Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[O:11][N:10]=[C:9]([C:12]([O:14]CC)=[O:13])[C:8]=1[C:17]([F:20])([F:19])[F:18].[OH-].[Na+]>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[O:11][N:10]=[C:9]([C:12]([OH:14])=[O:13])[C:8]=1[C:17]([F:20])([F:18])[F:19]
Reactant: CCOC(=O)c1noc(-c2ccccn2)c1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1noc(-c2ccccn2)c1C(F)(F)F
Yield: 74.9 %

Procedure:
A solution of ethyl 5-(pyridin-2-yl)-4-(trifluoromethyl)isoxazole-3-carboxylate (138 mg, 0.482 mmol) and 1N aqueous sodium hydroxide (579 μL, 0.579 mmol) in ethanol (4.5 mL) was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water (0.5 mL) and acidified with a 1N aqueous solution of hydrochloric acid to a pH of ˜3.0. The solution was extracted with ethyl acetate (3×2 mL). The organic layer was washed with water (1 mL), washed with brine (1 mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded 5-(pyridin-2-yl)-4-(trifluoromethyl)isoxazole-3-carboxylic acid (0.093, 0.361 mmol, 75% yield). The product had an HPLC retention. time=1.57 min.—Column: YMC S5 COMBISCREEN® 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=259.0. 1H NMR (400 MHz, CD3OD) δ ppm 7.60-7.65 (m, 2H), 7.92 (d, J=8.03 Hz, 2H), 8.02-8.09 (m, 2H), and 8.78 (d, 2H).
Reaction SMILES: CN(C)S([N:6]1[CH:10]=[C:9]([CH2:11][N:12]([CH2:21][CH3:22])[C:13]2[N:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][N:14]=2)[N:8]=[CH:7]1)(=O)=O.[OH-].[Na+]>Cl>[CH2:21]([N:12]([CH2:11][C:9]1[NH:8][CH:7]=[N:6][CH:10]=1)[C:13]1[N:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][N:14]=1)[CH3:22]
Reactant: CCN(Cc1cn(S(=O)(=O)N(C)C)cn1)c1nccc(OC)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCN(Cc1cnc[nH]1)c1nccc(OC)n1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
4-{[Ethyl-(4-methoxy-pyrimidin-2-yl)-amino]-methyl}-imidazole-1-sulfonic acid dimethylamide (0.265 g, 0.78 mmol) was dissolved in aqueous hydrochloric acid (4 N, 2 ml) and the mixture was stirred at 100° C. for 2 hours. After cooling concentrated sodium hydroxide solution was added slowly until basic pH. The mixture was extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and evaporated. The residue was purified by flash chromatography, column: Isolute® Flash-NH2 (Separtis); eluent: heptane/ethyl acetate=1:1) to yield a colorless liquid, (0.10 g, 55%); MS (ISP): 234.3 ((M+H)+.).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][CH:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15].[OH:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1>CN(C)C=O>[CH3:17][CH:10]([CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:9][CH2:8][O:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:27][CH:28]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CC(C)CCCC(C)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCC(C)CCCC(C)C)cc1
Temperature: 70 °C
Reaction time: 16 h
Yield: 95.9 %

Procedure:
Under an argon atmosphere, potassium carbonate (12.5 g, 90.3 mmol) was suspended in anhydrous N,N-dimethylformamide (100 ml), 1-bromo-3,7-dimethyloctane (13.3 g, 60.1 mmol) and methyl (4-hydroxy)benzoate (8.74 g, 57.4 mmol) were added, and the mixture was stirred at 70° C. for 16 hr. The reaction mixture was filtered to remove potassium carbonate. Water (50 ml) was added and the mixture was extracted with hexane (250 ml). The extract was washed successively with 1.0 mol/l aqueous hydrochloric acid solution (100 ml), aqueous sodium hydrogen carbonate solution (100 ml) and saturated brine (100 ml). The obtained organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (16.1 g, 95.7%) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[CH:12]([O:15][CH3:16])[O:13][CH3:14])[NH:8][CH2:7][CH2:6][CH2:5]2.[O:17]1[CH2:21][CH2:20][NH:19][C:18]1=[O:22].[O-]P([O-])([O-])=O.[K+].[K+].[K+].[C@H]1(N)CCCC[C@@H]1N>O1CCOCC1.[Cu]I>[CH3:14][O:13][CH:12]([O:15][CH3:16])[C:11]1[C:2]([N:19]2[CH2:20][CH2:21][O:17][C:18]2=[O:22])=[CH:3][C:4]2[CH2:5][CH2:6][CH2:7][NH:8][C:9]=2[N:10]=1
Reactant: O=C1NCCO1
Reactant: COC(OC)c1nc2c(cc1Br)CCCN2
Agent: [Cu]I
Agent: N[C@H]1CCCC[C@@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: COC(OC)c1nc2c(cc1N1CCOC1=O)CCCN2
Temperature: 120 °C

Procedure:
A suspension of 6-bromo-7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1,8-naphthyridine (intermediate 2) (1 g, 3.48 mmol), oxazolidin-2-one (0.364 g, 4.18 mmol), K3PO4 (1.552 g, 7.31 mmol), CuI (0.066 g, 0.348 mmol) and (1S,2S)-cyclohexane-1,2-diamin (0.063 mL, 0.522 mmol) in dioxane (7 ml) was heated to 120° C. for 4 days. Solvents were concentrated and the crude product was purified by silica gel column chromatography eluting with a gradient of MeOH (containing 0.3% of aqueous NH3, 0-10%) in DCM. Product fractions were combined, evaporated and dried to yield the title compound as an orange resin. (UPLC-MS 3) tR 0.44 min; ESI-MS 294.3 [M+H]+. 1H NMR (600 MHz, DMSO-d6) δ 7.14 (s, 1H), 6.83 (s, 1H), 5.12 (s, 1H), 4.39 (dd, 2H), 3.79 (dd, 2H), 3.31-3.19 (m, 8H), 2.69-2.61 (m, 2H), 1.80-1.70 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.Cl.[NH:25]1[CH2:29][CH2:28][C:27](=[O:30])[NH:26]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:16]=[CH:17][C:18]([C:19]([N:25]2[CH:29]=[CH:28][C:27](=[O:30])[NH:26]2)=[O:21])=[CH:22][CH:23]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: O=C1CCNN1
Agent: Cl
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)n2ccc(=O)[nH]2)cn1
Yield: 5 %

Procedure:
As described for example 191, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65 mmol) was converted, using 3-pyrazolidinone hydrochloride instead of 2-aminoethyl isopropylether, to the title compound (12 mg, 5%) which was obtained as a white solid. MS: m/e=375.0 [M−H]−.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[N:16]1[CH:20]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]3[CH2:28][CH2:29][NH:30][CH2:31][CH:32]=3)[CH:22]=2)[CH2:19][C:18]([C:33]([F:39])([F:38])[C:34]([F:37])([F:36])[F:35])=[N:17]1.C(N(CC)CC)C.[CH3:47][S:48](Cl)(=[O:50])=[O:49].ClCCl>O>[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[N:16]1[CH:20]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]3[CH2:28][CH2:29][N:30]([S:48]([CH3:47])(=[O:50])=[O:49])[CH2:31][CH:32]=3)[CH:22]=2)[CH2:19][C:18]([C:33]([F:38])([F:39])[C:34]([F:36])([F:37])[F:35])=[N:17]1
Reactant: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2cccc(C3=CCNCC3)c2)c(F)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CC=C(c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 7.1 %

Procedure:
1-(2,4-difluoro-phenyl)-5-[3-(1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole trifluoroacetate (30.0 mg, 0.05 mmol) prepared in Example 61, triethylamine (20.3 uL, 0.15 mmol) and methanesulfonyl chloride (1.9 uL, 0.06 mmol) were added at 0° C. to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 2 hours. Distilled water was added to the reaction mixture, which was then extracted with dichloromethane two times. The combined extract was washed with a 1N hydrochloric acid solution, a saturated sodium carbonate solution, and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3) to give 1.9 mg of the titled compound as a yellow liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.[CH2:27]([O:34][C:35]1[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:20][CH2:21][N:22]([CH2:39][C:38]4[CH:41]=[CH:42][C:35]([O:34][CH2:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)=[CH:36][CH:37]=4)[CH2:23][CH2:24]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:25][CH:26]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCNCC2)cc1
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCN(Cc3ccc(OCc4ccccc4)cc3)CC2)cc1

Procedure:
Using the general procedure described in Example 3, N1-(4-methoxybenzoyl)-N2-(piperidin-4-ylcarbonyl)-1,2-benzenediamine (0.070 mmol) was reacted with 4-benzyloxybenzaldehyde to provide 40 mg of the title product as the free base. Treatment with hydrochloric acid and concentration in vacuo yielded the salt of the title compound.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[C:11]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].N1C=CC=CC=1>C(Cl)Cl>[C:1]([NH:5][C:6]1[C:11]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:3])[CH3:2]
Reactant: CCOC(=O)Cc1cccc(Oc2ccccc2)c1N
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)Cc1cccc(Oc2ccccc2)c1NC(C)=O

Procedure:
A solution of acetyl chloride (1.38 g.) in methylene chloride (10 ml.) was added to a mixture of ethyl 2-(2-amino-3-phenoxyphenyl)acetate (4.3 g.), pyridine (1.9 g.) and dried methylene chloride (50 ml.) over 10 minutes at 5° C. with stirring and stirred for 30 minutes at the same temperature. The reaction mixture was concentrated under reduced pressure and to the residue was added 10% hydrochloric acid. The mixture was extracted with ethyl acetate, and the extract was washed with water, dried over magnesium sulfate and then evaporated. The residue was crystallized with a mixture of benzene and n-hexane to give the captioned compound (3.65 g.). mp 106° to 107° C.
Reaction SMILES: [Cl-:1].[Cl:2][C:3]1[N:12]=[C:11]([N+:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1>N1C=CC=CC=1>[Cl-:2].[Cl-:1].[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:11]([N+:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:12][C:3]=1[N+:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Clc1nc(-[n+]2ccccc2)c2ccccc2n1
Agent: [Cl-]
Solvent: c1ccncc1
Product: c1cc[n+](-c2nc(-[n+]3ccccc3)c3ccccc3n2)cc1
Reaction time: 72 h

Procedure:
A 10-g portion of 1-(2-chloroquinazoline-4-yl)pyridinium chloride was added to 100 ml of pyridine under a calcium sulfate drying tube, refluxed 11/2 hours, then allowed to stir 3 days. The reaction was filtered and the solid was rinsed with pyridine, then ether, and dried in vacuo giving 10.4 g of 1,1'-(2,4-quinazolinediyl)bis[pyridinium] dichloride (m.p. 156°-162° C.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:13]2[N:14]=[CH:15][N:16]([C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:17]=2)([OH:12])[CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1.[CH3:37][O:38][C:39]1[CH:40]=[C:41](B(O)O)[CH:42]=[CH:43][CH:44]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[CH3:37][O:38][C:39]1[CH:44]=[C:43]([C:2]2[CH:3]=[CH:4][C:5]([C:8]([C:13]3[N:14]=[CH:15][N:16]([C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH:17]=3)([OH:12])[CH:9]([CH3:10])[CH3:11])=[CH:6][CH:7]=2)[CH:42]=[CH:41][CH:40]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: CC(C)C(O)(c1ccc(Br)cc1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1cccc(-c2ccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)cc2)c1
Yield: 64.1 %

Procedure:
By the reaction in the same manner as in Example 29-(i) using 1-(4-bromophenyl)-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol (1.50 g), 3-methoxyphenylboronic acid (635 mg), 2M aqueous sodium carbonate solution (2.79 ml) and tetrakis(triphenylphosphine)palladium(0) (96.7 mg), the title compound (1.01 g) was obtained as colorless powder crystals.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].[S:12]1[C:20]2[C:15](=[N:16][CH:17]=[CH:18][C:19]=2O)[CH:14]=[CH:13]1.P(CCCC)(CCCC)CCCC>>[Cl:1][CH2:2][CH2:3][C@@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[O:5][C:19]1[CH:18]=[CH:17][N:16]=[C:15]2[CH:14]=[CH:13][S:12][C:20]=12
Reactant: Oc1ccnc2ccsc12
Reactant: O[C@H](CCCl)c1ccccc1
Agent: CCCCP(CCCC)CCCC
Product: ClCC[C@H](Oc1ccnc2ccsc12)c1ccccc1
Yield: 54 %

Procedure:
using (R)-(+)-3-chloro-1-phenyl-1-propanol, thieno[3,2-b]pyridin-7-ol (commercially available from the Aldrich Chemical Company), PBu3, and ADPP gave the title compound (0.71 g, 54%); Mass spectrum (ion spray): m/z=304.06 (m+1).
Reaction SMILES: [C-:1]1([CH2:6][C:7](O)=[O:8])[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1.[Fe+2:15].[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[C-:1]1([CH2:6][CH2:7][OH:8])[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1.[Fe+2:15]
Reactant: O=C(O)C[c-]1cccc1
Agent: [Fe+2]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: OCC[c-]1cccc1

Procedure:
2-ferrocenylethyl alcohol was synthesized by reducing ferrocenyl acetic acid with lithiumaluminum hydride. 1.4 g of LiAlH4 are placed in a flask containing ether and equipped with a soxhlet apparatus. Ferrocene acetic acid (0.9 g) is extracted by this apparatus for 48 hours. After cooling, the excess reagent is decomposed with water and the solution washed thoroughly with a solution of sodium bicarbonate, dried and evaporated to dryness. The residual oil is crystallized from hexane. It has a melting point of 41° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[C:18]([NH2:20])=[O:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:22][C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=2)[C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[C:18]([NH2:20])=[O:19])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: NC(=O)[C@@H]1CCCC[C@H]1NS(=O)(=O)c1ccc(Cl)cc1
Reactant: N#Cc1ccc(CBr)cc1
Product: N#Cc1ccc(CN([C@@H]2CCCC[C@H]2C(N)=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Yield: 43 %

Procedure:
The titled compound was prepared in 43% yield from trans-2-(4-chlorobenzenesulfonylamino)-cyclohexanecarboxylic acid amide and 4-bromomethyl-benzonitrile according to the procedure described in Example 11: 1H NMR (DMSO-d6) δ 7.71(m, 4 H), 7.53 (m, 4 H), 7.29 (s, 1 H), 6.76 (s, 1 H), 4.44 (AB2,2 H,Δv=16,Jab=84 Hz), 3.96 (m, 1 H), 1.80 (m, 1 H), 1.57 (m, 3 H), 1.17 (m, 5 H); MS m/e 432.01 (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][C:14]([Br:19])=[CH:13][C:12]=3[N:11]=[C:10]([NH2:20])[C:9]=2[N:8]=[C:7]1[CH2:21][CH2:22][CH3:23].C(N(CC)CC)C.[CH:31]1([C:36](Cl)=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32]1>C(Cl)(Cl)Cl>[NH2:20][C:10]1[C:9]2[N:8]=[C:7]([CH2:21][CH2:22][CH3:23])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:36]([CH:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:37])[C:18]=2[C:17]2[CH:16]=[CH:15][C:14]([Br:19])=[CH:13][C:12]=2[N:11]=1
Reactant: CCCc1nc2c(N)nc3cc(Br)ccc3c2n1CCCCN
Reactant: O=C(Cl)C1CCCC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCc1nc2c(N)nc3cc(Br)ccc3c2n1CCCCNC(=O)C1CCCC1
Temperature: 0 °C
Yield: 49.9 %

Procedure:
A suspension of 1-(4-aminobutyl)-7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine (2.42 g, 6.4 mmol) and triethylamine (0.99 mL, 7.1 mmol) in chloroform (240 mL) was cooled to 0° C., and cyclopentanecarbonyl chloride (0.78 mL, 6.4 mmol) was added dropwise over a period of five minutes. The reaction was stirred for ten minutes, washed sequentially with water (50 mL) and 1% aqueous sodium carbonate (100 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was triturated with isopropanol:water (10 mL/g and 1.7 mL/g) and isolated by filtration. The filtrate was concentrated under reduced pressure and recrystallized from isopropanol (5 mL/g). The two solids were combined and dried overnight in a vacuum oven to provide 1.51 g of N-{4-[4-amino-7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl]butyl}cyclopentanecarboxamide as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:24]([F:26])[F:25])=[CH:4][C:5]([N+:21]([O-])=O)=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH2:11][CH2:10]2)[CH:7]=1.O.NN>C(O)C.[Ni]>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:10][CH2:11][N:12]([CH:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)[CH2:13][CH2:14]2)[C:5]([NH2:21])=[CH:4][C:3]=1[CH:24]([F:26])[F:25]
Reactant: O=[N+]([O-])c1cc(C(F)F)c(Cl)cc1NC1CCN(C2CCOCC2)CC1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: Nc1cc(C(F)F)c(Cl)cc1NC1CCN(C2CCOCC2)CC1
Temperature: 25 °C
Yield: 59.5 %

Procedure:
A stirred suspension of N-[5-chloro-4-(difluoromethyl)-2-nitrophenyl]-1-(tetrahydro-2H-pyran-4-yl)-4-piperidinamine (D97, 330 mg, 0.84 mmol) in ethanol (20 ml) at room temperature under argon was treated with Raney Nickel (20 mg) followed by dropwise addition of hydrazine hydrate (0.25 ml, 8.0 mmol). The mixture was maintained at room temperature for 30 minutes, then heated at 45° C. for 1 hr. The mixture was filtered through a pad of Kieselguhr and the filtrate concentrated under vacuum to leave the title compound as a yellow solid (180 mg of ˜88% purity, 59% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:13]([NH2:17])([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C>C(Cl)Cl>[C:13]([NH:17][C:8](=[O:9])[C:7]1[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 2 h
Yield: 76.9 %

Procedure:
4-Nitrobenzoyl chloride (18.9 g, 0.1 mol) dissolved in 60 ml of methylene chloride is added, over 30 minutes at a temperature of 0-5° C., to a solution of tert-butylamine (8.3 g, 0.112 mol) and of triethylamine (15.6 ml, 0.112 mol) dissolved in 170 ml of dichloromethane in a reactor. The reaction mixture is brought back to laboratory temperature and left stirring for 2 hours. The organic phase is washed twice with water and dried. After removing the solvent under reduced pressure, the solid obtained is recrystallized from isopropanol. 17.1 g (Yield: 77%) of N-(tert-butyl)-4-nitrobenzamide are obtained in the form of a pale yellow powder (m.p. 161-2° C.) which is used as is in the following stage.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:11][S:12][CH:13]1[N:16]([CH2:17][C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)=[O:19])[C:15](=[O:31])[CH:14]1[CH:32]([O:34][C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=1)=[O:36])[CH3:33].[C:48](Cl)(=[O:53])[C:49]([CH3:52])([CH3:51])[CH3:50]>O1CCCC1.C1(C)C=CC=CC=1.Cl.C(Cl)Cl>[CH3:50][C:49]([CH3:52])([CH3:51])[C:48](=[O:53])[CH:17]([N:16]1[CH:13]([S:12][CH3:11])[CH:14]([CH:32]([O:34][C:35]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=2)=[O:36])[CH3:33])[C:15]1=[O:31])[C:18]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][CH:27]=1)=[O:19]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CSC1C(C(C)OC(=O)OCc2ccc([N+](=O)[O-])cc2)C(=O)N1CC(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CSC1C(C(C)OC(=O)OCc2ccc([N+](=O)[O-])cc2)C(=O)N1C(C(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)C(C)(C)C
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
1.1 ml of 1 M lithium bis(trimethylsilyl)-amide are added at -70° C. with stirring in the course of 5 minutes to a mixture of 275 mg (0.515 mmol) of p-nitrobenzyl 2-[4-methylthio-3-(1-(p-nitrobenzyloxycarbonyloxy)-ethyl)-2-oxoazetidinyl]-acetate and 67 μl (0.55 mmol) of pivaloyl chloride in 6.7 ml of dry tetrahydrofuran and the reaction mixture is stirred at -70° C. during the course of a further 30 minutes and then diluted with 40 ml of toluene and with 30 ml of 2 N HCl, then washed twice with 40 ml each of NaCl solution. The organic phase is dried over MgSO4 and filtered, and the solvent is removed in vacuo. The residue is chromatographed on 10 g of silica gel using toluene/ethyl acetate (9:1), 268 mg of a white non-crystalline solid being obtained. IR spectrum in CH2Cl2 : 2930, 2850, 1775, 1760, 1720, 1610, 1535, 1350 cm-1 .
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)[CH3:2].[CH3:16][Si:17]([CH3:30])([CH3:29])[CH2:18][CH2:19][O:20][CH2:21][N:22]1[CH:26]=[CH:25][N:24]=[C:23]1[CH2:27][NH2:28]>>[CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:28][CH2:27][C:23]2[N:22]([CH2:21][O:20][CH2:19][CH2:18][Si:17]([CH3:30])([CH3:29])[CH3:16])[CH:26]=[CH:25][N:24]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(OCC)c1ccc(C=O)cc1
Reactant: C[Si](C)(C)CCOCn1ccnc1CN
Product: CCOC(OCC)c1ccc(CNCc2nccn2COCC[Si](C)(C)C)cc1

Procedure:
The same operation as in Example 2 was performed, except for using 4-(diethoxymethyl)benzaldehyde in place of 2-formyl-N,N-dimethyl-1H-imidazole-1-sulfonamide and 1-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)methanamine in place of benzylamine, to obtain the title compound having the following physical properties.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]1=[O:11].[H-].[Na+].Br[CH2:15][CH:16]1[O:20][CH2:19][CH2:18][O:17]1.Cl>O.C(OCC)(=O)C.CN(C)C=O>[O:17]1[CH2:18][CH2:19][O:20][CH:16]1[CH2:15][N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]1=[O:11]
Reactant: O=c1cnc2ccccc2[nH]1
Reactant: BrCC1OCCO1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1cnc2ccccc2n1CC1OCCO1
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
To 20 mL of an N,N-dimethylformamide suspension containing 2.0 g of quinoxalin-2(1H)-one, 0.82 g of 60% sodium hydride was dividedly added at room temperature, and the mixture was stirred at 40° C. for 15 minutes. Thereto was added 2.1 mL of 2-bromomethyl-1,3-dioxolane, and the mixture was stirred at 60° C. for 30 minutes, and stirred at 110 to 120° C. for 1 hour. Thereto was added 2.1 mL of 2-bromomethyl-1,3-dioxolane, and the mixture was stirred at 110 to 120° C. for 5 hours. The reaction mixture was cooled to room temperature, ethyl acetate and water were added, and the resultant solution was adjusted to pH 2.0 with 6 mol/L hydrochloric acid. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was washed sequentially with water and an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; hexane:ethyl acetate 1:2] to obtain 1.5 g of a light brown oily substance, 1-(1,3-dioxolan-2-ylmethyl)quinoxalin-2(1H)-one.