Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([CH2:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=O)=[CH:29][CH:28]=2)=[C:8]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:14][CH:13]=2)[N:9]=1)(=[O:3])[CH3:2].Cl.CN.ON1C2C=CC=CC=2N=N1.[CH2:49]([N:51]=[C:52]=NCCCN(C)C)C>ClCCl.C(Cl)(Cl)Cl>[C:1]([NH:4][C:5]1[S:6][C:7]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([C:31]([N:51]([CH3:52])[CH3:49])=[O:33])=[CH:34][CH:35]=2)=[C:8]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:20])[O:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[CH:14][CH:13]=2)[N:9]=1)(=[O:3])[CH3:2]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(=O)Nc1nc(CCc2ccc(NC(=O)OC(C)(C)C)cc2)c(Cc2ccc(C(=O)O)cc2)s1
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1nc(CCc2ccc(NC(=O)OC(C)(C)C)cc2)c(Cc2ccc(C(=O)N(C)C)cc2)s1

Procedure:
To a solution of 4-{[2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl)amino]phenyl}ethyl)-1,3-thiazol-5-yl]methyl}benzoic acid (50 mg) in 0.5 ml of dichloromethane were added methylamine hydrochloride (10.7 mg), 1-hydroxybenzotriazole (20.4 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (55.3 μl), then, the mixture was stirred for 3. hrs. at 25° C. The reaction mixture was diluted with 10 ml of chloroform and washed with water and brine. The organic layer was dried over magnesium sulfate and evaporated under vaccum. The residue was triturated with ethyl acetate and diisopropylether, and collected by filtration to give tert-butyl {4-[2-(2-(acetylamino)-5-{4-[(dimethylamino)carbonyl]benzyl}-1,3-thiazol-4-yl)ethyl]phenyl}carbamate as a pale yellow solid.
Reaction SMILES: [F:1][CH:2]([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=2)[CH:15]=O)=[CH:6][CH:5]=1.[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:31][NH2:32])(=[O:30])=[O:29])=[CH:24][CH:23]=1.CCO>O>[F:1][CH:2]([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:13]=[C:14](/[CH:15]=[N:32]/[NH:31][S:28]([C:25]3[CH:26]=[CH:27][C:22]([CH3:21])=[CH:23][CH:24]=3)(=[O:29])=[O:30])[CH:17]=[CH:18][CH:19]=2)=[CH:6][CH:5]=1
Reactant: O=Cc1cccc(C#Cc2ccc(OC(F)F)cc2)c1
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Solvent: CCO
Solvent: O
Product: Cc1ccc(S(=O)(=O)N/N=C/c2cccc(C#Cc3ccc(OC(F)F)cc3)c2)cc1
Temperature: 25 °C
Yield: 90.3 %

Procedure:
A mixture of 3-{[4-(difluoromethoxy)phenyl]ethynyl}benzaldehyde (3.69 g, 13.57 mmol), 4-methylbenzenesulfonohydrazide (2.9 g, 15.6 mmol) and EtOH (11 mL) was refluxed for 30 minutes. cooled to room temperature, poured into water and extracted with ethyl ether. The organic extracts were combined dried over MgSO4 and concentrated in vacuo. The resultant residue was purified on silica gel (Biotage) using hexanes/EtOAc (2/1) as the eluting solvents to give N′-[(1E)-(3-{[4-(difluoromethoxy)phenyl]ethynyl}phenyl)methylene]-4-methylbenzenesulfonohydrazide as a tan solid (5.4 g, 90% yield), MS m/e (M+H)+ 441; 1H NMR (400 MHz, DMSO-d6) 2.32 (s, 3H), 7.2 (d, J=8.66 Hz, 2H), 7.3-7.6 (m, 8H), 7.72 (d, J=8.3 Hz, 2H), 7.88 (s, 1H), 11.54 (s, 1H).
Reaction SMILES: [C:1]1(=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]1=O.C(O)(=O)C.C(O)(=O)C.[NH2:21][C:22]1[C:30]([NH2:31])=[CH:29][CH:28]=[CH:27][C:23]=1[C:24]([OH:26])=[O:25].C1C2=C3C(=CC=C2C=CC=1)N=C1C(C=CC=C1C(O)=O)=N3>C(O)(=O)C>[CH:9]1[C:10]2=[C:1]3[C:2](=[CH:3][CH:4]=[C:5]2[CH:6]=[CH:7][CH:8]=1)[N:31]=[C:30]1[C:22]([C:23]([C:24]([OH:26])=[O:25])=[CH:27][CH:28]=[CH:29]1)=[N:21]3
Reactant: Nc1cccc(C(=O)O)c1N
Reactant: O=C1C=Cc2ccccc2C1=O
Agent: O=C(O)c1cccc2nc3c(ccc4ccccc43)nc12
Solvent: CC(=O)O
Product: O=C(O)c1cccc2nc3ccc4ccccc4c3nc12

Procedure:
A mixture of 1,2-naphthoquinone (commercially available, 2.0 g) and 2,3-diamino-benzoic acid, diacetate salt, (3.79 g) was heated to reflux in acetic acid (30 mL) for 2 hours. The reaction mixture was cooled and the solvent removed in vacuo to yield a gum. This was purified using flash chromatography to yield a 2:1 mixture of the desired title compound to the undesired benzo[a]phenazine-8-carboxylic acid (840 mg). The two isomers were separated after further modification (see Reference Example 3B below).
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[N+:9]([O-:11])=[O:10].[CH:12]1([NH2:15])[CH2:14][CH2:13]1.CCN(C(C)C)C(C)C>C(O)C>[CH:12]1([NH:15][C:3]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N+:9]([O-:11])=[O:10])[CH2:14][CH2:13]1
Reactant: COc1ccncc1[N+](=O)[O-]
Reactant: NC1CC1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cnccc1NC1CC1
Temperature: 0 °C
Yield: 71.7 %

Procedure:
4-Methoxy-3-nitropyridine 5-a (CAS 31872-62-5) (200 g, 1300 mmol), cyclopropyl-amine (CAS 765-30-0) (185.5 g, 3250 mmol) and DIEA (CAS 7087-68-5) (336 g, 2600 mmol) in dry ethanol (800 mL) was refluxed for 3 hours. The mixture was cooled to 0° C. The solid was collected by filtration. The filter cake was washed with cold ethanol (150 mL). The solid was dried to afford compound 5-b as a white powder (167 g, 72%).
Reaction SMILES: [CH3:1][C:2](=[N:4][OH:5])[CH3:3].[OH-].[Na+].[CH:8]1([N:14]=[C:15]=[N:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>C1COCC1.CCCCCC>[CH:17]1([NH:16][C:15](=[N:14][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[O:5][N:4]=[C:2]([CH3:3])[CH3:1])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CC(C)=NO
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)=NOC(=NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 98.8 %

Procedure:
To a solution of acetone oxime (3.65 g, 0.05 mol) in dry THF (35 ml) is added finely powdered NaOH (0.2 g) and dicyclohexylcarbodiimide (10.3 g, 0.05 mol). The mixture is then stirred 5 h at room temperature under argon. The turbid mixture is thereafter diluted with hexane (30 ml) filtered and evaporated under reduced pressure to afford 13.8 g of the title compound as a slightly yellow liquid.
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[C:7]([CH:19]=[CH:20][CH2:21][CH2:22][CH3:23])=[C:6]([CH:24]([CH3:26])[CH3:25])[N:5]=1)([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[C:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:6]([CH:24]([CH3:25])[CH3:26])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCCC=Cc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccccc1C
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCCCc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccccc1C

Procedure:
The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(2-methylphenyl)-5-(pent-1-enyl)pyridine (Example 141) by the procedure described in Example 126. 1H NMR (300 MHz, CDCl3): δ 0.76 (t, J=6.6 Hz, 3 H), 1.0-1.40 (m, 19 H), 1.97 (s, 3 H), 2.0 (m, 1 H), 2.35 (m, 1 H), 3.22 (m, 1 H), 3.42 (m, 1 H), 4.16 (dd, J=12.0, 5.0 Hz, 1 H), 4.40 (dd, J=12.0, 5.0 Hz, 1 H), 7.0-7.10 (m, 1 H), 7.20-7.40 (m, 3 H). FAB-MS: calculated for C24H5NO 354; found 354 (M+H, 100%). Rf=0.32 (10% ethyl acetate/n-hexane). mp 81-83° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C:10]2[NH:14][N:13]=[C:12]([CH:15]3[CH2:17][CH2:16]3)[CH:11]=2)[N:3]=1.[CH3:18][C@@:19]1([C:33]([O:35][CH3:36])=[O:34])[CH2:23][C:22]([CH3:25])([CH3:24])[CH2:21][N:20]1C(OC(C)(C)C)=O.ClC1N=C(NC2NN=C(C3CC3)C=2)N=C(N2CCC[C@@]2(C)C(NC2C=NC(F)=CC=2)=O)N=1>>[Cl:8][C:6]1[N:5]=[C:4]([NH:9][C:10]2[CH:11]=[C:12]([CH:15]3[CH2:17][CH2:16]3)[NH:13][N:14]=2)[N:3]=[C:2]([N:20]2[CH2:21][C:22]([CH3:24])([CH3:25])[CH2:23][C@@:19]2([CH3:18])[C:33]([O:35][CH3:36])=[O:34])[N:7]=1
Reactant: Clc1nc(Cl)nc(Nc2cc(C3CC3)n[nH]2)n1
Reactant: COC(=O)[C@]1(C)CC(C)(C)CN1C(=O)OC(C)(C)C
Agent: C[C@@]1(C(=O)Nc2ccc(F)nc2)CCCN1c1nc(Cl)nc(Nc2cc(C3CC3)n[nH]2)n1
Product: COC(=O)[C@]1(C)CC(C)(C)CN1c1nc(Cl)nc(Nc2cc(C3CC3)[nH]n2)n1

Procedure:
Compound 106E was prepared from 1A and 106D as described for 1C: LC/MS [M+H]+: 406/408; Ret time (Method F): 3.55 min.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]#[N:13])=[CH:4][CH:3]=1.C1C(=O)N([Br:21])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl.O>[Br:21][CH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]#[N:13])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C#N)c2ccccc12
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(CBr)c2ccccc12
Temperature: 25 °C
Yield: 51.5 %

Procedure:
To a stirred solution of 4-methyl-1-naphthonitrile (5 g, 30 mmol) in CCl4 (50 mL) under argon atmosphere was added NBS (6.06 g, 34.09 mmol), and the reaction mixture was degassed for 30 min AIBN (0.3 g, 2.1 mmol) was added, and the resultant reaction mixture was heated at reflux for 4 h. The reaction mixture was cooled to ambient temperature, diluted with water and extracted with CH2Cl2 (3×100 mL). The combined CH2Cl2 layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, 100-200 mesh; 5% EtOAc in n-Hexane) to afford the title compound as a white solid (3.8 g, 52%): mp 131-133° C.; 1H NMR (400 MHz, CDCl3) δ 8.33 (m, 1H), 8.24 (m, 1H), 7.88 (d, J=8.0 Hz, 1H), 7.78 (m, 2H), 7.62 (d, J=8.0 Hz, 1H), 4.95 (s, 2H); ESIMS m/z 245.92 ([M+H]+); IR (thin film) 2217 cm−1.
Reaction SMILES: [CH3:1][C:2]([CH3:36])([CH3:35])[CH2:3][C:4]([NH:6][C:7]1[C:8]([CH3:34])=[C:9]([CH3:33])[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:16]=[CH:17][C:18]([CH:28]([CH3:30])[CH3:29])=[C:19]([CH:27]=3)[O:20][CH2:21][C:22](OCC)=[O:23])[C:11]=2[C:31]=1[CH3:32])=[O:5].[Li].O>C1COCC1>[OH:23][CH2:22][CH2:21][O:20][C:19]1[CH:27]=[C:15]([CH:12]2[C:11]3[C:31]([CH3:32])=[C:7]([NH:6][C:4](=[O:5])[CH2:3][C:2]([CH3:36])([CH3:35])[CH3:1])[C:8]([CH3:34])=[C:9]([CH3:33])[C:10]=3[O:14][CH2:13]2)[CH:16]=[CH:17][C:18]=1[CH:28]([CH3:29])[CH3:30]
Reactant: CCOC(=O)COc1cc(C2COc3c(C)c(C)c(NC(=O)CC(C)(C)C)c(C)c32)ccc1C(C)C
Agent: [Li]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)c(OCCO)c1)CO2
Temperature: 25 °C
Reaction time: 60 h
Yield: 70.6 %

Procedure:
To a solution of ethyl (5-(5-((3,3-dimethylbutanoyl)amino)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-3-yl)-2-isopropylphenoxy)acetate (200 mg, 0.49 mmol) obtained in Example 188 in THF (5 mL) was added with ice-cooling lithium borotetrahydride (43 mg, 2.00 mmol). The reaction solution was warmed to room temperature and stirred for 60 hours. The reaction solution was added to ice and water was added to the reaction solution, and the product was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 157 mg (yield: 71%) of the title compound. Melting point: 155-156° C. (ethyl acetate-hexane).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][C:12]([O:14][CH2:15]C)=[O:13].[H-].[Na+].[Cl:19][C:20]1[N:25]=[C:24]2[N:26]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH:27]=[CH:28][C:23]2=[C:22]([N+]([O-])=O)[CH:21]=1>CN(C=O)C>[Cl:19][C:20]1[N:25]=[C:24]2[N:26]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH:27]=[CH:28][C:23]2=[C:22]([CH:11]([C:3]2[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=2[F:1])[C:12]([O:14][CH3:15])=[O:13])[CH:21]=1
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])cc1F
Reactant: C[Si](C)(C)CCOCn1ccc2c([N+](=O)[O-])cc(Cl)nc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(c1ccc([N+](=O)[O-])cc1F)c1cc(Cl)nc2c1ccn2COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
908 mg (4.26 mmol) of ethyl (2-fluoro-4-nitrophenyl)acetate are dissolved in 10 ml of DMF, and 170 mg (4.26 mmol) of sodium hydride (60% in mineral oil) are added. The mixture is stirred at RT for 30 min, and 698 mg (2.13 mmol) of 6-chloro-4-nitro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine are then added. The mixture is heated at 70° C. for 2 hours and then stirred into ice-water and extracted with ethyl acetate. The organic phase is washed with water and saturated sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. The product is purified by chromatography on silica gel (mobile phase: dichloromethane/pentane 2:1).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]2[CH2:17][C:16](=[O:18])[NH:15][C:14]3[CH:19]=[C:20]([Cl:26])[C:21]([N:23]([CH3:25])[CH3:24])=[CH:22][C:13]=3[N:12]=2)[CH:8]=[CH:9][CH:10]=1)=O.C(C([O:33][CH2:34][C:35]([NH2:37])=[S:36])=O)(C)(C)C>CCO.CCOC(C)=O>[Cl:26][C:20]1[C:21]([N:23]([CH3:24])[CH3:25])=[CH:22][C:13]2[N:12]=[C:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([C:3]4[N:37]=[C:35]([CH2:34][OH:33])[S:36][CH:2]=4)[CH:6]=3)[CH2:17][C:16](=[O:18])[NH:15][C:14]=2[CH:19]=1
Reactant: CC(C)(C)C(=O)OCC(N)=S
Reactant: CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(C(=O)CBr)c1)=N2
Solvent: CCOC(C)=O
Solvent: CCO
Product: CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3csc(CO)n3)c1)=N2
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 416.6 %

Procedure:
A mixture of 4-(3-bromoacetyl-phenyl)-8-chloro-7-dimethylamino-1,3-dihydro-benzo[b][1,4]diazepin-2-one (0.22 g) and 2-(tert.-butylcarbonyl-oxy)thioacetamide (0.11 g) in EtOH (3 mL) was heated at 80° C. for 0.5 h. The solution was diluted with AcOEt, washed with sat. NaHCO3 solution and with brine, dried and evaporated. The residue was stirred in a mixture of MeOH (8 mL) and 1.5N KOH (8 mL) at 20° C. for 20 min. H2O (30 ml) was added and the precipitated product collected by filtration to give the title compound (0.9 g) as yellow powder.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([C:9]1[CH:18]=[C:17]2[C:12]([C:13]([CH3:21])([CH3:20])[CH2:14][C:15](=[O:19])[NH:16]2)=[CH:11][CH:10]=1)[CH3:8].Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]#[N:37])=[CH:26][CH:25]=1>CN(C=O)C>[C:36]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C:27]1[CH:26]=[CH:25][C:24]([CH2:23][N:16]2[C:17]3[C:12](=[CH:11][CH:10]=[C:9]([CH2:7][CH3:8])[CH:18]=3)[C:13]([CH3:20])([CH3:21])[CH2:14][C:15]2=[O:19])=[CH:29][CH:28]=1)#[N:37]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: CCc1ccc2c(c1)NC(=O)CC2(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1ccc2c(c1)N(Cc1ccc(-c3ccccc3C#N)cc1)C(=O)CC2(C)C
Reaction time: 0.75 h

Procedure:
12.5 g of potassium tert-butoxide are added at 20° to a solution of 20.3g or 7-ethyl-1,2,3,4-tetrahydro-4,4-dimethyl-2-oxoquinoline [mip. 120°; obtainable by reaction of m-ethylaniline with 3,3-dimethylacryloyl chloride in toluene/methylene chloride to give N-(3,3-dimethylacryloyl)-m-ethylaniline (m.p. 90°) and cyclisation with AlCl3 at 60°-100°]in 700 ml of DMF. The mixure is stirred for 45 minutes, a solution of 30.5g of 4-bromomethyl-2'-cyanobiphenyl in 300 ml of DMF is then added dropwise and the mixture is stirred overnight, evaporated and worked up in conventional manner to give 1-(2'-cyanobiphenyl-4-ylmethyl)-7-ethyl-1,2,3,4-tetrahydro-4,4-dimethyl-2-oxoquinol ine, m.p. 171°-172°.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([CH:6]([P:8](=[O:15])([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11])[OH:7])=[CH:4][CH:3]=1.[N:18]1([C:27]2[O:28][C:29]([CH2:39][CH2:40][C:41](O)=[O:42])=[C:30]([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=3)[N:31]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[CH:19]1.ON1C2N=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.Cl>CN(C)C=O>[N:18]1([C:27]2[O:28][C:29]([CH2:39][CH2:40][C:41]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([CH:6]([P:8]([O:9][CH2:10][CH3:11])([O:12][CH2:13][CH3:14])=[O:15])[OH:7])=[CH:16][CH:17]=3)=[O:42])=[C:30]([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=3)[N:31]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[CH:19]1
Reactant: CCOP(=O)(OCC)C(O)c1ccc(N)cc1
Reactant: O=C(O)CCc1oc(-n2cnc3ccccc32)nc1-c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Product: CCOP(=O)(OCC)C(O)c1ccc(NC(=O)CCc2oc(-n3cnc4ccccc43)nc2-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.2 %

Procedure:
A mixture of diethyl 4-amino-α-hydroxybenzylphosphonate (50 mg), 3-{3-[2-(1H-benzoimidazol-1-yl)-4-(4-chlorophenyl)-5-oxazolyl]propionic acid (54 mg), 1-hydroxy-7-aza-1H-1,2,3-benzotriazole (38 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (43 mg) and N,N-dimethylformamide (0.5 ml) was stirred overnight at room temperature. To the reaction mixture was added 0.1N aqueous hydrochloric acid solution (2 ml) and the reaction mixture was extracted with ethyl acetate (2 ml). The organic layer was concentrated, introduced into preparative HPLC and purified to give 3-[2-(1H-benzoimidazol-1-yl)-4-(4-chlorophenyl)-5-oxazolyl]-N-(4-[(diethylphosphono)(hydroxy)methyl]phenyl}propionamide (52 mg, 58%). Recrystallization from ethyl acetate-isopropyl ether gave yellow prism crystals. melting point: 171–172° C. MS (ESI+): 609 (M+H)
Reaction SMILES: [CH2:1]([CH2:16]/[C:17](/[CH3:36])=[CH:18]/[CH2:19][CH2:20]/[C:21](/[CH3:35])=[CH:22]/[CH2:23][CH2:24]/[C:25](/[CH3:34])=[CH:26]/[CH2:27][CH2:28]/[C:29](/[CH3:33])=[CH:30]/[CH2:31]Br)[CH:2]=[C:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[CH3:9])[CH3:4].[CH2:37]([NH2:47])[C:38]1[CH:46]=[CH:45][C:44]2[O:43][CH2:42][O:41][C:40]=2[CH:39]=1.O>C1COCC1>[CH2:1]([CH2:16]/[C:17](/[CH3:36])=[CH:18]/[CH2:19][CH2:20]/[C:21](/[CH3:35])=[CH:22]/[CH2:23][CH2:24]/[C:25](/[CH3:34])=[CH:26]/[CH2:27][CH2:28]/[C:29](/[CH3:33])=[CH:30]/[CH2:31][NH:47][CH2:37][C:38]1[CH:46]=[CH:45][C:44]2[O:43][CH2:42][O:41][C:40]=2[CH:39]=1)[CH:2]=[C:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[CH3:9])[CH3:4]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CBr
Reactant: NCc1ccc2c(c1)OCO2
Solvent: C1CCOC1
Solvent: O
Product: CC(C)=CCCC(C)=CCCC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CNCc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.2 %

Procedure:
In 10 ml of THF was dissolved 4.56 g of farnesylgeranylgeranyl bromide, 3.01 g of piperonylamine was added and stirred at room temperature for one hour. To the reaction mixture was added water and extracted with ethyl acetate. The extract was washed with water and then brine, dried over magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography (using as a developing solvent hexane-ethyl acetate (4:1)→ethyl acetate) to give 1.14 g of N-farnesylgeranylgeranylpiperonylamine as a yellow liquid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](I)=[CH:9][N:10]=2)[CH:7]=1.[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1B(O)O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:16]3[CH:15]=[CH:14][C:13]([F:12])=[CH:18][C:17]=3[F:19])=[CH:9][N:10]=2)[CH:7]=1
Reactant: Brc1ccc2ncc(I)n2c1
Reactant: OB(O)c1ccc(F)cc1F
Product: Fc1ccc(-c2cnc3ccc(Br)cn23)c(F)c1

Procedure:
The title compound, off-white solid (0.33 g, 49%), MS (ISP) m/z=309.4 [(M+H)+], mp 137.5° C., was prepared in accordance with the general method of intermediate E from commercially available 6-bromo-3-iodoimidazo[1,2-a]pyridine (0.7 g, 2.17 mmol) and commercially available 2,4-difluoro-phenylboronic acid (0.38 g, 2.38 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:32]([F:35])([F:34])[F:33])[O:13][N:12]=[C:11]([C:14]3[CH:29]=[CH:28][C:17]([C:18]([NH:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)=[O:19])=[C:16]([NH:30][CH3:31])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl[CH2:37]OCCl>ClCCl>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2([C:32]([F:34])([F:33])[F:35])[O:13][N:12]=[C:11]([C:14]3[CH:15]=[C:16]4[C:17]([C:18](=[O:19])[N:20]([CH2:21][C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=5)[CH2:31][N:30]4[CH3:37])=[CH:28][CH:29]=3)[CH2:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: ClCOCCl
Reactant: CNc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCc1ccccn1
Solvent: ClCCl
Product: CN1CN(Cc2ccccn2)C(=O)c2ccc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)cc21
Reaction time: 15 h
Yield: 65.2 %

Procedure:
In a solution of 0.06 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methylamino-N-(2-pyridylmethyl)benzoic acid amide (Compound of the present invention No. 5-332) synthesized similarly to Synthetic Example 18 in 5 ml of dichloromethane, 0.03 g of chloromethylether was added, and stirred at the same temperature for 15 hours. After the completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (3:1) to obtain 0.04 g of the aimed product as colorless oily substance.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH3:23])=[N:11][C:12]([N:16]2[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]2[CH3:22])=[N:13][C:14]=1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][O:34][CH2:35][O:36][CH3:37].[Li]CCCC>C1COCC1.CCCCC>[CH2:1]([O:8][C:9]1[C:14]([CH2:15][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][O:34][CH2:35][O:36][CH3:37])=[N:13][C:12]([N:16]2[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]2[CH3:22])=[N:11][C:10]=1[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCOCCCCCCCCCBr
Reactant: Cc1nc(-n2c(C)ccc2C)nc(C)c1OCc1ccccc1
Agent: [Li]CCCC
Solvent: CCCCC
Solvent: C1CCOC1
Product: COCOCCCCCCCCCCc1nc(-n2c(C)ccc2C)nc(C)c1OCc1ccccc1
Temperature: 23 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution at −78° C. containing 486 mg (1.58 mmol) of 5-(benzyloxy)-2-(2,5-dimethyl-1H-pyrrol-1-yl)-4,6-dimethylpyrimidine and 281 mg (1.05 mmol) of 1-bromo-9-(methoxymethoxy)nonane in 10 mL of anhydrous THF was added 987 μL (1.58 mmol) of a 1.6 M solution of n-BuLi in pentane. The reaction mixture was stirred under argon atmosphere at 23° C. for 30 min. The reaction was quenched with saturated aqueous ammonium chloride and then poured into 50 mL of water. The mixture was then extracted with two 50-mL portions of ethyl acetate. The combined organic layer was washed with 80 mL of brine, dried (MgSO4) and concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column (15×3 cm). Elution with 5:1 hexanes-ethyl acetate afforded the expected product as a light yellow oil: yield 289 mg (56%); silica gel TLC Rf 0.55 (5:1 hexanes-ethyl acetate); 1H NMR (CDCl381.33 (m, 12H), 1.60 (m, 2H), 1.82 (m, 2H), 2.33 (s, 6H), 2.49 (s, 3H), 2.79 (dd, 2H, J=7.6, 7.6 Hz), 3.36 (s, 3H), 3.52 (t, 2H, J=6.4 Hz), 4.62 (s, 2H), 4.90 (s, 2H), 5.87 (s, 2H) and 7.37-7.48 (m, 5H); 13C NMR (CDCl3) δ14.4, 14.4, 19.3, 26.2, 27.7, 29.4, 29.4, 29.5, 29.5, 29.6, 29.8, 31.6, 55.1, 67.9, 75.7, 96.4, 108.0, 108.0, 128.0, 128.58, 128.62, 128.7, 129.3, 136.2, 147.4, 147.4, 152.6, 161.6, 161.6 and 165.1; mass spectrum (APCI), m/z 494.3395 (M+H)1 (C30H44N3O3 requires 494.3383).
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C:12]4[CH2:13][CH:14]=[C:15]([O:21][CH3:22])[CH2:16][C:17]=4[CH:18]([CH3:20])[CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C:4]2=[O:23])[CH3:2].C#C.[C-]#[C-].[Li+].[Li+].[CH2:30](N)[CH2:31]N>CC(N(C)C)=O>[CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C:12]4[CH2:13][CH:14]=[C:15]([O:21][CH3:22])[CH2:16][C:17]=4[CH:18]([CH3:20])[CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@:4]2([C:30]#[CH:31])[OH:23])[CH3:2]
Reactant: NCCN
Reactant: CC[C@]12CC[C@@H]3C4=C(CC(OC)=CC4)C(C)C[C@H]3[C@@H]1CCC2=O
Agent: C#C
Agent: [C-]#[C-]
Agent: [Li+]
Solvent: CC(=O)N(C)C
Product: C#C[C@]1(O)CC[C@H]2[C@@H]3CC(C)C4=C(CC=C(OC)C4)[C@H]3CC[C@@]21CC
Reaction time: 4 h
Yield: 89.8 %

Procedure:
Dissolve dl-13-ethyl-6-methyl-3-methoxygona-2,5(10)-dien-17-one (3.6 g) in dimethylacetamide (35 ml) and stir in a stream of acetylene for 0.5 hour. Add solid lithium acetylide-ethylenediamine (2.7 g) and stir the solution for 4 hours. Pour the reaction mixture onto ice, extract with ether, wash the ether layer with water, dry, and evaporate to obtain dl-13-ethyl-3-methoxy-6-methyl-17α-ethynyl-17-hydroxygona-2,5(10)-diene (3.5 g) as a gum; infrared absorption peaks (sodium chloride) at 2.90 μ, 3.05 μ, 5.90 μ, 6.03 μ.