Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[C:12]([O:16][C:17](=O)[O:18]C(C)(C)C)([CH3:15])([CH3:14])[CH3:13].[OH-].[Na+]>C1COCC1>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:17](=[O:18])[O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 89 %

Procedure:
A mixture of 4-trifluoromethylaniline (40 mmol, 5 ml), di-tert-butylcarbonate (40 mmol, 8.7 g), 1N solution of aqueous NaOH (20 ml) in THF (20 ml) was stirred at room temperature for 12 hours. di-tert-butylcarbonate (20 mmol, 4.2 g), 1N solution of aqueous NaOH (20 ml) were added and the mixture was stirred at room temperature for 24 hours. The solvent was evaporated and EtOAc was added. The solution was washed with 2N HCl aqueous solution and brine and then evaporated. The crude mixture was purified by chromatography over SiO2 eluting with hexane/EtOAc mixtures and affording 9.3 g (yield 90%) of the expected product.
Reaction SMILES: [CH2:1]([P:3]([C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[F:23])[CH:9]=[CH:8][C:7]=1[N+:24]([O-:26])=[O:25])(=[O:5])[OH:4])[CH3:2].Br[CH2:28][C:29]([O:31][CH3:32])=[O:30]>>[CH2:1]([P:3]([C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:22])[F:21])=[CH:15][C:14]=2[F:23])[CH:9]=[CH:8][C:7]=1[N+:24]([O-:26])=[O:25])(=[O:4])[O:5][CH2:28][C:29]([O:31][CH3:32])=[O:30])[CH3:2]
Reactant: COC(=O)CBr
Reactant: CCP(=O)(O)c1cc(Oc2ccc(C(F)(F)F)cc2F)ccc1[N+](=O)[O-]
Product: CCP(=O)(OCC(=O)OC)c1cc(Oc2ccc(C(F)(F)F)cc2F)ccc1[N+](=O)[O-]

Procedure:
In the same way, P-ethyl-2-nitro-5-(2-fluoro-4-trifluoromethylphenoxy)phenylphosphinic acid is reacted with methyl bromoacetate to give methoxycarbonylmethyl P-ethyl-2-nitro-5-(2-fluoro-4-trifluoromethylphenoxy)phenylphosphinate.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:16]([P:19](Cl)(Cl)=[O:20])([CH3:18])[CH3:17]>>[CH:16]([P:19]1(=[O:20])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][N:8]1[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:18])[CH3:17]
Reactant: CC(C)P(=O)(Cl)Cl
Reactant: c1ccc(CNCc2ccccc2)cc1
Product: CC(C)P1(=O)c2ccccc2CN1Cc1ccccc1
Yield: 12 %

Procedure:
The procedure of Example 1 was employed utilizing dibenzylamine and isopropyl phosphonic dichloride. The reaction of the dilithio compound and the isopropyl phosphonic dichloride was conducted at -65° C. The crude product produced as a result of the chromatographic separation was distilled at 160° C. and 0.2 mm to yield a colorless oil. The colorless oil was slurried in petroleum ether to yield 1-isopropyl-2-phenylmethyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (1.15 g, 12% yield) as a colorless solid having a melting point of 145°-147° C. and the following analysis:
Reaction SMILES: [ClH:1].Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:11][C:12]([NH:15][CH2:16][CH2:17][CH2:18][N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)([CH3:14])[CH3:13])=[CH:6][CH:5]=1.I([O-])(=O)(=O)=[O:25].[Na+].Cl>CO.CCOCC>[ClH:3].[ClH:1].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH2:11][C:12]([NH:15][CH2:16][CH2:17][CH2:18][N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)([CH3:13])[CH3:14])=[O:25])=[CH:6][CH:5]=1
Reactant: CC(C)(CSc1ccc(Cl)cc1)NCCCn1ccnc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: CC(C)(CS(=O)c1ccc(Cl)cc1)NCCCn1ccnc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
N-[2-(4-Chlorophenylthio)-1,1-dimethylethyl]-3-(imidazol-1-yl)propylamine dihydrochloride (1.0 g) was added in one portion to a stirred solution of sodium periodate (0.54 g) in aqueous methanol (15 ml of a 1:1 mixture) at 5-10° C. The mixture was stirred at ambient temperature for 24 hours and then evaporated to dryness. 5M Sodium hydroxide solution was added to the residue and the mixture extracted with dichloromethane to give an oil which was dissolved in ether containing a small amount of absolute alcohol and treated with ethereal hydrogen chloride. The mixture was filtered to give N-[2-(4-chlorophenylsulphinyl)-1,1-dimethylethyl]-3-(imidazol-1-yl)propylamine dihydrochloride, m.p. 208-211° C.
Reaction SMILES: Cl.Cl.Cl.[CH3:4][C:5]1[C:6]2[O:28][CH2:27][CH2:26][C:7]=2[C:8]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]3[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]3)[CH2:13][CH2:12]2)=[N:9][CH:10]=1.[O:29]1[CH2:34][CH2:33][CH:32]([CH2:35][C:36](O)=[O:37])[CH2:31][CH2:30]1>>[CH3:4][C:5]1[C:6]2[O:28][CH2:27][CH2:26][C:7]=2[C:8]([N:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C@H:19]3[CH2:20][CH2:21][C@H:22]([NH:25][C:36](=[O:37])[CH2:35][CH:32]4[CH2:33][CH2:34][O:29][CH2:30][CH2:31]4)[CH2:23][CH2:24]3)[CH2:15][CH2:16]2)=[N:9][CH:10]=1
Reactant: Cc1cnc(N2CCN(CC[C@H]3CC[C@H](N)CC3)CC2)c2c1OCC2
Reactant: O=C(O)CC1CCOCC1
Agent: Cl
Product: Cc1cnc(N2CCN(CC[C@H]3CC[C@H](NC(=O)CC4CCOCC4)CC3)CC2)c2c1OCC2

Procedure:
The title compound, white solid (52 mg, 74%), MS (ISP) m/z=471.6 [(M+H)+], mp 199° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(7-methyl-2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate G) (68.1 mg, 0.15 mmol) and tetrahydropyran-4-yl-acetic acid.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11]([CH2:26][C:27]([NH2:29])=[O:28])=[C:12]([CH3:25])[N:13]2[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)C.[OH-].[Na+]>CCO.O>[NH2:29][C:27](=[O:28])[CH2:26][C:11]1[C:10]2[C:14](=[CH:15][CH:16]=[CH:17][C:9]=2[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:30])=[O:3])[N:13]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:12]=1[CH3:25]
Reactant: CCOC(=O)CCCOc1cccc2c1c(CC(N)=O)c(C)n2Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1c(CC(N)=O)c2c(OCCCC(=O)O)cccc2n1Cc1ccccc1
Yield: 42.9 %

Procedure:
A solution of 100 mg (0.245 mmol) of 4-[[3-(2-amino-2-oxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]butanoic acid ethyl ester and 2 mL of 1N NaOH in 5 mL of EtOH was stirred for 3.0 hours, diluted with water and extracted with EtOAc. The aqueous layer was made acidic to pH 6 with 1N HCl and extracted with EtOAc, the EtOAc dried (MgSO4), and on concentrating at reduced pressure a precipitate formed that was separated and washed with MeOH to give 40 mg (42% yield) of 4-[[3-(2-amino-2-oxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]butanoic acid, mp, 192-193° C.
Reaction SMILES: N1C(C)=CC=CC=1C.Cl[CH2:10][N:11]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[S:12]([Cl:15])(=[O:14])=[O:13].C1CCCCC1.[CH3:28][OH:29]>>[CH3:28][O:29][CH2:10][N:11]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[S:12]([Cl:15])(=[O:14])=[O:13]
Reactant: O=S(=O)(Cl)N(CCl)C1CCCCC1
Reactant: CO
Solvent: C1CCCCC1
Solvent: Cc1cccc(C)n1
Product: COCN(C1CCCCC1)S(=O)(=O)Cl
Temperature: 45 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
22 parts of 2,6-lutidine are added in the course of 15 minutes, at from -5° to +5° C., to a mixture of 50 parts of N-chloromethyl-N-cyclohexylsulfamic acid chloride in 110 parts of cyclohexane and 55 parts of methanol. The reaction mixture is stirred for 20 minutes at 25° C. and one hour at 45° C. After concentrating the solvent under reduced pressure and removing the hydrochloride which has precipitated, distillation gives 30 parts (60% of theory) of N-methoxymethyl-N-cyclohexylsulfamic acid chloride of boiling point 102°-106° C./0.01 mbar and nD25 =1.4857.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH3:17])=[CH:11][CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.C([Li])CCC.CN([CH:26]=[O:27])C.Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH3:17])=[CH:11][CH:10]=2)[CH:5]=[C:6]([F:8])[C:7]=1[CH:26]=[O:27]
Reactant: CN(C)C=O
Reactant: CCCc1ccc(-c2cc(F)cc(F)c2)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCc1ccc(-c2cc(F)c(C=O)c(F)c2)cc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
In a 1-L three-neck flask equipped with a stirrer, a thermometer and a dropping funnel, a THF solution (300 ml) of 23.2 g (100 mmol) of 3,5-difluoro-4′-propylbiphenyl was cooled down to −70° C. under nitrogen atmosphere, and 69 ml (110 mmol) of n-butyllithium (1.6M hexane solution) was added dropwise thereto. The solution was stirred at 70° C. for one hour, and then a THF solution (10 ml) of 9.3 ml (120 mmol) of DMF was added dropwise and further stirred for one hour. The reaction mixture was poured into 200 ml of 1N hydrochloric acid and extracted with 200 ml of heptane. The heptane layer was washed in turn with 200 ml of water, 200 ml of a saturated aqueous sodium hydrogencarbonate solution and 200 ml of water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and then the concentrated residue was purified by means of a silica gel column chromatography (developing solvent: heptane/toluene={fraction (4/6)}) to obtain 26.0 g (100 mmol, yield: 100%) of 3,5-difluoro-4-formyl-4′-propylbiphenyl as colorless oily substance.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].Cl[C:12]([O:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)=[O:13]>C(Cl)Cl.N1C=CC=CC=1>[N+:21]([C:18]1[CH:17]=[CH:16][C:15]([O:14][C:12](=[O:13])[NH:8][C:7]2[CH:9]=[CH:10][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=2)=[CH:20][CH:19]=1)([O-:23])=[O:22]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)c1ccc(N)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)c1ccc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Reaction time: 0.01 h
Yield: 95.1 %

Procedure:
To a solution of 4-isopropylaniline (3.02 g, 22.3 mmol) in DCM (40 mL) and pyridine (10 mL) was added 4-nitrophenyl chloroformate (4.09 g, 20.3 mmol) portionwise with stirring over ˜30 sec with brief ice-bath cooling. After stirring at rt for 1 h, the homogeneous solution was diluted with DCM (100 mL) and washed with 0.6 M HCl (1×250 mL), 0.025 M HCl (1×400 mL), water (1×100 mL), and 1 M NaHCO3 (1×100 mL). The organic layer was dried (Na2SO4) and concentrated to give the title compound as a light peach-colored solid (5.80 g, 95%). 1H-NMR (300 MHz, CDCl3) δ 8.28 (m, 2H), 7.42-7.32 (m, 4H), 7.22 (m, 2H), 6.93 (br s, 1H), 2.90 (h, J=6.9 Hz, 1H), 1.24 (d, J=6.9 Hz, 6H). LC/MS (ESI): calcd mass 300.1, 601.3 (2MH)+.
Reaction SMILES: [O-]CC.[Na+].[CH3:5][C:6]([C:9]([NH2:11])=[NH:10])([CH3:8])[CH3:7].Cl.[C:13]([OH:21])(=[O:20])/[C:14](=[C:16](\[CH:18]=O)/[Br:17])/Br>C(O)C.Cl>[Br:17][C:16]1[C:14]([C:13]([OH:21])=[O:20])=[N:10][C:9]([C:6]([CH3:8])([CH3:7])[CH3:5])=[N:11][CH:18]=1
Reactant: CC(C)(C)C(=N)N
Reactant: O=C/C(Br)=C(/Br)C(=O)O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)c1ncc(Br)c(C(=O)O)n1
Temperature: 50 °C
Yield: 76.6 %

Procedure:
A 22% solution of sodium ethoxide in ethanol (53 mL, 165 mmol) was added dropwise to a magnetically stirred suspension of tert-butylcarbamidine hydrochloride (20.0 g, 146 mmol) in ethanol (100 mL). When the addition was complete, the yellow suspension was warmed to 50° C., the heating mantle was removed, and a solution of mucobromic acid (15.7 g, 61 mmol) in ethanol (50 mL) was added dropwise at a rate which did not allow the temperature to exceed 55° C. When this addition was complete, a 22% solution of sodium ethoxide in ethanol (32 mL, 98 mmol) was added dropwise, then the mixture was allowed to cool to room temperature. The suspension was filtered, the solids were rinsed with ethanol (2×20 mL), and the combined filtrates were concentrated in-vacuo. The residue thus obtained was stirred in 2 N aqueous HCl (30 mL). The resulting solids were collected by filtration, rinsed with ice-cold water (2×20 mL), and air dried to yield 12.1 g of 5-Bromo-2-tert-butyl-pyrimidine-4-carboxylic acid as a beige powder. MS (ES+)=259, 261 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][O:13][CH3:14])[CH:6]=1.[Li]CCCC.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[CH2:20]([C:6]1[C:7]([O:11][CH2:12][O:13][CH3:14])=[CH:8][CH:9]=[CH:10][C:5]=1[O:4][CH2:3][O:2][CH3:1])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: COCOc1cccc(OCOC)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCOc1cccc(OCOC)c1Cc1ccccc1
Temperature: -40 °C
Reaction time: 1 h
Yield: 29.5 %

Procedure:
A solution of 12 (500 mg, 2.52 mmol) in anhydrous THF (2.02 mL) was added dropwise to a solution of nBuLi (2.5 M in hexanes, 1.51 mL, 3.78 mmol) in anhydrous THF (1.65 mL) at room temperature. After one hour, the solution was cooled to −40° C. and benzyl bromide (1.22 mL, 10.10 mmol) was added. The resulting solution was warmed to room temperature over 12 hours, and the reaction was quenched by the addition of saturated aqueous NH4Cl. Water (5 mL) was added and the solution was extracted with CH2Cl2 (3×10 mL). Combined organic fractions were dried (Na2SO4), filtered, and concentrated. The residue was purified via column chromatography (SiO2, 4:1; Hexane:EtOAc) to afford 13 as a yellow oil (214 mg, 30%): 1H NMR (CDCl3, 500 MHz) 7.17 (d, J=7.9 Hz, 2H), 7.17-7.12 (m, 2H), 7.06-7.02 (m, 2H), 6.71 (d, J=8.3 Hz, 2H), 5.09 (s, 4H), 4.00 (s, 2H), 3.29 (s, 6H); 13C NMR (CDCl3, 125 MHz) 155.9 (2C), 141.6, 128.5 (2C), 128.0 (2C), 127.5, 125.4, 119.4, 107.7 (2C), 94.3 (2C), 56.0 (2C), 29.1; IR (film) νmax 2953, 2930, 1595, 1470, 1452, 1254, 1153, 1097, 1043, 941, 922, 727, 698 cm−1; HRMS (ESI+) m/z: [M+Na]+ calcd for C17H20O4, 311.1259; found, 311.1201.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].C(N(CC)CC)C.Cl[C:20](=[O:27])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH:7][C:20]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:27])[CH:8]=1
Reactant: CCOC(=O)CC(=O)Cl
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CC(=O)Nc1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To a solution of 5-chloro-2-nitroaniline (25.4 g, 147 mmol) in N,N-dimethylformamide (300 ml) were added triethylamine (22.6 ml, 162 mmol) and ethyl 3-chloro-3-oxopropionate (20.7 ml, 162 mmol), and the mixture was stirred for 1 hour at room temperature. The reaction mixture was poured into ice water and the precipitated crystals were collected by filtration. These were washed with water and diisopropyl ether in sequence and then air-dried, thereby obtaining 37.1 g of title compound as yellow powder. Yield 88%.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([CH2:17][CH3:18])=[N:11][N:12]2[CH2:15][CH3:16])=[CH:8][CH:7]=1)=[O:5].[CH3:20][Mg]Cl>O1CCCC1>[CH2:15]([N:12]1[C:13]2[C:9](=[CH:8][CH:7]=[C:6]([C:4](=[O:5])[CH3:20])[CH:14]=2)[C:10]([CH2:17][CH3:18])=[N:11]1)[CH3:16]
Reactant: C[Mg]Cl
Reactant: CCc1nn(CC)c2cc(C(=O)N(C)OC)ccc12
Solvent: C1CCOC1
Product: CCc1nn(CC)c2cc(C(C)=O)ccc12
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 107.5 %

Procedure:
1,3-Diethyl-1H-indazole-6-carboxylic acid methoxy-methyl-amide (0.22 g, 0.86 mmol) was dissolved in tetrahydrofuran (8 mL) and cooled to −70° C. Methylmagnesium chloride (2 mL, 3M in tetrahydrofuran, 0.06 mol) was added dropwise and the resulting mixture was stirred for 30 minutes at −70° C. After warming to room temperature, the mixture was stirred for a further 3 minutes, then quenched by the addition of a chilled saturated solution of ammonium chloride. Ethyl acetate (150 mL) and water (40 mL) were then added and the product was extracted. The aqueous layer was re-extracted with ethyl acetate (75 mL). The organic layers were combined, dried, filtered, and concentrated to afford 200 mg of 1-(1,3-Diethyl-1H-indazol-6-yl)-ethanone.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[CH:6]=[CH:5][C:4]=1[C:15]([OH:17])=O.C1N=C[N:20](C(N2C=NC=C2)=O)C=1.[NH4+].[OH-].CCCCCC>C1COCC1>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[CH:6]=[CH:5][C:4]=1[C:15]([NH2:20])=[O:17]
Reactant: COc1ccc2ccc(C(=O)O)c(OC)c2c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc2ccc(C(N)=O)c(OC)c2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 49 %

Procedure:
To a room temperature solution of 1,7-dimethoxy-2-naphthalenecarboxylic acid (131 mg, 0.56 mmol) in 3 mL of THF is added N,N-carbonyldiimidazole (105 mg, 0.65 mmol). The solution is heated at reflux for 2.5 hours and cooled slightly. Aqueous NH4OH (1 mL) is added and the reaction mixture is stirred at room temperature for 1.5 hours, then poured into 1:1 hexane:ethyl acetate and washed with brine. The organic layer is dried over MgSO4, filtered, and concentrated in vacuo. The crude product is chromatographed on silica gel eluting with hexane:ethyl acetate (1:1) to provide 1,7-dimethoxy-2-naphthalenecarboxamide in 49% yield; mp 134°-136° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[C:11](=[CH:14]/[C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)/[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Cl-].[CH3:23][O:24][C:25](=[O:31])[CH2:26][CH2:27][C:28](O)=[O:29]>N1C=CC=CC=1>[C:28]([O:21][C:18]1[CH:17]=[CH:16][C:15](/[CH:14]=[C:11](\[C:12]#[N:13])/[C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:20][CH:19]=1)(=[O:29])[CH2:27][CH2:26][C:25]([O:24][CH3:23])=[O:31]
Reactant: COC(=O)CCC(=O)O
Reactant: COc1ccc(/C(C#N)=C/c2ccc(O)cc2)cc1OC
Agent: [Cl-]
Solvent: c1ccncc1
Product: COC(=O)CCC(=O)Oc1ccc(/C=C(\C#N)c2ccc(OC)c(OC)c2)cc1
Yield: 90 %

Procedure:
Compound 1 (50 mg) and succinic acid monomethyl ester chloride (44 μL) were dissolved in pyridine (1 mL), followed by stirring for a whole day and night. After completion of reaction, the resultant reaction mixture was concentrated to dryness under reduced pressure, followed by purification by means of silica gel chromatography employing a chloroform/methanol system, to thereby produce the target product (63 mg, yield: 90%).
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([CH:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:6]=[N:5][CH:4]=1.[CH3:13][C:14]1[N:19]=[C:18]([SH:20])[N:17]=[C:16]([OH:21])[CH:15]=1>>[CH:8]1([N:7]2[C:3]([CH2:2][S:20][C:18]3[N:17]=[C:16]([OH:21])[CH:15]=[C:14]([CH3:13])[N:19]=3)=[CH:4][N:5]=[CH:6]2)[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: Cc1cc(O)nc(S)n1
Reactant: ClCc1cncn1C1CCCC1
Product: Cc1cc(O)nc(SCc2cncn2C2CCCC2)n1
Yield: 50 %

Procedure:
This example was synthesized from 5-(chloromethyl)-1-cyclopentyl-1H-imidazole and 6-methyl-2-sulfanylpyrimidin-4-ol following the general procedure as shown in the last step of Example 109 to provide 2-{[(1-cyclopentyl-1H-imidazol-5-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol as a white solid (700 mg, 50% yield); 1H NMR (400 MHz, DMSO-d6): δ 1.61 (m, 2H), 1.79 (m, 4H), 2.10 (m, 2H), 2.21 (s, 3H), 4.48 (s, 2H), 4.54 (m, 1H), 6.02 (br, 1H), 6.88 (s, 1H), 7.73 (s, 1H); M+291.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([CH2:11][CH:12]([OH:15])CO)[N:6]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])=[O:4]>CCOCC.[Cl-].[Na+].O>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([CH2:11][CH:12]=[O:15])[N:6]1[C:16]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:17])=[O:4]
Reactant: COC(=O)C1CCCC(CC(O)CO)N1C(=O)OCc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: COC(=O)C1CCCC(CC=O)N1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.8 %

Procedure:
6-(2,3-Dihydroxy-propyl)-piperidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester (Compound 235, 0.614 g, 1.75 mmol) was dissolved in Et2O (20 mL) and cooled to 0° C. Ten percent NaIO4 aqueous solution (4 mL) was added, and the reaction was stirred for 1 hour. The reaction mixture was poured into brine (15 mL) and extracted with Et2O (3×20 mL). The combined organic layer was further washed with aqueous NaS2O3 (10 mL), NaHCO3 saturated solution (10 mL), brine (10 mL) and finally dried over MgSO4. The solvents were removed to afford Compound 236 (0.53 g, 95%). Rf=0.67 (1:1 EtOAc/hexanes). The material was of sufficiently good quality to be used in the next reaction without purification.
Reaction SMILES: [CH:1]12[CH2:11][CH:7]3[CH:8](C[CH2:10]1)[CH:3]([CH2:4][CH2:5][CH2:6]3)[CH2:2]2.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:16](Cl)Cl>>[CH3:16][C:5]12[CH2:4][CH:3]3[CH2:2][CH:1]([CH2:11][CH:7]([CH2:8]3)[CH2:6]1)[CH2:10]2
Reactant: C1CC2CC3CCC2C(C1)C3
Reactant: ClCCl
Agent: [Al+3]
Agent: [Cl-]
Product: CC12CC3CC(CC(C3)C1)C2
Temperature: 0 °C

Procedure:
A solution of 15 g (0.1 mole) of tricyclo[5.3.1.03,8 ]-undecane (II) in 100 ml of methylene chloride was agitated at 0°C, and 2.0 g (0.015 mole) of anhydrous aluminum chloride was added to the solution. The mixture was heated and refluxed under agitation for 6 hours, and the resulting reaction mixture was allowed to cool and poured over 100 ml of ice water. The organic layer was separated, and the water layer was extracted with methylene chloride. The methylene chloride extract was combined with the organic layer, and the mixture was washed with a saturated aqueous solution of sodium hydrogencarbonate and then with water, and then dried over anhydrous sodium sulfate. Methylene chloride was distilled off and the residue was sublimed to obtain 13.7 g (yield: 91 wt.%) of 1-methyladamantane. All of the IR, NMR and MS spectra were in agreement with those of the authentic sample synthesized from tetramethylenenorbornane according to the method of Schleyer, et al. [Tetrahedron Letters, 305 (1961)].
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[NH:19][C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[CH2:21](I)[CH2:22][CH2:23][CH2:24][CH3:25].[H-].[Na+]>CN(C)C=O>[CH2:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[N:19]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH2:8][CH2:9]1)[CH:2]=[CH2:3]
Reactant: CCCCCI
Reactant: C=CCN1CCN(c2nc3ccccc3c(=O)[nH]2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCN1CCN(c2nc(OCCCCC)c3ccccc3n2)CC1
Temperature: 0 °C
Yield: 88.2 %

Procedure:
In 30 ml of N,N-dimethylformamide was suspended 3.6 g of 2-(4-allyl-l-piperazinyl)-4(3H)-quinazolinone obtained in Example 1. With stirring under ice cooling, 3.6 g of pentyl iodide and 0.95 g of sodium hydride (oily, 60 %) were added to the suspension. The mixture was then stirred at 60° C. for 2.5 hours. Ice water (100 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography [eluted with chloroform/methanol (30:1, v/v)] to give 4.0 g of 2-(4-allyl-l-piperazinyl)-4-pentyloxyquinazoline as a pale yellow oil.