Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].C(=O)([O-])[O-].[K+].[K+].I[CH2:32][CH3:33]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH2:32][CH3:33])=[CH:21][CH:22]=1)[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
32.94 g (100 mmol) of N-benzyloxycarbonyltyrosine methyl ester is mixed in 200 ml of DMF with 27.64 g (200 mmol) of ground potassium carbonate. 8.96 ml (110 mmol) of iodoethane is instilled in this suspension and stirred overnight at room temperature. The solution is concentrated by evaporation, distributed between ethyl acetate and water and, after drying (Na2SO4), the organic phase is mixed with hexane. The title compound crystallizes out.
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:9](SC)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH2:33])=[CH:30][CH:29]=1>CO>[C:21]([O:20][C:18]([N:10]1[C@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=[C:9]1[NH:33][CH2:32][C:31]1[CH:34]=[CH:35][C:28]([F:27])=[CH:29][CH:30]=1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: NCc1ccc(F)cc1
Reactant: CSC1=N[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1C(=O)OC(C)(C)C
Solvent: CO
Product: CC(C)(C)OC(=O)N1C(NCc2ccc(F)cc2)=N[C@@H](c2ccccc2)[C@H]1c1ccccc1
Temperature: 100 °C
Yield: 41.6 %

Procedure:
A mixture of intermediate 59 (1.0 g, 0.0027 mol), 4-fluorobenzylamine (0.372 mL, 0.00321 mol) and MeOH (0.4 mL) is heated at 100° C. for 2 days. The reaction mixture is cooled to RT, and partitioned between dichloromethane and water. The organic solution is separated, dried (MgSO4), and concentrated in vacuo. The residue is purified by chromatography on silica gel; gradient elution with heptane:EtOAc (80:20-40:60) gives 0.50 g of the product 85. 1H NMR (CDCl3) δ 7.60-7.35 (m, 3 H), 7.15-6.90 (m, 10 H), 6.85-6.70 (m, 2 H), 5.50-5.30 (m, 2 H), 5.75-5.55 (m, 2 H), 1.12 (s, 9 H); MS: m/z 446 (M++1).
Reaction SMILES: [C:1]1(=[O:7])[CH2:5][CH2:4][C:3](=O)[CH2:2]1.[NH:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]=O)=[CH:14][CH:15]=2)[CH:10]=[N:9]1.N1CCCCC1.[NH2:25][C:26]([CH3:30])=[CH:27][C:28]#[N:29]>C(O)C>[NH:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]3[C:27]([C:28]#[N:29])=[C:26]([CH3:30])[NH:25][C:3]4[CH2:4][CH2:5][C:1](=[O:7])[C:2]3=4)=[CH:14][CH:15]=2)[CH:10]=[N:9]1
Reactant: O=C1CCC(=O)C1
Reactant: CC(N)=CC#N
Reactant: O=Cc1ccc2[nH]ncc2c1
Solvent: CCO
Solvent: C1CCNCC1
Product: CC1=C(C#N)C(c2ccc3[nH]ncc3c2)C2=C(CCC2=O)N1

Procedure:
100 mg (1.026 mmol) cyclopentane-1,3-dione, 150 mg (1.026 mmol) 1H-indazole-5-carbaldehyde and piperidine (0.1 ml) in ethanol (8 ml) were heated to reflux for 4 h. The mixture was then evaporated to dryness, the remaining solid was dissolved in acetic acid (8 ml), and 84 mg (1.026 mmol) 3-aminobut-2-enenitrile were added. The solution was heated to reflux for 2 h. After cooling, the mixture was evaporated to dryness again, and the remaining solid was purified by preparative RP-HPLC (acetonitrile/water gradient) to yield 40 mg (13% of th.) of the title compound.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:24])/[CH:15]=[CH:16]/[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]([N:32]([CH2:36][Si](C)(C)C)[CH2:33]OC)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]([C@H:15]1[C@H:16]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH2:36][N:32]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:33]1)=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: O=C(/C=C/c1ccc(Cl)cc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1OC[C@H](Cc2ccccc2)N1C(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a cooled solution of (4S)-4-benzyl-3-[(2E)-3-(4-chlorophenyl)prop-2-enoyl]-1,3-oxazolidin-2-one, from preparation 23 (5 g, 14.62 mmol) and N-benzyl-1-methoxy-N-[(trimethylsilyl)methyl]methanamine (5.24 mL, 20.47 mmol) in dichloromethane (50 mL) was added trifluoroacetic acid (60 L, 0.73 mmol). The reaction mixture was stirred at 0° C. for 20 minutes and then warmed to room temperature and stirred for 24 hours. Sodium hydrogen carbonate solution (80 mL) was added and the reaction mixture was stirred for 10 minutes. The phases were separated and the organic phase was dried over magnesium sulfate and the solvent was removed in vacuo to give a yellow oil. Purification by column chromatography on silica gel using ethyl acetate:pentane (10:50-50:50) as eluent afforded the desired product (which is the second-eluting diastereomer) as a white crystalline solid, 733 mg (11%).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@:9]23[O:18][C:17]4[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=4[C@@H:10]2[CH2:11][N:12]([CH3:15])[CH2:13][CH2:14]3)=[CH:5][CH:4]=1.C[S-].[Li+].Cl>CN(C)P(N(C)C)(N(C)C)=O.O>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C@@:9]23[O:18][C:17]4[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=4[C@@H:10]2[CH2:11][N:12]([CH3:15])[CH2:13][CH2:14]3)=[CH:7][CH:8]=1
Reactant: COc1ccc([C@]23CCN(C)C[C@H]2c2ccccc2O3)cc1
Agent: C[S-]
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CN1CC[C@]2(c3ccc(O)cc3)Oc3ccccc3[C@@H]2C1
Yield: 84 %

Procedure:
A mixture of 3.46 g of cis-1,2,3,4,4a,9b-hexahydro-4a-(4-methoxyphenyl)-2-methyl-benzofuro[3,2-c]pyridine and 3.57 g of lithium thiomethoxide in 30 ml of dry hexamethylphosphoramide was heated under a drying tube at 140° for 41/2 hours. The reaction mixture was diluted with 350 ml of water, and the pH was adjusted to 7 by slow addition of 2N HCl with stirring. As the pH reached neutral, the product precipitated out. The mixture was cooled to 0° and stirred for 30 minutes. The precipitated material was filtered, washed with water and then with a small amount of ether, and dried to give 2.77 g (84.2%) of crystalline solid, m.p. s 209, 215°-217°. Recrystallization from ethanol afforded 2.33 g (70.8%) of crystals, m.p. s 215, 222°-224°.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:17])=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]1.[CH2:18]([O:20][C:21](=[O:29])[C:22]1[CH:27]=[CH:26][C:25](O)=NC=1)C.[C:30]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:35]=CC=C[CH:31]=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:18][O:20][C:21](=[O:29])[CH2:22][C:27]1[CH:26]=[CH:25][C:35]([O:16][CH2:15][CH2:14][N:11]2[CH2:10][CH2:9][N:8]([C:7]3[CH:6]=[C:5]([Cl:17])[N:4]=[N:3][C:2]=3[Cl:1])[CH2:13][CH2:12]2)=[CH:30][CH:31]=1
Reactant: OCCN1CCN(c2cc(Cl)nnc2Cl)CC1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCOC(=O)c1ccc(O)nc1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(OCCN2CCN(c3cc(Cl)nnc3Cl)CC2)cc1
Reaction time: 8 h
Yield: 37.6 %

Procedure:
To a 50 mL dry three-necked flask, 0.554 g (0.002 mol) of self-made 2-[4-(3,6-dichloro-pyridazin-4-yl)-piperazin-1-yl]-ethanol, 0.28 g (0.002 mol) of 6-hydroxy-nicotinic acid ethyl ester, 0.612 g of triphenylphosphine were added, 15 mL of anhydrous tetrahydrofuran was poured into the flask under condition of ice bath and nitrogen gas protection, then 0.35 mL of diethyl azodiformate (DEAD) dissolved in 5 mL of anhydrous tetrahydrofuran was added dropwise into the flask, after the dropwise addition, the temperature was elevated to room temperature, the agitation was kept overnight. The solvent was removed by evaporation using a rotation evaporator next day, the residue was poured into 100 mL of water, extracted for three times using total 150 mL of dichloromethane, the extract solutions were combined together, dried over anhydrous Na2SO4, concentrated, and separated by column chromatograph (eluent, petroleum ether:ethyl acetate:methanol=10:5:0.15) to obtain 0.32 g of 4-{2-[4-(3,6-dichloro-pyridazin-4-yl)-piperazin-1-yl]-ethoxy}-phenylacetic acid methyl ester, a white solid. Yield: 42.3%, m.p. 140˜141° C. 1H-NMR (400MHz, CDCl3) δppm: 1.37˜1.41(t, 3H, J=7.3Hz), 2.79(brs, 4H), 2.91(brs, 2H), 3.36(brs, 4H), 4.35˜4.40(q, 2H, J=7.3Hz), 4.57(brs, 2H), 6.78˜6.80(d, 2H, J=8.7Hz), 6.86(s, 1H), 8.16˜8.18(dd, 1H, J1=8.7Hz, J2=2.2Hz).
Reaction SMILES: Cl.[NH2:2][OH:3].[CH3:4][C:5]1([CH3:17])[C@@H:7]2[CH2:8][C:9]3[C:13]([C@H:6]12)=[C:12]([CH3:14])[S:11][C:10]=3[C:15]#[N:16]>CO>[OH:3][NH:2][C:15]([C:10]1[S:11][C:12]([CH3:14])=[C:13]2[C:9]=1[CH2:8][C@H:7]1[C:5]([CH3:17])([CH3:4])[C@H:6]12)=[NH:16]
Reactant: NO
Reactant: Cc1sc(C#N)c2c1[C@H]1[C@@H](C2)C1(C)C
Agent: Cl
Solvent: CO
Product: Cc1sc(C(=N)NO)c2c1[C@H]1[C@@H](C2)C1(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 84.6 %

Procedure:
To a stirred suspension of K-tert.-butylate (281 mg, 2.5 mmol), hydroxylamine hydrochloride (208 mg, 3.0 mmol) in methanol (4 mL) is added (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopro-pa[a]pentalene-4-carbonitrile (203 mg, 1.0 mmol). The reaction mixture is stirred at rt for 5 h before it is filtered. The filtrate is purified by prep. HPLC (Water XTerrra Prep MS C18 30×75 mm, 10% to 95% acetonitrile in water containing 0.5% sat. aq. NH3) to give (1aS,5aR)-N-hydroxy-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxamidine (200 mg) as a colourless solid; LC-MS: tR=0.72 min, [M+1]+=237.09.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]2[S:14][CH2:13][C:12]3([CH2:18][CH2:17][CH2:16][CH2:15]3)[N:11]2[CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[C:5]([CH2:24][CH3:25])[CH:4]=1)=O.[N+:26]([CH3:29])([O-:28])=[O:27]>>[CH2:24]([C:5]1[CH:4]=[C:3](/[CH:1]=[CH:29]/[N+:26]([O-:28])=[O:27])[CH:8]=[CH:7][C:6]=1[N:9]=[C:10]1[S:14][CH2:13][C:12]2([CH2:18][CH2:17][CH2:16][CH2:15]2)[N:11]1[CH:19]1[CH2:20][CH2:21][CH2:22][CH2:23]1)[CH3:25]
Reactant: CCc1cc(C=O)ccc1N=C1SCC2(CCCC2)N1C1CCCC1
Reactant: C[N+](=O)[O-]
Product: CCc1cc(/C=C/[N+](=O)[O-])ccc1N=C1SCC2(CCCC2)N1C1CCCC1

Procedure:
1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted with 4-cyano-2-ethylphenyl isothiocyanate according to Method C1e to give 2-(4-cyano-2-ethylphenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2-(4-cyano-2-ethylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane. The nitrile was reduced according to Method D11a to give 2-(4-formyl-2-ethylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane. The aldehyde was reacted with nitromethane according to Method D12b according to afford 2-(2-ethyl-4-((1E)-2-nitrovinyl)phenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([N:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:19])[CH3:18])[CH2:13][CH2:12]2)=[CH:4][C:3]=1[CH3:20].CO.[H][H]>[Pd].C(O)(=O)C>[NH2:8][C:7]1[CH:6]=[C:5]([N:11]2[CH2:12][CH2:13][N:14]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:16]2)[CH:4]=[C:3]([CH3:20])[C:2]=1[NH2:1]
Reactant: CC(=O)N1CCN(c2cc(C)c(N)c([N+](=O)[O-])c2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CC(=O)N1CCN(c2cc(C)c(N)c(N)c2)CC1
Yield: 99.4 %

Procedure:
To 1-[4-(4-amino-3-methyl-5-nitro-phenyl)-piperazin-1-yl]-ethanone (4.5 g, 16.2 mmol) and 10% palladium on carbon (400 mg) were added methanol (50 mL) and acetic acid (5 mL) under nitrogen. The reaction mixture was stirred under hydrogen atmosphere (hydrogen balloon) for 14 h. The dark solution was filtered through a pad of celite and the filtercake was washed with methanol. Concentration of the filtrate gave the title compound (4.00 g, 100%) which was used for the next step without purification. LCMS (M+H)+ m/z 207 (t=0.41 min.).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12]O[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:16]>>[CH2:1]([O:8][CH:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:16]=[CH:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1ccocc1OCc1ccccc1
Reactant: N
Product: O=C1C=CN=CC1OCc1ccccc1
Reaction time: 72 h

Procedure:
This method is adapted from that of Bartulin et al., J. Heterocyclic Chem. 29:1017-1019 (1992), which is hereby incorporated by reference. A 3-benzyloxy4-pyrone, prepared as in Method B, is added to an ethanolic solution of aqueous ammonia. The reaction mixture is stirred for approximately 3 days, concentrated under reduced pressure, triturated with acetone, and the solid recrystallized from ethanol to yield the corresponding 3-benzyloxypyrid-4-one. To a solution of this pyrid-4-one in aqueous ethanol containing one equivalent of sodium hydroxide was added an equivalent of n-alkyl bromide. The reaction mixture was heated under reflux for 24 hours after which it was cooled, concentrated under reduced pressure, and extracted with an appropriate solvent. After washing, the organic phase with water, it is dried over magnesium sulfate. The product is obtained upon concentration of the solution under reduced pressure. Crude 1-alkyl-3-benzyloxypyrid-4-one in acetic acid containing 40% hydrobromic acid is then heated on a steam bath for 30 minutes. The 1-alkyl-3-hydroxypyrid-4-one precipitates and is subsequently recrystallized from benzene in good yield with a narrow melting point and appropriate NMR spectrum. ##STR6##
Reaction SMILES: B(O)(O)[C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=1>O>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=2)=[CH:21][CH:20]=1
Reactant: COc1ccc(Br)cc1
Reactant: Cc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(-c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
In a reaction vessel were placed p-tolylboronic acid (0.177 g, 1.3 mmol) and (GLCAphos)2PdCl2 (11 mg, 0.01 mmol), and the atmosphere was replaced with argon. To the mixture were added water (2 ml), an aqueous solution of sodium carbonate (2M solution, 1 ml, 2 mmol) and 4-methoxybromobenzene (0.125 ml, 1.0 mmol) as an aryl halide derivative at room temperature and the mixture was heated at 80° C. with stirring for 16 hours. During the reaction, a white solid was gradually precipitated. After cooling to room temperature, toluene (10 ml) was added to extract the product. The organic layer was washed with water five times and dried under a reduced pressure to give a substantially pure 4-methoxy-4′-methylbiphenyl in an yield of 95%.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:17])[CH:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][CH2:6][CH2:7][N:8]([CH3:10])[CH3:9].[Li]CCCC.[CH:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1.CCCCCC>[CH3:1][NH:2][C:3](=[O:17])[C:4]([CH:23]([OH:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:5][CH2:6][CH2:7][N:8]([CH3:10])[CH3:9]
Reactant: O=Cc1ccccc1
Reactant: CNC(=O)C(CCCN(C)C)c1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CNC(=O)C(CCCN(C)C)(c1ccccc1)C(O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To N-methyl-5-dimethylamino-2-phenylpentanamide (5.0 g, 0.023 mol) dissolved in 50 ml THF was added 18.1 ml of a 2.5M solution of n-BuLi in n-hexane with ice-cooling under N2. After stirring at 0° C. for 30 min, benzaldehyde (2.4 g, 0.023 mol) dissolved in 10 ml THF was added dropwise to the foregoing solution. The reaction mixture was stirred for 5 min at 0° C. and then poured into ice-cold HCl. The resulting solution was washed with Et2O, basified by adding dilute NaOH while stirring in the cold, and extracted with CHCl3. The CHCl3 extract were combined, dried (Na2SO4), and evaporated Chromatography of the post-evaporation residue afforded the desired compound as a mixture of diastereoisomers as an oil. Dissolution in EtOH, acidification with HCl, followed by addition of Et2O gave the hydrochloride salt as a colorless solid. [Anal. Calc'd for C21H28N2O2.HCl.1/4EtOH: C, 66.17; H, 7.93; N, 7.18; Cl, 9.08. Found: C, 65.82; H, 8.02; N, 7.04; Cl 10.27.]
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCCC[Sn](CCCC)CCCC.CCCC[Sn](CCCC)CCCC.[I-:35].[Na+].CC1C=CC(S(NCl)(=O)=O)=CC=1>>[I:35][N:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[NH2:8]
Reactant: [I-]
Reactant: NNc1ccccc1
Agent: CCCC[Sn](CCCC)CCCC
Agent: Cc1ccc(S(=O)(=O)NCl)cc1
Agent: [Na+]
Product: NN(I)c1ccccc1

Procedure:
The starting reactant is phenylhydrazine. The hydrazine group is protected, the aromatic ring is nitrated and subsequently, the nitro-product is chromatographed, reduced to amine, reacted with nitrous acid and sodium iodide to give p-iodo-substituted protected phenylhydrazine. Subsequently it is reacted with hexabutylditin and tetrakis (triphenylphosphine)palladium(0) and then with sodium iodide (NaI125) in the presence of such oxidizing agent as Chloramine-T. The final step, deprotection, gives p-I125 -iodophenylhydrazine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Br:9])[C:3]=1I.C([Mg]Cl)(C)C.CN([CH:19]=[O:20])C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Br:9])[C:3]=1[CH:19]=[O:20]
Reactant: CN(C)C=O
Reactant: Fc1cc(Br)c(I)c(Br)c1
Agent: CC(C)[Mg]Cl
Solvent: Cc1ccccc1
Product: O=Cc1c(Br)cc(F)cc1Br
Temperature: -19 °C
Reaction time: 1.5 h
Yield: 53.7 %

Procedure:
A solution of 1,3-dibromo-5-fluoro-2-iodobenzene (50 g, 132 mmol) in anhydrous toluene (300 mL) was cooled to −35° C. A solution of isopropylmagnesium chloride (84 mL, 171 mmol, 2.0 M in diethyl ether) over a period of 30 minutes while maintaining the internal temperature below −25° C. See FIG. 1. A clear brown solution was obtained. Stirring was continued for 1.5 h. Then anhydrous DMF (34 mL, 436 mmol) was added over a period of 30 minutes. The temperature of the reaction mixture increased to −19° C. The reaction mixture was warmed to 10° C. (room temperature) over 1 h and stirred at this temperature for 1.5 h. The reaction was quenched with saturated aqueous NH4Cl (100 mL), filtered and evaporated under reduced pressure. The residue was purified by silica-gel column chromatography (eluting with petroleum ether/ethyl acetate: from 50:1 to 20:1) to give 101a (20 g, yield 54%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:34](=[O:40])OC(Cl)(Cl)Cl)Cl.[C:42]1([C@@H:48]([NH2:51])[CH2:49][CH3:50])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:34]([NH:51][C@H:48]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:49][CH3:50])=[O:40])=[CH:18][CH:17]=1
Reactant: CC[C@H](N)c1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC[C@H](NC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 121.9 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (70 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (33 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for 75 min. Next, a solution of (1S)-1-phenylpropylamine (31 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (62 mg, yield 57%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:14][O:15][CH2:16][C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:39]=[CH:38][C:25]([CH2:26][N:27]5[CH2:30][CH:29]([C:31]([O:33]C(C)(C)C)=[O:32])[CH2:28]5)=[CH:24][CH:23]=4)[N:18]=3)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CCOCC>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:14][O:15][CH2:16][C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][C:25]([CH2:26][N:27]5[CH2:30][CH:29]([C:31]([OH:33])=[O:32])[CH2:28]5)=[CH:38][CH:39]=4)[N:18]=3)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(-c3noc(COCC4(c5ccc(F)cc5)CCCCC4)n3)cc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: O=C(O)C1CN(Cc2ccc(-c3noc(COCC4(c5ccc(F)cc5)CCCCC4)n3)cc2)C1
Yield: 0 %

Procedure:
A solution of tert-butyl 1-(4-(5-(((1-(4-fluorophenyl)cyclohexyl)methoxy)methyl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate (37 mg, 69 mol) in trifluoroacetic acid (1.5 mL) was stirred at room temperature for 2 h. Trifluoroacetic acid was removed under reduced pressure, followed by co-evaporation with ether to obtain a solid which was stirred with ether (7 mL) for 3.5 h, filtered and dried to obtain 1-(4-(5-(((1-(4-fluorophenyl)cyclohexyl)methoxy)methyl)-1,2,4-oxadiazol-3-yl)benzyl) azetidine-3-carboxylic acid (26 mg, 63% yield) as a white solid. LC/MS: m/e 480.21 (M+H)+. 1H NMR (400 MHz, CD3OD): δ ppm 8.17 (d, J=8.03 Hz, 2H), 7.65 (d, J=7.78 Hz, 2H), 7.43 (dd, J=8.28, 5.52 Hz, 2H), 7.02 (t, J=8.53 Hz, 2H), 4.68 (s, 2H), 4.52 (s, 2H), 4.38 (d, J=7.53 Hz, 4H), 3.72 (ddd, J=16.63, 8.78, 8.47 Hz, 1H), 3.59 (s, 2H), 2.05-2.30 (m, 2H), 1.68-1.88 (m, 2H), 1.48-1.69 (m, 3H), 1.27-1.47 (m, 3H).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH3:8])[N:6]=[C:5]([C:9]([OH:11])=O)[CH:4]=1)[CH3:2].[CH3:12][N:13](C=O)C.[C:17](Cl)(=[O:21])C(Cl)=O>ClCCl>[CH3:17][O:21][N:13]([CH3:12])[C:9]([C:5]1[CH:4]=[C:3]([CH2:1][CH3:2])[N:7]([CH3:8])[N:6]=1)=[O:11]
Reactant: CN(C)C=O
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCc1cc(C(=O)O)nn1C
Solvent: ClCCl
Product: CCc1cc(C(=O)N(C)OC)nn1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
5-Ethyl-1-methylpyrazole-3-carboxylic acid (2.5 g) in dichloromethane (50 ml) was treated with DMF (0.12 ml) and cooled under argon in an ice-bath. The solution was treated with oxalyl chloride (2.2 g) in dichloromethane (25 ml) in a dropwise fashion. After complete addition the reaction mixture was maintained at 0° C. for 25 min. and then allowed to warm to room temperature. The solution was evaporated and the residue re-dissolved in toluene (100 ml) and concentrated again. The crude acid chloride was taken up in dichloromethane (50 ml), and treated with N,O-dimethylhydroxylamine hydrochloride (1.72 g), cooled in an ice-bath and pyridine (2.86 ml) added. The reaction mixture was allowed to stir at room temperature for 2 h. The reaction mixture was washed with brine, dried over anhydrous magnesium sulphate and concentrated to an oil. The product was purified by ‘flash’ silica gel chromatography to give the title compound as a yellow oil, (2.995 g, 94%); (Found: M+, 197.1167. C9H15N3O2 requires M, 197.1164); nmax (CH2Cl2) 1640, 1484 and 1374 cm−1; dH(CDCl3) 1.28 (3H, t, J7.5 Hz), 2.62 (2H, q, J7.5 Hz), 3.43 (3H, s), 3.76 (3H, s), 3.83 (3H, s) and 6.72 (1H, s).