Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5]/[CH:6]=[CH:7]/[CH2:8][N:9]1[C:14]([C:15](=[O:24])[C:16]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[CH:17]=2)=[C:13]([CH:25]([CH3:27])[CH3:26])[C:12](=[O:28])[NH:11][C:10]1=[O:29])(=O)C.C[O-].[Na+].C(O)(=O)C>CO>[OH:4][CH2:5]/[CH:6]=[CH:7]/[CH2:8][N:9]1[C:14]([C:15](=[O:24])[C:16]2[CH:17]=[C:18]([CH3:23])[CH:19]=[C:20]([CH3:22])[CH:21]=2)=[C:13]([CH:25]([CH3:26])[CH3:27])[C:12](=[O:28])[NH:11][C:10]1=[O:29]
Reactant: CC(=O)OC/C=C/Cn1c(C(=O)c2cc(C)cc(C)c2)c(C(C)C)c(=O)[nH]c1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc(C)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2C/C=C/CO)c1
Reaction time: 1 h
Yield: 84.2 %

Procedure:
To a stirred solution of 80 mg (0.2 mmol) of the compound obtained from Example 75 in 5 ml of methanol was added 20 mg (0.37 mmol) of sodium methoxide at room temperature. After 1 hour, the reaction mixture was neutralized with acetic acid and evaporated under reduced pressure to give a yellow-colored residue, which was purified by flash chromatography using a mixture of ethyl acetate and hexane (4:1) as an eluent to afford 60 mg (yield 82%) of the title compound as a colorless syrup.
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10]C(=O)C)[C@@H:8]([CH2:14][O:15]C(=O)C)[O:7][C@H:6]1C1N=NNC=1)(=O)C.N.OO.[C@@H]1([N:36]2[N:40]=[C:39]([C:41]([NH2:43])=[O:42])[CH:38]=[N:37]2)O[C@H](CO)[C@@H](O)[C@H]1O>CC(O)C>[C@@H:6]1([N:37]2[CH:38]=[C:39]([C:41]([NH2:43])=[O:42])[N:40]=[N:36]2)[O:7][C@H:8]([CH2:14][OH:15])[C@@H:9]([OH:10])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2c[nH]nn2)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: NC(=O)c1cnn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)n1
Agent: N
Agent: OO
Solvent: CC(C)O
Product: NC(=O)c1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)nn1

Procedure:
4-Cyano-1-(2,3,5-tri-O-acetyl-β -D-ribofuranosyl-1,2,3-triazole (8). (0.35 g, 0.001 mol) was added to 15% aqueous ammonia (30 ml) and 30% hydrogen peroxide (3 ml). The solution was stirred 4 hr before additional hydrogen peroxide was added. The procedure and product isolation was identical to that used in method 2 for compound 4. The compound was dissolved in hot 2-propanol; cooling of the solution and filtering provided 30 mg of crystalline 5 which was identical to an authentic sample prepared by the procedure of Alonso, et al. J. Heterocyclic Chem. 7, 1269 (1970).
Reaction SMILES: Br[C:2]1[C:10]2[S:9][CH:8]=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.[B:22](OC)([O:25]C)[O:23]C>CCOCC>[S:9]1[C:10]2[C:2]([B:22]([OH:25])[OH:23])=[CH:3][CH:4]=[CH:5][C:6]=2[CH:7]=[CH:8]1
Reactant: COB(OC)OC
Reactant: Brc1cccc2ccsc12
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: OB(O)c1cccc2ccsc12
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 59.8 %

Procedure:
A solution of 7-bromo-1-benzothiophene (19.9 g, 0.094 mol) in absolute ether (200 ml) was treated with a 1.6 M solution of n-butyllithium in hexane (0.14 mol, 88 ml) at −78° C. The solution was stiffed at −78° C. for 10 minutes then treated with trimethyl borate (15 ml, 0.14 mol). The mixture was allowed to warm to −10° C. then quenched with an excess of dilute hydrochloric acid. The organic layer was separated, dried, evaporated, and the residue was recrystallised from aqueous ethanol to yield the title compound (10 g, 60%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][C:9]([C:11]2[CH:16]=[C:15]([C:17]3[CH2:21][CH:20]([CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[O:19][N:18]=3)[N:14]=[C:13]([CH3:28])[N:12]=2)=[O:10])=[CH:5][C:4]=1[O:31][CH3:32].C(N(CC)CC)C.[C:40]([CH2:42][C:43](OCC)=[O:44])#[N:41]>O>[C:40]([CH2:42][C:43]([N:25]1[CH2:24][CH2:23][CH:22]([CH:20]2[O:19][N:18]=[C:17]([C:15]3[N:14]=[C:13]([CH3:28])[N:12]=[C:11]([C:9]([NH:8][CH2:7][C:6]4[CH:29]=[CH:30][C:3]([F:2])=[C:4]([O:31][CH3:32])[CH:5]=4)=[O:10])[CH:16]=3)[CH2:21]2)[CH2:27][CH2:26]1)=[O:44])#[N:41]
Reactant: CCOC(=O)CC#N
Reactant: COc1cc(CNC(=O)c2cc(C3=NOC(C4CCNCC4)C3)nc(C)n2)ccc1F
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cc(CNC(=O)c2cc(C3=NOC(C4CCN(C(=O)CC#N)CC4)C3)nc(C)n2)ccc1F
Temperature: 150 °C

Procedure:
A 100 mL sealed tube was charged with N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(piperidin-4-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide hydrochloride (0.15 g, 0.32 mmol, Preparation #K.1), triethyl amine (0.163 g, 1.6 mmol, Sd Fine Chem), and ethyl cyanoacetate (0.54 mL, 4.8 mmol). The reaction mixture was heated at about 150° C. for about 12 h, cooled to RT and water (15 mL) was added. The product was extracted with EtOAc (2×15 mL). The combined organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude material obtained was purified by preparative HPLC (Table 2, Method d) to afford 6-(5-(1-(2-cyanoacetyl)piperidin-4-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide as an off white solid 0.065 g (40.8%). LC/MS (Table 1, Method c) Rt=1.38 min; MS m/z: 495.3 (M+H)+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22]CC)=[O:21])=[CH:15][CH:14]=1.[OH-].[K+]>C(O)C.O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:17][CH:18]=1
Reactant: CCOC(=O)Cc1ccc(OCc2ccc3ccccc3n2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)Cc1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.8 %

Procedure:
To a stirred solution of ethyl 2-(4-(quinolin-2-ylmethoxy)phenyl)acetate (38.0 g, 106.741 mmol) in ethanol (200 mL) and water (100 mL) was added KOH (23.9 g, 426.964 mmol) at room temperature. The mixture was stirred at RT for 4 h and after complete consumption of starting material as monitored by TLC, the reaction mixture was diluted with water (50 mL) and acidified using 1 N HCl at 0° C. The aqueous layer was extracted with EtOAc (2×150 mL) and thecombined organic extracts were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, and evaporated in vacuo to afford 2-(4-(quinolin-2-ylmethoxy)phenyl)acetic acid (30.0 g, 95%) as a white solid.
Reaction SMILES: C[Si](C=[N+]=[N-])(C)C.[Br:8][C:9]1[C:17]([CH3:18])=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[C:11]([F:19])[CH:10]=1.[CH3:20]O>C1C=CC=CC=1>[Br:8][C:9]1[C:17]([CH3:18])=[CH:16][C:12]([C:13]([O:15][CH3:20])=[O:14])=[C:11]([F:19])[CH:10]=1
Reactant: CO
Reactant: Cc1cc(C(=O)O)c(F)cc1Br
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: c1ccccc1
Product: COC(=O)c1cc(C)c(Br)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
(Trimethylsilyl)diazomethane (4.0 ml, 8.0 mmol, 2 M in Et2O) was added dropwise to a solution of 4-bromo-2-fluoro-5-methyl-benzoic acid (1.88 g, 8.05 mmol) in benzene (7.5 ml)-MeOH (5.6 ml) at 10±2° C. over 10 minutes. The mixture was stirred at room temperature for 30 minutes and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=40/1) to give methyl 4-bromo-2-fluoro-5-methyl-benzoate (1.62 g, 82%).
Reaction SMILES: [F:1][C:2]1[C:10]2[C:9](=[O:11])[O:8][C:7](=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.C([NH2:15])=O>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[NH:15][C:7]2=[O:8]
Reactant: O=C1OC(=O)c2c(F)cccc21
Reactant: NC=O
Product: O=C1NC(=O)c2c(F)cccc21
Temperature: 0 °C

Procedure:
Under argon, 10.0 g (60.2 mmol) of 4-fluoro-2-benzofuran-1,3-dione were stirred at 130° C. in 50 ml of formamide for 1 h. The cooled reaction mixture was then added to ice-water. A solid precipitated out. This solid was filtered off with suction and washed with water. The product was dried under high vacuum. This gave 8.3 g (83% of theory) of the target compound.
Reaction SMILES: [C:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](O)=[O:14])=[C:6]([CH2:18][CH2:19][CH3:20])[C:5]=1[OH:21])(=[O:3])[CH3:2].Cl.[NH2:23][OH:24].C(N(CC)CC)C>C(Cl)Cl>[C:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([NH:23][OH:24])=[O:14])=[C:6]([CH2:18][CH2:19][CH3:20])[C:5]=1[OH:21])(=[O:3])[CH3:2]
Reactant: NO
Reactant: CCCc1c(OCCCCC(=O)O)ccc(C(C)=O)c1O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1c(OCCCCC(=O)NO)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Four and six-tenths grams of 5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentanoic acid were converted to the corresponding acid chloride according to the procedure of Example 55. The resulting acid chloride and 1.05 g. of hydroxylamine hydrochloride were dissolved in 50 ml. of methylene chloride, after which were added 4.15 ml. of triethylamine in about 50 ml. of methylene chloride. After stirring overnight at room temperature, the methylene chloride was removed by evaporation and the residue was partitioned between acetate and dilute hydrochloric acid. The layers were separated, and the ethyl acetate solution was evaporated in vacuo. The residue was dissolved in diethyl ether and the solution was extracted with dilute sodium hydroxide solution. The aqueous basic solution was then made acidic with dilute hydrochloric acid and the solution was extracted with ethyl acetate. The ethyl acetate layer was dried over sodium sulfate and evaporated to dryness. The residue was crystallized from methylene chloride/hexane to provide 400 mg. of the title product.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6].Cl.Cl[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N+:10]=1[O-:15].C([O-])(O)=O.[Na+]>C(O)(CC)(C)C.CCO>[OH:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N+:10]=1[O-:15]
Reactant: [O-][n+]1ccccc1Cl
Reactant: NCCCCO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCC(C)(C)O
Solvent: CCO
Product: [O-][n+]1ccccc1NCCCCO
Reaction time: 48 h

Procedure:
A mixture of 4-amino-1-butanol (1.76 g, 20 mmol), 2-chloropyridine N-oxide hydrochloride (3.98 g, 24 mmol), and NaHCO3 (8.40 g, 100 mmol) in tert-amyl alcohol (50 mL) is heated at reflux under argon. After 48 h, the reaction is cooled, diluted with EtOH, filtered, and concentrated. The residue is reconcentrated from toluene, and chromatographed (silica gel) to give the title compound.
Reaction SMILES: Cl[C:2]1[N:7]([CH2:8][CH2:9][CH3:10])[C:6](=[O:11])[N:5]([CH3:12])[C:4](=[O:13])[CH:3]=1.O.[SH-:15].[Na+]>C(O)C>[SH:15][C:2]1[N:7]([CH2:8][CH2:9][CH3:10])[C:6](=[O:11])[N:5]([CH3:12])[C:4](=[O:13])[CH:3]=1
Reactant: CCCn1c(Cl)cc(=O)n(C)c1=O
Reactant: [SH-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCn1c(S)cc(=O)n(C)c1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 6-chloro-3-methyl-1-propyl-pyrimidine-2,4(1H,3H)-dione (3.76 g), sodium hydrosulphide hydrate (6 g) and ethanol (100 ml) was stirred at room temperature for 48 hours then concentrated in vacuo. The residue was dissolved in water (500 ml) and washed with ethyl acetate (2×100 ml). The aqueous phase was acidified with dilute hydrochloric acid, then extracted with ethyl acetate (3×100 ml). The combined organic phase was dried (MgSO4) and evaporated to leave a pale yellow solid which was used directly in the next step.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3](O)(=[O:5])=[O:4].[NH2:9][C:10]1[S:11][C:12]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[N:14]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[F:1][C:2]([F:8])([F:7])[S:3]([NH:9][C:10]1[S:11][C:12]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)[N:14]=1)(=[O:5])=[O:4]
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: Nc1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)s1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=S(=O)(Nc1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)s1)C(F)(F)F

Procedure:
2.68 ml of anhydrous trifluoromethanesulfonic acid was slowly dropped into a solution of 2.88 g of 2-amino-4,5-bis(4-fluorophenyl)thiazole and 1.8 ml of triethylamine in chloroform under stirring in a nitrogen atmosphere at -20° to -15° C., and the resulting mixture was stirred as such for 1 hour. Then the reaction mixture was successively washed with diluted hydrochloric acid, a 5% aqueous solution of sodium hydrogencarbonate and water in this order and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the reaction product was separated with a silica gel column by using isopropyl ether as a developer. The crystals thus obtained were recrystallized from petroleum ether/diethyl ether to give 0.47 g of 2-trifluoromethanesulfonylamino-4,5-bis(4-fluorophenyl)thiazole. The melting point of this product was from 193° to 195° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][C:11]#[N:12])=[CH:5][CH:4]=1.O.[NH2:15][NH2:16]>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([NH2:12])[NH:16][N:15]=2)=[CH:5][CH:4]=1
Reactant: NN
Reactant: COc1ccc(C(=O)CC#N)cc1
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2cc(N)[nH]n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(4-methoxyphenyl)-3-oxopropanenitrile (5.0 g, 28.5 mmol) in ethanol (100 mL) was added hydrazine hydrate (2.8 mL, 57.1 mmol) at room temperature. The mixture was heated to reflux for 8 h, allowed to cool and concentrated under reduced pressure to about ¼ volume (25 mL). The resulting precipitate was allowed to stir overnight at room temperature, filtered and rinsed with ethanol (2 mL). The title product was dried under vacuum. Yield 4.15 g (77%); LCMS m/z 190.1 (M+H)+, ret. time=1.56 min.
Reaction SMILES: [C:1](#[N:5])[CH:2]([CH3:4])[CH3:3].Br[CH2:7][CH2:8][CH2:9][Cl:10].C[Si]([NH-])(C)C.C[Si]([NH-])(C)C.[Li+].[Li+]>>[Cl:10][CH2:9][CH2:8][CH2:7][C:2]([CH3:4])([CH3:3])[C:1]#[N:5]
Reactant: CC(C)C#N
Reactant: ClCCCBr
Agent: C[Si](C)(C)[NH-]
Agent: [Li+]
Product: CC(C)(C#N)CCCCl
Temperature: 69 °C
Reaction time: 2 h
Yield: 85.7 %

Procedure:
Isobutyronitrile (13.8 g, 0.20 mole), and 1-bromo-3-chloropropane (34.5 g, 0.22) are added sequentially to a stirred 1 M solution of lithium bis(trimethylsilylamide) (200 ml, 0.20 mole) in hexanes, stirred for two hours at 69° C. and quenched with water. The phases are separated and the organic phase is concentrated in vacuo to afford the title product as an oil, 38.9 g (64% pure, 85.7% yield), identified via gas chromatography.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][OH:5].[OH-].[Na+].[C:12]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH:13]=[CH2:14]>CS(C)=O>[OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][O:5][CH2:14][CH2:13][C:12]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: OCC(CO)(CO)CO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)CCOCC(CO)(CO)CO
Temperature: 80 °C
Yield: 42 %

Procedure:
To DMSO (100 mL) was added pentaerythritol 1 (68 g, 0.5 mol); the heterogeneous suspension was heated to 80° C. until the system became clear, then aqueous NaOH (4 g of NaOH in 9 mL of H2O) was added in one portion, tert-butyl acrylate (87 mL, 0.6 mol) was added to the solution dropwise, and vigorous stirring continued overnight at 80° C. After cooling, the solution was extracted with EtOAc. The combined organic phase was washed with H2O and brine, concentrated through rotary evaporation, and the residue was subjected to silica gel chromatography using CH2Cl2/MeOH as the eluent to give 2 (54.3 g, 0.21 mol, 41% yield) as a clear oil: 1H NMR (500 MHz, CDCl3) δ 3.63 (br, 3H), 3.56 (t, J=5.5 Hz, 2H), 3.52 (s, 6H), 3.37 (s, 2H), 2.38 (t, J=5.0 Hz, 2H), 1.37 (s, 9H); 13C NMR (126 MHz, CDCl3) δ 171.7, 81.2, 72.1, 67.2, 63.6, 45.3, 36.1, 28.1; MS (ESI) m/z 209 (M−tBu+2H)+, 265 (M+H)+, 287 (M+Na)+; HRMS (ESI) calcd for C12H25O6 265.1651 (M+H)+, 209.1025 [M−tBu+2H]+. found 265.1646, 209.1026, respectively.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[N:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:13]=[O:14]>C1COCC1>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH:9][C:13]([NH:12][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:14])=[O:7])=[CH:4][CH:3]=1
Reactant: NNC(=O)c1ccc(Cl)cc1
Reactant: CCOC(=O)CN=C=O
Solvent: C1CCOC1
Product: CCOC(=O)CNC(=O)NNC(=O)c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A suspension of 12.95 g (75.9 mmol) of 4-chlorobenzhydrazide in 50 ml of dry THF was introduced at 50° C. and admixed dropwise with a solution of 10.0 g (77.5 mmol) of ethyl 2-isocyanatoacetate in 100 ml of dry THF. First of all a solution formed, and then a precipitate was produced. After the end of the addition, the mixture was stirred at 50° C. for 2 h more, then left to stand overnight at RT. The crystals were isolated by filtration, washed with a little diethyl ether and dried in an HV. This gave 21.43 g (89% of theory) of the title compound.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].[NH2:21][CH2:22][CH:23]1[CH2:27][CH2:26][CH2:25][N:24]1[CH2:28][CH3:29]>>[CH2:28]([N:24]1[CH2:25][CH2:26][CH2:27][CH:23]1[CH2:22][NH:21][C:16](=[O:18])[C:15]1[CH:14]=[CH:13][C:12]([O:11][CH2:1]/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])\[CH3:4])=[CH:20][CH:19]=1)[CH3:29]
Reactant: CCN1CCCC1CN
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)O)cc1
Product: CCN1CCCC1CNC(=O)c1ccc(OC/C=C(\C)CCC=C(C)C)cc1
Yield: 98 %

Procedure:
In a manner identical to Example 15, 4-geranyloxybenzoic acid (1.45 g) was subjected to a condensation reaction with 2-aminomethyl-1-ethylpyrrolidine (0.7 ml), thereby yielding 1.96 g (98%) of the aimed compound.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@@H:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH2:9]1)=O)(C)(C)C.[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24]>C(Cl)Cl>[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24].[NH:8]1[CH2:12][CH2:11][C@@H:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Sc2ccc(O)cc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Oc1ccc(S[C@@H]2CCNC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 109.7 %

Procedure:
(R)-3-(4-Hydroxy-phenylsulfanyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (3.0 g, 10.2 mmol) in CH2Cl2 (36 ml) was treated with trifluoroacetic acid (7.8 ml, 0.1 mol). After 1 hour stirring at room temperature, the reaction mixture was concentrated to provide (R)-4-(pyrrolidin-3-yl-sulfanyl)-phenol trifluoroacetic acid (3.46 g) as an orange oil, MS: m/e=196.2 (M+H+) and [α]D20=+25.060 ° (c=1.2, MeOH).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)=[C:14]2[CH2:27][CH2:28][C:29]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)=[O:30]>N1C=CC=CC=1>[C:1]([N:34]1[CH2:35][CH2:36][N:31]([C:29](=[O:30])[CH2:28][CH2:27][C:14]2[C:13]3[C:17](=[CH:18][CH:19]=[C:11]([Cl:10])[CH:12]=3)[NH:16][C:15]=2[C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[CH2:32][CH2:33]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(CCc1c(-c2ccc(Cl)cc2)[nH]c2ccc(Cl)cc12)N1CCNCC1
Solvent: c1ccncc1
Product: O=C(CCc1c(-c2ccc(Cl)cc2)[nH]c2ccc(Cl)cc12)N1CCN(C(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58 %

Procedure:
Benzoyl chloride (0.011 mL) was added to a stirred solution of 1-{3-[5-chloro-2-(4-chlorophenyl)-1H -indol-3-yl]-1-oxopropyl}piperazine (Description 30, 35 mg) in pyridine (0.5 mL) and the mixture was stirred at room temperature for 3 h. The solvent was evaporated under reduced pressure, hydrochloric acid (2M, 5 mL) and ethyl acetate (5 mL) were added and the layers were separated. The organic layer was dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was crystallized from dichloromethane/ethyl acetate (4:1) to give the title compound as a colorless solid (25 mg, 58%). 1H NMR (360 MHz, CDCl3) δ2.56-2.68 (2H, m), 3.02-3.67 (10H, m), 7.17 (1H, dd, J 8.6, 1.8 Hz), 7.28 (1H, d, J 8.6 Hz), 7.33-7.50 (9H, m), 7.56 (1H, s), and 8.13 (1H, s). m/z (ES+) 506, 508 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[C:15](S(C)(=O)=O)[N:14]=[C:13]([NH:21][C:22]3[CH:31]=[CH:30][C:25]4[O:26][CH2:27][CH2:28][O:29][C:24]=4[CH:23]=3)[CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:32][O-:33].[Na+]>CO>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[C:15]([O:33][CH3:32])[N:14]=[C:13]([NH:21][C:22]3[CH:31]=[CH:30][C:25]4[O:26][CH2:27][CH2:28][O:29][C:24]=4[CH:23]=3)[CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C[O-]
Reactant: CC(C)(C)c1ccc(-c2cc(Nc3ccc4c(c3)OCCO4)nc(S(C)(=O)=O)n2)cc1
Agent: [Na+]
Solvent: CO
Product: COc1nc(Nc2ccc3c(c2)OCCO3)cc(-c2ccc(C(C)(C)C)cc2)n1

Procedure:
To a 50-mL, round-bottomed flask containing a solution of 6-(4-tert-butylphenyl)-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-(methylsulfonyl)pyrimidin-4-amine from step (c) above (0.20 g, 0.46 mmol) in MeOH (10 mL) was added NaOMe (76 mg, 1.4 mmol, Aldrich). The reaction mixture was refluxed for 2 h, and the solvent was removed in vacuo. Purification of the residue by silica gel column chromatography (4:1 hexane/EtOAc) provided the title product as a yellow solid. MS (ESI, pos. ion) m/z: 392 (M+1).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[N:15]2[C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N+:19]([O-])=[CH:18][C:17]=3[N:27]=[C:14]2[CH2:13][O:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+:28].[OH-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.O>C(Cl)Cl>[CH2:1]([O:8][CH2:9][C@@H:10]1[N:15]2[C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=[C:18]([NH2:28])[C:17]=3[N:27]=[C:14]2[CH2:13][O:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [O-][n+]1cc2nc3n(c2c2ccccc21)[C@@H](COCc1ccccc1)COC3
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Nc1nc2ccccc2c2c1nc1n2[C@@H](COCc2ccccc2)COC1
Reaction time: 2.5 h

Procedure:
(11S)-11-[(benzyloxy)methyl]-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinoline 5-oxide (0.96 g, 2.67 mmol) was dissolved in 25 mL of CH2Cl2 and treated with 2.5 mL of concentrated aqueous NH4OH solution. The mixture was stirred rapidly and then p-toluenesulfonyl chloride (0.51 g, 2.67 mmol) was carefully added. Rapid stirring was continued for 2.5 hours. The reaction mixture was then treated with 50 mL of CH2Cl2 and 25 mL of H2O. The layers were separated and the organic portion was washed successively with 5% Na2CO3 solution (3×25 mL), H2O and brine. The organic portion was dried over Na2SO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, 15-25% CMA/CHCl3) gave a light-brown foam. Crystallization from ethyl acetate and a small amount of methanol gave (11S)-11-[(benzyloxy)methyl]-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-6-amine (420 mg) fine white needles, mp 184.6-186.2° C.