Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.[Na].CN(C)C=O.[CH2:26](Br)[C:27]#[CH:28]>C[O-].[Na+].CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:28][C:27]#[CH:26])[C:10](=[O:12])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1
Reactant: O=C1CN=C(c2ccccc2)c2cc(Cl)ccc2N1
Reactant: C#CCBr
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: CN(C)C=O
Product: C#CCN1C(=O)CN=C(c2ccccc2)c2cc(Cl)ccc21
Reaction time: 4 h

Procedure:
100 ml. of a 1 N solution in sodium methoxide in methanol were added to a solution of 27.05 g (0.1 mol) of 7-chloro-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one in 500 ml. of anhydrous methanol. The solvent was driven off under reduced pressure, and the resulting sodium derivative was dissolved in 200 ml. of dimethylformamide. The temperature of the solution was maintained at 10°-15° C. while 10 ml. of propargyl bromide were added dropwise; and the mixture was stirred for about 4 hours, and then poured over ice. The product was filtered and dissolved in chloroform; and the chloroform solution was separated from the aqueous layer and dried over sodium sulphate. The chloroform was evaporated off from the solution, and the residue was dissolved in the minimum quantity of a 7:3 (by volume) mixture of benzene and ethyl acetate. This solution was chromatographed on a column of silica gel and eluted with a 7:3 (by volume) mixture of benzene and ethyl acetate. The portion of eluate containing the desired product, as determined by thin-layer chromatography, was collected and evaporated under reduced pressure. The residue was recrystallized from a 1:1 (by volume) mixture of benzene and hexane, giving 14 g of the pure desired product with a melting point of 141°-143° C.
Reaction SMILES: [CH:1]([CH:4]1[O:9][CH:8]([O:10][CH2:11][CH3:12])[CH:7]=[CH:6][C:5]1=[O:13])([CH3:3])[CH3:2].[CH2:14]=O.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>CO>[CH:1]([CH:4]1[O:9][CH:8]([O:10][CH2:11][CH3:12])[CH:7]=[C:6]([CH2:14][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:5]1=[O:13])([CH3:3])[CH3:2]
Reactant: C1COCCN1
Reactant: CCOC1C=CC(=O)C(C(C)C)O1
Reactant: C=O
Solvent: CO
Product: CCOC1C=C(CN2CCOCC2)C(=O)C(C(C)C)O1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.6 %

Procedure:
To 100 ml of methanol are added 19.8 g of 6-isopropyl-2-ethoxy-5-oxo-5,6-dihydro-2H-pyran, 7 g of 37% formalin and 9 g of morpholine. Then the mixture is stirred at room temperature for 4 hours. The reaction mixture is concentrated at reduced pressure and the residue is isolated and purified by silica gel column chromatography giving 23.6 g of light yellow oily 6-isopropyl-2-ethoxy-4-morpholinomethyl-5-oxo-5,6-dihydro-2H-pyran (compound No. 2 in Table 1). IR (neat)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10][OH:11].[CH2:20](Br)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].O>CN(C=O)C>[CH2:33]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10][OH:11])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH3:20]
Reactant: CC(C)(C)OC(=O)NC(CO)Cc1ccccc1O
Reactant: CCCCCCCCCCCCCCBr
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCCCCOc1ccccc1CC(CO)NC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
A mixture of the alcohol from Step A (218 mg, 0.82 mmol), tetradecyl bromide (170 μL, 0.9 mmol) and CSCO3 (532 mg, 1.63 mmol) in DMF (8 mL) was stirred for 16 hs at room temperature under argon. The mixture was poured into water and extracted with EtOAc. The organic extracts were combined, washed with water and brine, dried (MgSO4), and concentrated in vacuo to give an oil. Purification by chromatography (SiO2, 20% EtOAc in hexanes) gave the title compound as a solid.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].Cl.[NH2:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[OH:19])=[CH:16][CH:15]=[C:14]([C:20]([F:23])([F:22])[F:21])[CH:13]=2.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>O1CCCC1>[OH:19][C:18]1[C:17]2[C:12](=[CH:13][C:14]([C:20]([F:23])([F:21])[F:22])=[CH:15][CH:16]=2)[N:11]=[CH:10][C:9]=1[NH:8][C:1](=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: Nc1cnc2cc(C(F)(F)F)ccc2c1O
Reactant: CCCC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCC(=O)Nc1cnc2cc(C(F)(F)F)ccc2c1O
Reaction time: 16 h
Yield: 83.8 %

Procedure:
Butyryl chloride (1.5 mL, 14.5 mmol) was added dropwise to a mixture of 3-amino-7-(trifluoromethyl)-4-quinolinol hydrochloride (3.5 g, 13.2 mmol), triethylamine (6.1 mL, 43.6 mmol) and anhydrous tetrahydrofuran (30 mL). The reaction mixture was allowed to stir for 16 hours. A small amount of aqueous sodium bicarbonate was added and the reaction mixture was stirred for 0.5 hours. The tetrahydrofuran was removed under vacuum. The resulting solid was stirred with diethyl ether, isolated by filtration, washed with water and diethyl ether, and then dried in a vacuum oven at 80° C. overnight to provide 3.3 g of N-[4-hydroxy-7-(trifluoromethyl)quinolin-3-yl]butanamide as a cream colored solid.
Reaction SMILES: [CH2:1]([C:3]1[N:7]2[N:8]=[C:9]([CH3:28])[C:10]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)=[C:11]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)[C:6]2=[CH:5][CH:4]=1)[CH3:2].[OH-:29].[Na+].OO>CN(C)C=O>[CH2:1]([C:3]1[N:7]2[N:8]=[C:9]([CH3:28])[C:10]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)=[C:11]([C:12]3[CH:19]=[CH:18][C:15]([C:16]([NH2:17])=[O:29])=[CH:14][CH:13]=3)[C:6]2=[CH:5][CH:4]=1)[CH3:2]
Reactant: [OH-]
Reactant: CCc1ccc2c(-c3ccc(C#N)cc3)c(-c3ccc(OC)cc3)c(C)nn12
Agent: OO
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1ccc2c(-c3ccc(C(N)=O)cc3)c(-c3ccc(OC)cc3)c(C)nn12
Reaction time: 1 h
Yield: 78 %

Procedure:
To a solution of 4-[7-ethyl-3-(4-methoxyphenyl)-2-methylpyrrolo[1,2-b]pyridazin-4-yl]benzonitrile (22 mg) in N,N-dimethylformamide (1 mL) were added 1N sodium hydroxide (0.12 mL) and 30% hydrogen peroxide (0.07 mL) at ambient temperature. After 1 hour stirring, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water three times and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by flash silica gel column chromatography (silica gel, 30 mL) eluting with hexane-ethyl acetate=5-1 and 0-1 to give 4-[7-ethyl-3-(4-methoxyphenyl)-2-methylpyrrolo[1,2-b]pyridazin-4-yl]benzamide (18 mg, 78.0%) as an yellow solid.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:25])=[C:11]([N:15]4[CH2:19][CH2:18][CH:17]([N:20]5[CH:24]=[N:23][CH:22]=[N:21]5)[CH2:16]4)[C:12]=3[F:14])[C:7](=[O:26])[C:6]([C:27]([OH:29])=[O:28])=[CH:5]2)[CH2:3][CH2:2]1.[OH:30][CH2:31][CH2:32][N+:33]([CH3:36])([CH3:35])[CH3:34]>CO.O>[CH3:34][N+:33]([CH3:36])([CH3:35])[CH2:32][CH2:31][OH:30].[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:25])=[C:11]([N:15]4[CH2:19][CH2:18][CH:17]([N:20]5[CH:24]=[N:23][CH:22]=[N:21]5)[CH2:16]4)[C:12]=3[F:14])[C:7](=[O:26])[C:6]([C:27]([O-:29])=[O:28])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCC(n4cncn4)C3)c(F)cc2c1=O
Agent: C[N+](C)(C)CCO
Solvent: CO
Solvent: O
Product: O=C([O-])c1cn(C2CC2)c2c(F)c(N3CCC(n4cncn4)C3)c(F)cc2c1=O
Temperature: 25 °C

Procedure:
To a suspension of 100.25 mg (0.25 mmol) of 1-cyclopropyl-6,8-difluoro-7-[3-(1,2,4-triazol-1-yl) pyrrolidin-1-yl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid in 0.625 ml of methanol and 0.2 ml of water was added at room temperature slowly 0.075 ml of 45% choline in methanol. The solution was stirred at room temperature for an additional hour and after being through a cotton filter, the supernatant was evaporated to dryness under reduced pressure (30° C.). The residue was crystallized from acetone-methanol and dried to give 85 mg of off white solid, m.p. 193°-194° C. 1H NMR (CD3OD) δ: 8.61 (s, 1H), 8.42 (bs, 1H), 8.01 (s, 1H), 7.76 (dd, 14Hz, 1.8Hz, 1H), 5.3-5.15 (m, 1H), 4.3-3.75 (m, 7H), 3.5-3.44 (m, 2H), 3.21 (s, 9H), 2.62-2.45 (m, 2H), 1.22-1.02 (m, 4H). Anal. calcd. for C24H30F2N6O4H2O: C, 55.16; H, 6.13; N, 16.07. Found: C, 54.46; H, 5.91; N, 15.82.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:15][C:14](=[O:16])[O:13][C:11](=[O:12])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH2:18]1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:10][C:11](=[O:12])[CH:18]2[CH2:19][CH2:20][C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[NH:17]2)[CH2:15][C:14]([OH:13])=[O:16])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1CC(c2ccc(Cl)c(Cl)c2)CC(=O)O1
Reactant: c1ccc2c(c1)CCCN2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)CC(CC(=O)C1CCc2ccccc2N1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3-(3,4-Dichlorophenyl)glutaric anhydride (10 g, Example 1, Step C) in CH2Cl2 (300 mL) at 0° C. was treated sequentially with 1,2,3,4-tetrahydroquinoline (5.6 mL), triethylamine (6.3 mL) and N,N-dimethylaminopyridine (472 mg). The mixture was stirred at 0° C. for two hours then allowed to warm to room temperature and stirred for 12 hours. The reaction mixture was diluted with CH2Cl2 (500 mL) and washed with 1N HCl (1×200 mL) and water (1×200 mL). The organic layers were dried over MgSO4, filtered and concentrated to afford the title compound (14.3 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:3]1.C(N(CC)CC)C.[Cl:21][C:22]1[CH:31]=[CH:30][C:25]([C:26](=[O:29])[CH2:27]Br)=[CH:24][CH:23]=1.C(=O)(O)[O-].[Na+]>O1CCCC1.C(Cl)(Cl)Cl>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:27][C:26]([C:25]2[CH:30]=[CH:31][C:22]([Cl:21])=[CH:23][CH:24]=2)=[O:29])[CH:4]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:3]1
Reactant: CN1CCNC(c2ccccc2)C1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CN1CCN(CC(=O)c2ccc(Cl)cc2)C(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 95 %

Procedure:
To a stirred mixture of 14.0 g (0.08 mol) of 1-methyl-3-phenylpiperazine and 20 g (0.2 mol) of triethylamine in 160 ml of tetrahydrofuran was added dropwise a solution of 18.2 g (0.08 mol) of 4-chlorophenacyl bromide in 55 ml of chloroform. The resulting mixture was stirred at ambient temperature for 3.5 hours, poured into 50% aqueous sodium bicarbonate and extracted with chloroform. The organic extracts were combined, washed with water and saturated sodium chloride and dried over sodium sulfate. The filtrate was concentrated to dryness to give 25 g of crude 1-methyl-3-phenyl-4-(4-chlorophenacyl) piperazine. This material was used as such in the next step of the process.
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[S:21](=[O:23])(=[O:22])[N:20]([CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:19](=[O:30])[CH2:18]2)=[C:13]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:12]=1.C(N(CC)CC)C.[C:46](Cl)(=[O:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>C(Cl)Cl>[CH2:32]([O:31][C:13]1[CH:12]=[C:11]([CH2:10][CH2:9][NH:8][C:46](=[O:53])[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:16]=[CH:15][C:14]=1[N:17]1[CH2:18][C:19](=[O:30])[N:20]([CH2:24][CH2:25][Si:26]([CH3:27])([CH3:28])[CH3:29])[S:21]1(=[O:23])=[O:22])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(CCN)cc2OCc2ccccc2)S1(=O)=O
Reactant: O=C(Cl)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(CCNC(=O)c3ccccc3)cc2OCc2ccccc2)S1(=O)=O

Procedure:
To a solution of 5-[4-(2-aminoethyl)-2-benzyloxyphenyl]-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one TFA salt (235 mg, 0.356 mmol) in methylene chloride (2 mL) is added triethylamine (0.1 mL) then benzoyl chloride (56 mg, 0.4 mmol) and the mixture is stirred at RT for 2 h. The solvent is removed under reduced pressure and 1 N HCl is added. The mixture is extracted with ether and the organic phase is dried over magnesium sulfate. The solvent is removed under reduced pressure and the residue is purified by flash chromatography using hexane/EtOAc (7:3) as eluent to give the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH3:15])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9](SC)=[CH:8][C:7]=1[I:14])=[O:4].O[O:18][S:19]([O-:21])=O.[K+].[C:23](=O)([O-])O.[Na+]>O1CCCC1.O>[CH3:15][C:2]([CH3:1])([CH3:16])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([S:19]([CH3:23])(=[O:21])=[O:18])=[CH:8][C:7]=1[I:14])=[O:4]
Reactant: O=S([O-])OO
Reactant: O=C([O-])O
Reactant: CSc1ccc(NC(=O)C(C)(C)C)c(I)c1
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)C(=O)Nc1ccc(S(C)(=O)=O)cc1I
Temperature: 22.5 °C
Reaction time: 2 h

Procedure:
To a solution of 2,2-dimethyl-N-(2-iodo-4-methylthiophenyl)propionamide in a mixture of tetrahydrofuran/water mixture (2:1, 210 ml), OXONE (registered trademark) (22.0 mg) was added and the mixture was stirred at 15 to 30° C. for 2 hours. After completion of the reaction, the reaction solution was poured into a saturated aqueous sodium hydrogencarbonate solution, extracted with ethyl acetate, washed with a saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was recrystallized (ethyl acetate/n-hexane) to obtain 5.22 g of the desired product as a white crystal.
Reaction SMILES: Br[CH:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][C:7]([C:13]#[N:14])=[CH:8][CH:9]=2)[O:4][CH2:3]1.C(O)(=O)C.[N-:19]=[N+:20]=[N-:21].[Na+]>CN(C=O)C.O>[N:19]([CH:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][C:7]([C:13]#[N:14])=[CH:8][CH:9]=2)[O:4][CH2:3]1)=[N+:20]=[N-:21]
Reactant: N#Cc1ccc2c(c1)OCC(Br)C2=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: N#Cc1ccc2c(c1)OCC(N=[N+]=[N-])C2=O
Temperature: -15 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
3-Bromo-4-oxochroman-7-carbonitrile Int-2-A (140 mg, 0.55 mmol) was dissolved in DMF (3627 μL) and glacial acetic acid (91.0 μL) was added. The solution was cooled to −15° C. To this solution was added sodium azide (54.2 mg, 0.83 mmol) in water (725 μL) dropwise. After stirring for 2 h at −15° C., the reaction mixture was warmed to room temperature and stirred until all the starting material was consumed. The color of the solution turned dark red. The reaction mixture was diluted by the addition of 50 mL water and extracted by EtOAc twice. The combined organic layers were washed with saturated NaHCO3 solution then brine, dried (MgSO4), and filtered before it was concentrated to give racemic 3-azido-4-oxochroman-7-carbonitrile (110 mg, 0.51 mmol, 92.5% yield): LCMS=237.02 [M+Na]+.
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2[C:18]3[C:17]4[CH:19]=[C:20]([N+:23]([O-])=O)[CH:21]=[CH:22][C:16]=4[O:15][C:14]=3[C:13]([O:26][CH3:27])=[CH:12][CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN>[Ni].CO.CN(C=O)C>[C:1]1([NH:7][C:8]([C:10]2[C:18]3[C:17]4[CH:19]=[C:20]([NH2:23])[CH:21]=[CH:22][C:16]=4[O:15][C:14]=3[C:13]([O:26][CH3:27])=[CH:12][CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2)c2c1oc1ccc([N+](=O)[O-])cc12
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Nc2ccccc2)c2c1oc1ccc(N)cc12
Yield: 98.1 %

Procedure:
N1-phenyl-4-methoxy-8-nitro-dibenzo[b,d]furan-1-carboxamide (100 mg) (from step 1) was reduced using raney nickel (100 mg) in methanol (40 ml) and DMF (10 ml) in the presence of hydrazine hydrate (0.5 ml) under gentle reflux for 1 h. The reaction mixture was fliterd through celite and the filterate was concentrated in vaccuo. The residue was triturated with water, to obtain a solid which was filtered dried to give the product as white solid (90 mg).
Reaction SMILES: [C:1]1([Mg]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:9]([N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C:17]1=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C[O:26]CC1>>[CH2:9]([N:16]1[CH2:21][CH2:20][C:19]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([OH:26])[CH2:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1CCCCN1Cc1ccccc1
Reactant: C1CCOC1
Reactant: Cl[Mg]c1ccccc1
Product: OC1(c2ccccc2)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of phenylmagnesium chloride in THF (25%, 33 mL) was added at −10° C. to a solution of 1-Benzylpiperidone (10 g, dissolved in THF). The mixture was warmed to room temperature, stirred for 4 h and quenched by addition of 20% ammonium chloride solution. The mixture was extracted three times with methyl tert. butyl ether and the combined organic layer was dried over sodium sulfate and evaporated to dryness. The crude product was purified by silica gel chromatography to give 14.3 g of the desired product as an orange oil. Rt=1.09 min (Method B). Detected mass: 268.1 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[N:30][CH:29]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:27](=[O:34])[C:28]3[CH:33]=[CH:32][CH:31]=[N:30][CH:29]=3)[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: NCCCCn1c(-c2ccccc2)nc2c(N)nc3ccccc3c21
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Product: Nc1nc2ccccc2c2c1nc(-c1ccccc1)n2CCCCNC(=O)c1cccnc1

Procedure:
According to the general method of Example 61, 1-(4-aminobutyl)-2-phenyl-1H-imidazo[4,5-c]quinolin-4-amine and nicotinoyl chloride hydrochloride were combined to provide N3-[4-(4-amino-2-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]nicotinamide as a white crystalline solid, m.p. 84.5-86.1° C. 1H NMR (300 MHz, DMSO-d6) δ 8.91 (s, 1H), 8.69 (m, 1H), 8.56 (m, 1H), 8.07 (m, 2H), 7.75-7.41 (m, 8H), 7.21 (m, 1H), 6.72 (broad s, 2H), 4.60 (m, 2H), 3.15 (t, J=6.0 Hz, 2H), 1.86 (m, 2H), 1.40 (m, 2H); MS (CI) m/e 437 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]2[C:10]=1[C:9](=[O:11])[CH2:8][CH2:7]2.[N:13]1([S:19](Cl)(=[O:21])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[Cl-].[Al+3].[Cl-].[Cl-]>ClC(Cl)C>[OH:1][C:2]1[C:3]([S:19]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)(=[O:21])=[O:20])=[CH:4][C:5]([CH3:12])=[C:6]2[C:10]=1[C:9](=[O:11])[CH2:8][CH2:7]2
Reactant: Cc1ccc(O)c2c1CCC2=O
Reactant: O=S(=O)(Cl)N1CCCCC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: Cc1cc(S(=O)(=O)N2CCCCC2)c(O)c2c1CCC2=O
Yield: 32.5 %

Procedure:
Into a solution of 2 g of 7-hydroxy-4-methyl-1-indanone in 10 ml of dichloroethane was added 2.27 g of 1-piperidine sulfonyl chloride. Then 10 g of anhydrous aluminum chloride was gradually added to the mixture and stirred, and the reaction mixture was refluxed by heating for 8 hours. The reaction mixture was extracted with 200 ml of chloroform, washed with water, then the chloroform was removed by evaporation under a reduced pressure. The residue was purified by means of a silica gel column chromatography (eluent: chloroform), and recrystallized from ethanol to obtain 1.24 g of 7-hydroxy-4-methyl-6-(1-piperidinesulfonyl)-1-indanone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.CS(O[CH2:18][CH2:19][C:20]1[CH:21]=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=1)(=O)=O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:18][CH2:19][C:20]3[C:25](=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=3)[C:10]2=[O:12])=[CH:7][CH:8]=1
Reactant: Cc1cccc(CCOS(C)(=O)=O)c1
Reactant: COc1ccc(CC(=O)O)cc1
Product: COc1ccc(C2CCc3cc(C)ccc3C2=O)cc1

Procedure:
The process described in the third and fourth paragraphs of Example 1 was repeated using p-methoxyphenylacetic acid and 2-m-tolylethyl methanesulphonate as starting materials. The 3,4-dihydro-2-p-methoxyphenyl-6-methylnaphthalen-1(2H)-one thus obtained (1.33 g., m.p. 125°-126° C. after crystallisation from methanol) was added to a stirred solution of lithium diisopropylamide in tetrahydrofuran [prepared from n-butyllithium (5 ml. of a 1.5 molar solution in hexane) and a solution of diisopropylamine (0.8 g.; freshly distilled from potassium hydroxide) in tetrahydrofuran (20 ml.)] which was cooled to -20° C. under an atmosphere of argon. The mixture was stirred at -20° C. for 1 hour, methyl iodide (1.27 g.) was added and the mixture was stirred at laboratory temperature for 18 hours. Aqueous N-hydrochloric acid (50 ml.) was added and the mixture was extracted twice with diethyl ether (50 ml. each time). The combined extracts were dried and evaporated to dryness and the residue was purified by medium pressure chromatography on a silica gel column using a 12.5:1 v/v mixture of petroleum ether (b.p. 60°-80° C.) and ethyl acetate as eluent. The product was crystallised from petroleum ether (b.p. 60°-80° C.) and there was thus obtained 3,4-dihydro-2-p-methoxyphenyl-2,6-dimethylnaphthalen-1(2H)-one, m.p. 80°-82° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[O:12]=[S:13]1(=[O:19])[CH2:17][CH2:16][C@H:15](N)[CH2:14]1.C([O-])([O-])=O.[K+].[K+].CCN(CC)CC>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C@H:15]2[CH2:16][CH2:17][S:13](=[O:19])(=[O:12])[CH2:14]2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: Nc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: N[C@H]1CCS(=O)(=O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)ccc1N[C@H]1CCS(=O)(=O)C1
Temperature: 100 °C
Reaction time: 2 h
Yield: 66.4 %

Procedure:
To a mixture of 4-chloro-2-nitro-phenylamine (1.2 g, 6.8 mmol) and (S)-1,1-dioxo-tetrahydro-1λ6-thiophen-3-ylamine (0.97 g, 5.7 mmol) and K2CO3 (13.6 mmol) in DMF (8 mL) was added Et3N (13.6 mmol). The mixture was stirred at 100° C. for 2 h. After cooled to RT, the reaction mixture was poured into water, extracted with EtOAc. The organic phase was washed with saturated NH4Cl, aqueous NaHCO3 and brine. The organic phase was dried over Na2SO4. The nitro compound (1.1 g, yield: 66%) was obtained as yellow solid by flash column (ethyl acetate/petroleum ether=1/1). MS obsd. MS obsd. (ESI+) [(M+H)+] 291.0.
Reaction SMILES: [C:1]1([C:7]2[C:15]([CH:16]=O)=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18]([O:24][CH3:25])(=[O:23])[CH2:19][C:20]([CH3:22])=O.[NH3:26]>CO.C(Cl)(Cl)Cl>[CH3:22][C:20]1[NH:26][C:20]([CH3:22])=[C:19]([C:18]([O:24][CH3:25])=[O:23])[CH:16]([C:15]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:8][N:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=23)[C:19]=1[C:18]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)CC(C)=O
Reactant: N
Reactant: O=Cc1c(-c2ccccc2)nn2ccccc12
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1c(-c2ccccc2)nn2ccccc12
Temperature: 25 °C
Reaction time: 246 h

Procedure:
A mixture of 2-phenylpyrazolo[1,5-a]pyridine-3-carbaldehyde (1.00 g), methyl acetoacetate (1.10 g), and 14% methanolic ammonia (18 ml) in a mixture of methanol (20 ml) and chloroform (10 ml) was stirred for 246 hours at room temperature. The solvent was removed in vacuo and the residue was dissolved in methylene chloride (30 ml). The solution was washed with water (10 ml) and sodium chloride aqueous solution (10 ml), dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (15 g) with a mixture of n-hexane and ethyl acetate (2:1). The fractions containing the object compound were combined and evaporated in vacuo to give 3-[2,6-dimethyl-3,5-bis(methoxycarbonyl)-1,4-dihydropyridin-4-yl]-2-phenylpyrazolo[1,5-a]pyridine. This compound was purified from a mixture of ethyl acetate and n-hexane.