Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([CH2:30][CH3:31])[CH2:24][C:25](OCC)=[O:26])=[CH:4][CH:3]=1.[BH4-].[Li+].[Cl-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([CH2:30][CH3:31])[CH2:24][CH2:25][OH:26])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(CC)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(CCO)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.7 %

Procedure:
To a solution of ethyl 3-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]pentanoate (100 mg, 0.208 mmol) in tetrahydrofuran (10 mL) was added lithium tetrahydroborate (23 mg, 1.06 mmol) at 0° C. The mixture was stirred at room temperature for 18 hr. Then the mixture was warmed to. 40° C. and stirred at 40° C. for 5 hr. Aqueous ammonium chloride was added to the reaction mixture at 0° C. and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 50-100% ethyl acetate/n-hexane gradient mixture and recrystallization from ethyl acetate/n-hexane to give the title compound (41.7 mg, 0.095 mmol, 46%) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH2:16]([O:23][C:24]([NH:26][CH2:27][CH2:28][CH2:29][C@H:30]([NH:34]C(OC(C)(C)C)=O)[C:31](O)=[O:32])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[NH2:34][C@H:30]([C:31]([NH:11][C:10]1[CH:12]=[CH:13][C:7]([O:6][C:5]2[CH:14]=[CH:15][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:8][CH:9]=1)=[O:32])[CH2:29][CH2:28][CH2:27][NH:26][C:24](=[O:25])[O:23][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: Nc1ccc(Oc2ccc(F)cc2)cc1
Product: N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 80 %

Procedure:
Proceeding as in Reference 5, but substituting 4-(4-fluorophenoxy)aniline and (S)-5-(benzyloxycarbonylamino)-2-(tert-butoxycarbonylamino)pentanoic acid, gave (S)-benzyl 4-amino-5-(4-(4-fluorophenoxy)phenylamino)-5-oxopentylcarbamate (1901 mg, 80%).
Reaction SMILES: [Br-].[C:2]([O-:5])(=[O:4])[CH3:3].[Na+].[Cl:7][C:8]1[C:9]([N+:17]([O-:19])=[O:18])=[CH:10][C:11]([CH3:16])=[C:12]([CH:15]=1)[C:13]#[N:14]>CN(C=O)C.O>[C:2]([O:5][CH2:16][C:11]1[CH:10]=[C:9]([N+:17]([O-:19])=[O:18])[C:8]([Cl:7])=[CH:15][C:12]=1[C:13]#[N:14])(=[O:4])[CH3:3]
Reactant: Cc1cc([N+](=O)[O-])c(Cl)cc1C#N
Reactant: CC(=O)[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCc1cc([N+](=O)[O-])c(Cl)cc1C#N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
The above partially purified bromide was dissolved in DMF (300 mL) and cooled to 0° C. Sodium acetate (18.0 g, 0.22 mol) was added. The mixture was stirred at 60° C. for 30 min. After cooling, the mixture was diluted with H2O and extracted with EtOAc. The EtOAc extract was washed with H2O (2×), dried over anhydrous MgSO4 and concentrated in vacuo. Chromatography over silica gel and elution with hexanes:EtOAc (9:1) yielded a front fraction containing 5-chloro-4-nitro-2-methylbenzonitrile and dibromide. Further elution with hexanes:EtOAc (2:1) gave the title compound (19.5 g, 47%) as a pale yellow solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([OH:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.N([C:16]1[NH:17][CH2:18][CH2:19][N:20]=1)[N+]([O-])=O.C1(C)C(C)=CC=CC=1>CC(C)CC(=O)C>[NH:20]1[CH2:19][CH2:18][N:17]=[C:16]1[NH:1][CH2:2][CH2:3][CH:4]([OH:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=[N+]([O-])NC1=NCCN1
Reactant: NCCC(O)c1ccccc1
Solvent: Cc1ccccc1C
Solvent: CC(=O)CC(C)C
Product: OC(CCNC1=NCCN1)c1ccccc1

Procedure:
A mixture of 8 parts of α-(2-aminoethyl)benzylalcohol, 6.5 parts of 2-(nitramino)-2-imidazoline and 40 parts of xylene is stirred and refluxed for 3 hours with waterseparator. The reaction mixture is cooled and the separated oily product is dissolved in 4-methyl-2-pentanone. The solvent is evaporated in vacuo, yielding α-{2-[N-(2-imidazolin-2-yl)amino]ethyl} benzylalcohol as a residue.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]3[C:18]([N+:19]([O-])=O)=[CH:17][CH:16]=[C:15]4[C:11]=3/[C:12](=[CH:23]/[C:24]3[NH:25][CH:26]=[CH:27][C:28]=3[O:29][CH3:30])/[C:13](=[O:22])[NH:14]4)[CH:8]=2)[CH:3]=[CH:2]1.O.[Cl-].[NH4+]>CO.C1COCC1.[Zn]>[NH2:19][C:18]1[C:10]([C:7]2[CH:8]=[C:9]3[C:4]([CH:3]=[CH:2][NH:1]3)=[CH:5][CH:6]=2)=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:22])/[C:12]/2=[CH:23]\[C:24]1[NH:25][CH:26]=[CH:27][C:28]=1[O:29][CH3:30]
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(-c3ccc4cc[nH]c4c3)c21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(N)c(-c3ccc4cc[nH]c4c3)c21
Yield: 56.2 %

Procedure:
To a solution of (Z)-1,3-dihydro-4-(6-indolyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-nitro-2H-indol-2-one (48 mg, 0.12 mmol) (from Step A above) in 2 mL of a 10% water in methanol solution and 0.5 mL THF was added zinc dust (70 mg, 1.07 mmol) followed by ammonium chloride (19 mg, 0.36 mmol). The reaction was heated at gentle reflux for 4 hours, at which time the reaction mixture was filtered through a pad of Celite® and rinsed thoroughly with ethyl acetate. The resulting solution was diluted with 5 mL water and the product was extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulfate and concentrated. The resulting powder was recrystallized from EtOAc/hex to yield 25 mg (57%) of (Z)-5-amino-1,3-dihydro-4-(6-indolyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one as a red powder.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:12]([O-:14])=[O:13])[C:3]=1[OH:15].[C:16]([O-])([O-])=O.[K+].[K+].IC.Cl>CN(C=O)C.O>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:12]([O-:14])=[O:13])[C:3]=1[O:15][CH3:16]
Reactant: O=C(O)c1c(Cl)cc(Cl)c(O)c1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COc1c(Cl)cc(Cl)c(C(=O)O)c1[N+](=O)[O-]
Temperature: 60 °C
Yield: 88.1 %

Procedure:
To a solution of acid 1-6 (0.88 g, 3.5 mmol) in DMF (8 mL) was added K2CO3 (1.44 g, 10 mmol) followed by iodomethane (0.43 mL, 6.95 mmol). The reaction was heated to 60° C. for 17 h then DMF was removed under reduced pressure to give an orange gum. H2O (20 mL) was added and the solution was acidified to pH 1 with a 10% HCl solution. The aqueous solution was then extracted with EtOAc (30 mL) and washed with H2O and brine. After drying over Na2SO4 the reaction was filtered and concentrated to afford 1-7 as an orange gum (0.82 g, 88% yield). 1H NMR (400 MHz, CDCl3) δ 3.94 (s, 3H), 7.69 (s, 1H), 10.85 (br s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:29])=[C:14]([C:24](OCC)=[O:25])[C:15](=[O:23])[N:16]3[CH2:19][CH2:20][CH2:21][OH:22])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:30][CH2:31][C@H:32]([OH:34])[CH3:33]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:29])=[C:14]([C:24]([NH:30][CH2:31][C@H:32]([OH:34])[CH3:33])=[O:25])[C:15](=[O:23])[N:16]3[CH2:19][CH2:20][CH2:21][OH:22])=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCO)c1=O
Reactant: C[C@@H](O)CN
Product: C[C@@H](O)CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCO)c1=O
Yield: 25 %

Procedure:
In a similar manner to that described in example 196, from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-(3-hydroxypropyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (60 mg, 0.15 mmol) and (2R)-1-amino-2-propanol (0.05 mL) was prepared 7-[(4-fluorophenyl)methyl]-4-hydroxy-N-[(2R)-2-hydroxypropyl]-1-(3-hydroxypropyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (16 mg, 25% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.02 (s, 1 H), 8.35 (s, 1 H), 7.56 (s, 1 H), 7.06-7.03 (m, 2 H), 6.89-6.84 (m, 2 H), 4.17 (m, 2 H), 4.01 (s, 2 H), 3.89 (m, 1 H), 3.45-3.39 (m, 3 H), 3.19 (m, 1 H),1.71 (m, 2 H), 1.09 (m, 3 H); MS m/z 430 (M+1).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]([C:9](=[N:11][OH:12])[NH2:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[Cl:15][C:16]1[CH:20]=[CH:19][S:18][C:17]=1[C:21](Cl)=O>>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]2[N:10]=[C:21]([C:17]3[S:18][CH:19]=[CH:20][C:16]=3[Cl:15])[O:12][N:11]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=C(Cl)c1sccc1Cl
Reactant: CC(=O)Nc1ccc(C(N)=NO)cc1
Product: CC(=O)Nc1ccc(-c2noc(-c3sccc3Cl)n2)cc1

Procedure:
The title compound was prepared from 4-acetamidobenz amidoxime (55.4 mg, 0.287 mmol) and 3-chloro-thiophene-2-carbonyl chloride (52.4 mg, 0.289 mmol) similar to Example 16, and yielded 33.6 mg (37%) of light orange solid. 1H NMR (CDCl3): 8.12 (d, J=8.52 Hz, 2H), 7.66 (d, J=8.79 Hz, 2H), 7.60 (d, J=5.22 Hz, 1H), 7.35 (s, 1H), 7.12 (d, J=5.22 Hz, 1H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[Cl:22])[N:13]=[C:12]([C:23]3[NH:27][C:26](=[O:28])[C:25]([CH3:30])([CH3:29])[N:24]=3)[C:11]=2[CH3:31])=[CH:6][CH:5]=1.[CH3:32]I.O>CN(C=O)C>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[Cl:22])[N:13]=[C:12]([C:23]3[N:27]([CH3:32])[C:26](=[O:28])[C:25]([CH3:29])([CH3:30])[N:24]=3)[C:11]=2[CH3:31])=[CH:6][CH:5]=1
Reactant: Cc1c(C2=NC(C)(C)C(=O)N2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C2=NC(C)(C)C(=O)N2C)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.2 %

Procedure:
To a solution of sodium hydride (14.4 mg, 0.66 mole) in DMF (3 mL) at 0° C. was added compound 23 (100 mg, 0.22 mmol) in one portion. The mixture was allowed to warm to room temperature and stirred for 30 min, at which time methyl iodide (2 g, 14.08 mmol) was added. After the mixture was stirred for 2 h, water was added and the resulting mixture was extracted with ethyl acetate (2×50 mL). The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification of the crude residue by flash chromatography on silica gel with hexanes/ethyl acetate (1:1) gave the product 27 (70 mg, 0.15 mmol, 68%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.45 (d, 1H), 7.30 (d, 2H), 7.26 (dd, 1H), 7.18 (d, 1H), 7.07 (d, 2H), 3.28 (s, 3H), 2.24 (s, 3H), 1.87 (s, 6H); ESMS m/: 461.1 (M+1).
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:15][C:16]1[CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=[C:18]([C:31]([F:34])([F:33])[F:32])[N:17]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[CH3:15][C:16]1[CH:21]=[C:20]([C:2]2[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:19]=[C:18]([C:31]([F:33])([F:32])[F:34])[N:17]=1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C(F)(F)F)n1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(-c2nnc(N)nc2-c2ccccc2)cc(C(F)(F)F)n1
Yield: 90 %

Procedure:
6-bromo-5-phenyl-1,2,4-triazin-3-amine (1 molar eq.), 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)pyridine (1 molar eq.) and K2CO3 (1.5 molar eq.) are suspended in a mixture of 1,4-dioxane and water (2:1; 10 mL of solvent per gram of bromotriazine). The resulting mixture is degassed, treated with dichlorobis[di-tert-butyl(4-dimethylaminophenyl)phosphino]palladium(II) (2 mol %) and refluxed until full consumption of bromotriazine is observed by LCMS. The cooled reaction mixture is then diluted with water, extracted with DCM and passed through a phase separator. The organic phase is concentrated under reduced pressure and purified by gradient flash chromatography, eluting with mixtures of ethyl acetate and hexanes to afford 6-[2-methyl-6-(trifluoromethyl)pyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine (90%).
Reaction SMILES: [CH3:1][C@H:2]([NH2:28])[C@H:3]1[O:8][C@H:7]([O:9][C@H:10]2[C@H:15]([OH:16])[C@H:14]([N:17]([C:19]([CH2:21][NH2:22])=[O:20])[CH3:18])[C@@H:13]([O:23]C)[C@@H:12]([OH:25])[C@@H:11]2[NH2:26])[C@H:6]([NH2:27])[CH2:5][CH2:4]1.OS(O)(=O)=O.CC(N)C1OC(OC2C(O)C(NC)C(OC)C(O)C2N)C(N)CC1>>[CH3:1][CH:2]([NH2:28])[CH:3]1[O:8][CH:7]([O:9][CH:10]2[CH:15]([OH:16])[CH:14]([N:17]([C:19]([CH2:21][NH2:22])=[O:20])[CH3:18])[CH:13]([OH:23])[CH:12]([OH:25])[CH:11]2[NH2:26])[CH:6]([NH2:27])[CH2:5][CH2:4]1
Reactant: CO[C@H]1[C@@H](O)[C@H](N)[C@@H](O[C@H]2O[C@H]([C@H](C)N)CC[C@H]2N)[C@H](O)[C@@H]1N(C)C(=O)CN
Agent: CNC1C(O)C(OC2OC(C(C)N)CCC2N)C(N)C(O)C1OC
Agent: O=S(=O)(O)O
Product: CC(N)C1CCC(N)C(OC2C(N)C(O)C(O)C(N(C)C(=O)CN)C2O)O1

Procedure:
For illustrative purposes, ths invention will be exemplified by the O-demethylation of fortimicin A and fortimicin B. Generally speaking, in the practice of the preferred embodiment of this invention, to obtain a 3-O-demethylfortimicin, for example 3-O-demethylfortimicin A, in approximately thirty percent yield, fortimicin A free base is dissolved in methylene chloride, preferably in an amount of from about 1.0 to about 100 mg (0.0025 to 0.25 mmole) of fortimicin A free base to each ml of an inert solvent such as methylene chloride, and the reaction mixture is cooled to a temperature of from about -72° to about 4° C., preferably about 0° C. and treated with from about 10 to about 100 equivalents of a boron trihalide selected from the group consisting of boron tribromide, boron trichloride and boron triiodide with stirring for about 10 to 60 minutes, preferably for about 30 minutes at a temperature of from about -72° to about 4° C., preferably at about 0° C.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10].COC1C=CC(F)=CC=1OC.B(Br)(Br)Br.OC1C=CC=CC=1O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>CC(C)=O>[O:2]1[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[O:9][CH2:10]1
Reactant: COc1ccccc1OC
Agent: BrB(Br)Br
Agent: COc1ccc(F)cc1OC
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CC(C)=O
Product: c1ccc2c(c1)OCO2

Procedure:
The 3-(1,3-benzodioxol-4-yl)-6-fluoroalkyluracils of this invention may be synthesized by first reacting a 1,2-dimethoxybenzene, for example, 1,2-dimethoxy-4-fluorobenzene, with boron tribromide to give the corresponding 1,2-dihydroxybenzene. The dihydroxybenzene and a ketone or aldehyde, for example, acetone, are then reacted with phosphorous pentoxide to yield the 1,3-benzodioxole. The corresponding 1,3-benzodioxol-4-carboxylic acid is produced by treating the 1,3-benzodioxole with n-butyl lithium after which carbon dioxide is introduced into the reaction mixture. The tertiary butyl N-(1,3-benzodioxol-4-yl)carbamate is then prepared from the acid and t-butanol in the presence of diphenylphosphoryl azide. The carbamate is cleaved by stirring it in trifluoroacetic acid to give the corresponding 4-amino-1,3,benzodioxole, for example, 4-amino-2,2-dimethyl-5-fluoro-1,3-benzodioxole. The 4-amino-1,3-benzodioxole may be chlorinated in the 7-position using N-chlorosuccinimide in dimethylformamide. The dioxole is then converted to the corresponding isocyanate by reaction with trichloromethyl chloroformate. The isocyanate may be used in the next reaction without purification where it is reacted with sodium hydride and a 3-amino-3-fluoroalkylacrylate, for example, 3-amino-4,4,4-trifluorocrotonate, to produce the 3-( 1,3-benzodioxol-4-yl)-6-haloalkyluracil, for example, 3-(7-chloro-2,2-dimethyl-5-fluoro- 1,3-benzodioxol-4-yl)-6-trifluoromethyluracil. This compound may be isolated or, alternatively, reacted with an alkyl iodide and potassium carbonate without isolation to produce the 3-(1,3-benzodioxol-4-yl)-1-alkyl-6-haloalkyluracil, for example, 3-(7-chloro-2,2-dimethyl-5-fluoro-1,3-benzodioxol-4-yl)-1-methyl-6-trifluoromethyluracil. Example 1 provides details of this synthetic procedure.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][N:8]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]1.F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1>C1COCC1>[CH3:7][N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[CH2:9]1
Reactant: CN1CCC(O)C1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN1CCC(Oc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.1 %

Procedure:
To a solution of potassium tert-butoxide (1.43 g, 12.9 mmol) in THF (6 mL) was added 1-methylpyrrolidin-3-ol (645 mg, 6.39 mmol). The reaction mixture was stirred at room temperature for 1 h. Then 1-fluoro-4-nitrobenzene (900 mg, 6.39 mmol) was added to the above solution and stirred for another 2 h. After the removal of the volatile, the residual was dissolved in ethyl acetate (40 mL), and then washed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered, concentrated and purified by silica gel column chromatography (EA:PE=1:4) to give desired product as a yellow oil (626 mg, 44%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:12]1([C:15]([O:17]CC)=O)[CH2:14][CH2:13]1)[C:10]#[N:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].N.[H][H]>[Ni]>[C:1]([O:5][C:6]([NH:8][CH:9]1[C:12]2([CH2:14][CH2:13]2)[C:15](=[O:17])[NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C1(C(C#N)NC(=O)OC(C)(C)C)CC1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Product: CC(C)(C)OC(=O)NC1CNC(=O)C12CC2
Yield: 91.1 %

Procedure:
An autoclave was charged with 112 mg of 1-(1-t-butoxycarbonylamino-1-cyanomethyl)-1-ethoxycarbonylcyclopropane, 0.5 ml of Raney nickel and 3.0 ml of ammonia-saturated ethanol, and the contents were stirred at 80° C. for 2 hours in an atmosphere of hydrogen under a pressure of 65 kg/cm2. After completion of the reaction, the catalyst was removed by filtration and the resulting filtrate was concentrated under a reduced pressure to obtain 86 mg (91%) of the title compound in the form of colorless crystals. The thus obtained compound was recrystallized from ethyl acetate and diethyl ether, and used as a sample for analyses.
Reaction SMILES: CN(C)C([O:5][C@H:6]1[CH2:10][N:9]([C:11](OCCCCCCCC)=O)[C@H:8]([CH2:22][CH2:23][O:24][C:25]2[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=2[CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:7]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[OH:5][C@H:6]1[CH2:10][N:9]([CH3:11])[C@H:8]([CH2:22][CH2:23][O:24][C:25]2[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=2[CH2:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:7]1
Reactant: CCCCCCCCOC(=O)N1C[C@H](OC(=O)N(C)C)C[C@H]1CCOc1cc(OC)ccc1CCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CCc2ccccc2)c(OCC[C@@H]2C[C@@H](O)CN2C)c1
Yield: 41.1 %

Procedure:
1500 mg of (2R,4R)-4-dimethylcarbamoyloxy-2-{2-[5-methoxy-2-(2-phenylethyl)phenoxy]ethyl}-1-octyloxycarbonylpyrrolidine [prepared as described in step (a) above], 25 ml of tetrahydrofuran and 310 mg of lithium aluminum hydride were allowed to react together and subsequently treated in the same manner as described in step (b) of Example 1. The concentrated substance thus obtained was purified by silica gel column chromatography, using a 5:1 by volume mixture of methylene chloride and methanol as the eluent, to give 385 mg (yield 41%) of the title compound as a colorless solid substance.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][C:37]=1[O:38][CH3:39])[C:34](=[O:40])[CH2:33][CH2:32][CH2:31]2.C(#N)C>O>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][CH2:25][CH2:26][O:27][C:28]4[CH:29]=[C:30]5[C:35](=[CH:36][C:37]=4[O:38][CH3:39])[C:34](=[O:40])[CH2:33][CH2:32][CH2:31]5)[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: COc1cc2c(cc1OCCCCl)CCCC2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1cc2c(cc1OCCCN1CCC(c3noc4cc(F)ccc34)CC1)CCCC2=O
Yield: 117.4 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (0.78 g, 3.6 mmol), K2CO3 (0.60 g, 4.1 mmol), KI (100 mg), 6-(3-chloropropoxy)-7-methoxy-1-tetralone (0.87 g, 3.2 mmol), and acetonitrile (50 ml) was stirred at reflux under nitrogen for 17 hours. The cooled reaction was poured into 100 ml of water and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate extract was washed with brine, dried with MgSO4 and concentrate to yield 1.7 g of a brown oil. The oil was purified by preparative HPLC (Waters Associates Prep LC/system 500) to afford 1.0 g of a light brown solid. This was combined with an additional sample (2.3 g total) and recrystallization from ethanol yielded 1.7 g. A subsequent recrystallization from ethanol gave 1.25 g (36%) of 6-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl[propoxy-7-methoxy-1-tetralone as a beige powder, m.p.=129°-131° C.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH:13]=[O:14].[CH3:15][Mg]Br>C1COCC1>[Br:1][C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH:13]([OH:14])[CH3:15]
Reactant: O=Cc1nc2ccccn2c(=O)c1Br
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)c1nc2ccccn2c(=O)c1Br
Temperature: 9 °C

Procedure:
To a stirred solution of 3-bromo-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carbaldehyde (2.14 g, 8.46 mmol) in THF (85 mL) was added methylmagnesium bromide (3M in Et2O, 5.64 mL, 16.92 mmol) drop wise at 0° C. The mixture was allowed to warm to 9° C. over 4.5 h, when the reaction was quenched with sat. aq NH4Cl (50 mL), water (50 mL) and extracted with EtOAc (2×50 mL). The combined organic extract were washed with water(50 mL), brine(50 mL), dried over Na2SO4, filtered and cond under reduced pressure to give a dark brown solid, which was purified by silica gel column chromatography using 0-60% EtOAc in Hexane to give the desired product 3-bromo-2-(1-hydroxyethyl)-4H-pyrido[1,2-a]pyrimidin-4-one as a yellow solid: 1HNMR (400 MHz, DMSO-d6): δ 8.94-8.99 (dd,1H), 8.00-8.06 (m,1H), 7.76-7.78 (dd,1H), 7.40-7.47 (m,1H), 5.3(s,1H), 5.0 (m,1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:16])[CH:5]=[CH:6][C:7]=1[C:8]#[C:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13]>[Ni].CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:16])[CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][N:11]([CH2:12][CH3:13])[CH2:14][CH3:15]
Reactant: CCN(CC)CC#Cc1ccc(N)cc1Cl
Agent: [Ni]
Solvent: CO
Product: CCN(CC)CCCc1ccc(N)cc1Cl

Procedure:
2.00 g (7.498 mmol) of 3-chloro-4-(3-diethylamino-prop-1-ynyl)-phenylamine (intermediate product Z13b) was added to a suspension of 0.50 g Raney-Ni in 50 mL abs. MeOH and the mixture was hydrogenated for 2.5 hours at RT and 50 psi H2 atmosphere. The catalyst was filtered off, the filtrate evaporated down i. vac. and the residue was purified by column chromatography (silica gel, gradient dichloromethane/10% conc. aqueous ammonia in MeOH 100:0→5:95).