Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[NH4+:2].[F:3][C:4]([F:13])([F:12])[C:5]1([C:8]([F:11])([F:10])[F:9])[CH2:7][O:6]1>CCOCC.O>[NH2:2][CH2:7][C:5]([OH:6])([C:8]([F:11])([F:10])[F:9])[C:4]([F:13])([F:12])[F:3]
Reactant: [NH4+]
Reactant: FC(F)(F)C1(C(F)(F)F)CO1
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: NCC(O)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 1:1 mixture of ether (1.85 mL) and 30% ammonium hydroxide (1.85 mL) was added drop-wise 2,2-bis(trifluoromethyl)oxirane (1.00 g, 5.5 mmol). The reaction mixture was stirred for 2 h at rt, then diluted with ether and H2O. The aqueous layer was extracted twice with ether and the combined ether layer was dried over MgS O4, filtered and concentrated to give 2-(aminomethyl)-1,1,1,3,3,3-hexafluoropropan-2-ol as a semi solid (0.87 g, 81% yield). 1H NMR (400 MHz, CDCl3) ppm 3.14 (s, 2H), 3.25 (s, 1H).
Reaction SMILES: [Mg].Br[CH2:3][CH2:4]Br.CN([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1P(C1CCCCC1)C1CCCCC1)C.[C:34]([P:38]([C:40]([CH3:43])([CH3:42])[CH3:41])Cl)([CH3:37])([CH3:36])[CH3:35]>C1COCC1.[Cu]Cl>[C:34]([P:38]([C:40]([CH3:43])([CH3:42])[CH3:41])[C:4]1[CH:3]=[CH:11][CH:10]=[CH:9][C:14]=1[C:9]1[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:12]=[CH:13][CH:14]=1)([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)P(Cl)C(C)(C)C
Reactant: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Reactant: BrCCBr
Agent: Cl[Cu]
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)(C)P(c1ccccc1-c1ccccc1-c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 26 %

Procedure:
An oven-dried Schlenk tube was cooled to room temperature under an argon purge, and was charged with magnesium turnings (54 mg, 2.2 mmol), THF (2 mL), and 1,2-dibromoethane (9 μL). The mixture was stirred at room temperature for 15 min, then a solution of 2 (618 mg, 2.0 mmol) in 1 mL THF was added dropwise. The mixture was stirred at rt for 1 h, then the septum was removed from the flask, and copper (I) chloride (283 mg, 2.1 mmol) was added. The tube was capped with the septum and purged with argon for 1 min. The tube was charged with di-t-butylchlorophosphine (0.46 mL, 2.4 mmol) and additional THF (1 mL). The mixture was heated to 60° C. with stirring for 26 h. The mixture was cooled to room temperature and filtered, and the solids were washed with ether/hexanes (50 mL, 1/1 v/v). The organic solution was poured into a separatory funnel and washed with ammonium hydroxide solution (3×50 mL), and brine (50 mL). The organic phase was then dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was recrystallized from hot methanol to afford 191 mg (26%) of 3 as a white, crystalline solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[N:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[C:7]2[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH2:22])=[CH:16][CH:15]=1.C(N(CC)CC)C.[O:30]=[C:31]1[NH:36][C:35]2[CH:37]=[C:38]([CH:41]=O)[CH:39]=[CH:40][C:34]=2[S:33][CH2:32]1.[BH4-].[Na+]>C(Cl)Cl.CCO>[CH3:2][O:3][C:4]1[N:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[C:7]2[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][CH2:41][C:38]2[CH:39]=[CH:40][C:34]3[S:33][CH2:32][C:31](=[O:30])[NH:36][C:35]=3[CH:37]=2)=[CH:16][CH:15]=1
Reactant: O=Cc1ccc2c(c1)NC(=O)CS2
Reactant: COc1ccc2nccc(-c3ccc(CCN)cc3)c2n1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc2nccc(-c3ccc(CCNCc4ccc5c(c4)NC(=O)CS5)cc3)c2n1
Reaction time: 24 h
Yield: 68.4 %

Procedure:
To a stirred solution of 2-[4-(6-Methoxy-[1,5]naphthyridin-4-yl)phenyl]ethylamine hydrochloride salt (1.76 mmole) in dry CH2Cl2 (25 mL) and dry EtOH (10 mL) at RT was added triethylamine (0.74 mL, 5.28 mmole) and 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxaldehyde (0.34 g, 1.76 mmole). After 24 h, the reaction contents were concentrated and dried under high vacuum. To a stirred solution of the crude imine in dry EtOH (25 mL) at RT was added NaBH4 (0.66 g, 1.76 mmole). After 24 h, the reaction solution was concentrated under vacuum and to the residue was added 1M HCl (5 mL) and EtOAc (50 mL): After stirring for 1 h, 6M NaOH (1 mL) was added and the organic layer was separated, dried (Na2SO4) and concentrated. Purification on silica (CHCl3/MeOH, 9:1 containing 5% NH4OH) afforded the title compound (0.55 g, 69%) as light yellow solid: 1H NMR (400 MHz, CD3OD) δ 9.11 (d, J=4.5 Hz, 1H), 8.57 (d, J=9.1 Hz, 1H), 8.27 (d, J=4.5 Hz, 1H), 8.14 (m, 2H), 7.90 (s, 2H), 7.61 (m, 3H), 7.46 (d, J=7.1 Hz, 1H), 7.22 (m, 2H), 5.52 (m, 2H), 4.23 (s, 2H), 4.08 (s, 3H), 3.68 (s, 2H), 3.19 (m, 2H). LC-MS (ES) m/e 457 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[O:7][C:8]1[CH:9]=[N+:10]([O-])[CH:11]=[CH:12][CH:13]=1)[CH3:2].COS(OC)(=O)=O.C(OC1C=C(C=CC=1)OC1[CH:33]=[N+:34](OC)C=CC=1)C.[Na]>O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[O:7][C:8]1[C:9]([C:33]#[N:34])=[N:10][CH:11]=[CH:12][CH:13]=1)[CH3:2]
Reactant: CCOc1cccc(Oc2ccc[n+](OC)c2)c1
Reactant: CCOc1cccc(Oc2ccc[n+]([O-])c2)c1
Agent: [Na]
Solvent: COS(=O)(=O)OC
Solvent: O
Product: CCOc1cccc(Oc2cccnc2C#N)c1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A mixture of 68 g of 3-(3-ethoxyphenoxy)pyridine 1-oxide and 40 g of dimethylsulfate is heated at 100° C. for 4 hours. The 3-(3-ethoxyphenoxy)-1-methoxy pyridinium methosulfate is dissolved in 200 ml of water and is added dropwise to a cooled, stirred solution of 75 g sodium cyamide in 200 ml of water at 0°-5° C. under a nitrogen atmosphere. The mixture is stirred 16 hours and is extracted with 500 ml of dichloromethane. The dichloromethane layer is washed with 100 ml of water, dried, concentrated and distilled to yield 3-(3-ethoxyphenoxy)-2-pyridinecarbonitrile, bp 145°-150° C. at 0.2 mM, mp 83°-84° C. after recrystallization from methanol.
Reaction SMILES: [CH2:1]([N:8]([CH2:16][CH2:17][OH:18])[C:9]([CH2:11][O:12][C:13](=[O:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(C)=O.C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[CH2:1]([N:8]([CH2:16][CH:17]=[O:18])[C:9]([CH2:11][O:12][C:13](=[O:15])[CH3:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OCC(=O)N(CCO)Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(=O)OCC(=O)N(CC=O)Cc1ccccc1
Temperature: -15 °C
Reaction time: 8 h
Yield: 56.6 %

Procedure:
Acetic acid [benzyl-(2-hydroxyethyl)carbamoyl]methyl ester (1.28 g, 5.10 mmol) was weighed into a 200 mL round bottom flask and purged with nitrogen. Dichloromethane (50 mL) was added, and the reaction was cooled to −15° C. for 10 minutes. Dimethylsulfoxide (3.61 mL, 51.0 mmol.), N,N-diisopropylethylamine (4.43 mL, 25.5 mmol), and pyridine sulfur trioxide complex (4.06 g, 25.5 mmol) were then added sequentially at −15° C. The reaction was allowed to warm slowly to room temperature and stirred overnight. The reaction was complete by thin layer chromatography, and was diluted with ethyl acetate. The organic solution was washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The organic layer was separated and dried over anhydrous magnesium sulfate. The drying agent was removed via filtration and solvent was removed in vacuo to give crude title compound as a yellow oil. The crude material was chromatographed on silica gel using 1:1 ethyl acetate:dichloromethane as the mobile phase. Fractions were combined and solvent was removed in vacuo to give pure title compound as a colorless oil (0.72 g, 57% yield). (m/z): [M+H]+ calcd for C13H15NO4 250.11, found 250.0.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29](=[O:31])[NH2:30])=[CH:23][CH:22]=2)=[CH:16][CH:15]=1)[C:9](=[O:13])[N:10]([CH3:12])[CH3:11])(C)(C)C.C(Cl)[Cl:34]>>[ClH:34].[NH2:7][CH:8]([C:9](=[O:13])[N:10]([CH3:11])[CH3:12])[C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:22]=[CH:23][C:24]([CH2:27][CH2:28][C:29]([NH2:30])=[O:31])=[CH:25][CH:26]=2)=[CH:16][CH:15]=1
Reactant: CN(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Oc2ccc(CCC(N)=O)cc2)cc1
Reactant: ClCCl
Product: CN(C)C(=O)C(N)c1ccc(Oc2ccc(CCC(N)=O)cc2)cc1
Product: Cl
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
The amide compound 38 (0.6 g) was dissolved in CH2Cl2 (30 mL) and cooled to 0-5° C. Hydrogen chloride gas was bubbled through this solution for 20 min. The bubbling was discontinued and the reaction mixture was stirred at room temp for 1 h. The excess HCl was degassed and the CH2Cl2 was removed. The residual solid was triturated with EtOAc (2×50 mL), decanted, and dried to yield the desired compound 39 as a white amorphous solid that was extremely hygroscopic (0.44 g, 86%). 1H NMR (400 MHz, DMSO-d6): 7.47 (d, J=8.8 Hz, 2H), 7.34 (br, 1H), 7.26 (d, J=8.4 Hz, 2H), 7.03 (d, J=8.3 Hz, 2H), 6.95 (d, J=8.4 Hz, 2H), 6.78 (br, 1H), 5.51 (d, J=5.6 Hz, 1H), 2.89 (s, 3H), 2.83 (s, 3H), 2.80 (2.80 (t, J=8.0 Hz,2H), 2.36 (t, J=8.0 Hz, 2H).
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]([OH:14])=O)=[CH:10][N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.C(OC(Cl)=O)C.[N-:28]=[N+:29]=[N-:30].[Na+]>CC(C)=O.O>[N:28]([C:12]([C:11]1[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=[N:9][CH:10]=1)=[O:14])=[N+:29]=[N-:30]
Reactant: O=C(O)c1cnnn1-c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: [N-]=[N+]=NC(=O)c1cnnn1-c1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 17.7 %

Procedure:
To a solution of 1-phenyl-1H-1,2,3-triazole-5-carboxylic acid (500 mg, 2.64 mmol) in a mixture of acetone (10 mL) and water (5 mL) was added triethylamine (0.55 mL, 3.96 mmol). The mixture was cooled to 0° C. in a ice-bath. Ethylchloroformate (573 mg, 5.28 mmol) was then added and the resulting mixture was stirred for 1.5 hours at 0° C. To the mixture was added sodium azide (0.844 g, 13.0 mmol), and the mixture was stirred for another 1.5 hours. The mixture was concentrated, the residue was diluted with dichloromethane and washed with water. The organic layer was dried over MgSO4 and concentrated to give desired product (100 mg, 18%). 1HNMR (CDCl3) (δ) 8.30 (s, 1H), 7.57 (t, 3H), 7.51 (d, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:11][CH:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[CH2:14]([N:26]=[C:27]=[O:28])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>CCOCC>[CH2:14]([NH:26][C:27]([N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]([CH3:12])[CH2:11][C:2]1([CH3:13])[CH3:1])=[O:28])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCCN=C=O
Reactant: CC1CC(C)(C)Nc2ccccc21
Solvent: CCOCC
Product: CCCCCCCCCCCCNC(=O)N1c2ccccc2C(C)CC1(C)C
Temperature: -70 °C
Reaction time: 168 h
Yield: 66 %

Procedure:
0.1 mole of 2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline is dissolved in 50 ml of ether and the solution is mixed with 0.1 mole of n-dodecyl isocyanate. A spatula tip of diazadicyclooctane is then added, the mixture is left to stand for 7 days at 20° to 25° C. and cooled at -70° C. and the precipitate which has separated out is filtered off. N-n-Dodecylaminocarbonyl-2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline with a melting point of 48°-50° C. is obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:24])[NH:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:12][C:11]=1Br)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[C:27]([CH2:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)([OH:29])=[O:28]>COCCOC.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([NH:7][CH:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:24])[NH:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:12][C:11]=1[C:35]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:30][C:27]([OH:29])=[O:28])[CH:36]=1)[CH3:9])=[O:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(C(=O)Nc2ccncc2)cc1Br
Reactant: O=C(O)Cc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: CCO
Product: CC(NC(=O)OC(C)(C)C)c1ccc(C(=O)Nc2ccncc2)cc1-c1cccc(CC(=O)O)c1
Temperature: 160 °C

Procedure:
To a solution of {1-[2-bromo-4-(pyridine-4-ylcarbamoyl)-phenyl]-ethyl}-carbamic acid tert-butyl ester (1951 μmol) in a mixture of DME/EtOH/2N Na2CO3: 1/1/1 (10 ml) were added 3-carboxymethylphenylboronic acid (1.5 eq) and Pd tetrakis (0.05 eq). The reaction mixture was heated in the microwave at 160° C. for 15 minutes. The reaction mixture was cooled to RT, filtered over celite and washed with EtOAc and MeOH. The solvents were removed under reduced pressure. The compound was purified by column chromatography (silicagel, DCM/MeOH gradient).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH3:38])[CH2:9][N:10]([CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH2:28][C:29](=[CH:33][C:34]([O:36]C)=[O:35])[CH:30]=[CH:31][CH:32]=1)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[C:13]=1[Cl:22].[OH-].[Na+]>CO.O>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH3:38])[CH2:9][N:10]([CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH2:28][C:29](=[CH:33][C:34]([OH:36])=[O:35])[CH:30]=[CH:31][CH:32]=1)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:19])[F:21])[C:13]=1[Cl:22]
Reactant: COC(=O)C=C1C=CC=C(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(C)c2ccccc2Cl)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(CN(CCCOC1=CC=CC(=CC(=O)O)C1)Cc1cccc(C(F)(F)F)c1Cl)c1ccccc1Cl
Product: Cl

Procedure:
A solution of N-(2-[2-Chlorophenyl]-propyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carbomethoxymethylenephenoxy)propylamine (80 mg, 0.14 mmole) in 5 mL of MeOH was treated with 1 mL of H2O and 0.5 mL of 2.5N NaOH, and heated to 500 for 30 minutes. The reaction was diluted with H2O, and acidified to pH 4, and extracted with EtOAc. The extracts were washed with H2O, dried, and the solvent removed. The residue was dissolved in Et2O, a small amount of isopropanol was added, and treated with 4N HCl in dioxane. The precipitated solid was filtered, washed with Et2O and dried, and gave the titled compound, 65 mg (81%). MS (ESI) 554 (MH+).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].N1C=CC=CC=1.ClC(Cl)(O[C:18](=[O:24])[O:19][C:20](Cl)(Cl)Cl)Cl.[Si:26]([O:33][CH2:34]/[C:35](/[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[C:36](/[C:39]1[CH:44]=[CH:43][C:42]([S:45]([CH3:48])(=[O:47])=[O:46])=[CH:41][CH:40]=1)\CO)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27].[Cl-].[NH4+]>C(Cl)Cl>[C:18](=[O:24])([O:19][CH2:20]/[C:36](/[C:39]1[CH:44]=[CH:43][C:42]([S:45]([CH3:48])(=[O:47])=[O:46])=[CH:41][CH:40]=1)=[C:35](/[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)\[CH2:34][O:33][Si:26]([C:29]([CH3:32])([CH3:30])[CH3:31])([CH3:28])[CH3:27])[O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:1]
Reactant: CC(C)(C)[Si](C)(C)OC/C(=C(\CO)c1ccc(S(C)(=O)=O)cc1)c1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OCCCCCBr
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)OC/C(=C(\COC(=O)OCCCCCBr)c1ccc(S(C)(=O)=O)cc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a solution of 5-bromo-1-pentanol (1 eq, 0.35M) in CH2Cl2 was added pyridine (1.1 eq). The mixture was cooled at −78° C. and a solution of triphosgene (0.33 eq, 0.1M) was slowly added, the mixture was warmed to rt and stirred for 5 min. The reaction mixture was then slowly added to a mixture of (2Z)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-(methylsulfonyl)phenyl]-3-phenylbut-2-en-1-ol (L eq) and pyridine (1 eq) in CH2Cl (0.35M) precooled at −78° C. The reaction mixture was warmed to 0° C. and stirred 5 min. Saturated aqueous ammonium chloride was added and the mixture was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel eluted with 1:6 to 1:1 EtOAc/hexanes to give the titled compound.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[CH2:12]([O:14][CH:15]([O:20][CH2:21][CH3:22])[CH2:16][CH2:17][CH2:18][NH2:19])[CH3:13].NCCN1CCNCC1>ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>[CH2:5]([O:4][C:2](=[O:3])[NH:19][CH2:18][CH2:17][CH2:16][CH:15]([O:14][CH2:12][CH3:13])[O:20][CH2:21][CH3:22])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(CCCN)OCC
Agent: NCCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(CCCNC(=O)OCc1ccccc1)OCC
Reaction time: 0.83 h

Procedure:
Three portions of benzyl chloroformate (260 ml) in dichloromethane (170 ml) were added sequentially over 1 h 40 min to a vigorously stirred mixture of 4-aminobutyraldehyde diethyl acetal (910 ml) in dichloromethane (3 l) and aqueous sodium carbonate (1M, 3 l). Stirring was continued for 50 min until gas evolution ceased. N-(2-aminoethyl)piperazine (40 ml) was added and stirring was continued for 1 h 15 min. The layers were separated and the organic layer was washed with aqueous citric acid (1M, 3.8 l) and saturated aqueous sodium bicarbonate (2 l), dried (MgSO4), filtered and concentrated in vacuo to give the title compound as a yellow oil (1.6 kg). T.l.c. (Ether) Rf 0.5.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:5][N:6]([CH3:22])[C:7]([C:9]1[CH2:10][N:11]([CH2:16][CH:17](OC)OC)[C:12](=[O:15])[C:13]=1[OH:14])=[O:8].FC(F)(F)C(O)=O.[N:34]1[CH:39]=[CH:38][C:37]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[CH:36][CH:35]=1.C([BH3-])#N.[Na+]>C(#N)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:5][N:6]([CH3:22])[C:7]([C:9]1[CH2:10][N:11]([CH2:16][CH2:17][N:43]2[CH2:44][CH2:45][N:40]([C:37]3[CH:38]=[CH:39][N:34]=[CH:35][CH:36]=3)[CH2:41][CH2:42]2)[C:12](=[O:15])[C:13]=1[OH:14])=[O:8]
Reactant: COC(CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O)OC
Reactant: c1cc(N2CCNCC2)ccn1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCN2CCN(c3ccncc3)CC2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 1.2 %

Procedure:
A solution of 1-(2,2-dimethoxy-ethyl)-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dichloro-benzyl)-methyl-amide (0.29 g, 0.71 mmol) in acetonitrile/water (10 mL, 2.5:1) was stirred with trifluoroacetic acid (1 mL) overnight at room temp. The mixture was concentrated then dissolved in MeOH (3 mL). 1-(4-pyridyl)-piperazine (0.42 g, 2.6 mmol) was added and the resulting mixture was stirred at room temp 30 min. Sodium cyanoborohydride (0.013 g, 0.2 mmol) was added and the mixture was stirred an additional 5 h at room temp. The crude product was purified by preparative HPLC (YMC Combiprep ODS-A, 30 mm×50 mm, MeOH/H2O/0.1% TFA) to yield the title compound as an amber foam (0.0042 g, 12% yield). HRMS (M+H) calcd for C24H28N5Cl2O3: 504.15693; found: 504.1564.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[C:21]([CH3:23])[N:20]=[C:19]([NH2:24])[N:18]=3)=[CH:12][CH:11]=2)=[O:8])=[CH:5][CH:4]=1.CCO.Cl.[Cl:31][C:32]1[C:41]2[C:36](=[CH:37][CH:38]=[C:39]([N:42]([CH3:44])[CH3:43])[CH:40]=2)[N:35]=[CH:34][CH:33]=1>O>[ClH:31].[NH2:24][C:19]1[N:18]=[C:17]([NH:16][C:13]2[CH:12]=[CH:11][C:10]([NH:9][C:7](=[O:8])[C:6]3[CH:25]=[CH:26][C:3]([NH:2][C:32]4[C:41]5[C:36](=[CH:37][CH:38]=[C:39]([N:42]([CH3:44])[CH3:43])[CH:40]=5)[N:35]=[CH:34][CH:33]=4)=[CH:4][CH:5]=3)=[CH:15][CH:14]=2)[CH:22]=[C:21]([CH3:23])[N:20]=1
Reactant: CN(C)c1ccc2nccc(Cl)c2c1
Reactant: Cc1cc(Nc2ccc(NC(=O)c3ccc(N)cc3)cc2)nc(N)n1
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1cc(Nc2ccc(NC(=O)c3ccc(Nc4ccnc5ccc(N(C)C)cc45)cc3)cc2)nc(N)n1

Procedure:
To a solution of amide E5 (228 mg, 0.62 mmol) in 1:2 EtOH:H2O (20 mL) were sequentially added c.HCl (0.17 mL, 5.61 mmol) and 4-chloro-6-dimethylaminoquinoline (03) (140 mg, 0.68 mmol), and the resulting mixture was refluxed for ˜12 h. MS and TLC analysis (eluting with the top phase of a 5:4:1 mixture of n-BuOH:H2O:AcOH) after this time showed some starting material still present in the reaction mixture, thus more 03 (140 mg, 0.68 mmol) was added. After a further few hours refluxing, TLC showed the reaction was complete, and thus solvent was removed under reduced pressure. The residue was crystallized from MeOH:EtOAc to afford Cpd. P as an (extremely fine) amorphous yellow solid (170 mg, 51%). 1H NMR [(CD3)2SO] δ2.28 [s, 3H], 3.15 [s, 6H, ArN(CH3)2], 6.21 [br s, 1 H, ArH], 6.89 [d, J=6.71 Hz, 1 H, ArH], 7.65 [m, 5 H, ArH], 7.82 [m, 4 H, ArH & ArNH2], 7.96 [d, J=9.39 Hz, 1 H, ArH], 8.18 [d, J=8.57 Hz, 2 H, ArH], 8.35 [t, J=12.38, 6.19 Hz, 1 H, ArH], 10.44 [br s, 1 H, ArH], 10.65 [br s, 1 H, ArNHAr], 10.71 [s, 1 H, ArNHAr], 12.75 [br s, 1 H, ArC(O)NH], 14.56 [d, J=4.10 Hz, 1 H, quinolinyl N+H]. LCMS (APCI+): 506 (100%). HPLC: 97.6%.
Reaction SMILES: Br[C:2]1[N:3]([CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:4]2[C:9]([N:10]=1)=[C:8]([NH2:11])[N:7]=[C:6]([O:12][CH2:13][CH:14]([CH3:16])[CH3:15])[N:5]=2.Cl.[OH-:25].[Na+]>C(O)CCC>[NH2:11][C:8]1[N:7]=[C:6]([O:12][CH2:13][CH:14]([CH3:16])[CH3:15])[N:5]=[C:4]2[C:9]=1[NH:10][C:2](=[O:25])[N:3]2[CH2:17][CH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: [OH-]
Reactant: CC(C)COc1nc(N)c2nc(Br)n(CC3CCOCC3)c2n1
Agent: Cl
Agent: [Na+]
Solvent: CCCCO
Product: CC(C)COc1nc(N)c2[nH]c(=O)n(CC3CCOCC3)c2n1

Procedure:
8-Bromo-2-[(2-methylpropyl)oxy]-9-(tetrahydro-2H-pyran-4-ylmethyl)-9H-purin-6-amine (100 mg) in n-butanol (2 mL) was refluxed with concentrated hydrochloric acid (2 mL) at 100° C. (external temperature) for 3 hours. The reaction mixture was evaporated under reduced pressure to dryness. To the reaction mixture was then added a small volume of water and an equivalent volume of methanol to give a suspension, which was then neutralised to by the addition of 2M sodium hydroxide (from pH ˜3 to 7). This was then evaporated under reduced pressure to give a beige solid which was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid)-acetonitrile (containing 0.05% formic acid) as eluent (20-60%). This gave the title compound (13 mg) as white solid.
Reaction SMILES: O=[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].[NH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1>>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][CH2:14][NH:13][CH2:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: NCCc1ccccn1
Product: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CNCCc1ccccn1

Procedure:
The product was made from D-glucose and 2-(β-aminoethyl)-pyridine comparable as in Example A. A wax-like, colorless product was obtained.