Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:9]1[CH:20]=[CH:19][C:12]([O:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:11][C:10]=1[OH:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OC1[CH2:28][C:27]([CH3:30])([CH3:29])[N:26]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:25]([CH3:41])([CH3:40])[CH2:24]1>C1(C)C(C)=CC=CC=1>[OH:21][C:10]1[CH:11]=[C:12]([O:13][CH2:14][C:15]([O:17][CH:18]2[CH2:30][C:27]([CH3:28])([CH3:29])[N:26]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:25]([CH3:40])([CH3:41])[CH2:24]2)=[O:16])[CH:19]=[CH:20][C:9]=1[C:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:8]
Reactant: COC(=O)COc1ccc(C(=O)c2ccccc2)c(O)c1
Reactant: CCCCCCCCON1C(C)(C)CC(O)CC1(C)C
Solvent: Cc1ccccc1C
Product: CCCCCCCCON1C(C)(C)CC(OC(=O)COc2ccc(C(=O)c3ccccc3)c(O)c2)CC1(C)C
Temperature: 80 °C
Yield: 78.7 %

Procedure:
A mixture of 22.0 g (76.8 mmol) of methyl 4-benzoyl-3-hydroxyphenoxyacetate, 32.9 g (0.115 mol) of 4-hydroxy-1-octyloxy-2,2,6,6-tetramethylpiperidine, and 100 ml of xylene is heated at reflux. Water is removed by fractional distillation. The reaction mixture is cooled to 80° C., treated with 2.1 g of lithium amide, and diluted with 50 ml of xylene. The reaction mixture is heated at reflux for 2 hours, and methanol is removed by fractional distillation. The reaction mixture is cooled, then diluted with diethyl ether (250 ml). The organic solution is washed with 1N hydrochloric acid (200 ml), and solids are removed by filtration. The solution is washed with saturated sodium bicarbonate solution (100 ml), dried over magnesium sulfate, and concentrated to an oil. Purification by flash chromatography on silica gel (85:15 heptane: ethyl acetate) affords 32.6 g (79% yield) of the title compound, a yellow syrup.
Reaction SMILES: [C:1]([O:9][C@@H:10]1[CH2:18][C@@H:13]2[O:14][C:15](=[O:17])[CH2:16][C@@H:12]2[C@H:11]1[CH:19]=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:21]1[C:25]([C:26](=[O:36])[CH2:27]P(=O)(OCC)OCC)=[CH:24][C:23]2[CH:37]=[CH:38][CH:39]=[CH:40][C:22]1=2>C(Cl)Cl.[Cl-].[Li+].C1COCC1>[C:1]([O:9][C@@H:10]1[CH2:18][C@@H:13]2[O:14][C:15](=[O:17])[CH2:16][C@@H:12]2[C@H:11]1/[CH:19]=[CH:27]/[C:26]([C:25]1[S:21][C:22]2[CH:40]=[CH:39][CH:38]=[CH:37][C:23]=2[CH:24]=1)=[O:36])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOP(=O)(CC(=O)c1cc2ccccc2s1)OCC
Reactant: O=C[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C1C[C@@H]2[C@@H](/C=C/C(=O)c3cc4ccccc4s3)[C@H](OC(=O)c3ccccc3)C[C@@H]2O1
Temperature: -20 °C

Procedure:
A reactor equipped with a mechanical stirrer, under nitrogen, is charged with (3aR,4R,5R,6aS)-4-formyl-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl benzoate (99.2 g, 0.362 mol) in DCM and lithium chloride (1 molar equivalent) dissolved in THF. Diethyl 2-(benzo[b]thiophen-2-yl)-2-oxoethylphosphonate (1 molar equivalent) is added neat and rinsed with DCM. Some lithium chloride precipitates from solution when the THF and DCM solutions are mixed. The mixture is stirred under nitrogen and cooled to −20° C. After adding the phosphonate and subsequent stirring and cooling, the lithium chloride dissolved. After stirring for 2.5 hours, triethylamine (1 molar equivalent) is added neat via addition funnel and the temperature is held at −5° C. and stirred at this temperature for 19 hours. The temperature is adjusted to 0° C. and treated with 5% aqueous citric acid and the layers are separated. The organic layer is dried over magnesium sulfate and filtered. The crude product is purified on silica gel, eluted with ethyl acetate-hexanes (1:1) to afford the title intermediate 4a.
Reaction SMILES: [C:1]([O:5][P:6]([CH:13]([F:37])[C:14]1[CH:36]=[CH:35][C:17]([CH2:18][CH:19]([C:31]([O:33][CH3:34])=[O:32])[NH:20]C(OCC2C=CC=CC=2)=O)=[CH:16][CH:15]=1)([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:9]([O:8][P:6]([CH:13]([F:37])[C:14]1[CH:15]=[CH:16][C:17]([CH2:18][CH:19]([C:31]([O:33][CH3:34])=[O:32])[NH2:20])=[CH:35][CH:36]=1)([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])([CH3:10])([CH3:11])[CH3:12]
Reactant: COC(=O)C(Cc1ccc(C(F)P(=O)(OC(C)(C)C)OC(C)(C)C)cc1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(N)Cc1ccc(C(F)P(=O)(OC(C)(C)C)OC(C)(C)C)cc1
Reaction time: 0.5 h
Yield: 99.3 %

Procedure:
Compound 20 (1.09 g, 2.03 mmol) in anhydrous MeOH (50 mL) was hydrogenated over 10% Pd.C (436 mg) under H2 (45 psi) in a Parr apparatus. The vessel was evacuated and replenished with H2 at approximately 30 minute intervals. After 4 hours, the mixture was removed, filtered through celite and solvent removed under reduced pressure, yielding crude 21 (813 mg). Purification by silica gel chromatography afforded pure 21 (694 mg, 85%).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4](=[O:11])[C:5]([CH3:10])([CH:7]([CH3:9])[CH3:8])[N:6]=1.CN(C=O)C.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][CH:18]=1.[Na]>C1COCC1>[C:2]([NH:6][C:5]([CH3:10])([CH:7]([CH3:9])[CH3:8])[C:4]([NH:26][S:23]([C:20]1[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=1)(=[O:24])=[O:25])=[O:11])(=[O:3])[CH3:1]
Reactant: CC1=NC(C)(C(C)C)C(=O)O1
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(=O)NC(C)(C(=O)NS(=O)(=O)c1ccc(C)cc1)C(C)C

Procedure:
2,4-Dimethyl-4-isopropyl-2-oxazolin-5-one (2.0 g) is mixed with DMF (50 mL), THF (70 mL) and sodium p-toluene sulfonamide (5.0 g), and the resulting mixture is heated at reflux for 16 hours. At the end of this time the mixture is cooled, and the solvents are removed under vacuum. The residue is mixed with water and the pH adjusted to 8 with NaHCO3. The aqueous mixture is extracted with ethyl acetate and the organic layers are discarded. The aqueous mixture is acidified to pH-4 with HCl and saturated with NaCl and extracted with ethyl acetate. The organic extracts are combined, dried over MgSO4, filtered and evaporated to give 0.66 of the title product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)CCC>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=2)[CH:15]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: Oc1ccc(-c2cccnc2)cc1
Yield: 60 %

Procedure:
26.8 g of 4-bromophenol was taken under protective gas in 1000 ml of dioxane, mixed with 90 g 3-tributylstannylpyridine [preparation according to litt.: Org. Magn. Resonance, 7 (1975), 610] and 11.1 g of bis-(triphenylphosphine)-palladium(II) chloride and refluxed for 15 hours. After concentration by evaporation in a vacuum and purification on silica gel, 15.92 g of the above compound is isolated.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH2:6][CH2:5]2.I[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[CH3:20].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[CH3:20])[CH2:6][CH2:5]2
Reactant: Cc1ccncc1I
Reactant: Cc1ccc2c(c1)CCNC2=O
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccc2c(c1)CCN(c1cnccc1C)C2=O
Yield: 31.9 %

Procedure:
6-Methyl-3,4-dihydroisoquinolin-1(2H)-one (I-69f: 2 g, 12.422 mmol) was reacted with 3-iodo-4-methyl-pyridine (2.72 g, 12.422 mmol), 1,4-dioxane (70 mL), copper iodide (236 mg, 1.2422 mmol), trans-N,N′-dimethyl-cyclohexyl-1, 2-diamine (530 mg, 3.727 mmol) and potassium phosphate (6.58 g, 31.055 mmol) to afford the crude product. Purification by column chromatography on silica gel (1% methanol in DCM) afforded 1 g of the product (31.8% yield).
Reaction SMILES: B.[NH2:2][C:3]1[C:11]([CH3:12])=[CH:10][C:9]([I:13])=[CH:8][C:4]=1[C:5](O)=[O:6].O.[OH-].[Na+]>C1COCC1>[NH2:2][C:3]1[C:11]([CH3:12])=[CH:10][C:9]([I:13])=[CH:8][C:4]=1[CH2:5][OH:6]
Reactant: Cc1cc(I)cc(C(=O)O)c1N
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(I)cc(CO)c1N
Reaction time: 0.5 h

Procedure:
A solution of borane in THF (270 cm3 of a 1M solution) was added over 0.5 hours to a stirred suspension of 2-amino-5-iodo-3-methylbenzoic acid (18.48 g) in THF (400 cm3) at 0°. After stirring at 0° for 0.5 hours, the reaction mixture was warmed to 50° for a further 3 hours. After cooling in an ice-bath, water (25 cm3) was cautiously added dropwise with stirring, the resulting mixture was treated with an aqueous 10% solution of sodium hydroxide (100 cm3), and stirring was continued for a further 24 hours. Volatile material was then removed in vacuo and the residue was partitioned between water (100 cm3) and chloroform (200 cm3). The aqueous phase was re-extracted with chloroform (2×200 cm3), and the combined and dried (MgSO4) organic extracts were evaporated in vacuo to give an oil which was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting with chloroform. Combination and evaporation of appropriate fractions afforded the title compound, m.p. 101°-103° (14.22 g).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:15]4[CH:16]=[C:17]5[C:21](=[C:22]([F:24])[CH:23]=4)[CH2:20][N:19](S(C4C=CC(C)=CC=4)(=O)=O)[CH2:18]5)[C:12]=3[CH3:14])[C:7](=[O:35])[C:6]([C:36]([OH:38])=[O:37])=[CH:5]2)[CH2:3][CH2:2]1.C1(O)C=CC=CC=1.C(O)(=O)CC.[BrH:51]>>[BrH:51].[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:15]4[CH:16]=[C:17]5[C:21](=[C:22]([F:24])[CH:23]=4)[CH2:20][NH:19][CH2:18]5)[C:12]=3[CH3:14])[C:7](=[O:35])[C:6]([C:36]([OH:38])=[O:37])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)N2Cc3cc(-c4ccc5c(=O)c(C(=O)O)cn(C6CC6)c5c4C)cc(F)c3C2)cc1
Agent: Br
Solvent: Oc1ccccc1
Solvent: CCC(=O)O
Product: Cc1c(-c2cc(F)c3c(c2)CNC3)ccc2c(=O)c(C(=O)O)cn(C3CC3)c12

Procedure:
In 3.0 ml of 47% hydrobromic acid was suspended 0.30 g of 1-cyclopropyl-7-[7-fluoro-2-(p-toluenesulfonyl)isoindolin-5-yl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, followed by adding thereto 0.16 g of phenol and 1.8 ml of propionic acid, and the resulting mixture was heated at 100° C. for 10 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, after which ethanol was added to the resulting residue and the crystals were collected by filtration to obtain 0.21 g of colorless 1-cyclopropyl-7-(7-fluoroisoindolin-5-yl)-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrobromide. The hydrobromide obtained was suspended in 1.3 ml of ethanol and dissolved in 2.6 ml of a 0.5 N aqueous sodium hydroxide solution, after which carbon dioxide was bubbled into the resulting solution and the crystals were collected by filtration to obtain 0.10 g of colorless 1-cyclopropyl-7-(7-fluoroisoindolin-5-yl)-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[C:8]([OH:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[BH3-]C#N.[Na+].Cl.O>C1COCC1>[CH3:10][C:9]1[C:2]([OH:1])=[C:3]([CH3:4])[CH:6]=[CH:7][C:8]=1[OH:11]
Reactant: Cc1c(O)ccc(C=O)c1O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(O)c(C)c1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of compound 8 (0.90 g, 5.9 mmol) and NaBH3CN (1.1 g, 17.7 mmol) in THF (36 mL) was slowly added 1 M HCl (17.7 mL) to keep pH of the mixture at 3. The mixture was stirred at room temperature for 3 h. Water (50 mL) was added, and then the mixture was extracted with diethyl ether (50 mL×3). The combined organic layers were dried over Na2SO4 and then evaporated. The obtained white powder (0.58 g, 70%) was used to next step without further purification. 1H-NMR (CDCl3, 400 MHz): δ6.85 (1H, d, J=8.1 Hz), 6.37 (1H, d, J=8.1 Hz), 2.22 (3H, s), 2.19 (3H, s). 13C-NMR (CDCl3, 100 MHz) δ152.8, 127.6, 115.1, 109.9, 107.0, 15.5, 8.2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-])=O.[CH:12]([Mg]Br)=[CH2:13].[NH4+].[Cl-]>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]2[C:3]=1[NH:9][CH:13]=[CH:12]2
Reactant: C=C[Mg]Br
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Clc1ccc(Br)c2[nH]ccc12
Yield: 43.9 %

Procedure:
To a solution of 1-bromo-4-chloro-2-nitrobenzene (932 mg, 3.95 mmol) in tetrahydrofuran (10 mL), vinylmagnesium bromide (0.7 M in tetrahydrofuran) (12 mmol) in tetrahydrofuran (15 mL) was added drop wise at −40° C. After 1 h the reaction mixture was poured into saturated NH4Cl. The resulting organic layer was concentrated. The resulting residue was purified using a Teledyne ISCO chromatography system with a gradient eluent system of 2% ethyl acetate in hexane to yield the title compound (400 mg, 44%): 1H NMR (300 MHz, CDCl3) δ 6.73 (t, J=2.8 Hz, 1H), 7.02 (d, J=8.1 Hz, 1H), 7.19-7.39 (m, 2H), 8.43 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][CH:7]([CH2:13][CH2:14][CH3:15])[C:8]2=[O:12])=[CH:4][C:3]=1[O:16][CH3:17].[H-].[Na+].Cl[CH2:21][CH:22]=[C:23]([Cl:25])[CH3:24]>C1(C)C=CC=CC=1.CN(C)C=O>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH2:21][CH:22]=[C:23]([Cl:25])[CH3:24])([CH2:13][CH2:14][CH3:15])[C:8]2=[O:12])=[CH:4][C:3]=1[O:16][CH3:17]
Reactant: CC(Cl)=CCCl
Reactant: CCCC1Cc2cc(OC)c(Cl)c(Cl)c2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCCC1(CC=C(C)Cl)Cc2cc(OC)c(Cl)c(Cl)c2C1=O
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 80.2 %

Procedure:
6,7-Dichloro-2,3-dihydro-5-methoxy-2-propyl-1H-inden-1-one (13.66 g, 0.05 mole) dissolved in toluene (80 ml) was added over 15 minutes with stirring under N2 to a suspension of 56% sodium hydride (2.36 g, 0.055M) in dimethylformamide (65 ml) and toluene (15 ml) at 25°. The mixture was stirred without external heat for 11/2 hours, at 50° C. for 1/2 hour and then cooled to 30° C. A solution of 1,3-dichloro-2-butene (7.81 g, 0.0625 mole) in toluene (10 ml) was added, and the mixture was heated at 50°-55° for 2 hours, poured into ice water, and extracted with diethyl ether. The organic extracts were washed with water, dried over MgSO4, concentrated under vacuum and chromatographed on silica with elution with 1/1 hexane/methylene chloride to obtain 14.5 g of product as an oil which was a mixture of cis-trans isomers.
Reaction SMILES: [OH:1][C:2]([CH3:38])([CH3:37])[CH2:3][C@@:4]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4([C:28]([OH:30])=O)[CH2:27][CH2:26]4)[CH:20]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[CH3:39][NH:40][CH3:41]>>[CH3:39][N:40]([CH3:41])[C:28]([C:25]1([C:21]2[CH:20]=[C:19]([C:16]3[CH:17]=[CH:18][C:13]([C@@H:11]([N:7]4[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:38])[CH3:37])([C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=5)[O:9][C:8]4=[O:10])[CH3:12])=[CH:14][CH:15]=3)[CH:24]=[CH:23][N:22]=2)[CH2:26][CH2:27]1)=[O:30]
Reactant: CNC
Reactant: C[C@@H](c1ccc(-c2ccnc(C3(C(=O)O)CC3)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccnc(C3(C(=O)N(C)C)CC3)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Yield: 57 %

Procedure:
The title compound was prepared from 1-[4-(4-{(S)-1-[(S)-6-(2-hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-phenyl)-pyridin-2-yl]-cyclopropanecarboxylic acid and dimethylamine (2 mol/L in tetrahydrofuran) following a procedure analogous to that described in Step 2 for Intermediate 5. Yield: 57% of theory; LC (method 3): tR=3.07 min; Mass spectrum (ESI+): m/z=542 [M+H]+.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[CH:11][C:12]([N+:17]([O-:19])=[O:18])=[C:13]([CH:16]=1)[C:14]#[N:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:21]>O>[C:1]([C:9]1[CH:10]=[CH:11][C:12]([N+:17]([O-:19])=[O:18])=[C:13]([CH:16]=1)[C:14]([NH2:15])=[O:21])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: N#Cc1cc(C(=O)c2ccccc2)ccc1[N+](=O)[O-]
Solvent: O
Product: NC(=O)c1cc(C(=O)c2ccccc2)ccc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 54.8 %

Procedure:
A solution of 8.9 parts of intermediate 13, namely 5-benzoyl-2-nitrobenzonitrile, 166 parts of sulfuric acid and 10 parts of water was heated at 90° C. for 13/4 hours. The reaction mixture was poured into ice-water. The precipitate was filtered off and recrystallized from methanol. The product was filtered off, washed with methanol and 2,2'-oxybispropane and dried in vacuo at 60°-70° C., yielding 5.23 parts (54.8%) of 5-benzoyl-2-nitrobenzamide; mp. 244.3° C. (intermediate 14).
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH3:27])[C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:7][CH:6]=1)[CH3:2].[CH2:28]=O.[BH4-].[Na+]>CO.O>[CH2:26]([N:3]([CH2:1][CH3:2])[C:4](=[O:25])[C:5]1[CH:6]=[CH:7][C:8]([N:11]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:12]2[CH2:17][CH2:16][N:15]([CH3:28])[CH2:14][CH2:13]2)=[CH:9][CH:10]=1)[CH3:27]
Reactant: CCN(CC)C(=O)c1ccc(N(Cc2ccccc2)C2CCNCC2)cc1
Reactant: C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCN(CC)C(=O)c1ccc(N(Cc2ccccc2)C2CCN(C)CC2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of N,N-diethyl-4-[benzyl(piperidin-4-yl)amino]benzamide (Compound 8) (0.67 g, 0.207 mmole) in 10 mL of methanol was added 37% formalin solution (1 mL), and the resulting mixture was cooled in an ice bath under Argon. To this mixture was added sodium borohydride (0.69 g, 18.2 mmol) in small portions. The reaction mixture was allowed to warm to ambient temperature and was stirred for three days. The reaction mixture was diluted with water (25 mL), and the resulting solution was extracted three times with chloroform (25 mL). The organic extracts were combined, dried (Na2SO4), and concentrated to provide a pale yellow oil. This material was purified on a flash silica gel column (10% methanol-chloroform to 15% methanol-chloroform) to provide 0.54 g of N,N-diethyl-4-[benzyl(1-methylpiperidin-4-yl)amino]benzamide as a pale yellow semisolid. This material was dissolved in acetonitrile, and oxalic acid (0.13 g) was added. Upon addition of diethyl ether, a cream-colored precipitate came out of solution. Recrystallization from acetonitrile and diethyl ether afforded 0.18 g (18% yield) of a cream-colored solid, mp 101-105° C. MS (ES), m/z 380 (MH+). 300 MHz 1H NMR (DMSO-d6) δ0.85-1.15 (br m, 6H), 1.75-2.02 (br m, 2H), 2.72 (s, 3H), 2.95-3.15 (br m, 2H), 3.16-3.45 (m, 6H), 4.12-4.30 (br m, 1H), 4.49 (br s, 2H), 6.63-6.82 (br m, 2H), 7.10-7.40 (m, 7H). Elemental analysis: Calculated for C24H33N3O.C2H2O4.0.6H2O: C, 65.01; H, 7.60; N, 8.75; H2O, 2.25. Found C, 64.77; H, 7.25; N, 8.59; Karl Fischer H2O, 1.55.
Reaction SMILES: O[C:2]1[N:7]=[C:6]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]=[C:4]([CH3:16])[CH:3]=1.[OH-].[Na+].P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:2]1[N:7]=[C:6]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]=[C:4]([CH3:16])[CH:3]=1
Reactant: Cc1cc(O)nc(C=Cc2ccccc2)n1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(Cl)nc(C=Cc2ccccc2)n1

Procedure:
212 mg (1 mmol) of 6-hydroxy-4-methyl-2-(2-phenylethenyl)-pyrimidine in 1 ml of phosphorus oxychloride are boiled under reflux for 35 minutes under nitrogen. When cool, the reaction mixture is poured onto ice, and the aqueous solution is neutralised with sodium hydroxide solution and extracted several times with ether. The ether extracts are washed with water and saturated sodium chloride solution, dried over CaCl2, filtered with suction and concentrated. Purification is effected by sublimation in a bulb tube oven at 150° oven temperature and in vacuo (0.1 mm Hg=0.13 mbar). Colourless crystals of m.p. 71°-73° are obtained.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][CH2:21][O:22][CH3:23])[N:14]([CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([OH:24])=[CH:5][C:4]=2[N:3]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31]O)[CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.C(#N)C>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][CH2:21][O:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:18])([OH:19])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([O:24][CH2:31][C:27]3[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=3)=[CH:5][C:4]=2[N:3]=1
Reactant: COCCc1nc2c(N)nc3cc(O)ccc3c2n1CC(C)(C)O
Reactant: OCc1cccnc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CC#N
Product: COCCc1nc2c(N)nc3cc(OCc4cccnc4)ccc3c2n1CC(C)(C)O
Reaction time: 0.75 h
Yield: 41 %

Procedure:
4-Amino-1-(2-hydroxy-2-methylpropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-7-ol, (2.5 g, 7.5 mmol) was slurried in 75 mL of THF to which 3-pyridylcarbinol (350 mg, 3.18 mmol) and triphenylphosphine (1.59 g, 6.06 mmol) were added. To this was added 1.2 g (5.93 mmol) of diisopropyl azodicarboxylate (DIAD) and the reaction mixture was stirred for 45 minutes. Approximately 3 additional equivalents of each reagent were added to complete the reaction. The reaction mixture was then concentrated and partitioned between chloroform and aqueous sodium carbonate. The organic fraction was dried and passed through an ion exchange resin with methanol, followed by 1M ammonia in methanol as the eluents. The solvent was concentrated and the residue was purified by flash column chromatography on silica gel using a gradient of 0-40% CMA in chloroform. The desired fractions were concentrated to produce an oil which was taken up in 20 mL of refluxing acetonitrile. Upon cooling, white crystals formed which were filtered and dried to provide 0.55 g of 1-[4-amino-2-(2-methoxyethyl)-7-(pyridin-3-ylmethoxy)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol, mp 200.0-202.0° C.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([NH2:15])=[O:14].[CH3:16][C:17](=O)[CH2:18][CH3:19].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH2:17]([C:18]1([CH3:19])[NH:1][C:2]2[CH:6]=[C:5]([C:7]3[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=3)[S:4][C:3]=2[C:13](=[O:14])[NH:15]1)[CH3:16]
Reactant: CCC(C)=O
Reactant: NC(=O)c1sc(-c2ccncc2)cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCC1(C)NC(=O)c2sc(-c3ccncc3)cc2N1
Temperature: 70 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
A mixture of 3-amino-5-(pyridin-4-yl)thiophene-2-carboxamide (0.108 g, 0.500 mmol), 2-butanone (1.0 mL), p-toluenesulfonic acid monohydrate (0.0096 g, 0.050 mmol) and acetic acid (3.0 mL) was stirred for 1 h at 70° C. The reaction mixture was poured into aqueous sodium hydrogen carbonate (200 mL). Extraction with ethyl acetate (200 mL, 100 mL), washing with aqueous sodium hydrogen carbonate, drying over magnesium sulfate, filtration and concentration at reduced pressure gave a residue, which was triturated with dichloromethane/ethyl acetate (1:1, 6 mL), and the precipitate was collected by filtration to afford the title compound (0.095 g, 69%) as a yellow solid:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].C([O:14][C:15]([C:17]1[C:24]([CH3:25])=[CH:23][C:20]([CH:21]=O)=[C:19]([O:26][CH3:27])[C:18]=1[CH3:28])=[O:16])C>>[OH:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH:10]=[CH:21][C:20]1[CH:23]=[C:24]([CH3:25])[C:17]([C:15]([OH:16])=[O:14])=[C:18]([CH3:28])[C:19]=1[O:26][CH3:27]
Reactant: CC(=O)c1ccc(Cl)cc1O
Reactant: CCOC(=O)c1c(C)cc(C=O)c(OC)c1C
Product: COc1c(C=CC(=O)c2ccc(Cl)cc2O)cc(C)c(C(=O)O)c1C

Procedure:
This compound was synthesized from 2′-hydroxy-4′-chloroacetophenone and 4-ethyloxycarbonyldimethylmethyloxybenzaldehyde (starting material 9) according to general method 2 described earlier.