Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([SH:20])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.CN(C)C=O.[C:33]([NH:36][C:37](=[O:40])[CH2:38]Cl)(=[O:35])[CH3:34]>O.C1C=CC=CC=1>[C:33]([NH:36][C:37](=[O:40])[CH2:38][S:20][C:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:35])[CH3:34]
Reactant: CC(=O)NC(=O)CCl
Reactant: SC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: c1ccccc1
Product: CC(=O)NC(=O)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 0.009 mole of triphenylmethyl mercaptan and 0.009 mole of triethylamine in 10 ml. of dimethylformamide is cooled to 0°-5° C. in an ice bath and 0.009 mole of N-acetyl-2-chloroacetamide added. The reaction mixture is stirred at ambient temperature for three hours and then poured into 100 ml. of benzene and 100 ml. of water. The organic layer is separated, washed well with water, dried over sodium sulfate and concentrated to dryness. The residue is crystallized under petroleum ether to give 2.2 g. of Nacetyl-2-(triphenylmethylthio) acetamide.
Reaction SMILES: FC1C=C(F)C=CC=1C1C=C(CN2C(=O)C3=CC=CC=C3C2=O)C(=O)N(CC(C)C)N=1.[C:32]([C:35]1[C:36](=[O:60])[N:37]([CH2:50][CH:51]=[CH:52][C:53]2[CH:58]=[CH:57][C:56]([Cl:59])=[CH:55][CH:54]=2)[N:38]=[C:39]([C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([F:49])[CH:42]=2)[CH:40]=1)(O)=[O:33]>>[Cl:59][C:56]1[CH:57]=[CH:58][C:53]([CH:52]=[CH:51][CH2:50][N:37]2[C:36](=[O:60])[C:35]([CH2:32][OH:33])=[CH:40][C:39]([C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([F:49])[CH:42]=3)=[N:38]2)=[CH:54][CH:55]=1
Reactant: COc1ccc(-c2cc(C(=O)O)c(=O)n(CC=Cc3ccc(Cl)cc3)n2)cc1F
Agent: CC(C)Cn1nc(-c2ccc(F)cc2F)cc(CN2C(=O)c3ccccc3C2=O)c1=O
Product: COc1ccc(-c2cc(CO)c(=O)n(CC=Cc3ccc(Cl)cc3)n2)cc1F
Yield: 17 %

Procedure:
Following the procedure of Example 1 (8), 4-carboxy-2-(4-chlorocinnamyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one was reacted to yield the title compound as pale yellow crystals (yield: 17.0%).
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][CH:17]=2)=[N:9][S:10][C:11]=1[C:12]([F:15])([F:14])[F:13])(=O)=O.O[C:25]1[C:30]([C:31]([F:34])([F:33])[F:32])=[CH:29][C:28]([CH2:35][CH2:36][C:37]([O:39]CC)=[O:38])=[CH:27][C:26]=1[C:42]([F:45])([F:44])[F:43]>>[CH2:22]([C:19]1[CH:20]=[CH:21][C:16]([C:8]2[C:7]([CH2:6][O:5][C:25]3[C:26]([C:42]([F:44])([F:45])[F:43])=[CH:27][C:28]([CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[CH:29][C:30]=3[C:31]([F:32])([F:33])[F:34])=[C:11]([C:12]([F:15])([F:14])[F:13])[S:10][N:9]=2)=[CH:17][CH:18]=1)[CH3:23]
Reactant: CCc1ccc(-c2nsc(C(F)(F)F)c2COS(C)(=O)=O)cc1
Reactant: CCOC(=O)CCc1cc(C(F)(F)F)c(O)c(C(F)(F)F)c1
Product: CCc1ccc(-c2nsc(C(F)(F)F)c2COc2c(C(F)(F)F)cc(CCC(=O)O)cc2C(F)(F)F)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 1 starting following Step 5 and 6 coupling (3-(4-ethylphenyl)-5-(trifluoromethyl)isothiazol-4-yl)methyl methanesulfonate and ethyl 3-(4-hydroxy-3,5-bis(trifluoromethyl)phenyl)propanoate followed by hydrolysis to afford the desired product as an off-white solid. 1H-NMR (300 Hz, CD3OD): δ 7.75 (s, 1H), 7.69 (s, 1H), 7.46 (d, J=8.4 Hz, 2H), 7.28 (d, J=8.1 Hz, 2H), 5.36 (s, 2H), 2.67-2.74 (m, 4H), 2.45 (t, J=7.2 Hz, 2H), 1.27 (t, J=7.5 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C24H18F9NO3S, 572.1 (M+H). found 572.1.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[CH2:18])[C:10]3[NH:14][C:13](=[O:15])[NH:12][C:11]=3[CH:16]=2)=[C:5]([CH3:26])[O:4][N:3]=1>[Pd].C(O)C>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([CH:17]([C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[CH3:18])[C:10]3[NH:14][C:13](=[O:15])[NH:12][C:11]=3[CH:16]=2)=[C:5]([CH3:26])[O:4][N:3]=1
Reactant: C=C(c1ccc(F)cc1)c1cc(-c2c(C)noc2C)cc2[nH]c(=O)[nH]c12
Agent: [Pd]
Solvent: CCO
Product: Cc1noc(C)c1-c1cc(C(C)c2ccc(F)cc2)c2[nH]c(=O)[nH]c2c1
Reaction time: 2 h

Procedure:
A suspension of 6-(3,5-dimethylisoxazol-4-yl)-4-(1-(4-fluorophenyl)vinyl)-1H-benzo[d]imidazol-2(3H)-one (60 mg, 0.172 mmol) and 10% palladium on carbon (20 mg) in 5 mL ethanol was purged with hydrogen gas and allowed to stir for 2 hours. The reaction mixture was then filtered and the solvents evaporated. Residue was purified by preparative HPLC which afforded 6-(3,5-dimethylisoxazol-4-yl)-4-(1-(4-fluorophenyl)ethyl)-1H-benzo[d]imidazol-2(3H)-one.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[Br:12]Br.O>ClCCl.[Fe]>[Br:12][C:7]1[C:2]([OH:1])=[C:3]([C:9](=[O:11])[CH3:10])[CH:4]=[C:5]([CH3:8])[CH:6]=1
Reactant: CC(=O)c1cc(C)ccc1O
Reactant: BrBr
Agent: [Fe]
Solvent: O
Solvent: ClCCl
Product: CC(=O)c1cc(C)cc(Br)c1O
Reaction time: 0.33 h
Yield: 47.9 %

Procedure:
To a solution of 21.5 g (0.143 mol) of 28 in 40 mL of dry dichloromethane, 0.3 g of iron turnings was added. A solution of 10.7 mL (34.2 g, 0.215 mol) of bromine in 100 mL of dichloromethane was added dropwise with vigorous stirring for 20 min. This mixture was refluxed for 30 min, and then 300 mL of water was added. The organic layer was separated, and the aqueous layer was extracted with 2×100 mL of dichloromethane. The combined organic extracts were washed with saturated aqueous Na2SO3, dried over K2CO3, and then evaporated to dryness. Drying the residue in vacuum gave 15.7 g (48%) of 29 (bp 105-115° C./1 mm).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH:5]=[N:4][CH:3]=1.[CH3:26][Sn](C)(C)C.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>C1(C)C=CC=CC=1.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>[CH3:26][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH:5]=[N:4][CH:3]=1
Reactant: C[Sn](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cccc3cncc(Br)c23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1cncc2cccc(NC3CCN(C(=O)OC(C)(C)C)CC3)c12
Temperature: 150 °C
Reaction time: 48 h

Procedure:
A solution of Intermediate 71 (313 mg) in toluene (6 ml) was added with tetrakis(triphenylphosphine)palladium(0) (17.9 mg, Aldrich), tetramethyltin (165 μl, Kanto Chemicals) and 2,6-di-tert-butyl-4-methylphenol (several pellets, Tokyo Kasei Kogyo) and stirred in a sealed tube at 150° C. for 48 hours. The reaction mixture was cooled to room temperature, filtered through Celite and concentrated under reduced pressure. The residue was added with saturated brine (30 ml) and extracted three times with ethyl acetate (30 ml for each time). The organic layers were combined and dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain the title compound (61.7 mg).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([CH:47]=[CH:48][CH:49]=2)[C:43](OC)=[O:44])=[N:8]1.O.[OH-].[Li+].[NH2:53][CH:54]1[CH2:62][C:61]2[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=2)[CH2:55]1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O1CCCC1.O1CCCC1.O>[CH2:55]1[C:56]2[C:61](=[CH:60][CH:59]=[CH:58][CH:57]=2)[CH2:62][CH:54]1[NH:53][C:43]([C:42]1[CH:47]=[CH:48][CH:49]=[C:40]([C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[C:12]([C:16]4[N:20]=[CH:19][N:18]([C:21]([C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=5)([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[N:17]=4)[CH:11]=3)[N:7]([CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[N:8]=2)[CH:41]=1)=[O:44]
Reactant: COC(=O)c1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Reactant: NC1Cc2ccccc2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: O=C(NC1Cc2ccccc2C1)c1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Temperature: 60 °C
Reaction time: 18 h
Yield: 74 %

Procedure:
To a stirred solution of methyl 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}benzoate (0.400 g, 0.619 mmol) in a tetrahydrofuran/water mixture (2.50 mL/1.00 mL) was added lithium hydroxide monohydrate (0.0780 g, 1.86 mmol) and the mixture heated at 60° C. for 21 h. To this mixture was added tetrahydrofuran (2.00 mL), 2-aminoindane (0.316 g, 1.86 mmol), 1-hydroxybenzotriazole hydrate (0.251 g, 1.86 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.356 g, 1.86 mmol). This mixture was stirred for 18 h at ambient temperature. After the mixture was extracted with ethyl acetate (2×), the combined organic extracts were washed with aqueous saturated sodium bicarbonate, followed by brine, dried over anhydrous sodium sulfate, filtered and evaporated. Purification of the residue by flash chromatography with 30-60% ethyl acetate/hexanes gave the title compound (0.342 g, 74% yield). ES-MS (m/z) 505 [M+1(−Tr)]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:12]([NH:13]C(=O)C)=[N:11][NH:10][C:7]2=[N:8][CH:9]=1)([O-:3])=[O:2].[ClH:17]>CCO>[ClH:17].[N+:1]([C:4]1[CH:5]=[C:6]2[C:12]([NH2:13])=[N:11][NH:10][C:7]2=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(=O)Nc1n[nH]c2ncc([N+](=O)[O-])cc12
Agent: Cl
Solvent: CCO
Product: Nc1n[nH]c2ncc([N+](=O)[O-])cc12
Temperature: 85 °C
Yield: 96.6 %

Procedure:
A mixture of N-(5-nitro-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide (530 mg, 2.40 mmol), EtOH (2.4 mL, 1M) and concentrated HCl (37%) (2.5 mL, 68.6 mmol) was heated to 85° C. for 3 hours. The volatiles were removed to afford 5-nitro-1H-pyrazolo[3,4-b]pyridin-3-amine hydrochloride (500 mg, 97% yield) as a solid.
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:23](=[N:29][OH:30])[C:24]([O:26][CH2:27][CH3:28])=[O:25].O>CCOCC>[C:1]1([C:7]2([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[O:30][N:29]=[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=C(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C(Cl)=NO
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)C1=NOC(c2ccccc2)(c2ccccc2)C1
Reaction time: 1 h

Procedure:
13.52 g (0.075 mol) of 1,1-diphenylethene and 5.06 g (0.05 mol) of triethylamine are dissolved in 200 ml of ether at 0° C., and 7.58 g (0.05 mol) of ethyl 2-chloro-2-hydroximinoacetate, dissolved in 100 ml of ether, are subsequently added dropwise in the course of approximately two hours. After stirring has been continued for one hour at room temperature, 100 ml of H2O are added, and the mixture is subsequently extracted using ether. After drying over a MgSO4, the ether is distilled off and the residue is purified over a silica gel column (eluent: n-heptane:ethyl acetate=8:2). In this way, 12.7 g (86% of theory) of product of melting point 78° to 81° C. are obtained.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:13])=[N:4][NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:23].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[NH2:13][C:3]1[C:2]([Br:1])=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]([CH2:21][C:22]([N:24]2[CH2:25][CH2:26][N:27]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)[CH2:28][CH2:29]2)=[O:23])[N:4]=1
Reactant: O=C(CCl)N1CCN(c2ccc(Cl)cc2)CC1
Reactant: Nc1n[nH]c(-c2ccccc2)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Nc1nn(CC(=O)N2CCN(c3ccc(Cl)cc3)CC2)c(-c2ccccc2)c1Br

Procedure:
Protocol T was followed using 4-Bromo-5-phenyl-1H-pyrazol-3-ylamine, K2CO3, 2-Chloro-1-[4-(4-chloro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=1/4) afforded the title compound as white solid. 1H NMR (400 MHz, CDCl3): 7.7–7.8 (m, 2H), 7.24–7.3 (m, 3H), 6.8–6.92 (m, 2H), 6.74–6.78 (m, 2H), 4.9 (s, 2H), 4.2 (s, 2H), 3.6–3.7 (m, 4H), 2.86–3.04 (m, 4H). 13C NMR (400 MHz, CDCl3): 164, 146, 145, 128, 127, 118, 114.8, 60.2, 50.4, 50, 48.8, 46, 42, 22.
Reaction SMILES: [CH:1]([C:4]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:7](=[O:8])O[C:5]=1[C:15]([OH:17])=[O:16])([CH3:3])[CH3:2].[F:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1>C(OCC)C>[F:18][C:19]1[CH:25]=[CH:24][C:22]([N:23]2[C:5]([C:15]([OH:17])=[O:16])=[C:4]([CH:1]([CH3:2])[CH3:3])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:7]2=[O:8])=[CH:21][CH:20]=1
Reactant: Nc1ccc(F)cc1
Reactant: CC(C)c1c(C(=O)O)oc(=O)c2ccccc12
Solvent: CCOCC
Product: CC(C)c1c(C(=O)O)n(-c2ccc(F)cc2)c(=O)c2ccccc12

Procedure:
A suspension of 4-isopropylisocoumarin-3-carboxylic acid (24.68 g) in 4-fluoroaniline (74 ml) was refluxed under argon for 15 minutes. After cooling, the reaction mixture was dissolved in diethyl ether and the resulting solution extracted with aqueous sodium hydroxide (3×300 ml; 1M). The combined aqueous phases were washed with diethyl ether and acidified to pH1 with aqueous hydrochloric acid (2M). The resultant precipitate was filtered, washed with water and dried at 100° C. to give 2-(4-fluorophenyl)-4-isopropyl-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid (25.2 g) in the form of a white solid, m.p. 276°-277° C. (with decomposition) [Elemental analysis: C, 69.9; H, 4.9; N, 4.3%; calculated: C, 70.15; H, 4.9; N, 4.3%].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:17])[C:7]=1[C:8]1[C:12]([C:13]([OH:15])=O)=[C:11]([CH3:16])[O:10][N:9]=1.[CH2:18]([O:25][C:26](=[O:36])[NH:27][CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH:31]([NH2:35])[CH2:30]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:18]([O:25][C:26](=[O:36])[NH:27][CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH:31]([NH:35][C:13]([C:12]2[C:8]([C:7]3[C:6]([Cl:17])=[CH:5][N:4]=[CH:3][C:2]=3[Cl:1])=[N:9][O:10][C:11]=2[CH3:16])=[O:15])[CH2:30]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Cc1onc(-c2c(Cl)cncc2Cl)c1C(=O)O
Reactant: NC1CCCC(CNC(=O)OCc2ccccc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1onc(-c2c(Cl)cncc2Cl)c1C(=O)NC1CCCC(CNC(=O)OCc2ccccc2)C1
Yield: 82.5 %

Procedure:
Combine 3-(3,5-dichloro-pyridin-4-yl)-5-methyl-isoxazole-4-carboxylic acid (0.41 g, 0.0015 mol) with (3-amino-cyclohexylmethyl)-carbamic acid benzyl ester (0.45 g, 0.0015 mol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.29, 0.0015 mol), 1-hydroxy-7-azabenzo-triazole (0.20 g, 0.0015 mol), and N,N-diisopropylethyl amine (0.78 mL, 0.0045 mol), in N,N-dimethylformamide (10 mL) and stir over a weekend at ambient temperature. Concentrate the mixture in vacuo and take up in water and extracte with ethyl acetate. Dry over sodium sulfate. Concentrate and elute over silica gel using methanol/dichloromethane to give 0.64 g (82%) of the desired amide as a white foam. MS(ES): (M+1)+ 516.9, 518.9 m/z.
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]2[O:14][CH2:13][CH:12]([OH:15])[CH2:11][O:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C)C=O>[CH2:16]([O:15][CH:12]1[CH2:13][O:14][CH:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[O:10][CH2:11]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: OC1COC(c2ccccc2)OC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(COC2COC(c3ccccc3)OC2)cc1
Reaction time: 0.33 h
Yield: 90 %

Procedure:
To a suspension of about 19.63 g of about 50% sodium hydride in about 450 ml of dimethylformamide was added, portionwise, over about 15 minutes about 67 g of 2-phenyl-m-dioxan-5-ol. After stirring about 20 minutes, the mixture was cooled in ice and about 69.95 g of benzyl bromide was added dropwise over about 20 minutes. The mixture was stirred at room temperature overnight, water was added and the solid collected. This solid was dissolved in hot toluene, dried, filtered and diluted with an equal volume of petroleum ether. After standing about 4 hours at about 0° C. the solid was collected, giving about 90.5 g of the desired title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]([NH:8][NH:9][C:10](=[O:23])[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:13][CH:12]=1)=O>P(Cl)(Cl)(Cl)=O>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[O:23][C:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[N:13][CH:12]=2)=[N:9][N:8]=1
Reactant: COCCCC(=O)NNC(=O)c1ccc(-c2ccccc2)nc1
Solvent: O=P(Cl)(Cl)Cl
Product: COCCCc1nnc(-c2ccc(-c3ccccc3)nc2)o1
Temperature: 100 °C
Reaction time: 3 h
Yield: 65.1 %

Procedure:
To 6-phenylnicotinic acid N′-(4-methoxybutyryl)hydrazide (6.06 g) was added phosphorus oxychloride (100 ml), and stirred at 100° C. for 3 hours. After the reaction solution was cooled to ambient temperature, the solution was concentrated under reduced pressure. To the resulting residue was added aqueous 1 mol/liter sodium hydroxide solution under ice cooling, and extracted with chloroform. After the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/1 to 1/1 to 1/2 to 1/5), and washed with a mixture solvent of n-hexane and ethyl acetate, to afford the entitled compound 5-[5-(3-methoxypropyl)-1,3,4-oxadiazol-2-yl]-2-phenylpyridine 3.72 g, 65%). The physico-chemicalvalues are as follows.
Reaction SMILES: C(O[C:9](=[O:38])[CH2:10][N:11]1[C:16](=[O:17])[C:15]([NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][N:28]([CH3:35])[C:29](=[O:34])[C:30]([F:33])([F:32])[F:31])[CH:22]=2)=[N:14][C:13](Cl)=[C:12]1[CH3:37])C1C=CC=CC=1.[CH3:39][C:40]1[C:48]2[C:43](=[CH:44][CH:45]=[C:46]([CH2:49][NH2:50])[CH:47]=2)[NH:42][CH:41]=1.C1C=CC2N(O)N=NC=2C=1.Cl.CN1CCOCC1>CO.[OH-].[OH-].[Pd+2].CN(C=O)C>[F:33][C:30]([F:31])([F:32])[C:29]([N:28]([CH3:35])[CH2:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([CH2:20][CH2:19][NH:18][C:15]2[C:16](=[O:17])[N:11]([CH2:10][C:9]([NH:50][CH2:49][C:46]3[CH:47]=[C:48]4[C:43](=[CH:44][CH:45]=3)[NH:42][CH:41]=[C:40]4[CH3:39])=[O:38])[C:12]([CH3:37])=[CH:13][N:14]=2)[CH:22]=1)=[O:34]
Reactant: Cc1c(Cl)nc(NCCc2cccc(CN(C)C(=O)C(F)(F)F)c2)c(=O)n1CC(=O)OCc1ccccc1
Reactant: Cc1c[nH]c2ccc(CN)cc12
Agent: [Pd+2]
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1c[nH]c2ccc(CNC(=O)Cn3c(C)cnc(NCCc4cccc(CN(C)C(=O)C(F)(F)F)c4)c3=O)cc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 20.5 %

Procedure:
Benzyl-2-[3-chloro-2-methyl-5-[(3{[methyl(2,2,2-trifluoroacetyl)amino]methyl}phenethyl)amino]-6-oxo-1(6H) pyrazinyl]acetate (preparation 37) (200 mg, 0.36 mmol) was dissolved in methanol (80 ml), treated with Pearlman's catalyst (80 mg) and stirred under a hydrogen atmosphere (60 psi, room temperature, 2.5 hr). The catalyst was removed by filtration, followed by evaporation of the solvent and azeotroping with CH2Cl2 to yield a crude solid. To the crude mixture, (3-methyl-1H-indol-5-yl)methylamine (preparation 36) (60 mg, 0.37 mmol), HOBT (56 mg, 0.41 mmol), WSCDI.HCl (91 mg, 0.47 mmol), N-methylmorpholine (0.073 ml, 0.66 mmol) and DMF (10 ml) were added and stirred at room temperature for 18 hr. The resultant mixture was evaporated to dryness and triturated with water. The brown solid was filtered, dried, then purified by chromatography (SiO2, gradient elution with 1:2 ethyl acetate:hexane; 2:1 ethyl acetate:hexane) to give the desired product (42 mg, 20%). 1H NMR (CD3OD) δ 2.15 (s, 3H), 2.30 (s, 3H), 2.85-3.20 (m, 3H), 3.35 (s, 2H), 3.60 (m, 2H), 4.50 (s, 2H), 4.604.65 (m, 2H), 4.75 (s, 2H), 6.65 (s, 1H), 6.95-7.50 (m, 8H). LRMS m/z=596.5 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[NH2:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:23][CH2:22]1>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][CH:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:23][CH2:22]2)[N:3]=1
Reactant: COc1ccc(F)cc1C(=O)c1ccc(Cl)nc1N
Reactant: NC1CCN(Cc2ccccc2)CC1
Product: COc1ccc(F)cc1C(=O)c1ccc(NC2CCN(Cc3ccccc3)CC2)nc1N

Procedure:
The title compound was prepared from (2-amino-6-chloropyridin-3-yl)-(5-fluoro-2-methoxyphenyl)methanone (Example 19) and 4-amino-1-benzylpiperidine (Ardrich) using the procedure described in Step B. Example 6. HRMS, observed: 435.2196, Calcd for (M+H)+: 435.2191.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Cl)[CH:20]=[C:21]([CH2:23][CH2:24][CH:25]=[C:26]([CH2:28][CH2:29][CH:30]=[C:31]([CH3:33])[CH3:32])[CH3:27])[CH3:22].Cl>C(OCC)(=O)C.CN(C=O)C>[CH3:22]/[C:21](/[CH2:23][CH2:24]/[CH:25]=[C:26](\[CH3:27])/[CH2:28][CH2:29][CH:30]=[C:31]([CH3:33])[CH3:32])=[CH:20]\[CH2:19][O:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([OH:1])[CH:11]=1
Reactant: COC(=O)c1ccc(O)cc1O
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OC/C=C(\C)CC/C=C(\C)CCC=C(C)C)cc1O
Temperature: 60 °C
Reaction time: 3 h
Yield: 70.6 %

Procedure:
In 10 m of DMF were poured 1.28 g (7.6 mmol) of methyl 2,4-dihydroxybenzoate and 1.05 g (7.6 mmol) of potassium carbonate, and 1.84 g (7.6 mmol) of farnesyl chloride was added thereto dropwise at room temperature. After the addition, the mixture was stirred at 60° C. for 3 hours and then poured into a 12% hydrochloric acid aqueous solution. Ethyl acetate was poured thereinto to conduct extraction. The resulting extract was washed with water and a saturated sodium chloride aqueous solution, dried over sodium sulfate, and concentrated. The resulting crude product was purified by column chromatography on silica gel to obtain 2.0 g (yield: 71%) of methyl 4-{(2E,6E)-3,7,11-trimethyl-2,6,10-dodecatrienyloxy}-2-hydroxybenzoate represeted by the following structural formula (hereinafter referred to as compound 37) as a colorless, clear and oily substance. The analytical results are shown below. ##STR58##