Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:21])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:22][C:23]1[N:28]=[CH:27][C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][N:24]=1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[CH:11]=[C:10]([CH3:21])[N:9]=[C:8]([C:4]3[CH:3]=[C:2]([C:26]4[CH:25]=[N:24][C:23]([NH2:22])=[N:28][CH:27]=4)[CH:7]=[CH:6][CH:5]=3)[CH:13]=2)=[CH:15][CH:16]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: Cc1cc(-c2ccc(Cl)cc2)cc(-c2cccc(Br)c2)n1
Product: Cc1cc(-c2ccc(Cl)cc2)cc(-c2cccc(-c3cnc(N)nc3)c2)n1

Procedure:
The title compound was prepared 2-(3-bromo-phenyl)-4-(4-chloro-phenyl)-6-methyl-pyridine (example E.32) (0.075 g, 0.20 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.051 g, 0.2 mmol) according to the general procedure VI. Obtained as a white solid (0.035 g, 45%). MS (ISP) 373.2 [(M+H)+] and 375 [(M+2+H)+]; mp 197-199° C.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:5]=1[CH:6]=O)([O-:3])=[O:2].[CH:13]([NH2:16])([CH3:15])[CH3:14].[BH4-].[Na+].Cl>CO>[CH3:14][CH:13]([NH:16][CH2:6][C:5]1[C:8]([F:12])=[CH:9][CH:10]=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2])[CH3:15]
Reactant: O=Cc1c(F)cccc1[N+](=O)[O-]
Reactant: CC(C)N
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)NCc1c(F)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2-nitro-6-fluorobenzaldehyde(1.21 g, 7.16 mmol) in dry methanol (15 ml), was added isopropyl amine (1 ml, 11.4 mmol) and the mixture stirred for 24 hours at room temperature in argon atmosphere. Then NaBH4 (0.3 g, 7.9 mmol) was added and the reaction mixture was stirred for 36 hours. The suspension was neutralized by addition of HCl 5N, then was extracted with diethyl ether (1×100 ml) and dried over MgSO4 and evaporated at reduced pressure to afford N-(1-methylethyl)-(2-nitro-6-fluorophenyl)methylamine as a brown oil.
Reaction SMILES: C(O[C:4](=[O:31])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH:13]([CH3:15])[CH3:14])[CH:10]=[CH:9][C:8]=1[CH2:16][CH2:17][NH:18][S:19]([C:22]1[CH:27]=[C:26]([C:28]#[N:29])[CH:25]=[CH:24][C:23]=1[OH:30])(=[O:21])=[O:20])C.O.[NH2:33][NH2:34]>C(O)C>[C:28]([C:26]1[CH:25]=[CH:24][C:23]([OH:30])=[C:22]([S:19]([NH:18][CH2:17][CH2:16][C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:15])[CH3:14])=[CH:12][C:7]=2[O:6][CH2:5][C:4]([NH:33][NH2:34])=[O:31])(=[O:21])=[O:20])[CH:27]=1)#[N:29]
Reactant: CCOC(=O)COc1cc(C(C)C)ccc1CCNS(=O)(=O)c1cc(C#N)ccc1O
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(C)c1ccc(CCNS(=O)(=O)c2cc(C#N)ccc2O)c(OCC(=O)NN)c1

Procedure:
Ethyl[2-[2-(5-cyano-2-hydroxybenzenesulfonylamino)-ethyl]-5-isoproylphenoxy]acetate (0.266 g) was dissolved in 5 mL of ethanol. To the solution was added 0.087 mL of hydrazine monohydrate at room temperature, and the mixture was refluxed for 1 hour. The solvent was removed under reduced pressure to give 0.258 g of 5-cyano-N-[2-(2-hydrazinocarbonylmethoxy-4-isopropylphenyl)ethyl]-2-hydroxybenzenesulfonamide.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[N:11]=[C:10]([C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])[CH2:9]2)=[CH:4][CH:3]=1.[CH3:27][S:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>CN(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>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[N:12]1[CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[S:28][CH3:27])=[CH:3][CH:4]=2)[CH2:9][C:10]([C:20]([F:25])([F:26])[C:21]([F:22])([F:24])[F:23])=[N:11]1
Reactant: CSc1ccccc1B(O)O
Reactant: FC(F)(F)C(F)(F)C1=NN(c2ccccc2Cl)C(c2ccc(Br)cc2)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ccccc1-c1ccc(C2CC(C(F)(F)C(F)(F)F)=NN2c2ccccc2Cl)cc1
Yield: 57.2 %

Procedure:
A solution of 5-(4-bromo-phenyl)-1-(2-chloro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (100.0 mg, 0.19 mmol) prepared in Step 3 of Preparation 1, 2-(methylthio)phenylboronic acid (80.0 mg, 0.28 mmol), Pd(PPh3)4 (26 mg, cat.), and a 2N sodium carbonate solution (0.6 mL) in N,N-dimethylformamide (5 mL) was stirred at 80° C. for 6 hours. The reaction mixture was concentrated under reduced pressure and then diluted with ethyl acetate. The organic layer was washed with distilled water, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/20) to give 54.0 mg of 1-(2-chloro-phenyl)-5-(2′-methylsulfanyl-biphenyl-4-yl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole as a pale yellow liquid.
Reaction SMILES: C1(C([O:14][C:15](=[O:41])[C@@H:16]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24]=[CH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:20][CH:19]=2)C2C=CC=CC=2)C=CC=CC=1.[H][H]>C(O)(C)(C)C.[Pd]>[CH3:39][C:37]([CH3:40])([O:36][C:34]([NH:33][C@@H:16]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:20][CH:19]=1)[C:15]([OH:41])=[O:14])=[O:35])[CH3:38]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)C=Cc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(c2ccccc2)c2ccccc2)cc1
Agent: [Pd]
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)CCc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Yield: 92.9 %

Procedure:
(S)-2-[[(1,1-Dimethylethoxy)carbonyl]amino]-3-[4-[3-(1,1-dimethylethoxy)-3-oxo-l-propenyl]phenyl]propanoic acid diphenylmethyl ester (1.6 g. 2.8 mmol) and 10% Pd/C (300 mg) in t-butanol (20 mL) was blanketed with hydrogen (1 atm). To prevent the solvent from freezing, a warm water bath (40° C.) was used to heat the reaction mixture. Upon the consumption of 2 equivalents of hydrogen, the mixture was filtered through celite. The celite pad was washed with ethanol (50 mL) and the filtrates combined and concentrated. The residue was purified by recrystallization from hexanes to give (S)-2-[[(1,1-dimethylethoxy) carbonyl]amino]-3-[4-[3-(1,1-dimethylethoxy)3-oxopropyl]phenyl]propanoic acid (1.0 g, 2.6 mmol) in 94% yield. mp. 88.5°-90° C., [α]D +21.2° (0.90% in ethanol).
Reaction SMILES: [C:1]([NH:5][OH:6])(=[O:4])[CH2:2][CH3:3].[CH3:7][N:8]=[C:9]=[O:10]>C(N(CC)CC)C.C(Cl)Cl>[CH3:7][NH:8][C:9]([N:5]([O:6][C:9]([NH:8][CH3:7])=[O:10])[C:1](=[O:4])[CH2:2][CH3:3])=[O:10]
Reactant: CCC(=O)NO
Reactant: CN=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)N(OC(=O)NC)C(=O)NC
Reaction time: 48 h

Procedure:
Propiohydroxamic acid (4.5 grams), methyl isocyanate (6.0 grams), and a few drops of triethylamine were stirred for about one hour in about 50 ml of methylene chloride. The resulting solution was allowed to stand at room temperature for about 48 hours, after which the solvent was removed by evaporation leaving a residue. The residue was recrystallized from a mixture of methylene chloride and hexane leaving the desired, N-((methylamino)carbonyl)-N-(((methylamino)carbonyl)-oxy)propionamide as white crystals, m.p. 90.5°-92.5° C.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[C:7]([CH3:17])[C:6]=2[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=1.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[CH:30][C:31]([NH2:34])=[N:32][CH:33]=2)O1>>[NH2:34][C:31]1[N:32]=[CH:33][C:28]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[C:7]([CH3:17])[C:6]=3[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=2)=[CH:29][CH:30]=1
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCCNC2=O
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Cc1c2n(c3c(-c4ccc(N)nc4)cc(C#N)cc13)CCCNC2=O

Procedure:
The title compound, off-white solid (28 mg, 34%), MS (ISP) m/z=332.4 [(M+H)+], mp 306° C., was prepared in accordance with the general method of example 1 from 7-bromo-11-methyl-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 17) (79.5 mg, 0.25 mmol) and commercially available 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridin-2-amine (71.5 mg, 0.325 mmol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=1)[C:6]1[C:22](=[O:27])[O:23][C:24](=[O:26])[CH2:25][C:5]2=1.[OH:28][CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=1)[C:6]([C:22]([OH:23])=[O:27])=[C:5]2[CH2:25][C:24]([N:32]1[CH2:33][CH2:34][CH:29]([OH:28])[CH2:30][CH2:31]1)=[O:26]
Reactant: O=C1Cc2c(n(Cc3cccc4ccccc34)c3ccc(F)cc23)C(=O)O1
Reactant: OC1CCNCC1
Product: O=C(O)c1c(CC(=O)N2CCC(O)CC2)c2cc(F)ccc2n1Cc1cccc2ccccc12

Procedure:
6-Fluoro-9-naphthalen-1-ylmethyl-4,9-dihydro-pyrano[3,4-b]indole-1,3-dione (from example 34.1.) was ring opened with 4-hydroxypiperidine at 22° C. to give the title compound as a white solid. MS: 461.0 ([M+H]+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[N:17]=[C:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[O:19][C:20]=3[CH3:21])=[O:15])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.F[C:29]1[CH:37]=[CH:36][C:32]([C:33]([OH:35])=[O:34])=[CH:31][N:30]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[CH3:21][C:20]1[O:19][C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:17][C:16]=1[C:14]([NH:13][C:10]1[CH:9]=[CH:8][C:7]([CH:4]2[CH2:5][CH2:6][N:1]([C:29]3[CH:37]=[CH:36][C:32]([C:33]([OH:35])=[O:34])=[CH:31][N:30]=3)[CH2:2][CH2:3]2)=[CH:12][CH:11]=1)=[O:15]
Reactant: Cc1oc(-c2ccccc2)nc1C(=O)Nc1ccc(C2CCNCC2)cc1
Reactant: O=C(O)c1ccc(F)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1oc(-c2ccccc2)nc1C(=O)Nc1ccc(C2CCN(c3ccc(C(=O)O)cn3)CC2)cc1
Temperature: 175 °C
Yield: 50.8 %

Procedure:
A mixture of 5-methyl-2-phenyl-oxazole-4-carboxylic acid (4-piperidin-4-yl-phenyl)-amide (181 mg, 0.5 mmol) and 6-fluoronicotinic acid (113 mg, 0.8 mmol) in dioxane (2 mL) containing diisopropylethylamine (0.5 mL, 2.7 mmol) was heated in a microwave at 175° C. for 30 minutes. The mixture was evaporated and extracted with ethyl acetate and aqueous citric acid solution. The organic layer was dried over sodium sulfate and solvents were evaporated. The residue was triturated with ethyl acetate and filtered to give a pale pink solid as 4-{4-[(5-methyl-2-phenyl-oxazole-4-carbonyl)-amino]-phenyl}-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carboxylic acid (122.5 mg). LC-MS for C28H26N4O4 (m/e) calcd 482, obsd 483 (M+H). 1H-NMR is consistent with the desired structure.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]=12.[CH3:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][NH2:22].C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>O>[CH3:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][NH:22][C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2[C:3]=1[N:11]=[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:9]=2
Reactant: Cc1ccccc1CN
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3)cc-2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: Cc1nc(NCc2ccccc2C)c2nc(-c3ccccc3)cc-2[nH]1
Temperature: 140 °C
Reaction time: 1.5 h
Yield: 36.5 %

Procedure:
To a mixture of 4-chloro-2-methyl-6-phenylpyrrolo[3,2-d]pyrimidine (Example 1(e)) (85.0 mg, 0.35 mmol) and 2-methylbenzyl amine (Aldrich Chemical Company) (2.2 mL, 17.4 mmol) was added a solution of K2CO3 (0.35 g, 2.54 mmol) in H2O (2.5 mL). This mixture was stirred at 140° C. in a closed-capped Wheaton vial for 1.5 h. After cooling, CH2Cl2 (10 mL) and H2O (10 mL) were added. The organic solution was removed and the aqueous solution washed with CH2Cl2 (10 mL). The combined organic solutions were washed with saturated NaCl (15 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (3% MeOH:CHCl3 on silica gel) and then recrystallized from MeOH/CH2Cl2 to give 42 mg (35%) of the title compound as a white solid. Mp: 277-281° C. MS m/z: 329 (M+1). 1H NMR (DMSO-d6; 400 MHz): δ 2.38 (s, 3), 2.42 (s, 3), 4.69 (d, 2, J=4.8), 6.75 (s, 1), 6.98 (br t, 1), 7.19-7.25 (m, 3), 7.35-7.42 (m, 2), 7.49 (t, 2, J=7.8), 7.76 (d, 2, J=7.8), 11.27 (s, 1). Anal. Calcd for C21H20N4: C, 76.83; H, 6.10; N, 17.07. Found: C, 76.58; H, 6.20; N, 16.94.
Reaction SMILES: [CH:1]([C:3]1[C:4]2([CH3:14])[C:9]([CH2:10][CH2:11][CH:12]=1)=[CH:8][C:7](=[O:13])[CH2:6][CH2:5]2)=[CH2:2].C[O-].[Na+].[CH:18](OC)=[O:19].Cl>O1CCCC1>[CH:1]([C:3]1[C:4]2([CH3:14])[C:9]([CH2:10][CH2:11][CH:12]=1)=[CH:8][C:7](=[O:13])[C:6](=[CH:18][OH:19])[CH2:5]2)=[CH2:2]
Reactant: C=CC1=CCCC2=CC(=O)CCC12C
Reactant: COC=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CC1=CCCC2=CC(=O)C(=CO)CC12C
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
A solution of 50.0 g (0.265 mol) of 5-ethenyl-4,4a,7,8-tetrahydro-4a-methyl-2(3H)-naphthalenone in 350 mL of tetrahydrofuran was cooled to -5° C. in an ice-methanol bath and stirred under nitrogen while 57.2 g (1.06 mol) of sodium methoxide was added. The resulting mixture was stirred for 30 min at -5° C. and then a solution of 114 mL (1.85 mol) of methyl formate in 100 mL of tetrahydrofuran was added slowly. The mixture was stirred overnight at room temperature and then poured onto a mixture of ice-water (1500 mL) and 6 N hydrochloric acid (265 mL). The product was extracted with ether and the combined extracts were washed with water. The dried extract was dried over anhydrous magnesium sulfate and concentrated in vacuo to afford an oil. This oil was triturated with hexane (4×250 mL) and the combined triturates were dried over magnesium sulfate and concentrated in vacuo to afford 55.37 g of a red oil, consisting essentially of the above-entitled compound as established by proton NMR (PMR) spectral data.
Reaction SMILES: O=C1N(CC(O)=O)C2C=CC=CC=2N(C(=O)C)C[C@@H]1N[C:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[CH2:29]([O:36][C:37](=[O:63])[CH2:38][N:39]1[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[N:43]([C:50](=[O:52])[CH3:51])[CH2:42][C@H:41]([NH:53][C:54](=[O:61])[C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C:40]1=[O:62])C1C=CC=CC=1>CO.[Pd]>[CH3:29][O:36][C:37](=[O:63])[CH2:38][N:39]1[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[N:43]([C:50](=[O:52])[CH2:51][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:42][C@H:41]([NH:53][C:54](=[O:61])[C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C:40]1=[O:62]
Reactant: CC(=O)N1C[C@H](NC(=O)c2ccccc2)C(=O)N(CC(=O)OCc2ccccc2)c2ccccc21
Reactant: CC(=O)N1C[C@H](NC(=O)c2ccccc2)C(=O)N(CC(=O)O)c2ccccc21
Agent: [Pd]
Solvent: CO
Product: COC(=O)CN1C(=O)[C@@H](NC(=O)c2ccccc2)CN(C(=O)CCc2ccccc2)c2ccccc21
Reaction time: 0.5 h

Procedure:
Method B. (3S)2-Oxo-3-benzoylamino-5-acetyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-1-acetic acid (603d). A mixture of (3S)-2-oxo-3-(benzoylamino)-5-acetyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-1-acetic acid benzyl ester (602d; 510 mg, 1.08 mmol) and 5% Pd/C (250 mg) in MeOH (10 ml) stirred under H2 (1 atm) for 0.5 h. The reaction was filtered and concentrated in vacuo 410 mg of 603d as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5]P(OC)(OC)=O)=[O:4].CC(C)([O-])C.[K+].[CH:18]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]([CH3:34])[C:26]=1[C:35]1[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=1)=O>C1COCC1>[CH3:1][O:2][C:3]([CH:5]=[CH:18][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]([CH3:34])[C:26]=1[C:35]1[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=1)=[O:4]
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: Cn1c(-c2cccnc2)c(CCCCCC=O)c2ccccc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C=CCCCCCc1c(-c2cccnc2)n(C)c2ccccc12
Reaction time: 0.33 h

Procedure:
Trimethyl phosphonoacetate (328 mg) is added dropwise to a solution of potassium tert-butoxide (220 mg) in THF (5 ml) of 0° under a nitrogen atmosphere. The solution is stirred at 0° for 20 minutes, then cooled to -78°. A solution of 3-(5-formylpentyl)-2-(3-pyridyl)-1-methylindole (450 mg) in THF (5 ml) is added dropwise over 15 minutes. The mixture is kept at -78° for 15 minutes, then the cooling bath is removed. The mixture is stirred overnight at room temperature, then diluted with water (25 ml) and extracted with diethyl ether (3×25 ml). The combined extracts are washed with saturated sodium bicarbonate, then brine, and dried over anhydrous magnesium sulfate. Concentration in vacuo yields the α,β unsaturated ester, 3-(7-methoxycarbonylhept-6-enyl)-2-(3-pyridyl)-1-methylindole.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)[Br:21].[Si:25]([O:32][CH2:33][C:34]1[CH:35]=[C:36]([CH:50]=[CH:51][C:52]=1[CH2:53][O:54][Si:55]([C:58]([CH3:61])([CH3:60])[CH3:59])([CH3:57])[CH3:56])[O:37][CH2:38][C:39]1[S:43][C:42](/[C:44](/[CH2:48][CH3:49])=[CH:45]/[CH:46]=O)=[CH:41][CH:40]=1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].O>ClCCl.[Zn]>[Si:25]([O:32][CH2:33][C:34]1[CH:35]=[C:36]([CH:50]=[CH:51][C:52]=1[CH2:53][O:54][Si:55]([C:58]([CH3:60])([CH3:59])[CH3:61])([CH3:56])[CH3:57])[O:37][CH2:38][C:39]1[S:43][C:42](/[C:44](/[CH2:48][CH3:49])=[CH:45]/[CH:46]=[C:20]([Br:24])[Br:21])=[CH:41][CH:40]=1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: CC/C(=C\C=O)c1ccc(COc2ccc(CO[Si](C)(C)C(C)(C)C)c(CO[Si](C)(C)C(C)(C)C)c2)s1
Reactant: BrC(Br)(Br)Br
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: CC/C(=C\C=C(Br)Br)c1ccc(COc2ccc(CO[Si](C)(C)C(C)(C)C)c(CO[Si](C)(C)C(C)(C)C)c2)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
770 mg (11.7 mmol) of zinc, 3.09 g (11.7 mmol) of triphenylphosphine and 3.9 g (11.7 mmol) of carbon tetrabromide are stirred for 30 minutes at room temperature in 150 mol of dichloromethane. A solution of 3.3 g (5.9 mmol) of (E)-3-{5-[3,4-bis(tert-butyldimethylsilanyloxymethyl)phenoxymethyl]-2-thienyl}pent-2-enal (described in Example 7(c)) in 30 mL of dichloromethane is then added dropwise. After stirring for 1 h at room temperature the reaction medium is treated with water and extracted with dichloromethane. After purification on silica gel (eluent: 95 heptane/5 ethyl acetate), the desired product is obtained in the form of a brown oil (m=3.9 g; Y=93%).
Reaction SMILES: [OH:1][C@H:2]([C@H:6]1[O:11][CH2:10][CH2:9][N:8]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=2)[C:7]1=[O:23])[C:3]([OH:5])=O.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[NH:32][O:33][C:34](=[O:36])[N:35]=2)=[CH:27][CH:26]=1.NC1C=C2C(=CC=1)C(N(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=NC=C2>CN(C=O)C>[OH:1][C@H:2]([C@H:6]1[O:11][CH2:10][CH2:9][N:8]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=2)[C:7]1=[O:23])[C:3]([NH:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]2[NH:35][C:34](=[O:36])[O:33][N:32]=2)=[CH:29][CH:30]=1)=[O:5]
Reactant: O=C(O)[C@H](O)[C@H]1OCCN(c2ccc(OC(F)(F)F)cc2)C1=O
Reactant: Nc1ccc(-c2nc(=O)o[nH]2)cc1
Agent: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2cc(N)ccc12
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(-c2noc(=O)[nH]2)cc1)[C@H](O)[C@H]1OCCN(c2ccc(OC(F)(F)F)cc2)C1=O

Procedure:
According to the Step 1-3 in synthetic method for EXAMPLE 1, compound 55-6 (0.3 g) and 3-(4-aminophenyl)-1,2,4-oxadiazol-5(2H)-one with DMF were used instead of 1-2 and 6-amino-1-bis(tert-butoxycarbonyl)aminoisoquinoline to obtain compound 56-1 (26 mg) as a colorless amorphous solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)=O.[CH:33]([NH2:36])([CH3:35])[CH3:34]>CN(C=O)C.O>[CH:33]([NH:36][C:15]([C@@H:12]1[CH2:11][CH2:10][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:14][CH2:13]1)=[O:17])([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(=O)O)CC1
Reactant: CC(C)N
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)NC(=O)[C@H]1CC[C@@H](NC(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of cis-4-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid (54.58 g, 224 mmol) in dry DMF (200 mL) was added 1,1′-carbonyldiimidazole reagent grade (70 g, 432 mmol) portionwise with stirring. After the evolution of CO2 had ceased, the resulting solution was stirred at RT for 10 minutes. The solution was cooled to 0° C., and isopropylamine (38.5 mL, 449 mmol) was added with stirring. The reaction was stirred at 0° C. for 10 minutes and at RT for 24 hours. The reaction was diluted slowly with water (1 L) with stirring in an ice-water bath and then allowed to age for 1 hour. The precipitate was collected by filtration, washed with water, and dried in vacuo to generate tert-butyl cis-4-(isopropylcarbamoyl)cyclohexyl-carbamate as a white solid (39.11 g, 61% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH:11]1[CH2:13][CH2:12]1)[C:5]([OH:7])=[O:6].[Li]CCCC.CN(C)[CH:21]=[O:22]>O1CCCC1.CCOCC>[CH:11]1([C:10]2[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=2[CH:21]=[O:22])[CH2:13][CH2:12]1
Reactant: O=C(O)c1ccc(C2CC2)c(Br)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=Cc1cc(C(=O)O)ccc1C1CC1
Temperature: -78 °C
Yield: 76.2 %

Procedure:
Into a 100-mL three neck round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 3-bromo-4-cyclopropylbenzoic acid (compound 10.3, 500 mg, 2.07 mmol) in tetrahydrofuran/Et2O (1:1, 20 mL). The solution was cooled to −78° C. then n-BuLi (2.5 M in THF) (1.8 mL, 4.5 mmol) was added drop-wise with stirring. The resulting solution was stirred for an additional 30 min at −78° C., then N,N-dimethylformamide (0.49 mL, 6.3 mmol) was added drop-wise over 10 min. The mixture was stirred for 2 h at −78° C., then quenched with water (100 mL). The pH of the solution was adjusted to 3-4 with aqueous HCl (6 M), then extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (3×30 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:5) as the eluent to yield 0.3 g (76%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1)[CH3:2].Cl.[C:13]1([NH2:23])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1>ClC1C=CC=CC=1>[C:13]1([NH:23][C:10]([NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][CH3:2])[CH:4]=2)=[NH:11])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: CCc1cccc(NC#N)c1
Reactant: Nc1cccc2ccccc12
Agent: Cl
Solvent: Clc1ccccc1
Product: CCc1cccc(NC(=N)Nc2cccc3ccccc23)c1
Temperature: 25 °C
Yield: 6.4 %

Procedure:
A solution of m-ethylphenylcyanamide (730 mg, 2.99 mmol) and 1-naphthylamine hydrochloride (900 mg, 5.05 mmol) in chlorobenzene (20 ml) was heated at 140°-145° C. for 12 hours. It was allowed to cool to room temperature, concentrated and the residue was partitioned between dichloromethane and 10% NaOH solution. The organic layer was concentrated and the resulting residue was recrystallized from abs. EtOH-H2O to give N-(1-naphthyl)-N'-(m-ethylphenyl)guanidine (55 mg, 4%) as off-white needles, mp 96°-98° C.