Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[C:4]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:3]=1.[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[S:28](Cl)(=[O:30])=[O:29].C(N(C(C)C)CC)(C)C>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([S:28]([C:19]3[CH:20]=[CH:21][C:22]4[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:18]=3)(=[O:30])=[O:29])[CH2:12][CH2:13]2)=[C:4]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:3]=1
Reactant: CS(=O)(=O)c1cc(F)ccc1N1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1cc(F)ccc1N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Yield: 61.8 %

Procedure:
Sulfonylation of 1-(4-fluoro-2-(methylsulfonyl)phenyl)piperazine (316.6 mg, 1.23 mmol) with naphthalene-2-sulfonyl chloride (278 mg, 1.54 mmol) was carried out according to a similar procedure described for example 3A using anhydrous dichloromethane (5 mL) as solvent and diisopropylethylamine (0.256 mL, 1.47 mmol) as base. 1-[4-fluoro-2-(methylsulfonyl)phenyl]-4-(2-naphthylsulfonyl)piperazine was obtained in 61.8% yield (340 mg) as white solid.
Reaction SMILES: [Br-].[CH3:2][N:3]([CH3:25])[CH2:4][CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[O:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH:33]1[O:38][CH2:39][CH2:40][O:41][C:42]1[C:43]([CH:48]=O)=[N:44][CH:45]=[CH:46][CH:47]=1>C1COCC1.CC(O)(C)C>[CH3:2][N:3]([CH3:25])[CH2:4]/[CH:5]=[CH:48]\[C:43]1[C:42]([O:41][CH2:40][CH2:39][O:38][CH:33]2[CH2:34][CH2:35][CH2:36][CH2:37][O:32]2)=[CH:47][CH:46]=[CH:45][N:44]=1
Reactant: O=Cc1ncccc1OCCOC1CCCCO1
Reactant: CN(C)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: CN(C)C/C=C\c1ncccc1OCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 10.4 %

Procedure:
To a suspension of [2-(dimethylamino)ethyl](triphenyl)phosphonium bromide (32.1 g, 77.4 mmol) in dry THF (150 mL) was added a solution of potassium tert-butoxide (9.4 g, 83.7 mmol) in dry t-BuOH (100 mL). The suspension was sonicated for 15 minutes whereafter a solution of 3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]pyridine-2-carbaldehyde (from Step 1; 18.3 g, 72.8 mmol) in THF (30 mL) was added to the yellow suspension and stirred at room temperature for one hour and then for a further hour at 60° C. The solvent was removed under reduced pressure and the residue was mixed with water (0.8 L) and the pH was adjusted to 3–4 with HOAc (˜10 mL) and then extracted twice with CHCl3. The aqueous phase was made basic and extracted with CHCl3 (×3), the combined organic phases were dried (MgSO4) and the solvent was removed under reduced pressure. The crude product, consisting of the cis and trans* isomers were separated with preparative HPLC on an YMC ODS-AQ column (30×250 mm) with different gradients of 0.1% TFA in water/CH3CN. The cis isomer was isolated as a light yellow oil (2.33 g, 10%). HRMS m/z calcd for C17H26N2O3 (M)+ 306.1943. found 306.1942. *The corresponding trans isomer is described in Example 21, Step 1.
Reaction SMILES: C[O:2][C:3](=[O:24])[C@@H:4]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:5][C:6]1[CH:16]=[CH:15][C:9]2[O:10][C:11]([CH3:14])([CH3:13])[O:12][C:8]=2[CH:7]=1.[OH-].[Li+].O>C1COCC1>[C:20]([O:19][C:17]([C@@H:4]([CH2:5][C:6]1[CH:16]=[CH:15][C:9]2[O:10][C:11]([CH3:14])([CH3:13])[O:12][C:8]=2[CH:7]=1)[C:3]([OH:24])=[O:2])=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: COC(=O)[C@H](Cc1ccc2c(c1)OC(C)(C)O2)C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)[C@@H](Cc1ccc2c(c1)OC(C)(C)O2)C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.3 %

Procedure:
To a solution of (S)-methyl2-(tert-butoxycarbonyl)-3-(2,2-dimethylbenzo[d][1,3]dioxol-5-yl)propanoate (5000 mg, 14229 μmol) in 100 mL of THF at 0° C. was added lithium hydroxide (0.2 M, 28458 μl, 14229 μmol) over 10 minutes. After stirring at 0° C. for 1 hour the reaction was poured into a separatory funnel and 100 mL of water was added. The mixture was washed with 150 mL of ether, then acidified to pH 2-3-with 1 N HCl. Ethyl acetate was added, the layers were separated and the aqueous layer was extracted with ethyl acetate (3×100 mL). The combined organics were washed with water and then brine before being dried over sodium sulfate, filtered and concentrated to furnish (S)-2-(tert-butoxycarbonyl)-3-(2,2-dimethylbenzo[d][1,3]dioxol-5-yl)propanoic acid (4005 mg, 83% yield) as a colorless viscous oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22](Cl)[CH:21]=3)[C:12]2=[O:27])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:28]1([NH2:31])[CH2:30][CH2:29]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:31][CH:28]4[CH2:30][CH2:29]4)[CH:21]=3)[C:12]2=[O:27])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NC1CC1
Reactant: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccnc(Cl)c3)C(C)(C)C2=O)cc1
Product: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccnc(NC4CC4)c3)C(C)(C)C2=O)cc1
Temperature: 150 °C

Procedure:
A suspension of 0.6 g of 3-(4-tert-butylphenyl)-1-[(2-chloropyridin-4-yl)methyl]-5,5-dimethylimidazolidine-2,4-dione obtained in stage a) of Example 7 in 1.1 mL of cyclopropylamine is heated by microwave at 150° C. for 6 hours and then concentrated under reduced pressure. The residue is purified by chromatography on a column of silica, eluting with a mixture of petroleum ether and ethyl acetate (50/50 by volume) to give 48 mg of 3-(4-tert-butylphenyl)-1-{[2-(cyclopropylamino)pyridin-4-yl]methyl}-5,5-dimethylimidazolidine-2,4-dione, the characteristics of which are as follows:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=[O:10].[CH3:17][C:18]([C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1)([C:20]1[O:21][CH:22]=[CH:23][N:24]=1)[CH3:19]>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:31]([C:28]2[CH:27]=[CH:26][C:25]([C:18]([CH3:19])([C:20]3[O:21][CH:22]=[CH:23][N:24]=3)[CH3:17])=[CH:30][CH:29]=2)(=[O:32])=[O:33])=[C:3]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[O:10])[CH:4]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccn1
Reactant: CC(C)(c1ccc(S(=O)(=O)Cl)cc1)c1ncco1
Product: CC(C)(c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccccn2)cc1)c1ncco1

Procedure:
The title compound was prepared from (2-amino-5-chloro-phenyl)-pyridin-2-yl-methanone and 4-(1-methyl-1-oxazol-2-yl-ethyl)-benzenesulfonyl chloride following the general procedure described for the preparation of N-aryl-benzenesulfonamides. MS: m/z 482 (M++1).
Reaction SMILES: O.O[N:3]1C2C=CC=CC=2N=N1.[C:12]([C:15]1[N:16]=[C:17]([CH:23]2[CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]2[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[NH:18][C:19]=1[CH2:20][CH2:21][CH3:22])(O)=[O:13]>C(Cl)Cl>[NH2:3][C:12]([C:15]1[N:16]=[C:17]([CH:23]2[CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]2[C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[NH:18][C:19]=1[CH2:20][CH2:21][CH3:22])=[O:13]
Reactant: On1nnc2ccccc21
Reactant: CCCc1[nH]c(C2Cc3ccccc3N2C(=O)OC(C)(C)C)nc1C(=O)O
Solvent: O
Solvent: ClCCl
Product: CCCc1[nH]c(C2Cc3ccccc3N2C(=O)OC(C)(C)C)nc1C(N)=O
Reaction time: 1 h
Yield: 35.7 %

Procedure:
1-Hydroxybenzotriazole hydrate (0.00318 mole) was added to a solution of compound 105 (0.00159 mole) in DCM (160 mL) at room temperature. N,N′-methane-tetrayl-biscyclohexanamine (0.00206 mole) was added neat at room temperature. After 60 minutes, NH3 gas was bubbled in for 5 minutes, and a solid precipitated out. The mixture was allowed to sit over the weekend. The mixture was filtered, and the filtrate was extracted with saturated NaHCO3. The organic phases were dried over MgSO4, filtered, and concentrated. The residue was purified by liquid chromatography, yielding 0.21 g of 1,1-dimethylethyl 2-[4-(aminocarbonyl)-5-propyl-1H-imidazol-2-yl]-2,3-dihydro-1H-indole-1-carboxylate (compound 106).
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[OH:13].[Cl:14][CH2:15][CH2:16]OS(C1C=CC(C)=CC=1)(=O)=O.CN(C=O)C.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:14][CH2:15][CH2:16][O:13][C:3]1[CH:4]=[CH:5][C:6]([O:8][C:9]([F:11])([F:12])[F:10])=[CH:7][C:2]=1[I:1]
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Reactant: Oc1ccc(OC(F)(F)F)cc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)Oc1ccc(OCCCl)c(I)c1
Yield: 100 %

Procedure:
2-Iodo-4-(trifluoromethoxy)phenol (10 g, 33 mmol), 2-chloroethyl-p-toluenesulfonate (7.9 g, 34 mmol), N,N′-dimethylformamide (50 mL) and potassium carbonate (9.1 g, 66 mmol) were stirred together at 50° C. for 16 hours and then cooled. The suspension was diluted with water (100 mL) and extracted with 60% diethyl ether/hexane (2×100 mL). The extracts were dried (MgSO4) and concentrated to give the title compound as a solid (12.1 g, 33 mmol).
Reaction SMILES: [S:1]([OH:11])(=[O:10])([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1)=[O:2].OS(O)(=O)=O.[N:17]([O-])=O.[Na+]>O>[CH:7]1[C:6]([NH:9][NH2:17])=[CH:5][CH:4]=[C:3]([S:1]([OH:11])(=[O:10])=[O:2])[CH:8]=1
Reactant: Nc1ccc(S(=O)(=O)O)cc1
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: NNc1ccc(S(=O)(=O)O)cc1
Temperature: 10 °C
Reaction time: 0.25 h

Procedure:
Sulfanilic acid (52 g, 0.3 mol) was dissolved in 200 ml H2O containing 16.5 g Na2CO3. The resulting solution was cooled to 10° C. and 35 g of conc. H2SO4 was then added dropwise, followed by the addition of 75 ml 4N NaNO2. The diazotization step was carried out for 15 min at 10°-12° C., then the diazonium salt was collected by filtration, washed with a small amount of cold water and added, at 5° C., to a stirred solution of 85 g of Na2 SO3 in 250 ml H2O. After stirring the reaction mixture for 1 h, the temperature was raised to 95° C. and 240 ml of concentrated H2SO4 was added over a period of 30 min. The reaction mixture was left overnight and the precipitated product was collected, washed with cold water and dried. The phenylhydrazine-4-sulfonic acid obtained (52 g) was dissolved in 500 ml H2O containing 60 ml 30% NaOH, and 30 g (0.28 mol) of benzaldehyde was added at 50°-55° C. Stirring was continued for 1 h, the temperature was reduced to 30° C., and the product was precipitated by acidification with 36 ml 30% HCl. The product was collected, washed with a small amount of cold water and dried, to give 50 g of benzaldehyde phenylhydrazone-4-sulfonic acid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:24])[CH2:15]/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)[CH2:32][CH2:31]1)=[O:29])[CH3:26]>>[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([OH:24])[CH2:15]/[CH:16]=[CH:17]/[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:4][CH:3]=3)=[CH:35][CH:34]=2)[CH2:31][CH2:32]1)=[O:29])[CH3:26]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)C/C=C/c1ccccc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)C/C=C/c4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using (E)-1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-4-phenyl-but-3-en-1-ol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: O.[OH-].[Na+].[Cl:4][C:5]1[C:9]([Cl:10])=[C:8]([CH3:11])[NH:7][C:6]=1[C:12]([NH:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[C:23]([C:31]([O:33]C)=[O:32])[N:22]=2)[CH2:17][CH2:16]1)=[O:13].Cl>C1COCC1.CCOC(C)=O>[Cl:4][C:5]1[C:9]([Cl:10])=[C:8]([CH3:11])[NH:7][C:6]=1[C:12]([NH:14][CH:15]1[CH2:16][CH2:17][N:18]([C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[C:23]([C:31]([OH:33])=[O:32])[N:22]=2)[CH2:19][CH2:20]1)=[O:13]
Reactant: COC(=O)c1cc2ccccc2c(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1[nH]c(C(=O)NC2CCN(c3nc(C(=O)O)cc4ccccc34)CC2)c(Cl)c1Cl
Temperature: 80 °C
Reaction time: 1 h
Yield: 73.7 %

Procedure:
In a mixture of 20 ml THF, 5 ml H2O, and 1 ml 50 wt % NaOH (aq) was dissolved methyl 1-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)isoquinoline-3-carboxylate (Example 301; 70 mg). The solution was stirred at 80° C. for 1 hr. The solution was cooled to room temperature, diluted with EtOAc and acidified with dilute HCl (aq). The EtOAc fraction was isolated, at which time a white solid precipitated from solution. The solid was collected by filtration and washed with acetonitrile to yield 50 mg white solid product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.Br[CH2:10][CH2:11][CH3:12].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][CH2:11][CH3:12])=[CH:4][N:3]=1
Reactant: Oc1ccc(Br)nc1
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCOc1ccc(Br)nc1

Procedure:
10.0 g (57.5 mmol) 2-bromo-5-hydroxypyridine, 28.3 g (230 mmol) 1-bromopropane and 19.9 g (143.7 mmol) K2CO3 are added to 1 L ACN and stirred at reflux over night. Afterwards the reaction is quenched by the addition of water and extracted with TBME. The org. layers are combined, dried over MgSO4, filtered and the solvent is removed in vacuo. The crude product is purified by column chromatography (silica gel, PE/EtOAc).
Reaction SMILES: [NH2:1][C:2]([CH3:13])([CH3:12])[CH2:3][O:4][C:5]1[N:6]=[N:7][C:8]([Cl:11])=[CH:9][CH:10]=1.[CH3:14][O:15][CH2:16][CH2:17][C:18]1[CH:28]=[CH:27][CH:26]=[CH:25][C:19]=1[O:20][CH2:21][CH:22]1[O:24][CH2:23]1>C(O)C>[CH3:14][O:15][CH2:16][CH2:17][C:18]1[CH:28]=[CH:27][CH:26]=[CH:25][C:19]=1[O:20][CH2:21][CH:22]([OH:24])[CH2:23][NH:1][C:2]([CH3:13])([CH3:12])[CH2:3][O:4][C:5]1[N:6]=[N:7][C:8]([Cl:11])=[CH:9][CH:10]=1
Reactant: COCCc1ccccc1OCC1CO1
Reactant: CC(C)(N)COc1ccc(Cl)nn1
Solvent: CCO
Product: COCCc1ccccc1OCC(O)CNC(C)(C)COc1ccc(Cl)nn1
Yield: 38.7 %

Procedure:
A mixture of 4.83 g of 3-(2-amino-2-methylpropoxy)-6-chloropyridazine obtained in Example 1(a), 5.0 g of 1-[2-(2-methoxyethyl)phenoxy]-2,3-epoxypropane and 200 ml of ethanol was refluxed for 4 hours, and the solvent was evaporated under reduced pressure. A solution of the residue in benzene was extracted with 1N hydrochloric acid. The aqueous layer was extracted with chloroform, washed successively with 5% sodium carbonate and water, and the organic layer was dried over magnesium sulfate. The solvent was evaporated to give 3.8 g of 1-[2-(2-methoxyethyl)phenoxy]-3-[1,1-dimethyl-2-(3-chloro-6-pyridazinyloxy)ethylamino]-2-propanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]1=[CH:15][C:16](Cl)=[N:17][C:18](=[O:19])[N:8]1[CH2:7][CH2:6]2.[CH3:21][C:22]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:23]=1[NH2:24].C1C=CC=CC=1.C(OCC)(=O)C>C(O)CCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]1=[CH:15][C:16]([NH:24][C:23]3[C:25]([CH3:29])=[CH:26][CH:27]=[CH:28][C:22]=3[CH3:21])=[N:17][C:18](=[O:19])[N:8]1[CH2:7][CH2:6]2
Reactant: Cc1cccc(C)c1N
Reactant: COc1cc2c(cc1OC)-c1cc(Cl)nc(=O)n1CC2
Solvent: CCOC(C)=O
Solvent: CCCCO
Solvent: c1ccccc1
Product: COc1cc2c(cc1OC)-c1cc(Nc3c(C)cccc3C)nc(=O)n1CC2

Procedure:
A solution of 9,10-dimethoxy-2-chloro-6,7-dihydro-4H-pyrimido(6,1-a)isoquinolin-4-one (2.5 g), 2,6-dimethylaniline (5.0 ml) in butanol (20.0 ml) is heated under reflux for 10 hours. The solvent is evaporated under reduced pressure to give a gummy mass. Chromatography of the gummy mass over silica gel using benzene-ethyl acetate as the eluant gives the required product. The compound is crystallized from methanol, yield 2.0 g, m.p. 297°-299° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[C:5]([N+:14]([O-:16])=[O:15])=[CH:4][N:3]=1.CN(C)C1C=CC=CC=1.[C:26]([O:30][C:31]([NH:33][CH:34]1[CH2:38][CH2:37][N:36]([C:39]2[CH:44]=[CH:43][C:42]([NH2:45])=[CH:41][CH:40]=2)[CH2:35]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>C1COCC1.CC(O)C.C(O)(=O)C.O>[C:26]([O:30][C:31]([NH:33][CH:34]1[CH2:38][CH2:37][N:36]([C:39]2[CH:40]=[CH:41][C:42]([NH:45][C:2]3[N:7]=[C:6]([NH:8][CH:9]4[CH2:13][CH2:12][CH2:11][CH2:10]4)[C:5]([N+:14]([O-:16])=[O:15])=[CH:4][N:3]=3)=[CH:43][CH:44]=2)[CH2:35]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1NC1CCCC1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(N)cc2)C1
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(Nc3ncc([N+](=O)[O-])c(NC4CCCC4)n3)cc2)C1
Yield: 100.3 %

Procedure:
To a solution of 0.41 g (1.69 mmol) of 2-chloro-4-(cyclopentylamino)-5-nitropyrimidine and 0.25 g (2 mmol) N,N-dimethylaniline in 10 mL THF is added a solution of 0.47 g (1.69 mmol) of 3-(tert-butoxycarbonylamino)-1-(4-aminophenyl)pyrrolidine in 10 mL of 2-propanol, and the resulting mixture is heated under reflux for 2 hours. After cooling and acidification with acetic acid, the mixture is diluted with water to give 0.82 g (100%) of the title compound: mp (MeOH) 186–189° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH:14]=[CH:13][C:12]3=[N:15][C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[N:17][C:11]3=[C:10]2Cl)=[CH:4][CH:3]=1.[OH-:25].[Na+].O.Cl>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH:14]=[CH:13][C:12]3=[N:15][C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[N:17][C:11]3=[C:10]2[OH:25])=[CH:4][CH:3]=1
Reactant: Clc1c2nc(-c3ccccc3)nc-2ccn1Cc1ccc(Br)cc1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Oc1c2nc(-c3ccccc3)nc-2ccn1Cc1ccc(Br)cc1
Temperature: 60 °C
Yield: 81 %

Procedure:
5-[(4-Bromophenyl)methyl]-4-chloro-2-phenyl-5H-imidazo[4,5-c]pyridine (GPJN-96) (see example 63) (0.200 g) was dissolved in DMF (5 mL) and 2N aqueous sodium hydroxide solution (10 mL) was added. The resulting mixture was heated at 60° C. for 24 h. Then water (50 mL) was added and the resulting mixture was neutralized by addition of 2N HCl. The precipitate was collected by filtration to give the crude product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[F:20][C:21]([F:32])([C:28]([F:31])([F:30])[F:29])[C:22]([F:27])([F:26])[C:23](Cl)=[O:24]>ClCCl>[F:26][C:22]([F:27])([C:21]([F:20])([F:32])[C:28]([F:29])([F:30])[F:31])[C:23]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1)=[O:24]
Reactant: O=C(Cl)C(F)(F)C(F)(F)C(F)(F)F
Reactant: Nc1ccc(CCO)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccc(CCO)cc1)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.4 %

Procedure:
To a 0° C. solution of 2-[(4-amino)phenyl]ethanol (25 g), diisopropylethylamine (23.9 g) and dichloromethane (400 mL) was added heptafluorobutyryl chloride (41.8 g) dropwise over 0.5 hour. The mixture was allowed to warm gradually to room temperature and stirred for 2 hours. The precipitate was filtered off and the filtrate was diluted with ethylacetate (100 mL), washed with water (3×500 mL), dried over sodium sulfate, filtered and concentrated with a rotary evaporator. The residue was triturated with dichloromethane and collected by filtration. The combined solids were dissolved in diethyl ether and washed with water and saturated aqueous sodium chloride solutions, dried over sodium sulfate, filtered and concentrated to give 2,2,3,3,4,4,4-heptafluoro-N-[4-(2-hydroxyethyl)phenyl]butanamide as a white solid (39.2 g).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[C:4](O)(=O)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>>[CH3:1][N:2]([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH3:4])[CH3:3]
Reactant: CCCCCCCCCCCCCCCCC(=O)O
Reactant: CNC
Product: CCCCCCCCCCCCCCCCCN(C)C

Procedure:
N,N-dimethylheptadecylamine (b.p. 117° @ 0.15 mmHg) was prepared from dimethylamine and heptadecanoic acid by the method described in Example 14.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[C:16]2[C:19]2[NH:23][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:21][C:20]=2[C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C(Cl)Cl.CCOC(C)=O>CO.O1CCCC1.[Pd]>[C:24]1([C:22]2[NH:23][C:19]([C:16]3[CH:15]=[CH:14][CH:13]=[C:12]4[C:17]=3[CH:18]=[C:9]([OH:8])[CH:10]=[CH:11]4)=[C:20]([C:30]3[CH:31]=[CH:32][N:33]=[CH:34][CH:35]=3)[N:21]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: c1ccc(COc2ccc3cccc(-c4[nH]c(-c5ccccc5)nc4-c4ccncc4)c3c2)cc1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Oc1ccc2cccc(-c3[nH]c(-c4ccccc4)nc3-c3ccncc3)c2c1
Reaction time: 3 h
Yield: 79.9 %

Procedure:
To a solution of 4-[5-(7-benzyloxy-naphthalen-1-yl)-2-phenyl-1H-imidazol-4-yl]-pyridine (810 mg, 1.79 mmol) in methanol (50 mL) and tetrahydrofuran (10 mL) is added 10% Pd/C (100 mg) and the mixture is stirred for 3 hours under hydrogen atmosphere (1 atm). The catalyst is filtered and washed with ethyl acetate. The filtrate is concentrated and silica gel chromatography (CH2Cl2/EtOAc=1/1) afforded 8-(2-phenyl-5-pyridin-4-yl-3H-imidazol-4-yl)-naphthalen-2-ol (520 mg, 80% yield) as a syrup; 1H NMR 400 Hz (CD3OD) δ 6.89 (d, J=2.32 Hz, 1H), 7.17 (dd, J=2.38, 8.89 Hz, 1H), 7.48 (dd, J=7.15, 8.21 Hz, 1H), 7.55 (m, 3H), 7.66 (dd, J=1.09, 7.04 Hz, 1H), 7.91 (d, J=8.93 Hz, 1H), 7.95 (d, J=7.03 Hz, 3H), 8.04 (d, J=8.24 Hz, 1H), 8.10 (m, 2H), 8.47 (d, J=7.02 Hz, 2H); MS m/z (M+H+) 364.20.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][NH:7][C:6]2=[O:15].C1C=CC2N=CN[C:22](=[O:23])[C:20]=2C=1.BrCCO.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[OH:23][CH2:22][CH2:20][N:7]1[C:6](=[O:15])[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8]1
Reactant: O=c1[nH]cnc2ccccc12
Reactant: COc1cc2nc[nH]c(=O)c2cc1OC
Agent: O=C([O-])[O-]
Agent: OCCBr
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc2ncn(CCO)c(=O)c2cc1OC

Procedure:
3-(2-hydroxyethyl)-6,7-dimethoxy-4(3H)-quinazolinone was prepared from 6,7-dimethoxy-4(3H)-quinazolinone (3 g, 14.6 mmol). The quinazolinone was combined with 2-bromoethanol (1.14 mL, 16 mmol), an excess of potassium carbonate (10 g) and heated at reflux in 200 mL acetone. The salts were filtered off and the reaction mixture was concentrated. The residue was dissolved in chloroform and washed with water. The organic layer was dried over Na2SO4, filtered and concentrated, 1.39 g (38%); light brown powder; m.p. 130° C., MS: 250.9 (M+H)+
Reaction SMILES: [Cl-:1].[Na+].[C:3]12([CH2:13][C:14]([OH:16])=[O:15])[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2.S(=O)(=O)(O)O>C(Cl)(Cl)(Cl)Cl.C(O)(C)(C)C>[C:14]([CH2:13][C:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][C:5]([Cl:1])([CH2:6]3)[CH2:4]1)[CH2:10]2)([OH:16])=[O:15]
Reactant: [Cl-]
Reactant: O=C(O)CC12CC3CC(CC(C3)C1)C2
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(C)(C)O
Product: O=C(O)CC12CC3CC(CC(Cl)(C3)C1)C2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
18 Grams of sodium chloride were added in about 20 equal portions to a mixture of 3 g of 1-adamantyl-acetic acid, 60 ml. of carbon tetrachloride and 200 g of 96% sulfuric acid which was kept at 5° -10°C by external cooling under thorough stirring over a period of 6 hours while a mixture of 9 g of t-butanol and 20 ml. of carbon tetrachloride was added thereto dropwise over 30 minutes. The reaction mixture was poured onto 300 g of broken ice pieces. The crystalline precipitate was filtered out, washed with water sufficiently and air-dried to obtain 3.2 g (yield: 91.1%) of crude 1-carboxymethyl-3-chloroadamantane.