Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]2[CH2:6][CH2:7][C:8]3[C:9]([C:20]([NH2:22])=[O:21])=[N:10][N:11]([C:13]4[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=4)[C:12]=3[C:4]=2[CH:3]=1.[Cl:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][N:34]=1)[C:29](O)=[O:30]>>[Cl:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][N:34]=1)[C:29]([NH:1][C:2]1[CH:24]=[CH:23][C:5]2[CH2:6][CH2:7][C:8]3[C:9]([C:20]([NH2:22])=[O:21])=[N:10][N:11]([C:13]4[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=4)[C:12]=3[C:4]=2[CH:3]=1)=[O:30]
Reactant: O=C(O)c1ccnc(Cl)c1
Reactant: NC(=O)c1nn(-c2ccc(F)cc2)c2c1CCc1ccc(N)cc1-2
Product: NC(=O)c1nn(-c2ccc(F)cc2)c2c1CCc1ccc(NC(=O)c3ccnc(Cl)c3)cc1-2

Procedure:
This material was prepared from Example 244 (8-amino-1-(4-fluorophenyl)-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide) and 2-chloroisonicotinic acid by the method described for Example 246 step 3.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1F)([O-:3])=[O:2].[OH:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[N:23]=[CH:22][CH:21]=[CH:20]2.C(N(CC)CC)C>CC(C)=O>[N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[O:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[N:23]=[CH:22][CH:21]=[CH:20]2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Reactant: Oc1cccc2cccnc12
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(Oc2cccc3cccnc23)c([N+](=O)[O-])c1

Procedure:
J.D. Reinheimer et al, disclose (J. Org. Chem., 1957, vol. 22, p. 1743) that 2,4-dinitrofluorobenzene reacts with 8-hydroxyquinoline in acetone, in the presence of triethylamine, to form 8-(2,4-dinitrophenoxy)quinoline.
Reaction SMILES: ClS([N:5]=[C:6]=[O:7])(=O)=O.[NH2:8][C:9]1[S:10][C:11]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][C:13]=1[C:14]([NH2:16])=[O:15]>ClCCl>[CH2:17]([C:11]1[S:10][C:9]([NH:8][C:6]([NH2:5])=[O:7])=[C:13]([C:14]([NH2:16])=[O:15])[CH:12]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NC(=O)c1cc(Cc2ccccc2)sc1N
Reactant: O=C=NS(=O)(=O)Cl
Solvent: ClCCl
Product: NC(=O)Nc1sc(Cc2ccccc2)cc1C(N)=O
Yield: 67.6 %

Procedure:
Chlorosulfonyl isocyanate (0.09 mL, 1.03 mmol) was added dropwise under nitrogen to a solution of 2-amino-5-benzyl-thiophene-3-carboxylic acid amide (0.2 g, 0.86 mmol) in dry dichloromethane (9 mL) at 0° C. and. The temperature of the resulting stirred reaction mixture was slowly raised from 0° C. to room temperature over 1 h. Once the LC-MS showed no starting material remaining, the reaction was quenched with water (1 mL) and stirred for 10 additional min. The solvent was removed under vacuum and the residue was taken up into DMSO (2 mL) and purified utilizing a Gilson preparative HPLC to give the above titled compound as a light brown solid (0.16 g, 67%). LC-MS [M+H]+ m/z 276.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][NH:5][S:6]([C:9]1[S:13][C:12]([NH:14]C(=O)C)=[N:11][C:10]=1[CH3:18])(=[O:8])=[O:7].C([O-])(O)=O.[Na+]>Cl>[CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][NH:5][S:6]([C:9]1[S:13][C:12]([NH2:14])=[N:11][C:10]=1[CH3:18])(=[O:8])=[O:7]
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)NCCN(C)C)s1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1nc(N)sc1S(=O)(=O)NCCN(C)C
Temperature: 80 °C
Yield: 78.9 %

Procedure:
A stirred suspension of 2-acetamido-4-methyl-thiazole-5-sulfonic acid (2-dimethylamino-ethyl)-amide (1.0 g, 3.26 mmol) in 6N hydrochloric acid (13 ml) was heated for 2 h at 80° C., and 2N NaHCO3 solution (100 ml) was added. The mixture was extracted with ethyl acetate (3×50 ml), the combined organic layers washed with brine (50 ml) and dried (MgSO4). The crude product was further purified by crystallization (ethyl aceate) to yield the title compound (0.68 g, 79%) as a white solid. MS (ISP) 262.9 [(M−H)−]; mp 153° C.
Reaction SMILES: [CH2:1]([C:3]1[S:26][C:6]2[N:7]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:14][CH:13]=3)[C:8](=[O:10])[NH:9][C:5]=2[CH:4]=1)[CH3:2].Br[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1.CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[CH2:1]([C:3]1[S:26][C:6]2[N:7]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:14][CH:13]=3)[C:8](=[O:10])[N:9]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[C:5]=2[CH:4]=1)[CH3:2]
Reactant: Fc1ccc(CBr)cc1
Reactant: CCc1cc2[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1cc2c(s1)n(Cc1ccc(-c3ccccc3C#N)cc1)c(=O)n2Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a mixture of 4′-[(5-ethyl-2-oxo-1,2-dihydro-3H-thieno[2,3-d]imidazol-3-yl)methyl]biphenyl-2-carbonitrile (0.35 g), 1-(bromomethyl)-4-fluorobenzene (0.18 mL) and N,N-dimethylformamide (15 mL) was added 60% sodium hydride (0.057 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed successively with 5% aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.36 g, 80%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:28]([N:35]=[C:36]=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:36]([NH:35][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:37])=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: O=C=NCc1ccccc1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)NCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 7, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and benzyl isocyanate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([NH:9][C:10]2[C:11]([NH2:16])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.[CH3:19][N:20]([CH3:33])[S:21]([C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=1)(=[O:23])=[O:22]>>[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:28](=[O:29])[C:27]3[CH:31]=[CH:32][C:24]([S:21]([N:20]([CH3:19])[CH3:33])(=[O:23])=[O:22])=[CH:25][CH:26]=3)=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:17][CH:18]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2N)cc1
Reactant: CN(C)S(=O)(=O)c1ccc(C(=O)O)cc1
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)c2ccc(S(=O)(=O)N(C)C)cc2)cc1
Yield: 34.8 %

Procedure:
Using the procedure described in Example 55, Part B, N1-(4-methoxybenzoyl)-1,2-benzenediamine (534 mg, 2.21 mmol) was reacted with 4-(dimethylaminosulfonyl)benzoic acid (534 mg, 2.33 mmol) to yield 349 mg (35%) of the title compound.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].O.[C:6]1(C)[CH:11]=[CH:10][C:9](S(O)(=O)=O)=[CH:8][CH:7]=1.C1C=CC=CC=1>O>[CH2:2]1[CH2:1][O:4][CH2:9][CH:10]([CH2:11][CH2:6][CH:7]=[CH2:8])[O:3]1
Reactant: OCCO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: C=CCCC1COCCO1
Reaction time: 2 h
Yield: 90 %

Procedure:
A mixture of 5-oxy-1-hexene (9.8 g.), ethylene glycol (18.6 g.), p-toluene sulfonic acid monohydrate (1.56 g.) and benzene (250 ml.) is heated at reflux under a Dean-Stark water separator. After 2 hrs., the reaction mixture is washed with water and the organic layer is separated, dried with magnesium, and evaporated in vacuo. Distillation of the residue gives 5-ethylenedioxy-1-hexene (90% yield) b.p. 34°-37°/1.5 mm. nmr (CDCl3) δ: 1.27 (s, CH3), 1.5-2.4 (m, CH2 --CH2); 2.83 (s, --O--CH2 --CH2 --O); 4.80-6.1 (m, CH2 =CH--). IR (film) μ: 6.06 (CH2 =CH--).
Reaction SMILES: C(O[C:4](=[O:24])[CH2:5][N:6]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:7]([NH:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[CH3:17])=[S:8])C.C(N(CC)CC)C>C(O)C>[Cl:16][C:14]1[CH:13]=[CH:12][C:11]([CH3:17])=[C:10]([N:9]2[C:4](=[O:24])[CH2:5][N:6]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:7]2=[S:8])[CH:15]=1
Reactant: CCOC(=O)CN(C(=S)Nc1cc(Cl)ccc1C)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1ccc(Cl)cc1N1C(=O)CN(c2ccccc2)C1=S
Temperature: 25 °C
Yield: 73.5 %

Procedure:
A mixture of 2-[3-(5-chloro-2-methylphenyl)-1-phenyl-thioureido]-acetic acid ethyl ester (9.5 g), triethyl amine (1 mL), and ethanol (150 mL) was heated at reflux for 2 hours. The mixture was concentrated to one-half volume and cooled to ambient temperature. The solid was collected and air dried to give the title compound (6.1 g) as an off-white solid, m.p. 168°-170° C. Anal. Calcd. for. C16H13Cl N2O S: C, 60.66; H, 4.14; N, 8.84. Found: C, 60.81; H, 4.16; N, 8.81. Mass spectrum (EI, M.+) m/z 316/318.
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]=[C:9]1[N:13](C(OC(C)(C)C)=O)[CH:12]([CH2:21][CH2:22][C:23]([F:26])([F:25])[F:24])[CH2:11][N:10]1C(OC(C)(C)C)=O>ClCCl>[F:26][C:23]([F:24])([F:25])[CH2:22][CH2:21][CH:12]1[CH2:11][NH:10][C:9](=[O:8])[NH:13]1
Reactant: CC(C)(C)OC(=O)N1CC(CCC(F)(F)F)N(C(=O)OC(C)(C)C)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCC(CCC(F)(F)F)N1
Yield: 131 %

Procedure:
Trifluoroacetic acid (6.05 g, 53.04 mmol, 3 eq) in dichloromethane (50 ml) is added to a solution of di-tert-butyl 2-oxo-4-(3,3,3-trifluoropropyl)imidazolidine-1,3-dicarboxylate a7 (6.76 g, 17.68 mmol, 1 eq) in dichloromethane (60 ml) at room temperature overnight. The reaction mixture is condensed under reduced pressure to afford 4.22 g of 4-(3,3,3-trifluoropropyl)imidazolidin-2-one a10 as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:21][CH2:22][CH:23]([O:26][CH3:27])[O:24][CH3:25])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[N:13]=[C:14]([CH:17]([CH3:19])[CH3:18])[S:15][CH:16]=1)[CH:8]=[C:7]2O.O=P(Cl)(Cl)[Cl:30].CO.C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[Cl:30][C:7]1[C:6]2[C:11](=[C:2]([Cl:1])[C:3]([O:21][CH2:22][CH:23]([O:26][CH3:27])[O:24][CH3:25])=[CH:4][CH:5]=2)[N:10]=[C:9]([C:12]2[N:13]=[C:14]([CH:17]([CH3:19])[CH3:18])[S:15][CH:16]=2)[CH:8]=1
Reactant: COC(COc1ccc2c(O)cc(-c3csc(C(C)C)n3)nc2c1Cl)OC
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CO
Product: COC(COc1ccc2c(Cl)cc(-c3csc(C(C)C)n3)nc2c1Cl)OC
Temperature: 80 °C
Yield: 49.9 %

Procedure:
8-Chloro-7-(2,2-dimethoxy-ethoxy)-2-(2-isopropyl-thiazol-4-yl)-quinolin-4-ol (502 mg, 1.20 mmol) was dissolved in pyridine (10 mL). POCl3 (2.29 mL, 25.0 mmol) was added slowly. The reaction was heated at 80° C. for 4 hours. The reaction was cooled to 0° C. and methanol (5 mL) was added. The reaction was neutralized with a sat NaHCO3(aq) solution. The product was extracted with EtOAc (3×20 mL). The combined organics were dried with Na2SO4, filtered and was concentrated. 4,8-Dichloro-7-(2,2-dimethoxy-ethoxy)-2-(2-isopropyl-thiazol-4-yl)-quinoline (256 mg, 49%) was isolated by silica gel chromatography as a yellow solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH2:7][S:8]([CH2:11][CH2:12][C:13]([CH3:20])([CH3:19])[C:14](OCC)=[O:15])(=[O:10])=[O:9]>O1CCCC1>[OH:15][CH2:14][C:13]([CH3:20])([CH3:19])[CH2:12][CH2:11][S:8]([NH2:7])(=[O:9])=[O:10]
Reactant: CCOC(=O)C(C)(C)CCS(N)(=O)=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(CO)CCS(N)(=O)=O
Reaction time: 0.5 h
Yield: 77.2 %

Procedure:
To a suspension of 0.35 g of lithium aluminum hydride in 30 ml of tetrahydrofuran being stirred under ice cooling conditions, a solution of 1.5 g of ethyl 4-aminosulfonyl-2,2-dimethylbutyrate in 8 ml of tetrahydrofuran was added dropwise, followed by stirring at 0° C. for 30 minutes and then at room temperature (15° to 20° C.) for 30 minutes. To the reaction mixture was added aqueous tetrahydrofuran to decompose excess lithium aluminum hydride, followed by neutralization with 2 N hydrochloric acid and extraction with ethyl acetate. After the extract was washed with water and dried over MgSO4, the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with hexane:ethyl acetate (1:1) to yield 0.94 g of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([O:28][CH3:29])[CH:22]=1)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:30]([O:37][C:38]1[CH:46]=[CH:45][C:41]([C:42](Cl)=[O:43])=[CH:40][CH:39]=1)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>C(Cl)Cl>[CH2:30]([O:37][C:38]1[CH:39]=[CH:40][C:41]([C:42]([O:27][C:24]2[CH:25]=[CH:26][C:21]([CH2:20][CH:12]([NH:11][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:10])[C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])=[CH:22][C:23]=2[O:28][CH3:29])=[O:43])=[CH:45][CH:46]=1)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: COc1cc(CC(NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)ccc1O
Reactant: CCCCCCCOc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Product: CCCCCCCOc1ccc(C(=O)Oc2ccc(CC(NC(=O)OCc3ccccc3)C(=O)OC(C)(C)C)cc2OC)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 75 %

Procedure:
Prepared using General Procedure 3: To a stirred solution of tert-butyl 2-(((benzyloxy)carbonyl)amino)-3-(4-hydroxy-3-methoxyphenyl)propanoate INT-2 (4.7 g, 11.71 mmol) and TEA (3.05 mL, 21.07 mmol) in DCM (50 mL) at 0° C. was added 4-(heptyloxy)benzoyl chloride (2.95 mL, 12.29 mmol) dropwise. After warming to room temperature and stirring for 10 min, the mixture was quenched with saturated aqueous NaHCO3 (50 mL) and water (50 mL). The organic layer was dried over MgSO4 and concentrated. The product was purified by chromatography (EA/hexanes) to afford 5.46 g (75%) of 4-(2-(((benzyloxy)carbonyl)amino)-3-(tert-butoxy)-3-oxopropyl)-2-methoxyphenyl 4-(heptyloxy)benzoate INT-3. LCMS-ESI (m/z) calculated for C36H45NO8: 619; found 564 [M+H-tBu]+, tR=3.22 min (Method 4).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].I[C:15]1[CH:16]=[CH:17][C:18]2[S:22][CH:21]=[N:20][C:19]=2[CH:23]=1.N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[S:22]1[C:18]2[CH:17]=[CH:16][C:15]([N:10]3[CH2:11][CH2:12][N:8]([C:3]4[CH:4]=[N:5][CH:6]=[CH:7][C:2]=4[CH3:1])[C:9]3=[O:13])=[CH:23][C:19]=2[N:20]=[CH:21]1
Reactant: Ic1ccc2scnc2c1
Reactant: Cc1ccncc1N1CCNC1=O
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCN(c2ccc3scnc3c2)C1=O
Yield: 70.4 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.84650 mmol) was reacted with 5-iodo-benzothiazole (221 mg. 0.84650 mmol), 1,4-dioxane (25 mL), copper iodide (16 mg, 0.084650 mmol), trans-1,2-diamino cyclohexane (29 mg, 0.2539 mmol) and potassium phosphate (538 mg, 2.539 mmol) to afford the crude product. Purification by column chromatography on silica gel (2% MeOH in DCM) afforded 185 mg of the product (70.6% yield).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:13](Cl)=[O:14])=[C:9]([Cl:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH:16]1[CH2:20][CH2:19][CH:18]=[CH:17]1.[OH-].[Na+]>ClCCl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:13]([N:16]3[CH2:20][CH:19]=[CH:18][CH2:17]3)=[O:14])=[C:9]([Cl:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: C1=CNCC1
Reactant: O=C(Cl)c1cc2ncnc(Cl)c2cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(c1cc2ncnc(Cl)c2cc1Cl)N1CC=CC1

Procedure:
Prepared analogously to Example 2c from 4,6-dichloro-quinazoline-7-carboxylic acid chloride, pyrroline and sodium hydroxide solution in dichloromethane
Reaction SMILES: [CH2:1]([NH:3][CH:4]1[CH2:9][CH2:8][S:7](=[O:11])(=[O:10])[C:6]2[S:12][C:13]([S:15]([NH2:18])(=[O:17])=[O:16])=[CH:14][C:5]1=2)[CH3:2].C(N(CC)CC)C.[C:26](Cl)(=[O:28])[CH3:27].C([O-])(O)=O.[Na+]>C1COCC1>[CH2:1]([N:3]([CH:4]1[CH2:9][CH2:8][S:7](=[O:10])(=[O:11])[C:6]2[S:12][C:13]([S:15]([NH2:18])(=[O:16])=[O:17])=[CH:14][C:5]1=2)[C:26](=[O:28])[CH3:27])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCNC1CCS(=O)(=O)c2sc(S(N)(=O)=O)cc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCN(C(C)=O)C1CCS(=O)(=O)c2sc(S(N)(=O)=O)cc21
Reaction time: 2 h
Yield: 81.1 %

Procedure:
To a mixture of 4-(N-ethylamino)-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide-7,7-dioxide (1.2 g, 0.0035 mol) in THF (30 ml) and triethylamine (1.1 ml, 0.79 g, 0.0078 mol) under N2 was added dropwise at room temperature a solution of acetyl chloride (0.26 ml, 0.28 g, 0.0036 mol) in THF (15 ml). After 2 hours, the mixture was poured into a saturated solution of NaHCO3 and extracted with ethyl acetate (3x). The organic extracts were dried, filtered and concentrated to dryness to yield 1.0 g (83%) of product.
Reaction SMILES: B.CSC.[CH:5]1([CH2:15][C:16](O)=[O:17])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][O:6]1>C1COCC1>[CH:5]1([CH2:15][CH2:16][OH:17])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][O:6]1
Reactant: O=C(O)CC1OCCc2ccccc21
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: OCCC1OCCc2ccccc21
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Borane-methyl sulfide (10.5 ml) in THF is added to an ice-cooled solution of (-)-(isochroman-1-yl)acetic acid (LXI, EXAMPLE 45--Step 3, 7.08 g, 36.8 mmol). After stirring for 20 min at 0°, the ice bath is removed and the solution is stirred at 20°-25° for another 1.7 hr. The reaction flask is then placed in an ice-water bath and methanol is added slowly until no further gas evolution occurs. The solvents are then removed under reduced pressure and methanol is again added and removed a second and third time. The residue is partitioned between dichloromethane, aqueous sodium bicarbonate and saline. The organic phase is separated, dried over sodium sulfate and concentrated to give (-)-2-(isochroman-1-yl)ethanol (LXXIX). This material is added to dimethylaminopyridine (0.22 g, 1.8 mmol), diisopropylethylamine (16.0 ml, 92 mmol) and THF (60 ml). The mixture is cooled in an ice-water bath and methanesulfonyl chloride (3.4 ml, 44.2 mmol) is added dropwise over several minutes. After stirring for 55 min at 0°, 4-(piperazin-1-yl)benzamide (IV, EXAMPLE 47 Step 1, 9.06 g, 44.2 mmol) and ethylene glycol (60 ml) are added. The mixture is heated at 80° overnight and then water is added and the resulting solid is collected and washed with water and toluene. After drying, the solid is passed through silica gel using methanol/dichloromethane (4/96) to give (-)-4-[4-[2-(isochroman-1-yl)ethyl]piperazin-1-yl]benzamide, MS (m/z) 365; IR (mineral oil) 1610, 1239, 1643, 1112, 1622 cm-1.
Reaction SMILES: [Cl:1]([OH:5])(=[O:4])(=[O:3])=[O:2].Cl([O-])(=O)(=O)=O.[K+:11].[S:12](=[O:16])(=[O:15])([OH:14])[OH:13]>>[S:12]([O-:16])([O-:15])(=[O:14])=[O:13].[K+:11].[K+:11].[Cl:1]([OH:5])(=[O:4])(=[O:3])=[O:2]
Reactant: O=S(=O)(O)O
Agent: [K+]
Agent: [O-][Cl+3]([O-])([O-])O
Agent: [O-][Cl+3]([O-])([O-])[O-]
Product: O=S(=O)([O-])[O-]

Procedure:
One of the advantages of the present invention is, the present invention allows the recycling of perchloric acid. It can be recycled by treating the perchlorate salt with dilute sulphuric acid to yield potassium sulfate and perchloric acid. The potassium sulphate can then be precipitated from the solution and filtered off. The potassium sulfate salt precipitate could be used as a fertilizer; whereas the filtrate, perchloric acid, could be re-used for the hydrolysis of cellulosic materials as set forth in the foregoing description. One of the advantages of the present invention is that the present invention allows the recycling of perchloric acid. It can be recycled by treating the potassium perchlorate salt with dilute sulphuric acid to yield potassium sulfate and perchloric acid. The potassium sulphate can then be precipitated from the solution and filtered off. The potassium sulfate salt precipitate could be used as a valuable fertilizer; whereas the filtrate, perchloric acid, could be re-used for the hydrolysis of cellulosic materials as set forth in the foregoing description.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.Cl.Cl.[NH2:22][CH:23]1[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]1>>[N:25]12[CH2:30][CH2:29][CH:28]([CH2:27][CH2:26]1)[CH:23]([NH:22][C:17]([C:16]1[C:10]3[O:9][C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)=[N:12][C:11]=3[CH:13]=[CH:14][CH:15]=1)=[O:19])[CH2:24]2
Reactant: O=C(O)c1cccc2nc(-c3ccc(Cl)cc3)oc12
Reactant: NC1CN2CCC1CC2
Agent: Cl
Product: O=C(NC1CN2CCC1CC2)c1cccc2nc(-c3ccc(Cl)cc3)oc12
Yield: 55 %

Procedure:
N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(4-chlorophenyl)benzoxazole-7-carboxamide was prepared from 2-(4-chlorophenyl)benzoxazole-7-carboxylic acid and 3-aminoquinuclidine dihydrochloride using the method outlined in Step C of Example 14. This compound was obtained in 55% yield as a off-white solid: mp 181-183° C.; 1H NMR (500 MHz, CDCl3) δ 8.14 (d, J=8.6 Hz, 2H), 8.11 (dd, J=1.0, 11.1 Hz, 2H), 7.92 (dd, J=1.0, 7.9 Hz, 1H), 7.56 (d, J=8.6 Hz, 2H), 7.50 (t, J=7.8 Hz, 1H), 7.32 (d, J=7.1 Hz, 1H), 4.31 (m, 1H), 3.57 (dd, J=9.4, 14.4 Hz, 1H), 3.01 (t, J=7.9 Hz, 2H), 2.92 (m, 2H), 2.74 (m, 1H), 2.17 (m, 1H), 1.91 (m, 1H), 1.78 (m, 2H), 1.63 (m, 4H); MS (ESI) m/z 382 [M+H]+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21](=[O:46])[C@H:22]([CH2:39][C:40]2[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=2)[NH:23][C:24]([CH:26]2[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]2)=[O:25])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:14]1([CH2:13][CH2:12][CH2:11][CH:10]([NH:20][C:21](=[O:46])[C@H:22]([CH2:39][C:40]2[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=2)[NH:23][C:24]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:25])[CH2:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)N[C@@H](Cc2cccnc2)C(=O)NC(CCCc2ccccc2)CCCc2ccccc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(N[C@@H](Cc1cccnc1)C(=O)NC(CCCc1ccccc1)CCCc1ccccc1)C1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
N-(N-tert-Butoxycarbonyl-piperidine-4-carbonyl)-3-(3-pyridyl)-alanine [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (86) (1.30 g; 2.07 mmol) is dissolved in methylene chloride (40 mL) at ambient temperature. Trifluoroacetic acid (20 mL) is added in a slow stream, and the solution is stirred for 2 hours at ambient temperature. The solution is concentrated in vacuo at 40° C. The residue is dissolved in methylene chloride (200 mL) and poured onto saturated sodium bicarbonate solution. The pH is adjusted to 9 with saturated potassium carbonate solution. The mixture is shaken the layers separated. The water layer is extracted with methylene chloride (3×50 mL). The combined organic extracts are washed with water, dried over MgSO4, filtered, and concentrated in vacuo affording the desired product (0.98 g) as a white solid. ESMS: MH+ 527.2