Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]([CH2:11][CH3:12])[C:9]#N)[C:3]=1[O:13][CH3:14].CC(C[AlH]CC(C)C)C.C([O:26]CC)C>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]([CH2:11][CH3:12])[CH:9]=[O:26])[C:3]=1[O:13][CH3:14]
Reactant: CCOCC
Reactant: CCC(C#N)c1nccc(Cl)c1OC
Agent: CC(C)C[AlH]CC(C)C
Product: CCC(C=O)c1nccc(Cl)c1OC
Temperature: -74 °C

Procedure:
2-(4-Chloro-3-methoxy-2-pyridinyl)-butyronitrile (2.78 g) is dissolved in diethyl ether (150 ml), the solution is cooled to −74° C. and DIBAL (29 ml 1.0M) is added over a 30 min period. The solution is allowed to stir at −74° C. for an hour then at 0° C. for another hour. The reaction is quenched by addition of 5% sulfuric acid (25 ml), keeping the temperature around 0° C. The phases are separated and the organic phase washed with a solution of sodium bicarbonate, dried and evaporated to afford the desired product.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:11]([CH2:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C:17]#[N:18])(=[O:13])=[O:12])[CH:8]=2)[NH:3]1.[CH2:23]([N:25]([CH2:40][CH3:41])[CH2:26][CH2:27][NH:28][C:29]([C:31]1[C:35]([CH3:36])=[C:34](C=O)[NH:33][C:32]=1[CH3:39])=[O:30])[CH3:24].N1CCCC[CH2:43]1>C(O)C>[CH2:40]([N:25]([CH2:23][CH3:24])[CH2:26][CH2:27][NH:28][C:29]([C:31]1[C:35]([CH3:36])=[CH:34][N:33](/[CH:43]=[C:10]2\[C:2](=[O:1])[NH:3][C:4]3[C:9]\2=[CH:8][C:7]([S:11]([CH2:14][C:15]2[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=2[C:17]#[N:18])(=[O:12])=[O:13])=[CH:6][CH:5]=3)[C:32]=1[CH3:39])=[O:30])[CH3:41]
Reactant: N#Cc1ccccc1CS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: C1CCNCC1
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Solvent: CCO
Product: CCN(CC)CCNC(=O)c1c(C)cn(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4ccccc4C#N)cc32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 65 %

Procedure:
To a solution of 2-(2-Oxo-2,3-dihydro-1H-indole-5-sulfonylmethyl)-benzonitrile (100 mg, 0.32 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (85 mg, 0.32 mmol) in ethanol (4 mL) was added piperidine (0.1 mL). The reaction mixture was stirred at 25° C. for three days. The solvent was evaporated and the residue was purified on a silica gel column eluting with MeOH—CH2Cl2 1:9 to provide 116 mg (65%) of [5-(2-Cyano-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide as a pale orange solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][CH:8]([CH3:11])[CH2:7][C:6]=2[C:5]([N:12]2[C:17](=[O:18])[NH:16][C:15](=[O:19])[C:14](C(O)=O)=[N:13]2)=[CH:4][CH:3]=1>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[C:10]2[O:9][CH:8]([CH3:11])[CH2:7][C:6]=2[C:5]([N:12]2[C:17](=[O:18])[NH:16][C:15](=[O:19])[CH:14]=[N:13]2)=[CH:4][CH:3]=1
Reactant: CC1Cc2c(-n3nc(C(=O)O)c(=O)[nH]c3=O)ccc(Cl)c2O1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: CC1Cc2c(-n3ncc(=O)[nH]c3=O)ccc(Cl)c2O1
Temperature: 25 °C

Procedure:
A mixture of 8.0 g of 32D and 80 mL of Dowtherm® was heated at 200°-250° C. for 2 hours, cooled to room temperature, diluted with petroleum ether and filtered. The collected solid phase was dried under reduced pressure, and recrystallized from ethyl acetate/petroleum ether to give 2-(7-chloro-2,3-dihydro-2-methyl-4-benzofuranyl)-1,2,4-triazine-3,5(2H,4H)-dione, (32E) as a tan solid, m.p.: 184°-186° C.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.P(C#N)(=O)(OCC)OCC.[Cl:28][C:29]1[CH:37]=[C:36]2[C:32]([C:33](=[O:50])[N:34]([C:42]3[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=3)[CH:35]2[CH2:38][C:39](O)=[O:40])=[CH:31][CH:30]=1>CN(C)C=O>[Cl:28][C:29]1[CH:37]=[C:36]2[C:32](=[CH:31][CH:30]=1)[C:33](=[O:50])[N:34]([C:42]1[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=1)[CH:35]2[CH2:38][C:39]([N:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)=[O:40]
Reactant: C1CC2(CCN1)OCCO2
Reactant: COc1ccc(N2C(=O)c3ccc(Cl)cc3C2CC(=O)O)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(N2C(=O)c3ccc(Cl)cc3C2CC(=O)N2CCC3(CC2)OCCO3)cc1
Temperature: 0 °C
Yield: 90.3 %

Procedure:
With ice-cooling and stirring, 1.57 g of 1,4-dioxa-8-azaspiro[4.5]decane, 2.3 ml of triethylamine and 2.12 g of diethyl phosphorocyanidate were successively added to a solution of 3.32 g of 6-chloro-2-(4-methoxyphenyl)-3-oxoisoindoline-1-acetic acid in 30 ml of dimethylformamide. The mixture was stirred with ice-cooling for an hour. To the reaction mixture was added 150 ml of ice water and the mixture was allowed to stand to give a crystalline precipitate, which was collected by filtration, washed with water and dried. Recrystallization from ether gave 4.13 g of colorless crystals melting at 156°-157° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][C@@:12]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:17][C:16](=[O:18])[N:15]([C@H:19]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][OH:28])=[CH:23][CH:22]=2)[CH3:20])[CH2:14][CH2:13]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].[CH3:37]I>C1COCC1>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][C@@:12]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:17][C:16](=[O:18])[N:15]([C@H:19]([C:21]2[CH:22]=[CH:23][C:24]([CH2:27][O:28][CH3:37])=[CH:25][CH:26]=2)[CH3:20])[CH2:14][CH2:13]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CI
Reactant: C[C@@H](c1ccc(CO)cc1)N1CC[C@](CCCO[Si](C)(C)C(C)(C)C)(c2ccccc2)OC1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1ccc([C@H](C)N2CC[C@](CCCO[Si](C)(C)C(C)(C)C)(c3ccccc3)OC2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.5 %

Procedure:
To a solution of (R)-6-(3-(tert-butyldimethylsilyloxy)propyl)-3-((S)-1-(4-(hydroxymethyl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (10 mg, 0.02 mmol) in THF (5 mL) was added NaH (1.4 mg) at 0° C. After stirring for 1 h at rt, the mixture was cooled to 0° C., and CH3I (90 mg 0.78 mmol) was added. The mixture was stirred overnight at rt. The reaction was quenched with H2O, and the layers were separated. The aqueous layer was extracted with CH2Cl2 for two times. The organic layer was combined, washed with brine, dried over Na2SO4 and concentrated to give the crude product, which was purified by preparative TLC to give (R)-6-(3-(tert-butyldimethylsilyloxy)propyl)-3-((S)-1-(4-(methoxymethyl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (10 mg, 71%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:11])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[NH3:12]>O>[F:11][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([NH2:12])[CH:3]=1)[NH:9][CH:8]=[CH:7]2
Reactant: N
Reactant: Fc1cc(Br)c2[nH]ccc2c1
Solvent: O
Product: Nc1cc(F)cc2cc[nH]c12
Temperature: 155 °C

Procedure:
A mixture of 7-Bromo-5-fluoro-indole (1 g), Cu (0.31 g), CuBr (0.64 g) and NH3 (30 mL of a 33% aqueous solution) was heated in an autoclave for 1.5 h at 155° C. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried and the solvent removed to give 5-fluoro-7-amino-indole (0.67 g) as an oil which was used without further purification. UPLC/MS found for C8H7FN2 as (M+H)+ 151.0.
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]3[O:11][C:12]4[CH:18]=[CH:17][C:16]([C:19]#N)=[CH:15][C:13]=4[N:14]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.CC(C[AlH]CC(C)C)C.C[OH:31].O>C1COCC1.C1(C)C=CC=CC=1>[CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]3[O:11][C:12]4[CH:18]=[CH:17][C:16]([CH:19]=[O:31])=[CH:15][C:13]=4[N:14]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1
Reactant: CO
Reactant: N#Cc1ccc2oc(N3CCN(C4CC4)CC3)nc2c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: O=Cc1ccc2oc(N3CCN(C4CC4)CC3)nc2c1
Temperature: 20 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
To a solution of 2-(4-cyclopropylpiperazin-1-yl)benzooxazole-5-carbonitrile (1.5 g, 5.6 mmol) in THF-toluene (50 mL, 2:1) was added DIBAL (16.8 mL, 16.8 mmol) dropwise at −78° C. under a nitrogen atmosphere. Then the mixture was allowed to warm to 20° C. and then stirred for 1 h. Methanol (5 mL) was added dropwise, followed by water (20 mL). The mixture was extracted with ethyl acetate (3×20 mL) and the combined organic extracts were dried (Na2SO4) and concentrated. The residue was purified by column chromatography on silica gel (elute: 2% dichloromethane in methanol) to give 1.1 g (72%) of 2-(4-cyclopropyl-piperazin-1-yl)benzooxazole-5-carboxaldehyde.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@H:8]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:14][CH2:13]2)[CH2:9][CH2:10][OH:11])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.Cl[Si](C)(C)C.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>ClCCl.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C@H:8]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:14]=[CH:13]2)[CH2:9][CH2:10][OH:11])[CH:5]=[CH:6][CH:7]=1
Reactant: OCC[C@H](c1cccc(Br)c1)N1CCc2cccc(OCc3ccccc3)c21
Agent: C[Si](C)(C)Cl
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: OCC[C@H](c1cccc(Br)c1)n1ccc2cccc(OCc3ccccc3)c21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 80.4 %

Procedure:
A stirred solution of (3R)-(-)-3-(3-bromophenyl)-3-(7-benzyloxyindolin-1-yl)propan-1-ol (1.0 g, 2.28 mmol) in dry dichloromethane (30.0 ml) under nitrogen at 5° C. was treated with triethylamine (0.52 ml, 3.77 mmol) followed by chlorotrimethylsilane (0.32 ml, 2.52 mmol) dropwise. The resulting suspension was stirred at room temperature for 20 min, treated with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.57 g, 2.52 mmol) and stirred at room temperature until the reaction was judged to be complete from TLC inspection (~30 min). The solvent was removed by evaporation, the residue was taken up in ethyl acetate (200 ml), washed with 2M aqueous sodium hydroxide (3×100 ml), brine (100 ml) and 2M aqueous hydrochloric acid (2×100 ml). Evaporation of the dried organic extracts (Na2SO4) gave a yellow/brown oil. Column chromatography (ethyl acetate--light petroleum (b.p. 40-60° C.), 1:4) gave the title compound as a yellow oil (0.80 g, 80%). [α]D26 -157 (c=0.014 gml-1, CHCl3); Vmax (thin film)/cm-1 3418.5 (br. OH), 3064.5, 3033.5, 2935.5, 2879.0, 1593.5, 1570.5; δH (270 MHz) 2.35 (2H), m, 2×2-H); 3.50 (2H, m, 2×1-H); 5.13 (2H, q, CH2PH, 2J=11.1 Hz); 6.6 (m, 2H), 3-H, indole 3-H); 6.72 (1H, dd, indole 6-H, Jo =7.6 Hz, Ja =0.7 Hz); 6.90 (1H, dd, indole 4-H, Jo 8.3 Hz, Ja =0.8 Hz); 7.00 (2H, m, indole 5-H, 5'-H; 7.15 (1H, d, indole 2-H, 3H2.3 =3.0 Hz); 7.19-7.40 (8H, m, 8ArH). δc (67.8 MHz) 38.4 (2-C); 56.4 (3-C); 59.3 (1-C); 70.7 (PhCh2); 103.2 (indole 3-C); 104.3 (indole 6-C); 114.3 (indole 4-C); 120.1 (indole 5-C); 122.5 (3'-C); 125.0 (indole 2-C); 131.8 (1'-C); 136.4 (benzyl ipso-C); 144.9 (indole 7a-C); 146.5 (indole 7-C). The remaining signals lie between 126.5-130.7 ppm and cannot be assigned with any certainty.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][N:16]2[C:19]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[C:25]([O:32][CH:33]5[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35][CH2:34]5)[CH:26]=[CH:27][CH:28]=4)[N:23]=3)=[CH:20][N:21]=[C:15]2[CH:14]=1>ClCCl>[CH3:8][O:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][N:16]2[C:19]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[C:25]([O:32][CH:33]5[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]5)[CH:26]=[CH:27][CH:28]=4)[N:23]=3)=[CH:20][N:21]=[C:15]2[CH:14]=1
Reactant: COCCOc1ccn2c(-c3ccc4cccc(OC5CCN(C(=O)OC(C)(C)C)CC5)c4n3)cnc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCOc1ccn2c(-c3ccc4cccc(OC5CCNCC5)c4n3)cnc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.7 %

Procedure:
Trifluoroacetic acid 0.0862 ml, 1.12 mmol) was added to a solution of tert-butyl 4-(2-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl)quinolin-8-yloxy)piperidine-1-carboxylate (0.029 g, 0.0559 mmol) in dichloromethane (0.50 mL). After stirring overnight at ambient temperature, the reaction mixture was concentrated under reduced pressure and partitioned between dichloromethane and saturated NaHCO3. The organic layer was washed with saturated NaHCO3 and brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified via flash column chromatography (40:1 dichloromethane/MeOH followed by 5:1 dichloromethane/MeOH followed by 2:1 dichloromethane/MeOH) provided 10.0 mg of the desired compound. MS APCI (+) m/z 419.2 (M+1) detected.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.OO.C([O-])([O-])=O.[K+].[K+].O=P(Cl)(Cl)[Cl:23]>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][C:5]([Cl:8])=[CH:6][C:7]=1[Cl:23]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1nc(Cl)ccc1Cl
Agent: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1nc(Cl)cc(Cl)c1Cl
Temperature: 60 °C
Yield: 30.3 %

Procedure:
To a stirred solution of methyl 3,6-dichloropyridine-2-carboxylate (0.96 g, 4.66 mmol) in TFA (5 ml) was added hydrogen peroxide (30% w/w aqueous solution, 435 μl, 2.5 mmol) and the reaction mixture was heated at 60° C. for 20 h. The reaction mixture was then cooled and slowly poured onto saturated K2CO3 solution (100 ml), followed by extraction of the aqueous layer with EtOAc (2×200 ml), washing of the combined organic phases with brine (2×50 ml), drying (Na2SO4) and evaporation. The desired 3,6-dichloro-2-(methoxycarbonyl)pyridin-1-ium-1-olate was used crude in the next stage of the synthesis without any further purification. To the crude 3,6-dichloro-2-(methoxycarbonyl)pyridin-1-ium-1-olate (˜70% purity, 2.40 g, 7.7 mmol) was added POCl3 (3.5 ml, 38 mmol) and the solution was heated to 100° C. for 4 h. After cooling the POCl3 was removed in vacuo to give a white solid which was chromatographed over silica gel eluting with 0% to 10% of EtOAc in heptane to afford the title compound as colourless needles (340 mg, 30% over two steps). LC-MS 100%, 2.20 min (3.5 minute LC-MS method), m/z=239.8/241.7, 1H NMR (500 MHz, Chloroform-d) δ 7.51 (1H, s), 3.92 (3H, s).
Reaction SMILES: [C:1]([C:3]1[CH:32]=[CH:31][C:6]([O:7][CH2:8][C@@H:9]([OH:30])[CH2:10][N:11]2[CH2:18][CH:17]3[O:19][CH:13]([CH2:14][N:15]([CH2:20][CH2:21][NH:22]C(=O)OC(C)(C)C)[CH2:16]3)[CH2:12]2)=[CH:5][CH:4]=1)#[N:2].FC(F)(F)C(O)=O.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[NH2:22][CH2:21][CH2:20][N:15]1[CH2:16][CH:17]2[O:19][CH:13]([CH2:12][N:11]([CH2:10][C@H:9]([OH:30])[CH2:8][O:7][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:32][CH:31]=3)[CH2:18]2)[CH2:14]1
Reactant: CC(C)(C)OC(=O)NCCN1CC2CN(C[C@H](O)COc3ccc(C#N)cc3)CC(C1)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(OC[C@@H](O)CN2CC3CN(CCN)CC(C2)O3)cc1
Reaction time: 2 h
Yield: 70.4 %

Procedure:
tert-Butyl 2-{7-[(2S)-3-(4-cyanophenoxy)-2-hydroxypropyl]-9-oxa-3,7-di-azabicyclo[3.3.1]non-3-yl}ethylcarbamate (2.9 g, 6.56 mmol; see WO 01/28992) was dissolved in DCM (30 mL). Trifluoroacetic acid (22.2 g, 194.7 mmol) was added and the solution was stirred for 2 h. The mixture was concentrated under reduced pressure, redissolved in toluene and acetonitrile and concentrated in vacuo again. The product mixture was dissolved in acetonitrile (50 mL) and solid K2CO3 (9.7 g, 10.2 mmol) was added. The mixture was filtered and concentrated under reduced pressure. The mixture was then redissolved in a mixture of EtOAc and a saturated solution of NaHCO3. The mixture was extracted twice with DCM, the combined organic extracts dried (Na2SO4) and evaporated to afford 1.6 g (68.7%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]([C:11]#[N:12])=[C:6]1[O:10][CH2:9][CH2:8][O:7]1)[CH3:2].FC(F)(F)C(O)=O.[CH:21]1([NH:24][C:25](=[O:35])[C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[C:28]([NH:33][NH2:34])[CH:27]=2)[CH2:23][CH2:22]1.C(N(CC)CC)C>C(O)C>[CH2:1]([O:3][C:4]([C:5]1[C:6]([O:7][CH2:8][CH2:9][OH:10])=[N:34][N:33]([C:28]2[CH:27]=[C:26]([C:25](=[O:35])[NH:24][CH:21]3[CH2:23][CH2:22]3)[CH:31]=[CH:30][C:29]=2[CH3:32])[C:11]=1[NH2:12])=[O:13])[CH3:2]
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NN
Reactant: CCOC(=O)C(C#N)=C1OCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1c(OCCO)nn(-c2cc(C(=O)NC3CC3)ccc2C)c1N
Temperature: 25 °C
Yield: 62.1 %

Procedure:
A stirred solution of cyano-[1,3]dioxolan-2-ylidene-acetic acid ethyl ester (prepared as described by Neidlein and Kikelj, Synthesis, 1988, 981, 266 mg, 1.45 mmol, 1.0 eq), N-cyclopropyl-3-hydrazino-4-methyl-benzamide trifluoroacetate (Example 6C, 463 mg, 1.45 mmol, 1.0 eq), and triethylamine (405 μL, 2.9 mmol, 2.0 eq) in 20 mL of ethanol was heated to 65° C. overnight. After cooling to room temperature, the mixture was concentrated and the residue purified by flash chromatography on silica gel (eluted with 1/1 hexanes/EtOAc followed by 100% EtOAc) to provide the desired compound as a tan solid (350 mg, 62%). HPLC (4 minute 10-95 gradient) tR 1.59 min; MS m/z 389.06 [M+H]+; 1H NMR (CD3OD), δ 7.87 (d, J=7.9 Hz, 1 H), 7.78 (s, 1 H), 7.49 (d, J=7.8 Hz, 1 H), 4.29 (dd, J=14.9, 6.9 Hz, 2 H), 4.19 (d, J=4.3 Hz, 2 H), 3.84 (d, J=4.4 Hz, 2 H), 2.84 (m, 1 H), 2.22 (s, 3 H), 1.35 (t, J=7.3 Hz, 3 H), 0.81 (d, J=5.3 Hz, 2 H), 0.63 (s, 2 H) ppm.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:15]([CH2:25][O:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[O:14][C@@H:11]([O:12][CH3:13])[C@@H:10]1[OH:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.[Si:44](OS(C(F)(F)F)(=O)=O)([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45]>C(Cl)Cl>[CH2:1]([O:8][C@H:9]1[C@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:15]([CH2:25][O:26][CH2:27][C:28]2[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=2)[O:14][C@@H:11]([O:12][CH3:13])[C@@H:10]1[O:35][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CO[C@@H]1O[C@H](COCc2ccc(Cl)cc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1O
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CO[C@@H]1O[C@H](COCc2ccc(Cl)cc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.3 %

Procedure:
Methyl 3,4-di-O-benzyl-6-O-(4-chlorobenzyl)-β-D-glucopyranoside (0.258 g, 0.517 mmol) was dissolved in 3 mL CH2Cl2. 2,6-lutidine (240 μL, 2.06 mmol) and tert-butyldimethylsilyltrifluoromethane sulfonate (0.284 mL, 1.24 mmol) were added and the reaction mixture was stirred at room temperature for 30 min. The solution was filtered through silica, eluted with EtOAc and concentrated. Purification by flash column chromatography on silica gel (10% EtOAc/Hexanes) gave 283 mg (89%) of 22 as a colorless oil. [α]24D: −9.2° (c 2.01, CH2Cl2); IR (thin film) 2928, 2855, 1492, 1069 cm−1; 1H-NMR (CDCl3) δ 7.41-7.29 (m, 12H), 7.16-7.13 (m, 2H), 4.97 (d, J=11.3 Hz, 1H), 4.90 (d, J=11.3 Hz, 1H), 4.82 (d, J=11.0 Hz, 1H), 4.61 (d, J=12.5 Hz, 1H), 4.56-4.53 (m, 2H), 4.17 (d, J=7.3 Hz, 1H), 3.78-3.76 (m, 1H), 3.71 (dd, J=4.6, 10.7 Hz, 1H), 3.63-3.53 (m, 6H), 0.95 (s, 9H), 0.17 (s, 3H), 0.13 (s, 3H), 13C-NMR (CDCl3) δ 138.8, 138.1, 136.8, 133.5, 129.2, 128.6, 128.5, 128.4, 128.3, 128.0, 127.9, 127.5, 104.9, 86.0, 78.3, 75.8, 75.4, 75.1, 74.9, 72.8, 69.1, 57.9, 26.1, 18.4, −4.1, −4.2; FAB MS m/z (M+Na)+: calcd 635.2572, obsd 635.2574.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([CH2:11][CH2:12][CH2:13]C)[NH:7][C:8]=1[C:9]#[N:10])(=[O:3])[CH3:2].[CH2:15](C1NC(C#N)=C(C#N)N=1)[CH2:16]C.C([Mg]Br)CC>>[C:1]([C:4]1[N:5]=[C:6]([CH2:11][CH2:12][CH3:13])[NH:7][C:8]=1[C:9]#[N:10])(=[O:3])[CH2:2][CH2:15][CH3:16]
Reactant: CCCCc1nc(C(C)=O)c(C#N)[nH]1
Reactant: CCCc1nc(C#N)c(C#N)[nH]1
Agent: CCC[Mg]Br
Product: CCCC(=O)c1nc(CCC)[nH]c1C#N
Yield: 49.8 %

Procedure:
Following a procedure similar to that described in Preparation 24(i), but using 2-propylimidazole-4,5-dicarbonitrile (prepared as described in Preparation 10) and propylmagnesium bromide, the title compound, melting at 94°-95° C., was obtained in a 49.8% yield.
Reaction SMILES: [CH2:1]([NH:8][N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N+:14]([O-])=[CH:13][C:12]=2[N:11]=[C:10]1[CH2:23][CH2:24][CH2:25][CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+:27].[OH-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C(Cl)Cl>ClCCCl>[CH2:1]([NH:8][N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[C:13]([NH2:27])[C:12]=2[N:11]=[C:10]1[CH2:23][CH2:24][CH2:25][CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCc1nc2c[n+]([O-])c3ccccc3c2n1NCc1ccccc1
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClCCl
Solvent: ClCCCl
Product: CCCCc1nc2c(N)nc3ccccc3c2n1NCc1ccccc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A solution of N-benzyl(2-butyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)amine (393 mg, 1.14 mmol) in 20 mL of 1,2-dichloroethane was placed in a pressure vessel and heated to 70° C. The rapidly stirred solution was then treated with 5 mL of concentrated NH4OH solution and p-toluenesulfonyl chloride (239 mg, 1.25 mmol), the reaction vessel was capped, and heating was continued for 2 h. The reaction mixture was then cooled to ambient temperature and treated with 50 mL of CH2Cl2. The reaction mixture was washed with H2O, 1% Na2CO3 solution (3×), H2O and brine. The organic portion was dried over Na2SO4, filtered and concentrated. Chromatography (SiO2, 5% MeOH/CHCl3) followed by crystallization from propyl acetate/hexanes gave N-benzyl-2-butyl-1H-imidazo[4,5-c]quinoline-1,4-diamine (237 mg) as light-yellow crystals. mp 159.3–160.5° C. 1H NMR (300 MHz, DMSO-d6) δ 8.31 (d, J=8.2 Hz, 1H), 7.83 (d, J=8.4 Hz, 1H), 7.54 (m, 1H), 7.42–7.31 (m, 6H), 5.44 (s, 2H), 5.26 (t, J=5.6 Hz, 1H), 4.37 (d, J=5.6 Hz, 2H), 2.71 (t, J=8.4 Hz, 2H), 1.74 (m, 2H), 1.42 (m, 2H), 0.95 (t, J=7.3 Hz, 3H); MS m/z 346 (M+H)+; Anal. Calcd for C21H23N5: C, 73.02; H, 6.71; N, 20.27. Found: C, 72.75; H, 6.55; N, 20.46.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([NH:6][C@@H:7]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:8][CH2:9][C:10](=[O:12])[OH:11])=[O:5])[CH3:3].C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[C:35](Cl)(=[O:53])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52].O>C(Cl)Cl>[NH:1]([C:35]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])=[O:53])[C@H:2]([C:4]([NH:6][C@@H:7]([C:13]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:14])[CH2:8][CH2:9][C:10](=[O:11])[OH:12])=[O:5])[CH3:3]
Reactant: C[C@H](N)C(=O)N[C@H](CCC(=O)O)C(=O)OCc1ccccc1
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCCCCCCCCCCC(=O)N[C@@H](C)C(=O)N[C@H](CCC(=O)O)C(=O)OCc1ccccc1
Yield: 93.7 %

Procedure:
L-Ala-D-Glu(OH)OBzl (1) (942 mg) was suspended in methylene chloride (40 ml), and bis(trimethylsilyl)acetamide (1.20 g) was added to the suspension under stirring. The resulting solution was treated with stearoyl chloride (900 mg) at ambient temperature and left for an hour. Evaporation of the solvent gave an oily residue which was treated with water to give white solides. The solides were collected by filtration, washed with water and dried over magnesium sulfate to give stearoyl-L-Ala-D-Glu(OH)OBzl (2) (1.60 g).