Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OS(O)(=O)=O.[N+:6]([O-:9])(O)=[O:7].[O:10]=[C:11]1[N:20]2[CH2:21][CH2:22][N:23]=[C:19]2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:12]1>>[N+:6]([C:16]1[CH:15]=[CH:14][C:13]2[NH:12][C:11](=[O:10])[N:20]3[CH2:21][CH2:22][N:23]=[C:19]3[C:18]=2[CH:17]=1)([O-:9])=[O:7]
Reactant: O=C1Nc2ccccc2C2=NCCN12
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C1Nc2ccc([N+](=O)[O-])cc2C2=NCCN12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
7 ml of concentrated H2SO4 were added, whilst cooling, to 5 ml of 98% strength HNO3. 9.3 g (0.05 mol) of 5-oxo-2,3,5,6-tetrahydroimidazo-[1,2-c]-quinazoline were added in portions at 0° to 5° C. to this mixture, and the latter was stirred for 2 hours at room temperature. The reaction mixture was then poured into ice water, and the precipitated deposit was filtered off under suction. It was neutralised in water with NaHCO3, the mixture being heated to boiling for a short time. After the mixture had been cooled, the precipitate was again filtered off under suction, washed with ethanol and ether, and dried.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9](#[N:13])[CH:10]([CH3:12])[CH3:11]>C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:10]([CH3:12])([CH3:11])[C:9]#[N:13])=[N:3][CH:4]=1
Reactant: CC(C)C#N
Reactant: Brc1ccc(Br)nc1
Solvent: Cc1ccccc1
Product: CC(C)(C#N)c1ccc(Br)cn1

Procedure:
NaN[(SiCH3)3]2 (1 M in tetrahydrofuran, 6.3 mL) was added dropwise to a solution of 2,5-dibromo-pyridine (1.50 g) and isobutyronitrile (0.58 mL) in toluene (15 mL) chilled in an ice bath and kept under argon atmosphere. The resulting mixture was further stirred with cooling for 1 h and then at room temperature overnight. The mixture was filtered and the filtrate was washed with water, 10% aqueous K2CO3 solution, and brine. The organic phase was dried (MgSO4) and the solvent was evaporated. The residue was purified by chromatography on silica gel (dichloromethane/methanol 99:1->95:5) to furnish the title compound. Yield: 0.26 g (18% of theory); Mass spectrum (ESI+): m/z=220/222 (Br) [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:17])[C:13]([NH:15][NH2:16])=[O:14])[CH3:2].[CH:18](=O)[CH3:19]>CO>[CH:18](=[N:16][NH:15][C:13](=[O:14])[C:12]([C:4]1[C:5]([CH2:10][CH3:11])=[CH:6][C:7]([CH3:9])=[CH:8][C:3]=1[CH2:1][CH3:2])=[O:17])[CH3:19]
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)NN
Reactant: CC=O
Solvent: CO
Product: CC=NNC(=O)C(=O)c1c(CC)cc(C)cc1CC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 100 mL volume three-necked flask, 10.0 g of 2-(2,6-diethyl-4-methylphenyl)-2-oxoacetohydrazide ((12-1)-(11)-39), 38 ml of methanol and 4.79 ml of acetaldehyde were added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was washed with hexane and dried under reduced pressure to give 9.71 g of 2-ethylidene-1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]hydrazine ((40-a)-(14)-2) as a mixture (5:1) of geometrical isomer.
Reaction SMILES: [OH-].[K+].[SH:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23].O>C(O)C>[OH:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][S:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1
Reactant: Oc1ccc(S)cc1
Reactant: OCCCCCCCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: OCCCCCCCCCCCSc1ccc(O)cc1
Temperature: 25 °C

Procedure:
1.45 g of 85% potassium hydroxide was dissolved in 100 ml of ethanol at room temperature. 2.78 g of 4-mercaptophenol was then added to the above-prepared solution, and dissolved therein. To the above prepared reaction mixture, 5.0 g of 11-bromo-1-undecanol was added, and the reaction mixture was allowed to react for 3 hours under the condition that the ethanol was refluxed. The thus obtained reaction mixture was cooled to room temperature, and concentrated by use of a rotary evaporator. The concentrated reaction mixture was poured into 500 ml of water, followed by vigorous stirring. Thus, a white solid separated out. The resultant white solid was recrystallized from a mixed solvent of ethyl acetate and hexane, so that 4.5 g of 4-(11-hydroxyundecylmercapto) phenol was obtained.
Reaction SMILES: C(OC([NH:8][C@@:9]1([C:32]([O:34]C(C)(C)C)=[O:33])[C@H:14]([CH2:15][S:16][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[C@@H:13]([OH:24])[C@@H:12]2[C@H:10]1[C@H:11]2[C:25]([O:27]C(C)(C)C)=[O:26])=O)(C)(C)C.O.C(O)(=O)C>>[NH2:8][C@@:9]1([C:32]([OH:34])=[O:33])[C@H:14]([CH2:15][S:16][C:17]2[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=2)[C@@H:13]([OH:24])[C@@H:12]2[C@H:10]1[C@H:11]2[C:25]([OH:27])=[O:26]
Reactant: Cc1ccc(SC[C@@H]2[C@@H](O)[C@H]3[C@H](C(=O)OC(C)(C)C)[C@H]3[C@]2(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(SC[C@@H]2[C@@H](O)[C@H]3[C@H](C(=O)O)[C@H]3[C@]2(N)C(=O)O)cc1
Temperature: 140 °C
Yield: 89.6 %

Procedure:
Di-tert-butyl (1S,2R,3S,4S,5R,6R)-2-(tert-butoxycarbonylamino)-4-hydroxy-3-(p-tolylsulfanylmethyl)bicyclo[3.1.0]hexane-2,6-dicarboxylate (300 mg, 545.73 μmol) is placed in a microwave vial. To the vial is added water (2 mL, 110 mmol), and acetic acid (2 mL, 34.9 mmol). The mixture is heated in the microwave to 140° C. for 20 minutes. The solvent is removed under reduced pressure to give the title compound (165 mg, 489.04 μmol, 89.6%). MS (m/z): 338.0 (M+H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@H:2]1[C:10](O)=[O:11]>C1COCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@H:2]1[CH2:10][OH:11]
Reactant: O=C(O)[C@@H]1Cc2ccccc2N1
Solvent: C1CCOC1
Product: OC[C@@H]1Cc2ccccc2N1
Yield: 87 %

Procedure:
To a solution of (S)-indoline-2-carboxylic acid (9.2 mmol, 1.0 equiv.) in THF (18 ml) was added dropwise BH3-DMS solution (18.4 mmol, 2 equiv.) and the reaction mixture was heated to reflux for 12 h. The mixture was quenched with methanol (7.5 ml) and conc. HCl (2.5 ml) with cooling and was then refluxed for additional 2 h. The solvent was evaporated and the residue was basified with 40% NaOH solution and extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate and the solvent was evaporated under reduced pressure to give the crude product which was purified by silica gel column chromatography. Yield: 87%.
Reaction SMILES: Br.Br[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.BrCC1CCCCO1.[N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[C:20]([C:28]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:29]=2[C:30]2([C:49]4[C:40](=[CH:41][C:42]5[O:47][CH2:46][CH2:45][O:44][C:43]=5[CH:48]=4)[O:39][CH2:38]2)[C:31](=[O:37])[NH:32]3)[CH:19]=1>>[N:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:3][N:32]1[C:33]2[C:29](=[C:28]([C:20]3[CH:19]=[N:18][C:27]4[C:22]([CH:21]=3)=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:36]=[CH:35][CH:34]=2)[C:30]2([C:49]3[C:40](=[CH:41][C:42]4[O:47][CH2:46][CH2:45][O:44][C:43]=4[CH:48]=3)[O:39][CH2:38]2)[C:31]1=[O:37]
Reactant: BrCc1ccccn1
Reactant: O=C1Nc2cccc(-c3cnc4ccccc4c3)c2C12COc1cc3c(cc12)OCCO3
Agent: Br
Agent: BrCC1CCCCO1
Product: O=C1N(Cc2ccccn2)c2cccc(-c3cnc4ccccc4c3)c2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-(bromomethyl)pyridine hydrobromide to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 4′-quinolin-3-yl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 1′-(pyridin-2-ylmethyl)-4′-quinolin-3-yl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (73%) as a colorless solid: mp 228-230° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 10.70 (s, 1H), 7.42-7.32 (m, 2H), 7.26 (t, J=7.8 Hz, 1H), 7.13-7.05 (m, 1H), 6.96-6.90 (m, 3H), 6.79-6.70 (m, 5H), 6.23 (s, 1H), 6.12 (s, 1H), 4.47 (d, J=9.3 Hz, 1H), 4.32 (d, J=9.3 Hz, 1H), 4.15-4.01 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 177.8, 155.4, 150.3, 149.6, 147.2, 144.8, 142.7, 138.2, 137.2, 136.4, 135.7, 131.2, 130.4, 129.2, 128.0, 126.9, 125.9, 122.9, 122.7, 121.8, 111.3, 109.5, 99.6, 64.6, 64.1, 46.3; MS (ES+) m/z 513.9 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[S:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:6]2[N:5]=[C:4]([S:16][CH3:17])[N:3]=1.[C:18]1(S)[CH:23]=[CH:22]C=[CH:20][CH:19]=1>>[NH2:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[S:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:6]2[N:5]=[C:4]([S:16][C:17]2[CH:22]=[CH:23][CH:18]=[CH:19][CH:20]=2)[N:3]=1
Reactant: CSc1nc(N)n2nc(-c3cccs3)nc2n1
Reactant: Sc1ccccc1
Product: Nc1nc(Sc2ccccc2)nc2nc(-c3cccs3)nn12

Procedure:
Using a similar procedure to that described in Example 2 but starting from 7-amino-5-methylthio-2-(2-thienyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazine and using thiophenol, there was obtained 7-amino-5-phenylthio-2-(2-thienyl)-[1,2,4]triazolo[1,5-a][1,3,51triazine as a solid, m.p. >300° C. (decomposition); microanalysis, found: C, 51.9; H, 3.1; N, 25.6%; C14H10N6S2 requires: C, 51.5; H, 3.1; N, 25.8%; NMR 7.20(dd, 1H, thienyl-4H), 7.4-7.8(complex, 1H, phenyl-H, thienyl-3H,5H) and 8.83(d, 2H, NH2).
Reaction SMILES: [C:1]1([CH3:47])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:22](=[O:28])[C:23]3[S:27][CH:26]=[CH:25][CH:24]=3)[CH2:13][CH:12]([NH:29][C:30]([NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([O:41]C(C)(C)C)=[O:40])[CH:34]=3)=[O:31])[C:11]2=[O:46])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1>FC(F)(F)C(O)=O>[C:1]1([CH3:47])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:22](=[O:28])[C:23]3[S:27][CH:26]=[CH:25][CH:24]=3)[CH2:13][CH:12]([NH:29][C:30](=[O:31])[NH:32][C:33]3[CH:34]=[C:35]([CH:36]=[CH:37][CH:38]=3)[C:39]([OH:41])=[O:40])[C:11]2=[O:46])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc2c(c1)N(CC(=O)c1ccccc1C)C(=O)C(NC(=O)Nc1cccc(C(=O)OC(C)(C)C)c1)CN2C(=O)c1cccs1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(c1)N(CC(=O)c1ccccc1C)C(=O)C(NC(=O)Nc1cccc(C(=O)O)c1)CN2C(=O)c1cccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
1-[1-(2-Toluoylmethyl)-2-oxo-5-(2-thenoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-tert-butoxycarbonylphenyl)urea (3.35 g) was dissolved in trifluoroacetic acid (30 ml), and then stirred for one hour at room temperature. The reaction mixture was concentrated under reduced pressure, hexane was added to the residue for trituration, and collected by filtration, to thereby obtain 3.04 g of the title compound as colorless powder (Yield: 99%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CN1C(=O)CCC1.[Br:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19](Br)[CH:20]=1>C1(C)C=CC=CC=1>[Br:14][C:15]1[CH:20]=[C:19]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[CH:18]=[N:17][CH:16]=1
Reactant: C1COCCN1
Reactant: Brc1cncc(Br)c1
Solvent: CN1CCCC1=O
Solvent: Cc1ccccc1
Product: Brc1cncc(N2CCOCC2)c1
Temperature: 180 °C
Yield: 19.5 %

Procedure:
To a solution of morpholine (3.67 g, 4.23 mmol), NMP (2 mL) and toluene (4 mL) was added 3,5-dibromopyridine (1.00 g, 4.20 mmol) and the mixture was heated under microwave conditions at 180° C. for 1 h. The solution was partitioned between DCM and water, the organic layer was washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography eluting with (EtOAc: PE=1:5). (200 mg, yield 19.5%) MS (ESI+) e/z: 243.0 [M+1]+ LCMS.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCC)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH3:35][O:36][CH2:37][C@H:38]1[O:43][CH2:42][CH2:41][NH:40][CH2:39]1>>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:30])([F:32])[F:31])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:40]4[CH2:41][CH2:42][O:43][C@H:38]([CH2:37][O:36][CH3:35])[CH2:39]4)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: COC[C@@H]1CNCCO1
Product: COC[C@@H]1CN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)CCO1

Procedure:
5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[2-(S)-(methoxymethyl)morpholin-4-yl]-1,3-thiazol-4(5H)-one was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and (2S)-2-Methoxymethyl-morpholine following General Procedure C.
Reaction SMILES: [CH3:1][C:2](=[CH2:4])[CH3:3].[Cl:5][C:6]([Cl:13])([Cl:12])[CH2:7][CH2:8][C:9](Cl)=[O:10].C(N(CC)CC)C>C1CCCCC1>[Cl:5][C:6]([Cl:13])([Cl:12])[CH2:7][CH:8]1[C:2]([CH3:4])([CH3:3])[CH2:1][C:9]1=[O:10]
Reactant: C=C(C)C
Reactant: O=C(Cl)CCC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCCCC1
Product: CC1(C)CC(=O)C1CC(Cl)(Cl)Cl
Reaction time: 4 h

Procedure:
261 g of isobutylene is injected into a 1 liter autoclave containing 49 g (0.23 mol) of 4,4,4-trichlorobutyric acid chloride in 280 ml of cyclohexane. A solution of 28.3 g (0.28 mol) of triethylamine in 233 ml of cyclohexane is pumped in at 70° C. in the course of 4 hours. The reaction mixture is afterwards held at 70° C. for a further 4 hours. The precipitated hydrochloride of the triethylamine is filtered off; the filtrate obtained is washed with dilute hydrochloric acid and then with water, dried over sodium sulphate and concentration by evaporation. Distillation of the residue yields 2-(2',2',2'-trichloroethyl)-3,3-dimethylcyclobutanone as a clear liquid, b.p. 118°-122° C./14 mm Hg.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[N:5]=[N:6][C:7]2[C:12]([C:13]=1Cl)=[CH:11][CH:10]=[CH:9][CH:8]=2.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(O)C=CC=CC=1>C(Cl)(Cl)Cl>[CH2:15]([N:22]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[N:5][C:4]=2[CH:3]=[CH:2]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCc1ccccc1
Reactant: ClCCc1nnc2ccccc2c1Cl
Solvent: Oc1ccccc1
Solvent: ClC(Cl)Cl
Product: c1ccc(Cn2ccc3nnc4ccccc4c32)cc1

Procedure:
3-(2-Chloroethyl)-4-chlorocinnoline (2 g, 0.0088 mol), benzylamine (4 g, 0.037 mol) and phenol (2 g, 0.0212 mol) were heated in an oil bath at 160° for 20 hours. The reaction had not gone to completion so the temperature was raised to 190° for a further 6 hours. The reaction mixture was dissolved in chloroform (300 ml) and extracted with 2N sodium hydroxide (3×100 ml). The chloroform extracts were washed with water (100 ml), dried over magnesium sulphate, filtered and evaporated under reduced pressure to give an oil. The oil was purified by chromatography using chloroform as eluant. The fractions containing the product were combined and evaporated to dryness to give a brown solid. Recrystallization from isopropyl alcohol gave the title compound, 0.5 g, m.p. 190-192°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([NH:11][C:12](=[O:18])[CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[C:4]([CH3:19])[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.C(O)(=O)C.[Zn]>[NH2:8][C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[C:4]([CH3:19])[C:5]=1[NH:11][C:12](=[O:18])[CH2:13][C:14]([CH3:16])([CH3:15])[CH3:17]
Reactant: Cc1cc(Br)cc([N+](=O)[O-])c1NC(=O)CC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1cc(Br)cc(N)c1NC(=O)CC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.2 %

Procedure:
Zinc dust (16 g) was added in portions over 2 hours to N-(4-bromo-2-methyl-6-nitro-phenyl)-3,3-dimethyl-butyramide (2.74 g) in tetrahydrofuran (50 mL) and acetic acid (12 mL) cooled to 0° C., and then stirred 30 minutes at 25° C. The reaction mixture was poured into a suspension of sodium carbonate (16 g) in tetrahydrofuran and filtered through silica (50 g), which was washed with ethyl acetate (100 mL). The organic phase was concentrated in vacuo to furnish 2.47 g (100% yield) of the title compound as a pale red solid. LC-MS (m/z) 300 (MH+); tR=2.54, (UV, ELSD) 96%, 99%. 1H NMR (500 MHz, DMSO-d6): 1.04 (s, 9H), 2.05 (s, 3H), 2.21 (s, 2H), 4.94 (s, 2H), 6.59 (d, 1H), 6.74 (d, 1H), 8.85 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22](=O)(O)[O-:23].[K+].C=O.Cl>C(#N)C>[CH2:1]([O:8][CH2:9][CH2:10][C:11]([CH2:22][OH:23])([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(CCOCc1ccccc1)C(=O)OCC
Reactant: O=C([O-])O
Agent: C=O
Agent: Cl
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C(CO)(CCOCc1ccccc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
2.85 g (9.67 mmol equivalents) of diethyl 2-(2-benzyloxyethyl)malonate was dissolved in 20 mL of acetonitrile, 1.60 g (11.7 mmol equivalents) of potassium bicarbonate and 465 mg (11.7 mmol equivalents as formaldehyde) of paraformaldehyde were added thereto, and the mixture was stirred at room temperature (25° C.) overnight. After completion of the reaction, a 0.5 mol/L aqueous solution of hydrochloric acid was added dropwise to the reaction liquid, and the mixture was extracted three times with chloroform. The combined chloroform layers were dried with anhydrous magnesium sulfate and then concentrated under vacuum, and the obtained crude product was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (v/v)=4/1) to give 2.78 g (8.76 mmol equivalents) of diethyl 2-(2-benzyloxyethyl)-2-hydroxymethylmalonate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[C:13](=O)[CH2:14][CH2:15][CH2:16][C:11]=2[N:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18]([O:22][C:23](=[O:30])[NH:24][CH2:25][CH2:26][CH2:27][CH2:28][NH2:29])([CH3:21])([CH3:20])[CH3:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]([NH:29][CH2:28][CH2:27][CH2:26][CH2:25][NH:24][C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:30])[CH2:14][CH2:15][CH2:16][C:11]=2[N:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCCCN
Reactant: CC(C)(C)OC(=O)n1cnc2c1C(=O)CCC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCCNC1CCCc2ncn(C(=O)OC(C)(C)C)c21
Temperature: 25 °C
Reaction time: 17 h
Yield: 48.4 %

Procedure:
To a solution of 7-oxo-4,5,6,7-tetrahydorbenzoimidazole-1-carboxylic acid tert-butyl ester (632 mg, 2.82 mmol) in CH2Cl2 (50 mL) at room temperature under inert atmosphere was added (4-amino-butyl)carbamic acid tert-butyl ester (745 mg, 4.23 mmol) followed by sodium triacetoxyborohydride (896 mg, 4.23 mmol). The reaction mixture was stirred at room temperature for 17 hours. Saturated sodium bicarbonate solution (20 mL) was added and the mixture was extracted with dichloromethane (3×30 mL). The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated. The resultant material was purified by column chromatography on silica gel (20:1:1 CH2Cl2:MeOH:NH4OH) to provide the product (558 mg, 48%): 1H NMR (CDCl3): δ 1.42 (s, 9H), 1.59 (s, 9H), 1.50-1.62 (m, 4H), 1.71-1.77 (2H), 1.82-2.00 (m, 2H), 2.06 (s, 1H), 2.73-2.87 (m, 4H), 3.09-3.13 (m, 2H), 3.33 (br s, 1H), 3.75-3.80 (m, 1H), 5.01 (br s, 1H), 7.96 (s, 1H).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].C[O-].[Na+].F[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1>CO>[CH2:1]([C:5]1[N:6]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)[C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(C=O)[nH]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCc1nc(Cl)c(C=O)n1-c1ccc([N+](=O)[O-])cc1
Temperature: 100 °C
Yield: 29.8 %

Procedure:
2-n-Butyl-4-chloroimidazole-5-carboxaldehyde (10.00 g, 53.6 mmol, 1 eq.) was dissolved in a freshly prepared solution of sodium methoxide (1.23 g Na, 53.6 mmol, 1 eq.) in methanol (175 mL). The methanol was removed in vacuo and replaced with DMF (100 mL). 4-Fluoro-1-nitrobenzene (11.37 mL, 107.0 mmol, 2 eq.) was then added. The mixture was heated at 100° C. for 36 h. Two more equivalents of 4-fluoro-1-nitrobenzene were then added and the mixture heated at 100° C. for an additional 48 hours. The DMF was removed in vacuo and the residue partitioned between ethyl acetate and water. The aqueous phase was extracted twice more with ethyl acetate, the organic layers combined, dried (MgSO4) and the solvent removed in vacuo. Flash chromatography of the residue over silica gel in 9:1 toluene/ethyl acetate yielded 4.92 g (30%) of an amber oil. NMR (CDCl3): δ9.74 (s, 1H); 8.42 (d, 2H, J=9 Hz); 7.46 (d, 2H, J=9 Hz); 2.51 (t, 2H, J=7 Hz); 1.67 (t of t, 2H, J=7,7 Hz); 1.30 (t of q, 2H, J=7,7 Hz); 0.84 (t, 3H, J=7 Hz). Anal. calcd. for C14H14ClN3O3 : C, 54.64; H, 4.59; Cl, 11.52, N, 13.65. Found: C, 54.91; H, 4.67; Cl, 11.20; N, 13.62.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:27][C:26]2[CH:29]=[CH:30][C:23]([Cl:22])=[CH:24][CH:25]=2)=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(O)cc1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(OCc2ccc(Cl)cc2)cc1
Yield: 57.4 %

Procedure:
Followed the same procedure as that of step 2 in Example 91 with the use of (R)-2-(4-hydroxy-phenoxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (150 mg, 0.5 mmol) and 4-chloro-benzyl bromide (125 mg, 0.6 mmol) to afford the title product (120 mg, 58% yield); LCMS; 100% APCI+, Calcd: 417.94; Found m/z: 418.23 (M); 1H NMR (400 MHz, CDCl3); δ 1.47 (s, 9H), 1.80-2.09 (m, 4H), 3.28-3.43 (m, 2H), 3.69-3.91 (m, 1H), 4.02-4.18 (m 2H), 4.97 (s, 2H), 6.86 (s, 4H), 7.35 (s, 4H).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[N:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[N:16]=2)[C:5]=1[C:6]([O:8][CH3:9])=[O:7])(=O)[CH3:2].Cl.[CH2:26]([O:28][NH2:29])[CH3:27].C([O-])(=O)C.[K+].CO>O>[CH3:22][O:21][C:19]1[CH:18]=[C:17]([O:23][CH3:24])[N:16]=[C:15]([O:14][C:10]2[CH:11]=[CH:12][CH:13]=[C:4]([C:1](=[N:29][O:28][CH2:26][CH3:27])[CH3:2])[C:5]=2[C:6]([O:8][CH3:9])=[O:7])[N:20]=1
Reactant: CCON
Reactant: COC(=O)c1c(Oc2nc(OC)cc(OC)n2)cccc1C(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCON=C(C)c1cccc(Oc2nc(OC)cc(OC)n2)c1C(=O)OC
Reaction time: 5 h
Yield: 67.3 %

Procedure:
1.0 g of methyl 2-acetyl-6-[(4,6-dimethoxypyrimidin-2-yl)oxy]benzoate, 1.18 g of ethoxyamine hydrochloride and 1.18 g of potassium acetate were added to 30 ml of methanol, and the resultant mixture was refluxed with stirring for 5 hours. The reaction mixture was then poured into a cold water, and was extracted with ethyl acetate. The organic layer thus formed was washed with firstly dilute hydrochloric acid, then aqueous solution of sodium hydrogencarbonate and water in sequence. The organic layer was then dried and concentrated to obtain a solid. The solid product thus obtained was washed with n-hexane to obtain 0.76 g of the aimed compound (melting point=93° to 95° C.) at a yield of 67% as a colorless transparent crystal.