Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:11]([OH:13])[CH3:12]>>[C:5]1([N:4]2[CH:3]=[CH:2][CH:12]=[CH:11][O:13]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCO
Reactant: OCCNc1ccccc1
Product: C1=CON(c2ccccc2)C=C1
Temperature: 80 °C

Procedure:
0.271 g of P-(2-phenyl-2-chloro acetyl) dimethylamino-benzene (1 mmole) and 0.274 g of N-(2 hydroxy ethyl) aniline (2.0 mmole) were dissolved in 3 ml of dry ethanol and heated in a sealed tube at 80° C. for 8 hours. On cooling the product crystallized out as pale yellow needles, which was filtered and dried to yield 0.2 g of N-phenyl oxazine Compound 15.
Reaction SMILES: C([O:8][CH2:9][C@@H:10]([C@H:20]1[CH2:24][CH2:23][NH:22][CH2:21]1)[O:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[CH3:19])C1C=CC=CC=1.C(O)(C(F)(F)F)=O.Cl>CCO.[OH-].[OH-].[Pd+2]>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][C@@H:10]([C@@H:20]2[CH2:24][CH2:23][NH:22][CH2:21]2)[CH2:9][OH:8])=[C:13]([CH3:19])[CH:14]=1
Reactant: Cc1cc(Cl)ccc1O[C@@H](COCc1ccccc1)[C@H]1CCNC1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: Cc1cc(Cl)ccc1O[C@H](CO)[C@@H]1CCNC1

Procedure:
To a solution of (S)-3-[(R)-2-benzyloxy-1-(4-chloro-2-methylphenoxy)ethyl]-pyrrolidine.TFA (4.6 mg, 10 μmol) in EtOH (2.0 mL) at room temperature, was added concentrated HCl (˜50 μL). To the stirred mixture was added 20% Pd(OH)2/C (50 wt % water, 4.0 mg). The resulting mixture was degassed and flushed with hydrogen three times and then hydrogenated under a hydrogen balloon for 25 minutes. The mixture was filtered and the filtrate was concentrated. The resulting residue was redissolved in a mixture of AcOH (0.5 mL) and water (1.0 mL), filtered and purified by reverse phase preparative HPLC to yield the title compound as a mono-TFA salt (0.6 mg, 98% purity). MS m/z: [M+H]+ calcd for C13H18ClNO2, 256.10. found 256.2.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[CH:14]=[CH:13][O:12][N:11]=1)=S.[N:15]#[C:16][NH2:17].[Pb]>>[C:16]([NH:17][C:3]([NH:2][CH3:1])=[N:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[CH:14]=[CH:13][O:12][N:11]=1)#[N:15]
Reactant: N#CN
Reactant: CNC(=S)NCCSCc1ccon1
Agent: [Pb]
Product: CNC(=NCCSCc1ccon1)NC#N

Procedure:
Reaction of N-methyl-N'-[2-(3-isoxazolylmethylthio)ethyl]thiourea with lead cyanamide by the procedure of Example 121 gives N-cyano-N'-methyl-N"-[2-(3-isoxazolylmethylthio)ethyl]guanidine.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15]3=[N:17][C@H:18]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:19][N:14]3[C:13](=[O:27])[N:12]([CH2:28][CH2:29][CH3:30])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].[C:39](=[O:41])=[O:40].Cl>O1CCCC1.C1CCCCC1>[CH2:1]([N:8]1[C:16]2[C:15]3=[N:17][C@H:18]([CH2:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:19][N:14]3[C:13](=[O:27])[N:12]([CH2:28][CH2:29][CH3:30])[C:11]=2[N:10]=[C:9]1[C:39]([OH:41])=[O:40])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=O
Reactant: CCCN1C(=O)N2C[C@@H](Cc3ccccc3)N=C2c2c1ncn2Cc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CCCN1C(=O)N2C[C@@H](Cc3ccccc3)N=C2c2c1nc(C(=O)O)n2Cc1ccccc1
Reaction time: 1 h
Yield: 26 %

Procedure:
Compound 35a (3.95 g, 9.90 mmol) obtained in Example 35 was dissolved in tetrahydrofuran (100 mL), to the solution was added a 1.50 mol/L solution (9.9 mL) of lithium diisopropylamide (14.9 mmol, 1.5 equivalents) in cyclohexane at −78° C., and then the mixture was stirred for 1 hour. Into the reaction solution was poured carbon dioxide generated from dry ice and the mixture was stirred at room temperature for 1 hour. To the reaction solution was added 1 mol/L aqueous hydrochloric acid and the mixture was extracted with chloroform. The organic layer was washed with saturated aqueous sodium chloride and dried. The solvent was evaporated, and the residue was purified by silica gel column chromatography (chloroform:methanol=95:5 to 10:1). To the residue were added acetone and diethyl ether, and the deposited crystals were collected by filtration to obtain (R)-1,8-dibenzyl-2-carboxy-7,8-dihydro-4-(n-propyl)-1H-imidazo[2,1-i]purin-5(4H)-one (Compound 47a, 1.13 g, 26%). To Compound 47a (740 mg, 1.67 mmol) was added thionyl chloride (10.0 mL, 137 mmol, 82 equivalents) and the mixture was stirred at 60° C. for 2 hours. The reaction solution was concentrated under reduced pressure, and then to the reaction residue was added methanol (3 mL). The mixture was concentrated and the residue was directly purified by silica gel column chromatography (chloroform:methanol=95:5) to obtain the title compound (211 mg, 28%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([Br:12])[CH:9]=[C:8]2[C:3]=1[NH:4][C:5](=[O:14])[C:6](=[O:13])[NH:7]2.[N+:15]([O-])([O-:17])=[O:16].[K+]>OS(O)(=O)=O>[N+:15]([C:11]1[C:2]([Br:1])=[C:3]2[C:8](=[CH:9][C:10]=1[Br:12])[NH:7][C:6](=[O:13])[C:5](=[O:14])[NH:4]2)([O-:17])=[O:16]
Reactant: O=c1[nH]c2cc(Br)cc(Br)c2[nH]c1=O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=c1[nH]c2cc(Br)c([N+](=O)[O-])c(Br)c2[nH]c1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 84.6 %

Procedure:
The method of Cheeseman, supra. was adapted. 5,7-Dibromo-1,4-dihydroquinoxaline-2,3-dione (74 mg, 0.23 mMol) was dissolved in concentrated H2SO4 (1 mL) at 0° C. for 30 mins., and then KNO3 (28 mg, 0.27 mMol, Baker) was added to this solution. The mixture was stirred at 0° C. for 3 h and then at room temperature for 30 h. It was poured into ice water (8 g) and the precipitate was collected by filtration, was dissolved into iN KOH (5 mL), and the red precipitate was removed by filtration. The solution then was acidified to pH=2 with 4N HCl to obtain a cream precipitate, which was collected by filtration, then was dried in the air at 50° C. for 4 h, affording the pure 6-nitro-5,7-dibromo-1,4-dihydro-2,3-quinoxalinedione (71 mg, 84.5%), as a yellow powder; mp: 318°-20° C. (dec.). IR (KBr, cm-1): 3468, 3131, 3062, 2931, 1712, 1593, 1537. NMR (1H, DMSO-d6): δ7.392 (s, 1H), 11.566 (s, H), 12.274 (s, 1H). HRMS: calcd. for C8H3N3O4Br2 m/z: 362.8489, found: 62.8478.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:16]([O-:18])=[O:17])=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=2)[CH:7]=1.[Na].[CH3:20][OH:21]>>[CH3:20][O:21][C:2]1[CH:3]=[CH:4][C:5]([N+:16]([O-:18])=[O:17])=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=2)[CH:7]=1
Reactant: CO
Reactant: Cc1cccc(Nc2cc(Cl)ccc2[N+](=O)[O-])c1
Agent: [Na]
Product: COc1ccc([N+](=O)[O-])c(Nc2cccc(C)c2)c1
Temperature: 0 °C

Procedure:
39 g of 5-chloro-2-nitrophenyl-m-tolylamine was added to a solution of 9 g of sodium in 670 ml of methanol, and it was refluxed for 72 hours. Then, it is cooled to 0° C., and the crystalline product is suctioned off.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1)#[N:2].C(OC1C=C(C=C(OCC2C=CC=CC=2)C=1)CN)C1C=CC=CC=1>>[OH:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([CH2:1][NH2:2])=[CH:4][CH:5]=1
Reactant: N#Cc1ccc(C=O)cc1
Agent: NCc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Product: NCc1ccc(CO)cc1
Yield: 46 %

Procedure:
This compound was prepared by reduction of 4-cyanobenzaldehyde according to the procedure described in preparation of 3,5-dibenzyloxybenzylamine. Yield was 46%: MP 102–123° C.; 1H NMR (Acetone-d6, 500 MHz) 7.27 (m, complex 4H), 4.58 (s, 2H), 3.72 (s, 2H), 3.69 (s, 1H) 2.77 (br, 1H), 2.45 (br, 1H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4](O)[CH2:3]1.[P:9](Cl)([Cl:12])([Cl:11])=[S:10].N1C=CC=CC=1>ClC=C(Cl)Cl>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([P:9]([Cl:12])([Cl:11])=[S:10])[CH2:3]1
Reactant: CC1CCCC(O)C1
Reactant: S=P(Cl)(Cl)Cl
Solvent: ClC=C(Cl)Cl
Solvent: c1ccncc1
Product: CC1CCCC(P(=S)(Cl)Cl)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.8 %

Procedure:
A mixture of 3-methylcyclohexanol (5.0 g, 43.8 mmol) in trichloroethylene (300 mL) is added dropwise to a 0°-4° C. mixture of thiophosphoryl chloride (11.13 g, 65.7 mmol) and anhydrous pyridine (5.20 g, 65.7 mmol) in trichloroethylene (125 mL) over a 1 hour period under a nitrogen atmosphere. The resultant reaction mixture is stirred at 0°-4° C. for 1 hour and is then warmed to room temperature and stirred at room temperature for 8 hours. A white solid gradually precipitates. The white solid is filtered from the reaction mixture. The resultant reaction mixture is concentrated in vacuo to a residue. Successive aliquots of toluene (100 mL) are added to the residue and then separately are evaporated in vacuo to give 7.57 g (70%) of (3-methylcyclohexyl)-thiophosphoryl dichloride which can be used directly without further purification as the starting material for Example 23.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:17][CH3:18])[C:10]([CH:19]=O)=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:22][OH:23].C([O-])(=O)C.[Na+]>C(O)C.O>[CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:17][CH3:18])[C:10]([CH:19]=[N:22][OH:23])=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NO
Reactant: COc1cccc2c(C=O)cn(CC3CCCCC3)c12
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1cccc2c(C=NO)cn(CC3CCCCC3)c12
Temperature: 25 °C
Reaction time: 64 h
Yield: 44.8 %

Procedure:
To a solution of 1-(cyclohexyl)methyl-7-methoxy-1H-indole-3-carbaldehyde (780 mg, 2.9 mmol) in a mixture of ethanol (8 ml) and water (2 ml) was added hydroxylamine hydrochloride (403 mg, 5.8 mmol) and sodium acetate (713 mg, 8.7 mmol) and the solution stirred for 64 h at room temperature. The mixture was concentrated in vacuo and the residue diluted with water (50 ml) and extracted with ethyl acetate (3×50 ml). The product was recrystallised from diethyl ether/hexane to yield 1-cyclohexylmethyl-7-methoxy-1H-indole-3-carbaldehyde oxime (380 mg, 1.3 mmol) as a yellow powder.
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][N:2]1[C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:20][C:21]3[C:27]([CH:28]([CH3:30])[CH3:29])=[CH:26][C:25]([C:31]#[N:32])=[CH:24][C:22]=3[N:23]=2)=[CH:15][CH:14]=1)=[O:12].C(N(C(C)C)CC)(C)C.[F:42][C:43]([F:53])([F:52])[C:44]1[CH:51]=[CH:50][C:47]([CH2:48]Br)=[CH:46][CH:45]=1>ClCCl>[CH:28]([C:27]1[C:21]2[O:20][C:19]([C:16]3[CH:15]=[CH:14][C:13]([C:11]([N:2]4[CH2:3][CH2:4][C:5]5([CH2:10][CH2:9][N:8]([CH2:48][C:47]6[CH:46]=[CH:45][C:44]([C:43]([F:42])([F:52])[F:53])=[CH:51][CH:50]=6)[CH2:7][CH2:6]5)[CH2:1]4)=[O:12])=[CH:18][CH:17]=3)=[N:23][C:22]=2[CH:24]=[C:25]([C:31]#[N:32])[CH:26]=1)([CH3:30])[CH3:29]
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)N4CCC5(CCNCC5)C4)cc3)oc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)N4CCC5(CCN(Cc6ccc(C(F)(F)F)cc6)CC5)C4)cc3)oc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
To a solution of 2-[4-(2,8-diazaspiro[4.5]dec-2-ylcarbonyl)phenyl]-7-isopropyl-1,3-benzoxazole-5-carbonitrile (25 mg, 0.046 mmol, EXAMPLE 121, Step B) in dichloromethane (2 ml) were added diisopropylethylamine (20 μl, 0.115 mmol) and 4-(trifluoromethyl)benzyl bromide (17 mg, 0.071 mmol). The mixture was stirred at room temperature overnight, at which point LC/MS analysis showed a peak at the desired molecular weight. The reaction mixture was purified by flash chromatography on a Biotage Horizon, 25S column, eluting with 1 column volume of 100% dichloromethane followed by a gradient of 0 to 100% ethyl acetate in dichloromethane over 10 column volumes to provide the title compound (21.4 mg, 0.036 mmol, 79% yield). Mass spectrum (ESI) 587.3 (M+1).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=2[CH2:9][S:10][C:11]2[NH:12][C:13]3[C:14]([N:19]=2)=[N:15][CH:16]=[CH:17][CH:18]=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:32])C=1>C(Cl)(Cl)Cl>[CH:1]1([NH:6][C:7]2[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=2[CH2:9][S:10]([C:11]2[NH:12][C:13]3[C:14]([N:19]=2)=[N:15][CH:16]=[CH:17][CH:18]=3)=[O:32])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: c1ccc(NC2CCCC2)c(CSc2nc3ncccc3[nH]2)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: O=S(Cc1ccccc1NC1CCCC1)c1nc2ncccc2[nH]1

Procedure:
2-Mercaptoimidazo[4,5-b]pyridine and 2-(N-cylopentylamino)benzyl chloride hydrochloride were reacted in an aqueous ethanol solution to obtain 2-[2-(N-cyclopentylamino)benzylthio[-imidazo[4,5-b]pyridine in the same manner as in Example 9-(2). The obtained 2-[2-(N-cyclopentylamino)benzylthio]imidazo[4,5-b]pyridine was oxidized by m-chloroperbenzoic acid in chloroform in the same manner in Example 9-(3) to give 2-[2-(N-cyclopentylamino)benzylsulfinyl]imidazo[4,5-b]pyridine as a pale yellow crystalline product. m.p.: 134° C. (decompn.)
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[O:6]1)#[N:2].[N+:15]([O-])([O-:17])=[O:16].[Na+]>FC(F)(F)C(O)=O>[C:1]([CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:7]=2[O:6]1)#[N:2]
Reactant: O=[N+]([O-])[O-]
Reactant: N#CCCC1CCc2ccccc2O1
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: N#CCCC1CCc2cc([N+](=O)[O-])ccc2O1
Temperature: 0 °C

Procedure:
A solution of 7.7 g (41 mmol) of 2-cyanoethyl-3,4-dihydro-2H-1-benzopyran in 150 ml of trifluoroacetic acid is reacted for 15 min with 10.5 g (123 mmol) of sodium nitrate, and then the mixture is poured into ice water and the product is extracted with dichloromethane. The organic phase is then dried over sodium sulfate and concentrated under reduced pressure. By chromatography of the residue on a silica column using cyclohexane containing 30% ethyl acetate, 4.5 g of product are obtained.
Reaction SMILES: [C:1]([C:3]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[Cl:15])=[N:5][C:4]=1C(O)=O)#[N:2].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>CC(O)(C)C>[C:1]([C:3]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[Cl:15])=[N:5][CH:4]=1)#[N:2]
Reactant: N#Cc1[nH]c(-c2ccc(Cl)cc2Cl)nc1C(=O)O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Product: N#Cc1cnc(-c2ccc(Cl)cc2Cl)[nH]1
Yield: 65.7 %

Procedure:
A mixture of 5-cyano-2-(2,4-dichlorophenyl)imidazole-4-carboxylic acid (40.0 g, 0.142 mol), diphenylphosphoryl azide (37.0 g, 0.142 mol) and triethylamine (14.4 g, 19.8 ml, 0.142 mol) in 2-methyl-2-propanol (dried by distillation from calcium hydride, 1400 ml) was heated at reflux for 24 hours. After cooling the mixture was filtered and the filtrate evaporated to dryness. The residue was dissolved in ethyl acetate (2250 ml) and washed with hydrochloric acid (1 M, 250 ml) saturated aqueous sodium bicarbonate solution (2×250 ml) dried over anhydrous magnesium sulphate and evaporated to dryness. The residue was recrystallized from ethanol to give 4-tert.butoxycarbonylamino)-5-cyano-2-(2,4-dichlorophenyl)imidazole (22.2 g) m.p. 185° C. (with decomposition) as an off-white solid.
Reaction SMILES: [CH3:1]COCC.C[Mg]Br.[O:9]=[C:10]1[CH2:14][O:13][CH2:12][CH:11]1[NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C>O1CCCC1>[OH:9][C:10]1([CH3:1])[CH2:14][O:13][CH2:12][CH:11]1[NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCOCC
Reactant: O=C(NC1COCC1=O)OCc1ccccc1
Agent: C
Agent: C[Mg]Br
Solvent: C1CCOC1
Product: CC1(O)COCC1NC(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
A 3 M ether solution of methylmagnesium bromide (4.07 mL, 12.20 mmol) was added dropwise to a solution of benzyl 4-oxotetrahydrofuran-3-ylcarbamate (1.305 g, 5.55 mmol, from Step 3) in tetrahydrofuran (50 mL) at 0° C. Gas evolution was observed during the addition, indicating formation of methane. After 1 h at 0° C., the mixture was quenched with saturated ammonium chloride (75 mL) and extracted with ethyl acetate three times. The combined extracts were dried (MgSO4) and concentrated. Silica gel chromatography, eluting with 20-70% ethyl acetate in hexanes, gave impure material. 1H NMR showed presence of the desired product. The impure material was combined with the material from another run (from 2.18 g of ketone starting material) and taken to the next reaction without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[OH:25][C:26]1([CH2:50][CH2:51][CH2:52][OH:53])[CH2:31][C:30]2[CH:32]=[CH:33][C:34]([O:36][CH:37]([CH2:39][CH2:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH3:38])=[CH:35][C:29]=2[O:28][C:27]1([CH3:49])[CH3:48].C(N(CC)CC)C.[C:61](OC(=O)C)(=[O:63])[CH3:62]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[C:61]([O:25][C:26]1([CH2:50][CH2:51][CH2:52][OH:53])[CH2:31][C:30]2[CH:32]=[CH:33][C:34]([O:36][CH:37]([CH2:39][CH2:40][CH2:41][C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH3:38])=[CH:35][C:29]=2[O:28][C:27]1([CH3:48])[CH3:49])(=[O:63])[CH3:62]
Reactant: CC(=O)OC(C)=O
Reactant: CC(CCCc1ccccc1)Oc1ccc2c(c1)OC(C)(C)C(O)(CCCO)C2
Agent: CN(C)c1ccncc1
Agent: COc1cc(CNCCCNCCCCNCCCN)ccc1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC1(CCCO)Cc2ccc(OC(C)CCCc3ccccc3)cc2OC1(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 29.4 %

Procedure:
To a solution of 3.177 g (7.96 mmole) dl-5-hydroxy-3-(3-hydroxypropyl)-2,2-dimethyl-7-(5-phenyl-2-pentyloxy)-3,4-dihydro-2H-benzopyran in 40 ml methylene chloride, under a nitrogen atmosphere, was added 805 mg (7.96 mmole) triethylamine, the mixture stirred for 15 minutes and cooled to 0° C. At this temperature, 970 mg (7.79 mmole) 4-dimethylaminopyridine in 3 ml methylene chloride followed by 813 mg (7.96 mmole) acetic anhydride was added and the resulting mixture stirred at 0°-5° C. for one hour. After allowing the mixture to warm to room temperature, it was extracted three times with 30 ml portions methylene chloride. The extracts were washed with saturated sodium bicarbonate solution, dried (MgSO4) and evaporated to obtain 4.158 g of crude oil. The crude product was purified by column chromatography on silica gel eluting with ethyl ether/methylene chloride 3:97 (v/v) for 7 fractions and 1:9 (v/v) for 43 fractions. Fractions 18-27 contained the diacetate. Fractions 28-45 containing desired monoacetate were combined and evaporated to afford 1.823 g of the title compound. 1H-NMR(CDCl3)ppm(delta): 2.20 (s, 3H), 3.50 (t, 2H), 6.20 (m, 2H), 7.10 (s, 5H).
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[CH3:67][N:68]1[CH2:73][CH2:72][N:71]([CH2:74][C:75]2[CH:76]=[C:77]([CH:80]=[CH:81][CH:82]=2)[CH:78]=O)[CH2:70][CH2:69]1>C(O)C.CN(C=O)C>[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]2[N:43]=[C:78]([C:77]3[CH:80]=[CH:81][CH:82]=[C:75]([CH2:74][N:71]4[CH2:72][CH2:73][N:68]([CH3:67])[CH2:69][CH2:70]4)[CH:76]=3)[NH:42][C:39]2=[N:40][CH:41]=1
Reactant: CN1CCN(Cc2cccc(C=O)c2)CC1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3cccnc3)CC2)c1[N+](=O)[O-]
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CN1CCN(Cc2cccc(-c3nc4c(N5CCN(Cc6cccnc6)CC5)c(Br)cnc4[nH]3)c2)CC1
Reaction time: 6 h
Yield: 17.8 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-(pyridin-3-ylmethyl)piperazin-1-yl)pyridin-2-amine (75 mg, 0.19 mmol), DMF (0.85 mL), ethanol (0.15 mL), 1M Na2S2O4 (3 eq, 0.57 mmol, 0.57 mL) and 3-[(4-methylpiperazin-1-yl)methyl]benzaldehyde (1.1 eq, 0.21 mmol, 46 mg). After 6 h, concentration in vacuo and preparation by preparative tlc (CH2Cl2-MeOH, 9:1) gave the product (19 mg, 18%) as a colourless solid; 1H-NMR (500 MHz, DMSO-d6) 2.15 (s, 3H, NCH3), 2.50 (hidden by DMSO peak, 4H, piperazine N(CH2)2), 2.64 (br, 4H, piperazine N(CH2)2), 3.30 (hidden by watert-in-DMSO peak, 4H, piperazine N(CH2)2), 3.56 (s, 2H, CH2), 3.63 (s, 2H, CH2), 3.68 (t, J=4.8 Hz, 4H, piperazine N(CH2)2), 7.40 (dd, J=7.8, 4.8 Hz, 1H, pyridine H-5), 7.43 (d, J=7.8 Hz, 1H, phenyl H-4 or H-6), 7.50 (t, J=7.8 Hz, 1H, phenyl H-5), 7.79 (d, br, J=7.7 Hz, 1H, pyridine H-4), 8.07 (d, br, J=8.5 Hz, 1H, phenyl H-4 or H-6), 8.14 (s, br, 1H, phenyl H-2), 8.25 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.50 (dd, J=4.8, 1.5 Hz, 1H, pyridine H-6), 8.57 (d, J=1.6 Hz, 1H, pyridine H-2), 13.52 (br s, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][N:4]=[C:3]1[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:31])[CH:15]([CH2:27][C:28]([OH:30])=O)[NH:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[O:18])=[CH:9][CH:8]=1.Cl.[NH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[CH3:1][N:2]1[CH2:6][CH2:5][N:4]=[C:3]1[C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14](=[O:31])[CH:15]([CH2:27][C:28]([NH:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:30])[NH:16][C:17]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)=[O:18])=[CH:11][CH:12]=1
Reactant: CN1CCN=C1c1ccc(NC(=O)C(CC(=O)O)NC(=O)Nc2ccc(Cl)cc2)cc1
Reactant: Nc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CN1CCN=C1c1ccc(NC(=O)C(CC(=O)Nc2ccccc2)NC(=O)Nc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1:1 mixture of the R and S isomers of N-[4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)phenyl]-2-carboxymethyl-2-(4-chlorophenylaminocarbonylamino)-acetamide (from EXAMPLEs 60 and 62, 45 mg, 0.10 mmol) and aniline hydrochloride (28 mg, 0.22 mmol) in pyridine (2 mL) cooled in an ice-bath, POCl3 (0.040 mL, 0.44 mmol) was added. After being stirred at room temperature overnight, the mixture was concentrated in vacuo. The residue was purified by HPLC to the titled compound as a powder (12 mg). MS 519.1 and 521.1 (M+H, Cl pattern).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=[O:5].[C:12](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH3:12])[CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=[O:5]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1c(Cl)cc(O)cc1Cl
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc(Cl)c(C=O)c(Cl)c1

Procedure:
Combine 2,6-dichloro-4-hydroxy-benzaldehyde (120 g, 628.24 mmol) and potassium carbonate (173.65 g, 1256.5 mmol) in 900 mL dimethylformamide and treat with iodomethane (107 g, 753.9 mmol). Stir the reaction at room temperature for 3 hours. Filter off solids and pour into 6 L of water. Filter solids, wash several times with water, air dry and dissolve in ethyl acetate. Wash with water, followed by brine and then dry over sodium sulfate. Filter and concentrate under vacuum to ˜100 mL volume, at which point, solids start to crash out. Filter then concentrate down the filtrate to yield a second crop. Wash with hexane, combine all solids and vacuum dry to yield 112.3 g of off-white, solid: 1H NMR (400 MHz, CDCl3) δ 10.41 (s, 1H), 6.90 (s, 2H), 3.87 (s, 3H).