)nc1Cl)C1CC1
Solvent: CCN(CC)CC
Product: COC(=O)C(Oc1c(Cl)nc(Cl)nc1N1CCOCC1)C1CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 89.3 %

Procedure:
To a suspension of cyclopropyl-(2,4,6-trichloro-pyrimidin-5-yloxy)-acetic acid methyl ester (224 mg, 0.72 mmol) in IMS (4 mL) was added triethylamine (150 μL, 1.08 mmol) followed by morpholine (63 μL, 0.72 mmol). The yellow solution was stirred for 2.5 hours at RT before being concentrated in vacuo. The resultant residue was purified by column chromatography (SiO2, gradient 0-20% ethyl acetate in cyclohexane) affording Cyclopropyl-(2,4-dichloro-6-morpholin-4-yl-pyrimidin-5-yloxy)-acetic acid methyl ester as a colourless gum (233 mg, 89%). 1H NMR (CDCl3): δ 3.99 (1H, d, J=9.54 Hz), 4.03-3.83 (4H, m), 3.80-3.75 (4H, m), 3.78 (3H, s), 1.32-1.21 (1H, m), 0.70-0.57 (2H, m), 0.52-0.45 (1H, m), 0.33-0.26 (1H, m).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]#[N:25])=[CH:14][CH:13]=2)[C:7](=[S:10])[NH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)C(C)C)(C)C.[CH:35]1([CH2:41]Br)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>COCCO>[CH2:1]([C:5]1[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]#[N:25])=[CH:14][CH:13]=2)[C:7]([S:10][CH2:41][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)=[N:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: BrCC1CCCCC1
Reactant: CCCCc1n[nH]c(=S)n1Cc1ccc(-c2ccccc2C#N)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCO
Product: CCCCc1nnc(SCC2CCCCC2)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 59.4 %

Procedure:
A mixture of 147 mg (0.42 mmole) of 5-n-butyl-4-[(2'-cyanobiphenyl-4-yl)methyl]-2,4-dihydro-3H-1,2,4-triazole-3-thione (from Example 15, Step C), 146 μl (108 mg, 0.84 mmole) of N,N-diisopropylethylamine, 117 μl (148 mg, 0.84 mmole) of cyclohexylmethyl bromide, and 1.5 ml of 2-methoxyethanol was stirred under N2 at 70° C. overnight and then at reflux for an additional 4 hours. The solution was concentrated in vacuo, and the residue was partitioned between 25 ml of ethyl acetate and 25 ml of 0.2 N HCl. The ethyl acetate layer was washed with saturated NACl, then dried over anhydrous MgSO4, filtered, and rotary evaporated in vacuo. Column chromatography of the residue on silica gel (elution with a gradient of 0-0.8% methanol in CH2Cl2) afforded 111 mg (59%) title compound as an oil, homogeneous by TLC in 19:1 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 445 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.[CH2:13]([O:15][C:16](=[O:20])[C@H:17]([CH3:19])[NH2:18])[CH3:14]>>[CH2:13]([O:15][C:16](=[O:20])[C@H:17]([CH3:19])[NH:18][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1)[CH3:14]
Reactant: CCOC(=O)[C@H](C)N
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Product: CCOC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure G′ and using 3,5-difluorophenylacetic acid (Aldrich) and alanine ethyl ester (Aldrich), the title compound was prepared as a solid with a melting point of 93°-95° C. The reaction was monitored by tlc on silica gel (Rf=0.8 in EtOAC) and purification was by chromatography on silica gel using. EtOAc as the eluant followed by recrystallization from 1-chlorobutane.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[CH2:7]([O:9][C:10]([CH2:12][N:13]1[C:18]([CH3:19])=[CH:17][C:16]([S:20][CH2:21][CH2:22]O)=[C:15]([N+:24]([O-:26])=[O:25])[C:14]1=[O:27])=[O:11])[CH3:8]>C(Cl)Cl>[Cl:2][CH2:22][CH2:21][S:20][C:16]1[CH:17]=[C:18]([CH3:19])[N:13]([CH2:12][C:10]([O:9][CH2:7][CH3:8])=[O:11])[C:14](=[O:27])[C:15]=1[N+:24]([O-:26])=[O:25]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CCOC(=O)Cn1c(C)cc(SCCO)c([N+](=O)[O-])c1=O
Solvent: ClCCl
Product: CCOC(=O)Cn1c(C)cc(SCCCl)c([N+](=O)[O-])c1=O

Procedure:
Phosphorus pentachloride (229 mg, 1.1 mmol) was added to a stirred solution of 1-ethyloxycarbonylmethyl-4-(2-hydroxyethylthio)-6-methyl-3-nitro-2-pyridinone (316 mg, 1.0 mmol) in methylene chloride (5 mL). After 15 min the reaction was diluted with methylene chloride and was washed with water, dried (Na2SO4) and evaporated to give the title compound as a yellow crystalline solid:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1.[CH3:20]O>>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:20])[CH:5]=[CH:4][C:3]=1[C:9](=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1
Reactant: CO
Reactant: COc1ccc(CC(=O)c2ccc(O)cc2O)cc1
Product: COc1ccc(CC(=O)c2ccc(OC)cc2O)cc1
Yield: 228.7 %

Procedure:
Using the previous procedure and starting from 1-(2,4-dihydroxyphenyl)-2-(4-methoxyphenyl)ethanone (8.0 g, 11.0 mmol) and methanol (1.32 mL, 32.55 mmol), 6.85 g (81%) of the title compound was obtained as a white solid: mp 101-102° C. (lit. 104° C.); IR (KBr) 1637, 1611, 1513, 1459, 1346, 1301, 1237, 1174, 1148, 1026, 797, 787, 626, 0.522 cm−1; 1H NMR (400 MHz, CDCl3) δ 12.72 (br s, 1H), 7.73 (d, J=8.8 Hz, 1H), 7.17 (d, J=8.6 Hz. 2H), 6.86 (d, J=8.6 Hz, 2H), 6.40-6.44 (m, 2H), 4.13 (s, 2H), 3.81 (s, 3H), 3.77 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 202.73, 166.55, 166.27, 159.07, 132.42, 130.78, 126.73, 114.61, 113.53, 108.21, 101.42, 55.99, 55.67, 44.37.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[N:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7].[CH3:13][N:14]1[CH2:18][CH2:17][CH:16]([SH:19])[CH2:15]1>CN(C)C=O>[CH3:13][N:14]1[CH2:18][CH2:17][CH:16]([S:19][C:4]2[C:5]([C:6]([OH:8])=[O:7])=[CH:9][CH:10]=[CH:11][N:12]=2)[CH2:15]1
Reactant: O=C(O)c1cccnc1Cl
Reactant: CN1CCC(S)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCC(Sc2ncccc2C(=O)O)C1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of 80 g (2 mole) of 60% sodium hydride (in mineral oil) in 800 ml of dry dimethylforamide, all heated to 60° C. and using nitrogen gas flow was added dropwise, a solution of 157.0 g (1 mole) of 2-chloronicotinic acid and 117 g (1 mole) of 1-methyl-3-pyrrolidinethiol in 300 ml of dimethylformamide at a rate which maintained a temperature of 60°-67° C. The mixture was heated to 65° C. for 6 hr and allowed to stand overnight at room temperature and then filtered. The collected solid was suspended in one liter of isopropyl alcohol and hydrogen chloride was bubbled into the suspension until a pH of 6.2 was reached. The mixture was brought to a boil and filtered. The solid was dissolved in 2 liters of water and extracted with isopropyl ether. The pH was adjusted to 6.0 and the solution was concentrated to a volume of 800 ml and placed in a refrigerator. The resulting solid (85 g) collected by filtration, was a mixture consisting of about 85% of the title compound and 15% sodium chloride. A sample portion of this was crystallized once from ethanol and twice from isopropyl alcohol-water. The recrystallized product decomposed at about 225° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][CH:9]=[N:10][CH2:11][CH2:12][CH3:13])[N:3]=1.[CH2:14](I)[CH2:15][CH3:16].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:13][CH2:12][CH2:11][N:10]([CH:9]=[N:8][C:4]1[NH:3][C:2](=[O:1])[CH:7]=[CH:6][CH:5]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCN=CNc1cccc(O)n1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCCN(C=Nc1cccc(=O)[nH]1)CCC

Procedure:
1.8 g (10 mmol) of N-(2-pyridon-6-yl)-N'-propylformamidine and N-(2-hydroxy-6-pyridyl)-N'-propylformamidine, 1.9 g (11 mmol) of propyl iodide and 1.5 g (11.mmol) of potassium carbonate are stirred at 80° for 24 hours in 30 ml of absolute ethanol. The reaction mixture is then filtered and concentrated by evaporation The residue is taken up in methylene chloride, washed with water and then dried over Na2SO4 and concentrated by evaporation. The resulting crude product is purified chromatographically. Crystallisation from methylene chloride/ether yields N-(2-pyridon-6-yl)-N',N'-di-n-propylformamidine and N-(2-hydroxy-6-pyridyl)-N',N'-di-n-propylformamidine having a melting point of 102°-104°.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[CH3:10].[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1OB(O)O)#[N:12].ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1(C)C=CC=CC=1>[OH:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([C:14]2[C:13]([C:11]#[N:12])=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:3]([CH3:10])[CH:4]=1
Reactant: N#Cc1ccccc1OB(O)O
Reactant: Cc1cc(CO)ccc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1cc(CO)ccc1-c1ccccc1C#N
Yield: 24.5 %

Procedure:
A mixture of 4-bromo-3-methylbenzylalcohol (15.16 g), 2-cyanophenylboric acid (14.80 g), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane adduct (3.08 g), tetrabutylammonium bromide (1.22 g), 2M aqueous sodium carbonate solution (75 mL) and toluene (300 mL) was refluxed under an argon atmosphere for 30 hr. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate. The obtained ethyl acetate solution was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow oil (4.12 g, 24%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.Br[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O>[C:16]1([CH2:15][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)CCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)CCc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A reaction mixture of methyl 3-(4-hydroxyphenyl)propanoate (commercially available, from Aldrich) (4.0 g, 22 mmol), 1-(bromomethyl)benzene (3.8 g, 22 mmol (commercially available from Aldrich)) and cesium carbonate (14.30 g, 44 mmol) in DMSO (20.0 mL) was stirred at room temperature for 2.5 hours. The reaction mixture was poured into water (50.0 mL) and extracted with EtOAc (100.0 mL), and the organic layer was washed with water (3×30 mL) and brine (30 mL), and dried with MgSO4. The crude product was recrystallized with hexane/EtOAc (98/2) to the title compound 23.1. 1H NMR (500 MHz, CDCl3) δ ppm 2.65 (t, J=7.83 Hz, 2H) 2.94 (t, J=7.83 Hz, 2H) 3.71 (s, 3H) 5.08 (s, 2H) 6.95 (d, J=8.56 Hz, 2H) 7.16 (d, J=8.56 Hz, 2H) 7.34-7.50 (m, 5H).
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][N:6]([S:19]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH:31]=[CH2:32])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)=[CH:10][CH:9]=1)C.O.[OH-].[Li+].Cl>C1COCC1.CO>[CH2:29]([O:28][C:25]1[CH:24]=[CH:23][C:22]([S:19]([N:6]([CH2:5][C:4]([OH:33])=[O:3])[CH2:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH:18]=[N:17][CH:16]=[N:15]3)=[CH:10][CH:9]=2)(=[O:21])=[O:20])=[CH:27][CH:26]=1)[CH2:30][CH:31]=[CH2:32]
Reactant: C=CCCOc1ccc(S(=O)(=O)N(CC(=O)OCC)Cc2ccc(-n3cncn3)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C=CCCOc1ccc(S(=O)(=O)N(CC(=O)O)Cc2ccc(-n3cncn3)cc2)cc1
Reaction time: 3.5 h

Procedure:
To a solution of 3.61 g (7.67 mmol) of [(4-but-3-enyloxy-benzensulfonyl)-(4-[1,2,4] triazol-1-yl-benzyl)-amino]-acetic acid ethyl ester in 38 ml of THF and 38 ml of MeOH, 0.966 g (23 mmol) of lithum hydroxide monohydrate and 4 ml of H 20 are added at 0–5° C. After being stirred for 3.5 h, the reaction mixture is acidified with 2 N aqueous hydrochloride at 0–5° C. and concentrated under reduced pressure to give [(4-but-3-enyloxy-benzensulfonyl)-(4-[1,2,4]triazol-1-yl-benzyl)-amino]-acetic acid as a colorless powder. To a solution of 3.76 g of the above prepared acid and 1.87 g (13.81 mmol) of 1-hydroxybenztriazole (HOBT) in 35 ml of DMF, 1.61 g (15.34 mmol) of O-(1-methyoxy-1-methyl-ethyl)-hydroxylamine and 1.91 g (12.275 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide are added successively at 0° C. After being stirred for 3.5 h at r.t., the reaction mixture is poured into ice water and the mixture is extracted with AcOEt. The combined extracts are washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (eluent: n-Hexane: AcOEt=1:3˜1:4) to give the title compound. 1H-NMR (400 MHz, CDCl3): 1.34 (s, 6H), 2.55–2.65 (m, 2H), 3.29 (s, 3H), 3.73 (s, 2H), 4.09 (t, J=6.60 Hz, 2H), 4.44 (s, 2H), 5.10–5.25 (m, 2H), 5.85–5.95 (m, 1H), 7.01 (d, 2H, J=8.52 Hz), 7.44 (d, 2H, J=8.0 Hz), 7.64 (d, 2H, J=8.52 Hz), 7.81 (d, 2H, J=8.0 Hz), 8.10 (s, 1H), 8.54 (s, 1H), 8.62 (brs, 1H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1Br.C([Li])CCC.[CH3:18][C:19]1[C:20](=[O:27])[CH:21]([CH3:26])[CH:22]([CH3:25])[C:23]=1[CH3:24].C1(C)C=CC=CC=1>C(OCC)C.CCCCCC.O>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:20]1([OH:27])[CH:21]([CH3:26])[CH:22]([CH3:25])[C:23]([CH3:24])=[C:19]1[CH3:18]
Reactant: Brc1ccccc1C1OCCO1
Reactant: CC1=C(C)C(C)C(C)C1=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CC1=C(C)C(O)(c2ccccc2C2OCCO2)C(C)C1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Under a nitrogen atmosphere, a solution of 2-(1,3-dioxolan-2-yl)-bromobenzene (34.36 g, 150.0 mmol) in diethyl ether (206 g) was cooled to −70° C. and a solution of n-butyllithium in n-hexane (1.56 M, 100.96 mL) was added dropwise thereto. After keeping the temperature for 1 hr, a solution of 2,3,4,5-tetramethylcyclopentenone (21.77 g, 157.5 mmol) in diethyl ether (137 g) was added dropwise to the mixture. After raising the temperature to 25° C., the mixture was stirred for 3 hrs. After quenching the reaction by addition of toluene and water, the aqueous layer was removed. The obtained organic layer was washed with saturated brine and then dried over sodium sulfate. The solvent was removed to give a crude product of 1-(1,3-dioxolan-2-yl)-2-(1-hydroxy-2,3,4,5-tetramethyl-2-cyclopentenyl)benzene. To the obtained crude product were added tetrahydrofuran (770 g), 3% aqueous hydrochloric acid solution (385.2 g) and acetone (77 g) and the mixture was stirred at 25° C. for 24 hrs. After the reaction, toluene was added the reaction mixture. The organic layer was washed with water and saturated brine and then dried over sodium sulfate, and the solvent was removed. The residue was purified by silica gel column chromatography to give 2-(2,3,4,5-tetramethylcyclopentadienyl)benzaldehyde (15.78 g, yield 46.5%).