Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C([N:12](CC)CC)C.S.[NH2:18][NH2:19].N([O-])=O.[Na+]>CO>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]1[NH:5][N:12]=[N:19][N:18]=1
Reactant: CCN(CC)CC
Reactant: NN
Reactant: N#Cc1ccccc1Cl
Agent: O=N[O-]
Agent: S
Agent: [Na+]
Solvent: CO
Product: Clc1ccccc1-c1nnn[nH]1
Reaction time: 48 h

Procedure:
First, 35.6 mmol of 2-chlorobenzonitrile was dissolved in 50 ml of methanol, and 35.6 mmol of triethylamine and 105 mmol of hydrogen sulfide were added thereto at room temperature, followed by adding 180 mmol of anhydrous hydrazine and keeping at the reflux temperature for 48 hours. The reaction mixture was evaporated under reduced pressure. The residue was dissolved in 50 ml of 5% hydrochloric acid, and 75 mmol of sodium nitrite was added thereto at 0° C. to cause reaction. After completion of the reaction, the reaction mixture was extracted with ethyl acetate to give 5-(2-chlorophenyl)tetrazole. Yield, 54%
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@@H:4]1[CH2:8][C:7](=O)[CH2:6][N:5]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1.CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]([CH:4]1[N:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH:7]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:8]1)=[O:17]
Reactant: C1CCNC1
Reactant: COC(=O)[C@@H]1CC(=O)CN1C(=O)OC(C)(C)C
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)C1CC(N2CCCC2)CN1C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
To a solution of N-t-butoxycarbonyl-4-oxo-L-proline methyl ester (1.0 g, 4 mmol) (J. Org. Chem. 2001, 10, 3593), pyrrolidine (0.4 ml, 5 mmol), acetic add (0.3 ml, 5 mmol) in CH2Cl2 (20 ml) was added sodium triacetoxyborohydride (1.0 g, 5 mmol) and the mixture stirred for 2 h. After which time it was washed with saturated sodium hydrogen carbonate, dried (Na2SO4) and concentrated. Flash column chromatography (EtOAc:MeOH 95:5) afforded the title compound (1.0 g, 81%) as a yellow oil.
Reaction SMILES: C([Li])CCC.[CH3:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9].[CH2:13]([C:17](=[CH2:23])[C:18](OCC)=[O:19])[CH2:14][CH2:15][CH3:16].C(O)(=O)C>C(OCC)C.O1CCCC1>[O:19]=[C:18]([C:17](=[CH2:23])[CH2:13][CH2:14][CH2:15][CH3:16])[CH2:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9]
Reactant: COP(C)(=O)OC
Reactant: C=C(CCCC)C(=O)OCC
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=C(CCCC)C(=O)CP(=O)(OC)OC
Reaction time: 0.17 h
Yield: 69 %

Procedure:
A 2N solution (400 ml.) of n-butyllithium in diethyl ether was added dropwise to a solution of dimethyl methylphosphonate (110 g.) in pure anhydrous tetrahydrofuran (700 ml.) with stirring under nitrogen, while the reaction temperature was kept within the range of -50° to -60°C. After 10 minutes, a solution of ethyl 2-n-butylacrylate (prepared as described in (1) above; 60 g.) in tetrahydrofuran (150 ml.) was added dropwise to the reaction mixture at -65° to -70°C. and stirred for 4 hours at the same temperature. The reaction mixture was further stirred overnight at 0°C, acidified with acetic acid and concentrated under reduced pressure. Diethyl ether and water were added to the residue in order to remove the water soluble materials. The ethereal solution was dried over magnesium sulphate and concentrated. The residue was distilled under reduced pressure to give pure dimethyl 2-oxo-3-methylene-n-heptylphosphonate (67 g; 69%), having the following physical characteristics:-
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[C:12]([NH2:16])([CH3:15])([CH3:14])[CH3:13]>>[C:12]([NH:16][S:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])(=[O:10])=[O:9])([CH3:15])([CH3:14])[CH3:13]
Reactant: O=S(=O)(Cl)c1ccccc1F
Reactant: CC(C)(C)N
Product: CC(C)(C)NS(=O)(=O)c1ccccc1F

Procedure:
30 g (0.13 mol) of (N-tert-butyl)-2-fluorobenzenesulfonamide, obtained from the reaction of 2-fluorobenzenesulfonyl chloride with N-tert-butylamine in analogy to example A1, are introduced in 300 ml of dry tetrahydrofuran. The solution is cooled to −70° C. and a solution of 18.28 g (0.285 mol) of n-butyllithium (2.5 molar in tetrahydrofuran) is added dropwise. Thereafter the reaction solution is warmed to −30° C. over 30 min, after which it is cooled again to −70° C. Then 36.21 g (0.143 mol) of iodine in 200 ml of dry tetrahydrofuran are added dropwise. Following the addition the reaction solution is warmed slowly to room temperature and stirred for 12 h. Thereafter it is washed with 50% strength aqueous sodium thiosulfate solution and water. The organic phase is dried and evaporated. This gives 40.8 g (88% of theory) of N-(tert-butyl)-2-fluoro-6-iodobenzenesulfonamide.
Reaction SMILES: N[CH2:2][CH2:3][N:4]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]2[C:6]([N:7]([CH3:22])[C:8](=[O:21])[N:9]([CH3:20])[C:10]2=[O:19])=[CH:5]1.C(CN)[OH:24].C(Cl)Cl.O>CCO>[OH:24][CH2:2][CH2:3][N:4]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]2[C:6]([N:7]([CH3:22])[C:8](=[O:21])[N:9]([CH3:20])[C:10]2=[O:19])=[CH:5]1
Reactant: Cn1c(=O)c2c(-c3ccccc3)n(CCN)cc2n(C)c1=O
Reactant: NCCO
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: Cn1c(=O)c2c(-c3ccccc3)n(CCO)cc2n(C)c1=O
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
5-Benzoyl-6-(bromomethyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (Intermediate A step 3) (400 mg 1.19 mmol) in EtOH (4 mL) was treated with TEA (0.16 mL, 1.19 mmol) and ethanolamine (72.5 mg, 1.19 mmol). The mixture was heated to 100° C. for 1 h under microwave irradiation. A further portion of ethanolamine (96 μL) was added and heating continued for a further 20 min. The reaction was poured into DCM (75 mL) and water (75 mL). The layers were separated and the aqueous phase extracted with DCM (2×50 mL). The combined organic phases were washed with water (2×50 mL), then passed through a hydrophobic frit. The solvent was removed under reduced pressure affording a pale yellow solid. The solid was triturated in hot EtOH and allowed to cool. The title product was collected by reduced pressure filtration as a white powder.
Reaction SMILES: [Cl:1][C:2]1[N:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:4]2[C:9]([C:10]=1[C:11](O)=[O:12])=[CH:8][C:7]([O:14][CH3:15])=[CH:6][CH:5]=2.[N:22]1([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C>[C:31]([O:30][C:28]([N:22]1[CH2:27][CH2:26][N:25]([C:11]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH3:15])[CH:8]=3)[N:3]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:2]=2[Cl:1])=[O:12])[CH2:24][CH2:23]1)=[O:29])([CH3:34])([CH3:32])[CH3:33]
Reactant: COc1ccc2c(c1)c(C(=O)O)c(Cl)n2-c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COc1ccc2c(c1)c(C(=O)N1CCN(C(=O)OC(C)(C)C)CC1)c(Cl)n2-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.4 %

Procedure:
To a solution of 602 mg (1.99 mmol) of the compound of step 4, tert-butyl 1-piperazinecarboxylate (372 mg, 1.99 mmol), EDC (421 mg, 2.19 mmol) and HOAT (312 mg, 2.29 mmol) in DMF (5 ml) was added NMM (0.66 ml, 5.98 mmol), and the reaction mixture was stirred at room temperature overnight. The mixture was quenched with water and extracted with EA. The organic layer was separated, dried over sodium sulfate, filtered and evaporated to give 930 mg of the title compound.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Na].Br.[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH2:21][CH2:22]Br)[CH:15]=1>C(O)C>[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH2:21][CH2:22][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])[CH:15]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: BrCCCc1cccnc1
Agent: Br
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(CCCc1cccnc1)C(=O)OCC

Procedure:
To a solution of 48 ml (0.37 mole) of diethyl malonate in 960 ml ethanol is added 14.03 g (0.61 mole) sodium metal and the mixture is stirred until all of the metal dissolved. The solution is heated to reflux and a solution of 80.04 g (0.28 mole) of 3-(3-pyridyl)-propyl bromide hydrobromide in 960 ml ethanol is added rapidly and the mixture is maintained at reflux for 10 h. The reaction mixture is evaporated and the residue is taken up in 400 ml of 1N aqueous hydrochloric acid and washed with 400 ml hexane. The aqueous phase is adjusted to pH 8 using solid sodium bicarbonate. The mixture is then extracted with methylene chloride (3×200 ml). Combined organic extracts are dried (MgSO4), filtered and evaporated to dryness to give diethyl [3-(3-pyridyl)propyl]-malonate as an oil.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11]3[CH:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:10]=3[C:9]([NH2:21])=[N:8][C:7]=2[CH:22]=1.C(N(C(C)C)CC)(C)C.[F:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][CH:41]2[CH2:46]N[CH2:44][CH2:43][NH:42]2)=[CH:35][CH:34]=1>CN1CCCC1=O.C(OCC)(=O)C>[F:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11]3[CH:13]=[CH:14][C:15]([C:17]([F:18])([F:20])[F:19])=[CH:16][C:10]=3[C:9]([N:21]3[CH2:44][CH2:43][NH:42][CH:41]([CH2:40][CH2:39][C:36]4[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=4)[CH2:46]3)=[N:8][C:7]=2[CH:22]=1
Reactant: NC1=Nc2cc(F)ccc2Nc2ccc(C(F)(F)F)cc21
Reactant: Fc1ccc(CCC2CNCCN2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Fc1ccc(CCC2CN(C3=Nc4cc(F)ccc4Nc4ccc(C(F)(F)F)cc43)CCN2)cc1
Temperature: 195 °C
Reaction time: 0.5 h
Yield: 28.3 %

Procedure:
Heat a solution of 8-fluoro-2-trifluoromethyl-5H-dibenzo[b,e][1,4]diazepin-11-ylamine hydrochloride (0.2 g, 0.60 mmol) and diisopropylethylamine (0.086 g, 0.66 mmol) in 1-methyl-2-pyrrolidinone (4 mL) to 60° C. After 30 minutes, add 2-[2-(4-fluoro-phenyl)-ethyl]-piperazine (0.38 g, 1.81 mmol) and heat the reaction mixture to 195° C. for 16 hours. Cool reaction mixture to ambient temperature. Dilute with of ethyl acetate (50 ml) and wash twice with saturated aqueous sodium chloride then twice with water. Collect the organic layer and dry over sodium sulfate. Remove solvent under reduced pressure. Purification via flash chromatography, eluting with a linear gradient starting with 100% dichloromethane and going to 85% of dichloromethane with 15% 2M ammonia in methanol, gives the free base of the title compound (0.083 g, 0.17 mmol, 28% yield) as a yellow amorphous solid: Mass Spectrum (m/e): 487(M+1).
Reaction SMILES: [C:1]([N:5]1[C:14]2[C:9](=[CH:10][C:11](F)=[C:12](F)[CH:13]=2)[C:8](=[O:17])[C:7]([C:18]([O:20]CC)=[O:19])=[CH:6]1)([CH3:4])([CH3:3])[CH3:2].[OH-:23].[K+].[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][OH:32])=[CH:29][CH:28]=1>>[C:1]([N:5]1[C:14]2[C:9](=[CH:10][C:11]([O:23][CH2:31][C:30]3[CH:33]=[CH:34][C:27]([O:26][CH3:25])=[CH:28][CH:29]=3)=[C:12]([O:32][CH2:31][C:30]3[CH:33]=[CH:34][C:27]([O:26][CH3:25])=[CH:28][CH:29]=3)[CH:13]=2)[C:8](=[O:17])[C:7]([C:18]([OH:20])=[O:19])=[CH:6]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)c1cn(C(C)(C)C)c2cc(F)c(F)cc2c1=O
Reactant: [OH-]
Reactant: COc1ccc(CO)cc1
Agent: [K+]
Product: COc1ccc(COc2cc3c(=O)c(C(=O)O)cn(C(C)(C)C)c3cc2OCc2ccc(OC)cc2)cc1
Temperature: 80 °C
Yield: 72.8 %

Procedure:
A mixture of ethyl 1-(tert-butyl)-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate (50 g, 162 mmol), KOH (136 g, 2425 mmol) and 4-methoxybenzyl alcohol (201 ml, 1617 mmol) was heated at 80° C. under N2 for 8 h. LCMS showed completion of reaction. The solution was adjusted to pH 2, extracted with EA and washed with water. The organic phase was concentrated in vacuo and the crude product was triturated in Et2O to afford 1-(tert-butyl)-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (61 g, 118 mmol, 72.9% yield) as pale yellow solid. LCMS: (M+H)+: 518.3.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.C(Cl)[Cl:11].S(Cl)(Cl)=O>N1C=CC=CC=1>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([Cl:11])=[O:9]
Reactant: ClCCl
Reactant: O=C(O)c1cnccn1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: O=C(Cl)c1cnccn1
Temperature: 30 °C

Procedure:
A mixture of 68.2 g (0.55 moles) 2-pyrazine carboxylic acid and methylene chloride (about 200 ml) containing a catalytic amount of pyridine was warmed (to about 30° C.). To that mixture, 78.5 g (0.66 mole) thionyl chloride was added dropwise. The reaction mixture was refluxed for 24 hours. The methylene chloride was removed under reduced pressure and heat to give the 2-pyrazine carboxylic acid chloride which was used in step (b) without further isolation.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]([CH:15]=1)=[CH:13][C:12]1[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:6]=2[CH:16]=O.[NH2:18][C:19]([CH3:24])([CH2:22][OH:23])[CH2:20][OH:21]>CO.CCOCC>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]([CH:15]=1)=[CH:13][C:12]1[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:6]=2[CH2:16][NH:18][C:19]([CH3:24])([CH2:22][OH:23])[CH2:20][OH:21]
Reactant: CC(N)(CO)CO
Reactant: O=Cc1c2ccccc2cc2cc(Cl)ccc12
Solvent: CCOCC
Solvent: CO
Product: CC(CO)(CO)NCc1c2ccccc2cc2cc(Cl)ccc12
Product: Cl

Procedure:
Using the reductive amination procedure outlined in 1, 3-chloro-9-anthracenecarbaldehyde (17B) and 2-amino-2-methyl-1,3-propanediol (Aldrich) gave 2-(((3-chloro-9-anthracenyl)methyl)amino)-2-methyl-1,3-propanediol hydrochloride mp 268°-269° (dec), CH3OH/Et2O, (C, H, Cl, N).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][C:11]#[CH:12].C([Li])CCC.[CH3:18][CH2:19][CH2:20][CH2:21][CH2:22]C.C(Br)CCCC>CN1C(=O)N(C)CCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][C:11]#[C:12][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: C#CCCCOC1CCCCO1
Reactant: CCCCCC
Agent: [Li]CCCC
Solvent: CN1CCCN(C)C1=O
Solvent: CCCCCBr
Product: CCCCCC#CCCCOC1CCCCO1
Yield: 58 %

Procedure:
1-(Tetrahydopyran-2-yloxy)-4-pentyne (1) (0.66 g, 3.90 mmol) was metallated with n-butyllithium solution (2.5M) in hexane (1.87 ml, 1.2 eq.). Addition of a solution of n-pentyl bromide (0.725 ml, 1.5 eq.) in DMPU (2 ml) produced 0.54 g (58% yield) of the title compound (15). 1H NMR (200 MHz) δ: 4.60 (m, 1H, CH-2'), 3.65 (m, 4H, CH2 -1, 6'), 2.26 (tt, J=7.0, 7.0, 2.0, 2.0 Hz, 2H, CH2 -3), 2.13 (tt, J=7.0, 7.0, 2.5, 2.5 Hz, 2H, CH2 -6), 1.77 (tt, J=6.8, 6.8, 7.07 7.0 Hz, 2H, CH2 -2), 1.33 (m, 6H, CH2 -7, 8, 9), 1.52 (m, 6H, CH2 -3', 4', 5'), 0.89 (t, J=7.0 Hz, 3H, CH3). MS [FAB, m/z(%)] 237 (M+ -1), 85 (100). IR (CCl4, cm-1) 2229, 1322, 1331, 1201, 1138, 1121, 1034.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+].[CH3:20][C:21]1[CH:22]=[C:23]([N+:29]([O-:31])=[O:30])[CH:24]=[C:25]([CH3:28])[C:26]=1F.C(OCC)(=O)C>CS(C)=O.O>[CH:11]([C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([O:1][C:26]3[C:21]([CH3:20])=[CH:22][C:23]([N+:29]([O-:31])=[O:30])=[CH:24][C:25]=3[CH3:28])[CH:3]=2)[NH:7][CH:6]=1)([CH3:13])[CH3:12]
Reactant: CC(C)c1c[nH]c2ccc(O)cc12
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc([N+](=O)[O-])cc(C)c1Oc1ccc2[nH]cc(C(C)C)c2c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
11.44 g (58.76 mmol) of 5-hydroxy-3-isopropyl-indole are dissolved in 350 ml of DMSO, 8.93 g (64.63 mmol) of potassium carbonate in solid form are introduced and subsequently 9.94 g (58.76 mmol) of 3,5-dimethyl-4-fluoronitrobenzene are added. The reaction solution is stirred for 2 hours at 100° C. under argon. Afterwards it is cooled to room temperature, 100 ml of ethyl acetate and 600 ml of H2O are added; ethyl acetate is separated off after phase separation and the aqueous phase is reextracted twice with ethyl acetate. The combined organic phases are washed twice with sodium chloride solution, dried over sodium sulphate, filtered and concentrated to dryness. The residue is purified by chromatography on silica gel by means of cyclohexane/ethyl acetate (10:1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:12]2[N:11]=[C:10]([NH2:15])[C:9]3[N:16]=[C:17]([CH2:22][O:23][CH2:24][CH3:25])[N:18]([CH2:19][CH2:20][CH3:21])[C:8]=3[C:7]=2[CH:6]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[O:53]1[CH2:57][CH2:56][CH2:55][CH:54]1[C:58](O)=[O:59].C(N(CC)CC)C>ClCCl.O>[NH2:15][C:10]1[C:9]2[N:16]=[C:17]([CH2:22][O:23][CH2:24][CH3:25])[N:18]([CH2:19][CH2:20][CH3:21])[C:8]=2[C:7]2[CH:6]=[C:5]([O:4][CH2:3][CH2:2][NH:1][C:58]([CH:54]3[CH2:55][CH2:56][CH2:57][O:53]3)=[O:59])[CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: CCCn1c(COCC)nc2c(N)nc3ccc(OCCN)cc3c21
Reactant: O=C(O)C1CCCO1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCCn1c(COCC)nc2c(N)nc3ccc(OCCNC(=O)C4CCCO4)cc3c21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 8-(2-aminoethoxy)-2-ethoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine (0.500 g, 1.46 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (1.282 g, 2.90 mmol) in dichloromethane (15 mL) was cooled to 0° C. A solution of tetrahydro-2-furoic acid (0.168 g, 1.45 mmol) in dichloromethane (5 mL) and triethylamine (0.811 mL, 5.82 mmol) were sequentially added. The reaction was stirred at 0° C. for 30 minutes, allowed to warm to ambient temperature, stirred for two hours, and poured into water. The aqueous layer was extracted with dichloromethane. The combined organic fractions were washed sequentially with water (2×) and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluting with dichloromethane:methanol ranging in ratios from 99:1 to 96:4) to provide the desired product and a bis amide by-product. The bis amide by-product was treated with 1N aqueous hydrochloric acid, heated at reflux for 1.5 hours, and cooled to 0° C. The mixture was adjusted to pH 13 with the addition of 10% aqueous sodium hydroxide and extracted with dichloromethane. The combined extracts were washed with water and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide a yellow oil. The oil and the previously recovered amide were combined and recrystallized from acetonitrile to provide 0.220 g of N-(2-{[4-amino-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-yl]oxy}ethyl)tetrahydrofuran-2-carboxamide as a tan, crystalline solid, mp 202.5-204.5° C.
Reaction SMILES: [C:1]1([C:7]([NH:9][C:10]2[S:11][C:12]([C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])=[C:13]([CH3:22])[C:14]=2[C:15]([O:17]C(C)(C)C)=[O:16])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:26]([O:25][C:23]([C:12]1[S:11][C:10]([NH:9][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:8])=[C:14]([C:15]([OH:17])=[O:16])[C:13]=1[CH3:22])=[O:24])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Cc1c(C(=O)OCc2ccccc2)sc(NC(=O)c2ccccc2)c1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(C(=O)OCc2ccccc2)sc(NC(=O)c2ccccc2)c1C(=O)O
Reaction time: 19 h
Yield: 94.6 %

Procedure:
To a solution of the compound prepared in Example 8 (1.33 g, 2.94 mmol) in DCM (20 ml). was added TFA (20 ml) dropwise. After 19 hours, the reaction was concentrated under reduced pressure, and partitioned between CHCl3 and H2O. The aqueous phase basified with sat. NaHCO3, and the layers were separated. The aqueous phase was extracted with CHCl3. The combined organic layers were washed with H2O, dried over MgSO4 and concentrated under reduced pressure to yield 1.10 g (95%) of a tan solid. 1H-NMR (CDCl3) 2.76 (s, 3H) 5.23 (s, 2H), 7.20-7.60 (m, 8H), 7.93 (d, 2H, J=8.0 Hz)
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([N:11]([CH3:13])[CH3:12])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5](Br)[N:6]2[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C[OH:23]>Cl>[NH2:1][C:2]1[N:10]=[C:9]([N:11]([CH3:13])[CH3:12])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:23])[N:6]2[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CN(C)c1nc(N)c2nc(Br)n(Cc3ccccc3)c2n1
Reactant: CO
Agent: Cl
Product: CN(C)c1nc(N)c2nc(O)n(Cc3ccccc3)c2n1
Yield: 91 %

Procedure:
6-Amino-9-benzyl-2-dimethylamino-8-bromopurine (51 mg, 0.15 mmol) in concentrated hydrochloric acid (30 ml) and methanol (10 ml) were refluxed for 5 hours under heating. After removal of methanol, the reaction mixture was made basic with 28% aqueous ammonia. The resulting crystals were filtered, washed with water and dried to give the subject compound (38 mg, yield 91%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[S:12][CH:11]=[N:10][CH:9]=2)[N:5]=[C:4]([NH:13][C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][N:15]=2)[CH:3]=1.C([N-]C(C)C)(C)C.[Li+].[O:32]=[C:33]1[CH2:42][CH2:41][CH2:40][C:39]2[CH:38]=[C:37]([C:43]([O:45][CH3:46])=[O:44])[CH:36]=[CH:35][C:34]1=2>C1COCC1>[OH:32][C:33]1([C:11]2[S:12][C:8]([C:6]3[CH:7]=[C:2]([CH3:1])[CH:3]=[C:4]([NH:13][C:14]4[CH:19]=[C:18]([C:20]([F:23])([F:21])[F:22])[CH:17]=[CH:16][N:15]=4)[N:5]=3)=[CH:9][N:10]=2)[CH2:42][CH2:41][CH2:40][C:39]2[CH:38]=[C:37]([C:43]([O:45][CH3:46])=[O:44])[CH:36]=[CH:35][C:34]1=2
Reactant: COC(=O)c1ccc2c(c1)CCCC2=O
Reactant: Cc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2cncs2)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)CCCC2(O)c1ncc(-c2cc(C)cc(Nc3cc(C(F)(F)F)ccn3)n2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.3 %

Procedure:
To a solution of 4-methyl-6-(1,3-thiazol-5-yl)-N-[4-(trifluoromethyl)pyridin-2-yl]pyridin-2-amine (500 mg, 1.487 mmol) in THF (5.9 mL) under argon at −78° C. was added lithium diisopropylamide (2.0 M in tetrahydrofuran, 2.2 mL, 4.46 mmol), and the resulting mixture was stirred as such for 30 minutes. To this mixture was added a solution of methyl 5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate (379 mg, 1.858 mmol) in THF (2 mL), and the reaction was then allowed to warm to rt over a period of 2 h. After stirring for an additional 14 h, the reaction was quenched with methanol (10 mL) and directly concentrated. Chromatography on silica gel (dichloromethane-methanol) afforded (rac)-methyl 5-hydroxy-5-[5-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl)-1,3-thiazol-2-yl]-5,6,7,8-tetrahydronaphthalene-2-carboxylate as a light brown solid (718.0 mg, 1.328 mmol, 89% yield). MS ESI calcd for C27H23F3N4O3S [M+H]+ 541, found 541. 1H NMR (500 MHz, DMSO) δ 10.20 (s, 1H), 8.63 (s, 1H), 8.48 (d, J=5.0 Hz, 1H), 8.23 (s, 1H), 7.74 (s, 1H), 7.69 (d, J=8.2 Hz, 1H), 7.36 (s, 1H), 7.23-7.17 (m, 2H), 7.09 (s, 1H), 6.63 (s, 1H), 3.82 (s, 3H), 2.92-2.85 (m, 2H), 2.33-2.30 (m, 4H), 2.15-2.09 (m, 1H), 2.02-1.88 (m, 2H) ppm.
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([Cl:11])=[CH:4][N:3]=1.[CH3:12][C:13]([OH:17])([C:15]#[CH:16])[CH3:14].CCN(CC)CC>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.O>[Cl:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([C:16]#[C:15][C:13]([CH3:14])([OH:17])[CH3:12])=[N:3][CH:4]=1
Reactant: O=[N+]([O-])c1cc(Cl)cnc1Br
Reactant: C#CC(C)(C)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(O)C#Cc1ncc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 2-bromo-5-chloro-3-nitro-pyridine (2.5 g, 10.6 mmol), Cul (141 mg, 0.74 mmol), Pd(PPh3)4, (367 mg, 0.32 mmol) and 2-Methyl-3-butyn-2-ol (1.5 mL, 15.8 mmol) was added 1-methyl-2-pyrorolidone (20 mL) followed by Et3N (6 mL, 22 mmol). After stirring for 4 h 30 min at room temperature, the reaction mixture was poured into water (20 mL) and extracted with EtOAc (3×30 mL). The combined organic extracts were washed with brine (20 mL), dried (Na2SO4), filtered and concentrated under reduced pressure, and the residue was purified by flash column chromatography over silica gel (EtOAc/Hexanes, 2:98, then 5:95) to provide 4-(5-chloro-3-nitro-pyridin-2-yl)-2-methyl-but-3-yn-2-ol. MS m/z: 241.0 (M+H).