Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])[CH2:9][C:10]([NH:12][NH2:13])=[O:11])([CH3:4])([CH3:3])[CH3:2].[CH3:25][C:26]1[N:34]=[C:33]2[N:28]([C:29](SC)=[N:30][CH2:31][CH2:32]2)[N:27]=1>C(O)CCC>[C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])[CH2:9][C:10]([NH:12][NH:13][C:29]1[N:28]2[N:27]=[C:26]([CH3:25])[N:34]=[C:33]2[CH2:32][CH2:31][N:30]=1)=[O:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CSC1=NCCc2nc(C)nn21
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)NN)Cc1cc(F)c(F)cc1F
Solvent: CCCCO
Product: Cc1nc2n(n1)C(NNC(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C)=NCC2

Procedure:
A solution of 139 mg (0.4 mmol) of tert-butyl[(1R)-3-hydrazino-3-oxo-1-(2,4,5-trifluorobenzyl)propyl]carbamate (Intermediate 4) and 72.9 mg (0.4 mmol) of 2-methyl-5-(methylthio)-7,8-dihydro[1,2,4]triazolo[1,5-c]pyrimidine (Intermediate 30) in 5 mL of 1-butanol was stirred at reflux for 76 h. The cooled solution was concentrated, and the residue containing the title compound was used directly in the next step. LC-MS 482 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]2[CH3:14])[N:3]=1.[CH2:15]([Mg]Cl)[CH:16]([CH3:18])[CH3:17]>C1COCC1.CN1C(=O)CCC1>[CH3:14][C:9]1[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH2:15][CH:16]([CH3:18])[CH3:17])[N:3]=2)[C:12]([CH3:13])=[CH:11][CH:10]=1
Reactant: Cc1ccc(C)n1-c1cccc(Cl)n1
Reactant: CC(C)C[Mg]Cl
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: Cc1ccc(C)n1-c1cccc(CC(C)C)n1

Procedure:
The product from Example 12b (1.0 g, 4.84 mmol) was treated with 2.0 M isobutylmagnesium chloride (2.90 mL, 5.81 mmol) in 30 mL THF and 3 mL NMP at room temperature under a N2 atmosphere. Added Fe(acac)3 (85 mg, 0.242 mmol) and stirred at room temperature for 18 h. During the course of the reaction two additional charges of Grignard reagent and catalyst were added. The reaction was quenched by pouring into 5% acetic acid and extracting with ether. Dried over Na2SO4, filtered and concentrated under vacuum giving the title compound that was purified by silica gel column chromatography eluting with 10% EtOAc/hexane to give (620 mg, 56%).
Reaction SMILES: [CH2:1]=[C:2]([C:4]1[C:12]2[C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[O:9][C:8]=2[C:7]([NH:17][C:18](=[O:20])[CH3:19])=[C:6]([C:21]([CH3:23])=[CH2:22])[CH:5]=1)[CH3:3]>C(O)C.[Pd].[Pt]>[CH:2]([C:4]1[C:12]2[C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[O:9][C:8]=2[C:7]([NH:17][C:18](=[O:20])[CH3:19])=[C:6]([CH:21]([CH3:23])[CH3:22])[CH:5]=1)([CH3:3])[CH3:1]
Reactant: C=C(C)c1cc(C(=C)C)c2c(oc3ccccc32)c1NC(C)=O
Agent: [Pd]
Agent: [Pt]
Solvent: CCO
Product: CC(=O)Nc1c(C(C)C)cc(C(C)C)c2c1oc1ccccc12
Yield: 82.1 %

Procedure:
In a 500 mL hydrogenation container was added N-(1,3-di(prop-1-en-2-yl)dibenzo[b,d]furan-4-yl)acetamide (22.6 g, 74.0 mmol), Pd/C, 10% (3 g, 74.0 mmol) and Pt/C, 5% (3 g, 74.0 mmol) in Ethanol (200 mL). After two days reaction, the solution was filtered through a Celite plug and washed with dichloromethane. The filtration was concentrated to give crude N-(1,3-diisopropyldibenzo[b,d]furan-4-yl)acetamide (18.8 g, 82% yield) as white solid.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[OH:13]CC([C@H:17]([C@@H:19]([C@@H:21]([CH2:23][OH:24])O)O)O)=O.[Cl-:25].C([N+]1C=CN(C)C=1)C.[Na+:34].[Br-].B([O-])([O-])[O-]>[Cr].Cl.CN(C)C=O.CC(N(C)C)=O.O>[O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[ClH:25].[OH2:13].[Na+:34].[Cl-:25].[CH2:19]1[CH2:17][O:24][CH2:23][CH2:21]1
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Cr]
Agent: CC[n+]1ccn(C)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Solvent: O
Product: C1CCOC1

Procedure:
Recent studies have been published on developing new processing strategies focused on isomerizing glucose to fructose with a subsequent acid-catalyzed dehydration of fructose to HMF. Lewis acid catalysts in ionic liquids have been shown to be the most promising systems for the conversion of glucose to HMF.1e Zhao, et al. first reported HMF yields of 68-70% in a system consisting of 1-ethyl-3-methyl-imidazolium chloride and a CrCl2 catalyst.1b It is believed that the high activity and selectivity observed for the production of HMF in ionic liquids with chromium catalysts are caused by the stabilization of the transition state for ring opening of glucose by the Lewis acidic Cr center during glucose isomerization.7 Other studies have been carried out on this same reaction using different ionic liquids or Lewis acid catalysts.8 However, the reactions require ionic liquids, which are expensive and subject to deactivation by small amounts of water formed during dehydration reactions.9 Binder, et al. reported that a mixture consisting of dimethylacetamide (DMA), NaBr, and a Lewis acid, CrCl2, could reach HMF yields of 81%, being as effective as ionic liquid systems.1c Huang, et al. reported an HMF yield of 63% from glucose by a two-step process consisting of the isomerization of glucose to fructose in the presence of glucose isomerase and borate ions, followed by the acid catalyzed dehydration of fructose to HMF using HCl as a catalyst in a biphasic system.10 Takagaki, et al. reported HMF yields of 42% at a 73% conversion by a similar two step process by combining a solid acid catalyst, Amberlyst-15, and a solid base catalyst, Mg—Al hydrotalcite, in N,N-dimethylformamide.11 Nikolla, et al. reported HMF yields of 57% at 79% conversion of glucose using a Lewis acidic Sn-Beta zeolite and HCl in a water/NaCl/THF biphasic reaction system.12
Reaction SMILES: [BrH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7]O>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][Br:1]
Reactant: Br
Reactant: COc1cccc(CO)c1
Product: COc1cccc(CBr)c1
Reaction time: 96 h
Yield: 89.3 %

Procedure:
To cooled (15° to 20° C.) hydrobromic acid (3.22 kg) (48%) is added 3-methoxybenzyl alcohol (1 kg) dropwise over a period of 1 hour. A slight exotherm results with pot temperature rising from 20° to 23° C. After the addition, the reaction mixture was stirred at 23° to 27° C. for four days. The product separated as an oil during this period. The reaction mixture was transferred to a separatory funnel, and the lower layer containing the product was separated. The aqueous phase was extracted with methylene chloride (750 mL). The methylene chloride extract was combined with the main product and washed with water (500 mL×3). The pH of the last wash was 6.5 to 7.0. The product was dried over anhydrous sodium sulfate (200 g), filtered and concentrated under reduced pressure (bath temperature 50° to 55° C.) to remove most of the solvent, then further concentrated at 40° to 45° C. under 5 mm Hg to constant weight to yield 1.30 kg (89% yield) of crude product. The presence of 5.5% of starting material in this product does not interfere with the subsequent alkylation reaction.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[Na].Br[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].O>C(O)C>[CH2:11]([O:2][C:1]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4])[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: Oc1ccccc1O
Reactant: CCCCCBr
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CCCCCOc1ccccc1O
Reaction time: 1 h
Yield: 87.1 %

Procedure:
110 g (1 mole) of catechol was added to a solution of 23 g (1 mole) of metallic sodium in 1 liter of absolute ethanol and the mixture was stirred under nitrogen for one hour. Then, 166 g (1.1 mole) of 1-bromopentane were added dropwise to the mixture over 15 minutes and the mixture was refluxed with stirring for 3 hours, was cooled and poured into 3 liters of water. The mixture was extracted with 1000 ml of ether and the ether extracts were washed with 20% sodium carbonate solution and then water, dried over magnesium sulfate and evaporated to dryness under reduced pressure to obtain 157 g of 2-(n-pentyloxy)-phenol as a yellow oil. IR spectrum showed OH at 3540 cm - 1.
Reaction SMILES: N[C:2]1[S:3][C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.S(=O)(=O)(O)O.N([O-])=O.[Na+].[C:27]([Cu])#[N:28].[C-]#N.[Na+].C([O-])(O)=O.[Na+]>CCOC(C)=O.C(O)(=O)C>[C:27]([C:2]1[S:3][C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1)#[N:28]
Reactant: N#C[Cu]
Reactant: CCOC(=O)c1nc(N)sc1-c1ccccc1
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)c1nc(C#N)sc1-c1ccccc1
Reaction time: 1 h

Procedure:
To a mixed solution of ethyl 2-amino-5-phenyl-1,3-thiazole-4-carboxylate, acetic acid, and sulfuric acid was slowly added an aqueous NaNO2 solution (5 mL) at 0° C., followed by stirring at the same temperature for 1 hour. This solution was added to an aqueous solution (40 mL) containing CuCN, NaCN, and NaHCO3 (30 g) over 30 minutes, followed by stirring at the same temperature for 1 hour. EtOAc was added thereto, and the insolubles were filtered through Celite. The filtrate was extracted with EtOAc, the organic layer was dried, and the solvent was removed by evaporation under reduced pressure. The residue was purified by silica gel column chromatography (hexane:EtOAc=from 5:1 to 3:1 to 2:1) to obtain ethyl 2-cyano-5-phenyl-1,3-thiazole-4-carboxylate as a yellow solid.
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:16](=[O:17])[CH2:15][NH:14][C:13](=O)[C:12]([CH3:19])=[C:7]12.O=P(Cl)(Cl)Cl.[CH:25]1([C:28]2[N:29]=[CH:30][NH:31][CH:32]=2)[CH2:27][CH2:26]1.N1C=CC=CC=1>ClCCCl>[CH:25]1([C:28]2[N:29]=[CH:30][N:31]([C:13]3[C:12]([CH3:19])=[C:7]4[C:8]5[C:3]([CH2:4][CH2:5][N:6]4[C:16](=[O:17])[CH2:15][N:14]=3)=[C:2]([I:1])[CH:11]=[CH:10][CH:9]=5)[CH:32]=2)[CH2:27][CH2:26]1
Reactant: CC1=C2c3cccc(I)c3CCN2C(=O)CNC1=O
Reactant: c1nc(C2CC2)c[nH]1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: CC1=C2c3cccc(I)c3CCN2C(=O)CN=C1n1cnc(C2CC2)c1
Temperature: 100 °C
Reaction time: 0.02 h
Yield: 29.6 %

Procedure:
107-1. A mixture of 9-iodo-1-methyl-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione (30 mg, 81 μmol) in DCE (2 mL) is treated with POCl3 (15 μL, 0.16 mmol) and heated to 100° C. for 3 h. The mixture was then allowed to cool to RT, poured onto H2O and extracted with DCM. The org. phases were dried over Na2SO4, filtered and concentrated in vacuo. The brown residue obtained was taken up in DCE (2 mL) and 4-cyclopropyl-1H-imidazole (31 mg, 0.28 mmol) and pyridine (20 μL, 0.24 mmol) were then added. The mixture was heated to 100° C. for 4.5 h, and then allowed to cool to RT, poured onto H2O and extracted with DCM. The org. layers were then dried over Na2SO4, filtered and concentrated in vacuo. Filtration through a pad of SiO2 (AcOEt) afforded a brown solid that was purified by SFC (column: Diol 5 μm, 250×30 mm, 60 A, Princeton; eluent: 13% MeOH/CO2 for 1 min, then from 13% MeOH/CO2 to 18% MeOH/CO2 in 6 min; then from 18% MeOH/CO2 to 50% MeOH/CO2 in 1 min; flow 100 mL/min; UV detection at 220 nm) to give the title compound (11 mg) as a white powder. UPLC-MS: MS 459.0 (M+H+); UPLC rt 0.98 min.
Reaction SMILES: Cl[CH2:2][C:3](=[O:11])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:12]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.O>ClCCl>[CH2:12]([N:19]1[CH2:24][CH2:23][N:22]([CH2:2][C:3](=[O:11])[CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:21][CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=C(CCl)Cc1ccccc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(Cc1ccccc1)CN1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.2 %

Procedure:
To a solution of 1-chloro-3-phenyl-propan-2-one (10 g, 59 mmol) in dichloromethane (100 ml) was added benzylpiperazine (12.3 ml, 71 mmol) and triethylamine (8.2 ml, 59 mmol). The yellow solution was stirred overnight at ambient temperature and water was added (50 ml). The organic phase was decanted, washed with brine (50 ml), dried (sodium sulphate) and evaporated. The residue was purified by column chromatography on silica using petroleum ether (60-80) ethyl acetate to afford a yellow oil (2.4 g, 13%). 1H NMR (250 MHz, CDCl3) δ 2.30-2.64 (8H, m), 3.19 (2H, s), 3.51 (2H, s), 3.74 (2H, s), 7.17-7.38 (10H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:28])[CH:5]=[C:6]([Cl:27])[C:7]=1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15]COC)=[C:11]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH:10]=1.CC1C=CC(S(O[CH2:40][P:41]([CH3:46])(=[O:45])[O:42][CH2:43][CH3:44])(=O)=O)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[Cl:27][C:6]1[CH:5]=[C:4]([CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[CH:10]=1)[O:28][CH2:40][P:41]([CH3:46])(=[O:45])[O:42][CH2:43][CH3:44]
Reactant: CCOP(C)(=O)COS(=O)(=O)c1ccc(C)cc1
Reactant: COCOc1ccc(Cc2c(Cl)cc(O)cc2Cl)cc1Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOP(C)(=O)COc1cc(Cl)c(Cc2ccc(O)c(Cc3ccc(F)cc3)c2)c(Cl)c1
Temperature: 25 °C

Procedure:
To a solution of 3,5-dichloro-4-[3′-(4-fluorobenzyl)-4′-methoxymethoxybenzyl]phenol (0.08 gm, 0.19 mmol), acetonitrile (3 mL), ethyl [(4-methylphenyl)sulfonyloxymethyl]methylphosphinate (compound 74, 0.105 gm, 0.38 mmol), was added cesium carbonate (0.153 gm, 0.47 mmol). The reaction was heated at reflux for 2 hours, then stirred over night at r.t. The reaction was filter into 25 ml ethyl acetate, washed 1× with brine, dried over Na2SO4, filtered and concentrated. Ethyl [(3,5-dichloro-4-(3-(4-fluorobenzyl)-4-hydroxybenzyl)phenoxy)methyl]methylphosphinate was obtained by prep plate TLC using a 2 mm×20×20 cm SiO2 plate eluted with ethyl acetate. (0.06 gm, 60%); 1H NMR (300 MHz, DMSO-d6): δ 7.23 (s, 2H), 7.17 (m, 2H), 7.07 (t, J=8.7 Hz, 2H), 6.95 (m, 2H), 6.86 (m, 1H), 5.14 (s, 2H), 4.41 (m, 2H), 4.07 (s, 2H), 4.04 (m, 2H), 3.86 (s, 2H), 3.25 (s, 3H); 31p NMR (121.4 MHz, DMSO-d6): δ 46.13; TLC conditions: Uniplate silica gel, 250 microns; ethyl acetate; Rf=0.22.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][CH2:6][C:7]1([CH3:20])[C:12]2[NH:13][C:14]3[C:19]([C:11]=2[CH2:10][CH2:9]O1)=[CH:18][CH:17]=[CH:16][CH:15]=3)=O.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]2[C:3]([CH2:2][Cl:1])=[N:5][CH:6]=[C:7]([CH3:20])[C:12]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC1(CNC(=O)CCl)OCCc2c1[nH]c1ccccc21
Product: Cc1cnc(CCl)n2c1c(CCCl)c1ccccc12

Procedure:
A mixture of 2-chloro-N-[(1,3,4,9-tetrahydro-1-methylpyrano[3,4-b]indol-1-yl)methyl]-acetamide (9.0 g, described in Example 8) and phosphorus oxychloride (200 ml) is refluxed for 60 minutes and evaporated slowly to dryness under reduced pressure (10 mm Hg, the final bath temperature 140° C.). The residue is dissolved in chloroform and the solution is washed quickly with ice-cold 5% solution of sodium hydroxide, dried over magnesium sulfate, filtered and evaporated. The residue is chromatographed through a column of silica gel (300 g) using chloroform. The eluates are evaporated and the residue is crystallized from ethyl acetate to obtain the title compound (5.5 g); mp 160°-161° C., nmr(CDCl3) δ2.53(s), 3.62(m), 4.94(s) and 7.10-8.20(m).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[N:10]=[C:9]2[CH:11]=[CH:12][NH:13][C:8]2=[CH:7][CH:6]=1.[Br:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17]Br>CN(C)C=O>[Br:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][N:13]1[C:8]2[C:9](=[N:10][C:5]([O:4][CH3:3])=[CH:6][CH:7]=2)[CH:11]=[CH:12]1
Reactant: BrCc1ccccc1Br
Reactant: COc1ccc2[nH]ccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(ccn2Cc2ccccc2Br)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under argon and in an anhydrous medium, 590 mg (14.75 mmol) of sodium hydride (60% in oil) are added slowly to a solution of 1.81 g (12.23 mmol) of the compound obtained in Step B in 50 ml of N,N-dimethylformamide at 0° C. After 30 minutes' stirring at room temperature, 2.27 ml (14.75 mmol) of 2-bromobenzyl bromide in 15 ml of N,N-dimethylformamide are added dropwise to the reaction mixture. Stirring is maintained at room temperature under argon for two hours. After hydrolysis and then extraction with ethyl acetate, the organic phase is washed several times with water, dried over magnesium sulphate, concentrated and purified by flash chromatography over silica gel (eluant: petroleum ether/ethyl acetate, 8:2) to yield the title compound in the form of a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].[Br:14]Br.S(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Br:14][C:6]1[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[C:3]([O:2][CH3:1])=[CH:8][C:7]=1[O:9][CH3:10]
Reactant: BrBr
Reactant: COc1ccc([N+](=O)[O-])c(OC)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1cc(OC)c([N+](=O)[O-])cc1Br
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 2,4-dimethoxy-nitrobenzene (0.50 g) in chloroform (3 mL) is added dropwise a solution of bromine (0.23 g) in chloroform (1 mL) and the mixture is allowed to stir at room temperature for approximately 15 hours. Additional bromine (0.15 g) in chloroform (1 mL) is added and the reaction is stirred for an additional 4 hours. The mixture is then poured onto 5% aqueous sodium bisulfite and then extracted with chloroform. Pooled organic extracts are then washed successively with 5% aqueous sodium bisulfite then saturated sodium chloride, and then dried over anhydrous sodium sulfate. Removal of the solvent under reduced pressure and recrystallization of the residue from toluene provides the desired product as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH2:9][CH:10]1[CH2:26][CH2:25][C:13]2([CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15][CH2:14]2)[CH2:12][CH2:11]1.CCN(CC)CC>CCO>[Cl:1][C:2]1[N:7]=[C:6]([NH:9][CH:10]2[CH2:11][CH2:12][C:13]3([CH2:17][N:16]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:15][CH2:14]3)[CH2:25][CH2:26]2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(N)CC2)C1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC2(CCC(Nc3ccnc(Cl)n3)CC2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 32.1 %

Procedure:
To a solution of 2,4-dichloropyrimidine (0.5 g, 3.4 mmol) and tert-butyl 8-amino-2-azaspiro[4.5]decane-2-carboxylate (0.89 g, 3.5 mmol) in EtOH (20 mL) was added Et3N (0.5 g, 5 mmol). The mixture was stirred at rt for 24 h, then the reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/2) to give the product as a white solid (0.4 g, 33%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([NH:12][NH2:13])=[N:7][N:6]=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH2:20](O)C>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]1=[N:12][N:13]=[CH:20][N:7]1[N:6]=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCO
Reactant: NNc1nnc(-c2ccccc2)c2cc(Cl)ccc12
Product: Clc1ccc2c(c1)c(-c1ccccc1)nn1cnnc21

Procedure:
The compound of the title is prepared by following essentially the same procedure outlined in example 114 above but using 6-chloro-4-phenyl-1-hydrazinophthalazine instead of 4-phenyl-1-hydrazinophthalazine. M.p. 189°-90° C. (from ethanol).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[CH:10][O:11][C:7]=2[C:6]([C:12]([OH:14])=[O:13])=[CH:5][CH:4]=1.CN(C1C=CC=CN=1)C.[N+:24]([C:27]1[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=1)([O-:26])=[O:25].Cl.C(N=C=NCCCN(C)C)C>ClCCl>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[CH:10][O:11][C:7]=2[C:6]([C:12]([O:14][C:30]2[CH:31]=[CH:32][C:27]([N+:24]([O-:26])=[O:25])=[CH:28][CH:29]=2)=[O:13])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)O)c2ocnc12
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(C(=O)Oc2ccc([N+](=O)[O-])cc2)c2ocnc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-methoxybenzoxazole-7-carboxylic acid (0.16 g), dimethylaminopyridine (catalytic) 4-nitrophenol (0.17 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.17 g) in dichloromethane (30 ml) was stirred at room temperature under nitrogen overnight. The mixture was diluted with dichloromethane (20 ml) and washed with water (2×50 ml). The combined organic phases were dried over magnesium sulphate and evaporated in vacuo to give 4-nitrophenyl 4-methoxybenzoxazole-7-carboxylate. 4-Amino-3,5-dichloropyridine (0.15 g) was dissolved in N,N-dimethylformamide (5 ml) at room temperature under nitrogen. Sodium hydride (40 mg; 60% disopersion in oil) was added, and the mixture stirred for 1 h before addition of the 4-nitrophenyl ester (0.26 g) in N,N-dimethylformamide (20 ml). After stirring for 60 h, the N,N-dimethylformamide was evaporated in vacuo, and the residue partitioned between ethyl acetate (40 ml) and water (40 ml). The combined organic phases were washed with water (2×40 ml), dried over magnesium sulphate, evaporated onto silica and purified by flash chromatography eluting with 50% ethyl acetate in hexane) to yield the title compound as a white solid (51 mg).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][CH:15]2[CH2:17][CH2:16]2)[CH2:10][C:11](O)=[O:12])=[CH:5][C:4]=1[C:18]([F:21])([F:20])[F:19])#[N:2].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.[N:37]1C=CC=CC=1.[NH4+]>C(#N)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][CH:15]2[CH2:17][CH2:16]2)[CH2:10][C:11]([NH2:37])=[O:12])=[CH:5][C:4]=1[C:18]([F:21])([F:20])[F:19])#[N:2]
Reactant: c1ccncc1
Reactant: N#Cc1ccc(N(CC(=O)O)CC2CC2)cc1C(F)(F)F
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [NH4+]
Solvent: CC#N
Product: N#Cc1ccc(N(CC(N)=O)CC2CC2)cc1C(F)(F)F
Reaction time: 12 h
Yield: 39.7 %

Procedure:
A mixture of N-[4-cyano-3-(trifluoromethyl)phenyl]-N-(cyclopropylmethyl)glycine (0.298 g, 1 mmol), di-tert-butyl dicarbonate (0.436 g, 2 mmol), pyridine (0.100 g, 1.25 mmol), and ammonium hydrocarbonate (0.160 g, 2.25 mmol) was stirred for 24 h in acetonitrile (8 mL). The solvent was removed under reduced pressure, then water (10 mL) was added to the residue. The resulting solid was filtered, washed with water (3×5 mL), and then dried. After drying, the solid was suspended in diethyl ether (10 mL) and stirred for 12 h. The mixture was filtered, washed with diethyl ether (5 mL), and dried to obtain 0.118 g (40%) of the title compound as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.63 (d, J=8.6 Hz, 1H), 7.03 (d, J=2.3 Hz, 1H), 6.84 (dd, J=8.8, 2.5 Hz, 1H), 6.02 (bs, 1H), 5.57 (bs, 1H), 4.10 (s, 2H), 3.38 (d, J=6.6 Hz, 2H), 1.08 (m, 1H), 0.67 (m, 2H), 0.33 (m, 2H).