Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[CH3:16][C:17]1[CH:18]=[C:19]([CH:25]=[C:26]([CH3:29])[C:27]=1[OH:28])[CH:20](O)[C:21](O)=[O:22]>C(O)(=O)C.CS(O)(=O)=O>[CH3:16][C:17]1[CH:18]=[C:19]([CH:20]2[C:7]3[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=3[O:15][C:21]2=[O:22])[CH:25]=[C:26]([CH3:29])[C:27]=1[OH:28]
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Reactant: Cc1cc(C(O)C(=O)O)cc(C)c1O
Agent: CS(=O)(=O)O
Solvent: CC(=O)O
Product: Cc1cc(C2C(=O)Oc3c2cc(C(C)(C)C)cc3C(C)(C)C)cc(C)c1O
Temperature: 95 °C
Reaction time: 0.07 h
Yield: 88.1 %

Procedure:
1.5 ml (23 mmol) of methanesulfonic acid are added to a mixture of 154.8 g (0.75 mol) of 2,4-di-tert-butylphenol and 98.1 g (0.50 mol) of 3,5-dimethyl-4-hydroxymandelic acid in 500 ml of acetic acid which is stirred at 95° C. under nitrogen. After about 4 minutes, crystallisation of the product in the form of fine, white crystals begins. The reaction mixture is refluxed for another hour, then cooled to about 15° C., and the precipitated product is filtered off. The residue is washed with 250 ml of acetic acid and with 1500 ml of water. Drying gives 161.5 g (88%) of 3-(3,5-dimethyl-4-hydroxyphenyl)-5,7-di-tert-butylbenzofuran-2-one, melting point 225°-228° C. (compound (107), Table 1).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[N-:7]=[C:8]=[S:9].[NH4+].[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:31])=[C:16]([C:18]2[C:19](=[O:30])[N:20]([CH3:29])[C:21]3[C:26]([CH:27]=2)=[CH:25][N:24]=[C:23]([CH3:28])[CH:22]=3)[CH:17]=1>CC(C)=O>[CH3:29][N:20]1[C:21]2[C:26](=[CH:25][N:24]=[C:23]([CH3:28])[CH:22]=2)[CH:27]=[C:18]([C:16]2[CH:17]=[C:12]([NH:11][C:8]([NH:7][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])=[S:9])[CH:13]=[CH:14][C:15]=2[CH3:31])[C:19]1=[O:30]
Reactant: CC(C)C(=O)Cl
Reactant: Cc1cc2c(cn1)cc(-c1cc(N)ccc1C)c(=O)n2C
Reactant: [N-]=C=S
Agent: [NH4+]
Solvent: CC(C)=O
Product: Cc1cc2c(cn1)cc(-c1cc(NC(=S)NC(=O)C(C)C)ccc1C)c(=O)n2C
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
The mixture of isobutyryl chloride (160 mg, 1.5 mmol) and ammonium isothiocyanate (114.2 mg, 1.5 mmol) in acetone (2.0 mL) was heated at 40° C. for 3 h. To the above reaction mixture, 3-(5-amino-2-methylphenyl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one (15) (419 mg, 1.5 mmol) was added at rt and stirred for 30 min. The solvent was removed under vacuum to yield N-(3-(1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-methylphenylcarbamothioyl)isobutyramide 22, which was used without purification. MS m/z 409.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]1[C:10]3[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=3[S:8][CH2:7][C:6]2=1.[O:20](C(C)(C)C)[K].O=O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]1[C:10]3[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=3[S:8](=[O:20])[CH2:7][C:6]2=1
Reactant: CC(C)(C)O[K]
Reactant: COc1ccc2[nH]c3c(c2c1)CSc1ccccc1-3
Agent: O=O
Solvent: CN(C)C=O
Product: COc1ccc2[nH]c3c(c2c1)CS(=O)c1ccccc1-3

Procedure:
8-Methoxy-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene (79 mg, 0.281 mmoL) in DMF (5 mL) was treated with KO-t-Bu (1.0 M in THF, 0.48 mL, 0.48 mmoL) under a flow of O2 for 6 hours. The reaction mixture was then partitioned between water and EtOAc. The EtOAc layer was washed with saturated NH4Cl, water, brine, dried over anhydrous Na2SO4, filtered and concentrated to yield a brown oil. The crude material (the oil) was then purified by column chromatography (silica gel, CH2Cl2:MeOH 9:1 as eluent) to yield the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[C:6]([OH:8])[CH:7]=1.Br[C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])=[C:16]([C:25]([F:28])([F:27])[F:26])[CH:15]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[C:6]([O:8][C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH2:23][CH3:24])(=[O:21])=[O:22])=[C:16]([C:25]([F:27])([F:28])[F:26])[CH:15]=2)[CH:7]=1
Reactant: CCS(=O)(=O)c1ccc(Br)cc1C(F)(F)F
Reactant: O=C(O)Cc1cc(O)cc(Cl)c1
Product: CCS(=O)(=O)c1ccc(Oc2cc(Cl)cc(CC(=O)O)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared as described in example 2 step (iii) but instead using the product from example 18 step (iv) and the product from step (i).
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[C:23]([O:25][CH3:26])[C:22]([Br:27])=[CH:21][C:5]=1[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([OH:17])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH3:20])([O-])=O>CO.[Pd]>[BrH:27].[NH2:1][C:4]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:5]=1[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([OH:17])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH3:20]
Reactant: COc1cc2c(cc1O)C(Cc1cc(Br)c(OC)cc1[N+](=O)[O-])N(C)CC2
Agent: [Pd]
Solvent: CO
Product: Br
Product: COc1ccc(CC2c3cc(O)c(OC)cc3CCN2C)c(N)c1
Yield: 92.4 %

Procedure:
A mixture of 1-(2'-nitro-4'-methoxy-5'-bromobenzyl)-2-methyl-6-methoxy-7-hydroxy-1,2,3,4-tetrahydroisoquinoline (3c) (850 mg) in absolute methanol (80 ml) containing palladium-charcoal catalyst (5%, 250 mg) was stirred under hydrogen until absorption ceased (approximately 6-8 hours). The catalyst was filtered, washed with methanol and the filtrate evaporated to give an oil which was crystallized from acetone to give white crystals of 1-(2'-amino-4'-methoxybenzyl)-2-methyl-6-methoxy-7-hydroxy-1,2,3,4-tetrahydroisoquinoline hydrobromide (4f) (735 mg, 81%), mp 136°-137.5°. An analytical sample was prepared by recrystallization from acetone, mp 137.5°-138°; nmr δ (CDCl3), 2.05 (s, 6H, acetone CH3COCH3), 2.78 (s, 3H, NCH3), 3.88 and 3.92 (2s, 6H, 2OCH3), and 5.94-6.57 (CM, 5H, aromatic H).
Reaction SMILES: [NH2:1][OH:2].O.C(N(CC)CC)C.Cl[C:12]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:13]>C(OCC)(=O)C>[O:14]([C:12]([NH:1][OH:2])=[O:13])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: NO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(NO)Oc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To an aqueous solution comprising 48 g of a 50% hydroxylamine aqueous solution and 50 ml of deionized water were successively added 30 g of triethylamine and 400 ml of ethyl acetate under cooling, and then, 94 g of phenyl chloroformate was added dropwise to the mixture at 0° C. or lower over 1.5 hours. Thereafter, the mixture was stirred at room temperature for 1.5 hours. After the reaction, an organic layer was collected by separation and washed with a saturated saline solution. After drying over anhydrous sodium sulfate, the solvent was removed. Cyclohexane was added to the residue to crystallize the reaction product, and the crystal was washed with chloroform and dried to obtain white colored N-phenoxycarbonyl hydroxylamine which is an intermediate. Yield: 31 g, Melting point: 108° C.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][OH:9])[CH2:4][CH2:3]1.Br[CH:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH:11]([N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][OH:9])[CH2:4][CH2:3]1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OCC1CCNCC1
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: OCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In 20 ml of N,N-dimethylformamide, 2.291 g (15.108 mM) of 4-piperidylmethanol hydrochloride, 4.48 g (18.1 mM) of bromodiphenylmethane, and 6.26 g (45.3 mM) of potassium carbonate were stirred together at 100° C. for 3.5 days and, then, at 150° C. for 2 hours. After cooling to room temperature, this reaction mixture was poured in water and extracted with 2 portions of ethyl acetate. The organic layers were pooled and dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1 to 2/1 to 1/1) to provide the title compound.
Reaction SMILES: [CH:1]1([C:4]#[C:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1.I[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][O:20][CH3:21])=[CH:14][CH:13]=1.[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl.O>[CH:1]1(/[C:4](/[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][O:20][CH3:21])=[CH:14][CH:13]=2)=[C:5](/[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)\[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1
Reactant: OB(O)c1ccccc1
Reactant: COCOc1ccc(I)cc1
Reactant: CCOC(=O)C#CC1CC1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: N#Cc1ccccc1
Solvent: O
Product: CCOC(=O)/C(=C(/c1ccc(OCOC)cc1)C1CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 29 %

Procedure:
To a mixture of 2 (385 mg, 2.79 mmol), 1-iodo-4-(methoxymethoxy)benzene (1.47 g, 5.57 mmol), Phenylboronic acid (680 mg, 5.58 mmol) and K2CO3 (771 mg, 5.58 mmol) in DMF (8.5 ml)-H2O (2.2 ml) was stirred at room temperature for 10 min. Then PdCl2(PhCN)2 (10.7 mg, 0.0279 mmol) was added under Ar atmosphere, and the mixture was stirred at room temperature for 24 h. The reaction was quenched with H2O under ice cooling, and the whole was extracted with Et2O. The organic layer was washed with H2O, brine, dried over Na2SO4, then concentrated. Purification by silica gel flash column chromatography (eluent: hexane/AcOEt, 30:1 to 10:1) gave 5 (29%). 5: colorless oil; 1H-NMR (CDCl3) δ 0.44 (2H, m), 0.79 (2H, m), 1.29 (3H, t, J=7.2 Hz), 2.30 (1H, m), 3.43 (3H, s), 4.28 (2H, q, J=7.1 Hz), 5.08 (2H, s), 6.78 (2H, d, J=8.8 Hz), 6.85 (2H, d, J=8.8 Hz), 6.99 (2H, m), 7.03-7.09 (3H, m).
Reaction SMILES: [C:1]([CH:6]1[CH2:13][C:9]2=[CH:10][O:11][CH:12]=[C:8]2[CH2:7]1)([O:3]CC)=[O:2].[OH-].[K+]>C(O)C.O>[C:1]([CH:6]1[CH2:13][C:9]2=[CH:10][O:11][CH:12]=[C:8]2[CH2:7]1)([OH:3])=[O:2]
Reactant: CCOC(=O)C1Cc2cocc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C1Cc2cocc2C1

Procedure:
Dissolve 5-(carboethoxy)-2,4,5,6-tetrahydrocyclopenta[c]furan (6.2 g, 34.1 mmol) in ethanol (95%, 150 mL) and water (75 mL). Add potassium hydroxide (9.5 g, 0.17 mol) and stir at room temperature for 1 hour. Partition between water (150 mL) and ethyl ether (2×150 mL). Acidify the aqueous phase with hydrochloric acid to pH 1. Extract with methylene chloride (2×150 mL), dry (Na2SO4) and evaporate the solvent in vacuo to give 5-(carboxy)-2,4,5,6-tetrahydrocyclopenta[c]furan.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][N:12]2[N:21]=[C:20]([S:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:29])=[O:10])=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:35]>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][N:12]2[N:21]=[C:20]([S:22]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:35])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:29])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(Cc1ccc(Cl)cc1)Nn1nc(Sc2ccccc2)c2ccccc2c1=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(Cc1ccc(Cl)cc1)Nn1nc(S(=O)c2ccccc2)c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.9 %

Procedure:
A mixture of the product from Example 58 (0.0200 g, 0.047 mmol) and 3-chlorobenzoperoxoic acid (0.0125 g, 0.051 mmol) in DCM (0.5 mL) was stirred at room temperature for 1 hour, diluted with EtOAc, washed with sat NaHCO3 and brine, dried (Na2SO4), filtered, and chromatographed (8-10% EtOAc/DCM) to give 4.5 mg of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.90 (s, 1H), 8.44-8.48 (m, 1H), 8.30-8.34 (m, 1H), 7.86-7.96 (m, 2H), 7.70-7.76 (m, 2H), 7.50-7.61 (m, 3H), 7.38-7.46 (m, 4H), 3.76 (s, 2H); MS (ESI−) M/Z 436 (M−H)−.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH3:11])=[CH:4][CH:3]=1.[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[C:13]#[CH:14].O>CN(C=O)C.[Cu-]=O>[CH3:11][O:10][CH2:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:14]#[C:13][C:12]([O:16][CH2:17][CH3:18])=[O:15])=[CH:3][CH:4]=1
Reactant: COCOc1ccc(I)cc1
Reactant: C#CC(=O)OCC
Agent: O=[Cu-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C#Cc1ccc(OCOC)cc1
Temperature: 110 °C
Yield: 52 %

Procedure:
Under an Ar atmosphere, a mixture of 1-iodo-4-(methoxymethoxy)benzene (500 mg, 1.89 mmol), Ethyl propiolate (371 mg, 3.78 mmol) and Copper(I) oxide (270 mg, 1.89 mmol) in DMF (10 ml) was heated at 110° C. for 16 h. After cooling, H2O was poured into the reaction mixture under ice cooling, and the whole was extracted with AcOEt. The organic layer was washed with H2O, brine, dried over Na2SO4, then concentrated. Purification by silica gel flash column chromatography (eluent: hexane/AcOEt, 15:1) gave 2e (52%). 2e: colorless oil; 1H-NMR (CDCl3) δ 1.36 (3H, t, J=7.1), 3.48 (3H, 2), 4.29 (2H, q, J=7.1), 5.20 (2H, s), 7.02 (2H, d, J=8.8 Hz), 7.54 (2H, d, J=8.8 Hz).
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[S:5])[CH3:2].[S:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[CH2:11][CH2:12][NH2:13].C(N(CC)CC)C.Cl>ClCCl.O>[CH2:1]([NH:3][C:4]([NH:13][CH2:12][CH2:11][C:7]1[S:6][CH:10]=[CH:9][CH:8]=1)=[S:5])[CH3:2]
Reactant: CCN=C=S
Reactant: NCCc1cccs1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCNC(=S)NCCc1cccs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.9 %

Procedure:
Ethyl isothiocyanate (1.3 g, 15.0 mmol) was slowly added dropwise to a solution of thiopheneethylamine (1.3 g, 10.2 mmol) in dichloromethane (150 mL). Triethyl amine (3.8 mL, 20.4 mmol) was added dropwise to the mixture and stirred at room temperature for 2 h. After completion of the reaction, pH of the resulting solution was adjusted to about 7 using aqueous 1N HCl, to which water was added. The resulting mixture was extracted with dichloromethane. The residue was purified by flash column chromatography (ethyl acetate:hexanes=1:3), to give the title compound (1.9 g, 89%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:21][CH:22]=O)[CH2:10][N:11]([CH3:20])[C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[O:24]=[C:25]1[CH2:29][CH2:28][CH2:27][N:26]1[CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO.C(=O)(O)[O-].[Na+]>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:21][CH2:22][N:33]2[CH2:32][CH2:31][CH:30]([N:26]3[CH2:27][CH2:28][CH2:29][C:25]3=[O:24])[CH2:35][CH2:34]2)[CH2:10][N:11]([CH3:20])[C:12](=[O:19])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN(CC(CC=O)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Reactant: O=C1CCCN1C1CCNCC1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN(CC(CCN1CCC(N2CCCC2=O)CC1)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Product: Cl
Reaction time: 0.08 h
Yield: 149.4 %

Procedure:
N-[2-(3,4-Dichlorophenyl)-4-oxobutyl]-N-methylbenzamide (870 mg) in methanol (2.4 mL) was added to a solution of 4-(2-oxopyrrolidin-1-yl)piperidine (0.460 g) and acetic acid (0.16 mL) in methanol (2.4 mL). After 5 minutes, sodium cyanoborohydride (0.173 g) in methanol (2.4 mL) was added in a single portion. After being stirred for 3 hours, the reaction mixture was diluted with aqueous sodium bicarbonate, stirred for 30 minutes, and extracted with dichloromethane. The organic extracts were dried, evaporated, and chromatographed, with dichloromethane:methanol (gradient 98:2, 90:10) as the eluent. The resulting material was dissolved in dichloromethane, precipitated out as the hydrochloride salt with ethereal hydrogen chloride, evaporated, and placed under high vacuum overnight to give the title compound (1.0 g) as a white solid; MS: m/z=502(M+1). Analysis for C27H33Cl2N3O2.1.50 HCl: Calculated: C, 58.20; H, 6.24; N, 7.54; Found: C, 58.18; H, 6.27; N, 7.44.
Reaction SMILES: [NH2:1][CH:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.[CH:10]1([CH2:13][O:14][C:15]2[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=2[C:17]([NH2:19])=[O:18])[CH2:12][CH2:11]1.C([O-])(=O)[C:25]([O-])=[O:26]>>[N:4]12[CH2:9][CH2:8][CH:7]([CH2:6][CH2:5]1)[CH:2]([NH:1][C:25]([NH:19][C:17](=[O:18])[C:16]1[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=1[O:14][CH2:13][CH:10]1[CH2:12][CH2:11]1)=[O:26])[CH2:3]2
Reactant: NC1CN2CCC1CC2
Reactant: O=C([O-])C(=O)[O-]
Reactant: NC(=O)c1ccccc1OCC1CC1
Product: O=C(NC(=O)c1ccccc1OCC1CC1)NC1CN2CCC1CC2

Procedure:
The above compound was prepared, following the procedure of Example 1, from 3-aminoquinuclidine (0.63 g, 5 mmol) and crude 2-((cyclopropyl)methoxy)benzamide (1.4 g, ca 5 mmol). The product was converted to the 1:1 oxalate, half hydrate mp 128°-131° C.
Reaction SMILES: [NH:1]1[C:10](=[O:11])[C:9]2[NH:8][CH:7]=[N:6][C:5]=2[N:4]=[C:2]1[NH2:3].C(N(CC)CC)C.[C:19]([O:27][CH2:28][CH2:29][CH2:30][O:31][CH2:32]Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1C=CC=CC=1>[C:19]([O:27][CH2:28][CH2:29][CH2:30][O:31][CH2:32][N:6]1[CH:7]=[N:8][C:9]2[C:10](=[O:11])[NH:1][C:2]([NH2:3])=[N:4][C:5]1=2)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1nc2nc[nH]c2c(=O)[nH]1
Reactant: O=C(OCCCOCCl)c1ccccc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: Nc1nc2c(ncn2COCCCOC(=O)c2ccccc2)c(=O)[nH]1
Yield: 21.2 %

Procedure:
A solution of trimethylsilylated guanine in benzene (25 ml) prepared as in Example 6 (from 2.0 g of guanine) containing triethylamine was heated at reflux and 3-benzoyloxypropoxymethyl chloride (2.96 g) dissolved in benzene (15 ml) was added over a 3 hour period. The reaction mixture was heated at reflux under nitrogen overnight. The solvent was removed under reduced pressure, and 95% ethanol and methanol were added to the residual oil. The mixture was heated on a steam bath for several minutes and the solvent then evaporated under reduced pressure. Chloroform (200 ml) was added and the resulting solid removed by filtration. The solid was dissolved in a minimal amount of DMF, filtered (to remove any guanine present) and reprecipitated by the addition of water. Recrystallization from methanol (with charcoaling) gave 9-(3-benzoyloxypropoxymethyl)guanine (0.94 g) as a pale yellow solid, m.p. 198°-201° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13](Cl)=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:16][NH:17][C@H:18]1[CH2:37][N:22]2[C:23]3[C:28]([C:29]([CH2:30][C:31]([O:33]CCC)=[O:32])=[C:21]2[CH2:20][CH2:19]1)=[CH:27][CH:26]=[CH:25][CH:24]=3>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]([N:17]([CH3:16])[C@H:18]3[CH2:37][N:22]4[C:23]5[C:28]([C:29]([CH2:30][C:31]([OH:33])=[O:32])=[C:21]4[CH2:20][CH2:19]3)=[CH:27][CH:26]=[CH:25][CH:24]=5)=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)C1(c2ccc(Cl)cc2)CCCC1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Product: CN(C(=O)C1(c2ccc(Cl)cc2)CCCC1)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 2 (Method B) from 1-(4-chlorophenyl)cyclopentanecarbonyl chloride and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 487.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([NH2:14])=[O:13])=[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:21](OCC)(=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(O)(=O)C>CCOCC>[C:15]1([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]3[N:1]=[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[NH:14][C:12](=[O:13])[C:11]=23)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: NC(=O)c1c(N)nc2ccccc2c1-c1ccccc1
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCOC(=O)c1nc2nc3ccccc3c(-c3ccccc3)c2c(=O)[nH]1

Procedure:
A mixture of 2-amino-4-phenylquinoline-3-carboxamide (263 mg., 1.0 millimole), diethyl oxalate (5 ml.) acetic acid (5 ml.) is heated to reflux overnight. It is then cooled, diluted with ether (50 ml.) and the brown solid which forms filtered off. The filtrate is evaporated in vacuo and the oily residue triturated with saturated aqueous sodium bicarbonate solution. The resulting solid (110 mg.) is recovered by filtration and recrystallized from hot ethyl acetate (8 ml.). A small amount of insoluble material is filtered off from the hot solution. Upon cooling, the title product separates as crystals (25 mg.). M.P. = 255° C. (dec.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](CC2C=CC=CC=2)([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].S(Cl)(Cl)=O.Cl.CN[O:31][CH3:32].[CH2:33]([N:35](CC)CC)C>C1COCC1.ClCl.N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:16])[NH:35][CH2:33][O:31][CH3:32])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccccc2)(C(=O)O)CC1
Reactant: CNOC
Agent: Cl
Agent: ClCl
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: COCNC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 121.6 %

Procedure:
To a stirring solution of 4-benzylpiperidine-1,4-dicarboxylic acid tert-butyl ester (12.5 mmol, 4.0 g) in THF (60 mL) was added thionyl chloride (13.8 mmol, 1.64 g) and pyridine (0.2 mL). The reaction was stirred at r.t. for 1 h. The reaction was then evaporated under reduced pressure and the residue taken up in CH2Cl2 (50 mL). To this solution was added N,O-Dimethylhydroxylamine hydrochloride (13.8 mmol, 1.35 g) and triethylamine (25.0 mmol, 2.53 g). The reaction was stirred at room temperature for 1 h. The reaction was then diluted with CH2 Cl2 (100 mL) and washed with 10% KHSO4. (100 mL) and saturated sodium bicarbonate (100 mL). The organic layers were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was evaporated from ethyl ether:hexanes to give 4.14 g of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2SC)[C:3]=1[CH3:23].O[O:25][S:26]([O-:28])=O.[K+].[CH2:30]1COCC1>O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[S:26]([CH3:30])(=[O:28])=[O:25])[C:3]=1[CH3:23]
Reactant: O=S([O-])OO
Reactant: CSc1ccc(F)cc1-c1nc2cc(F)cc(F)c2c(Cl)c1C
Reactant: C1CCOC1
Agent: [K+]
Solvent: O
Product: Cc1c(-c2cc(F)ccc2S(C)(=O)=O)nc2cc(F)cc(F)c2c1Cl
Reaction time: 16 h

Procedure:
The 4-chloro-5,7-difluoro-2-(5-fluoro-2-(methylthio)phenyl)-3-methylquinoline (320 mg, 0.90 mmol) was dissolved in a mixture of THF (6.7 mL) and water (2.2 mL). To the solution was added Oxone™ (1.40 g, 2.2 mmol) and the resulting slurry was stirred vigorously for 16 h. The reaction mixture was added to 25 mL of water and stirred vigorously for 10 min and then filtered. The precipitate was dissolved in EtOAc and then dried over magnesium sulfate. The filtrate was cond to give 4-chloro-5,7-difluoro-2-(5-fluoro-2-(methylsulfonyl)phenyl)-3-methylquinoline. Mass Spectrum (ESI) m/e=386.0 (M+1).
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].CN1CCCC1=O.[CH2:21]([NH:24][CH2:25][CH:26]=[CH2:27])[CH:22]=[CH2:23].C(=O)([O-])[O-].[K+].[K+]>O>[CH2:21]([N:24]([CH2:25][CH:26]=[CH2:27])[C:5]1[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[CH:22]=[CH2:23]
Reactant: C=CCNCC=C
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: C=CCN(CC=C)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 111 %

Procedure:
A mixture of 2,4-dinitrofluorobenzene (9.3 g), N-methylpyrrolidinone (NMP, 50 mL), diallylamine (5.82 g) and potassium carbonate (6.9 g) was stirred at ambient temperature for 1 h. The mixture was poured into water and extracted with ethyl ether. The extract was washed twice with water, once with saturated brine solution, and dried over magnesium sulfate. Concentration of the extract gave N,N-diallyl-2,4-dinitrobenzenamine as a yellow oil (14.6 g).