Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:14][O:15][C:16]1[CH:23]=[C:22](Br)[CH:21]=[CH:20][C:17]=1[CH:18]=[O:19].C1(B(O)O)C=CC=CC=1>O>[CH3:14][O:15][C:16]1[CH:23]=[C:22]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:21]=[CH:20][C:17]=1[CH:18]=[O:19]
Reactant: Cc1ccccc1
Reactant: COc1cc(Br)ccc1C=O
Agent: O=C([O-])[O-]
Agent: OB(O)c1ccccc1
Agent: [Na+]
Solvent: O
Product: COc1cc(-c2ccccc2)ccc1C=O
Temperature: 25 °C

Procedure:
A mixture of toluene (30 mL) and water (5 mL) was degassed with nitrogen for 30 min. A mixture of sodium carbonate (2.26 g, 6.9 mmol) was added followed by 2-methoxy-4-bromobenzaldehyde (0.5 g, 2.3 mmol), phenylboronic acid (0.337 g, 2.7 mmol) and tetrakis triphenyl phosphene palladium(0) (0.261 g, 0.022 mmol) to the above degassed water/toluene mixture. The reaction mixture was then refluxed overnight. After the reaction is completed, it was cooled to room temperature and extracted with ethyl acetate. The combined organic layers were dried over sodium sulphate and concentrated. The obtained residue was purified by column chromatography using 3% ethyl acetate in hexane to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[C:3](OS(C(F)(F)F)(=O)=O)=[C:4]2[C:9]3=[C:10]([C:12](=[O:19])[C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:14][N:8]3[N:7]([CH3:20])[CH2:6][CH2:5]2)[CH:11]=1.[Cl-].[Li+].NC1CCN([C:37]2[C:46](F)=[CH:45][C:44]3C(=O)C(C(O)=O)=CN4[C:43]=3[C:38]=2CCN4C)C1.[O:56]1CCCC1>>[F:1][C:2]1[C:3]([C:37]2[CH2:46][CH2:45][CH2:44][C:43](=[O:56])[CH:38]=2)=[C:4]2[C:9]3=[C:10]([C:12](=[O:19])[C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:14][N:8]3[N:7]([CH3:20])[CH2:6][CH2:5]2)[CH:11]=1
Reactant: CN1CCc2c(N3CCC(N)C3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reactant: COC(=O)c1cn2c3c(c(OS(=O)(=O)C(F)(F)F)c(F)cc3c1=O)CCN2C
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [Li+]
Product: COC(=O)c1cn2c3c(c(C4=CC(=O)CCC4)c(F)cc3c1=O)CCN2C

Procedure:
424 mg of the compound (170) obtained in Example 47, 404 mg of 3-tributylstanyl-2-cyclohexen-1-one, 127 mg of lithium chloride and 14 mg of bis(triphenylphosphine)palladium (11) chloride were added to 5 ml of tetrahydrofuran, and the solution was heated at reflux for three days under nitrogen. The solvent was removed by distillation. To the residue, n-hexane was added, and the solid matter was filtered off. The obtained solid matter was separated by column chromatography (silica gel, eluent solvent; chloroform:ethyl acetate=8:1) to obtain 120 mg of the subject compound (171).
Reaction SMILES: [O:1]1[CH2:17][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:6]=1.[ClH:18].[NH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].C(N(CC)CC)C>C(O)(C)C>[ClH:18].[OH:1][CH:2]([CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:6]=1)[CH2:17][NH:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)CCN
Reactant: COC(=O)CCc1ccc(OCC2CO2)cc1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNCC(O)COc1ccc(CCC(=O)OC)cc1

Procedure:
A mixture of 5 gm (0.02 mole of methyl 3-[4-(2,3-epoxypropoxy)phenyl]propionate, 3 gm (0.02 mole) of ethyl 3-aminopropionate hydrochloride and 2.8 ml (0.02 mole) of triethylamine in25 mL of isopropanol was heated to reflux for 4 hours. The reaction medium was then cooled and the triethylamine hydrochloride side-product which crystallized was removed by filtration. The mother liquor was then evaporated under reduced pressure and the resulting residue taken up in ethanol and treated with ethereal HCl to provide 1 gm (12%) as a crystalline solid: mp 110°-111°. The NMR spectrum was consistent with the assigned structure and the elemental analysis was consistent with the formula C18H28NO6Cl.
Reaction SMILES: [Br-].[Br:2][CH2:3][CH2:4][CH2:5][P+:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:25][NH:26][CH3:27].C(Br)(=O)C>C(O)C>[Br-:2].[CH3:25][N:26]([CH3:27])[CH2:3][CH2:4][CH2:5][P+:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: BrCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CNC
Agent: CC(=O)Br
Agent: [Br-]
Solvent: CCO
Product: CN(C)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 22.5 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of 3-bromopropyltriphenylphosphonium bromide (Olo-IM3) (420 g, 0.90 mol) in absolute ethanol (664 g) a solution of dimethylamine in absolute ethanol (368 g, 2.69 mol, assay: 33%) was added slowly within 30 minutes at room temperature. After complete addition the suspension was stirred 1 hour at reflux whereupon a solution was obtained. The solution was cooled to a temperature of 0-10° C. and acetyl bromide (202.7 g, 1.65 mol) was added dropwise until the pH was ≦1, and the resulting suspension was allowed to warm to 20-25° C. After the white suspension was filtered the wet product washed with absolute ethanol (237 g) and then dried under vacuum (15 h, 70° C.) to give 3-dimethylaminopropyltriphenylphosphonium bromide*HBr (Olo-IM4) as a white solid (yield: 471.2 g, 0.77 mol, 85.1%; HPLC assay: 83.2%, HPLC purity: 98.72%).
Reaction SMILES: [C:1]1([CH3:42])[C:2]([S:7]([O:10][CH2:11][C@H:12]([CH2:21][O:22][C:23](=[O:41])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:13][CH:14](OCC)[O:15]CC)(=[O:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.OS(C(F)(F)F)(=O)=O.CCCCCCC>C(#N)C.O>[C:23]([O:22][CH2:21][C@@H:12]([CH2:11][O:10][S:7]([C:2]1[C:1]([CH3:42])=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:9])=[O:8])[CH2:13][CH:14]=[O:15])(=[O:41])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](COS(=O)(=O)c1ccccc1C)CC(OCC)OCC
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O
Solvent: CCCCCCC
Solvent: CC#N
Product: CCCCCCCCCCCCCCCCCC(=O)OC[C@H](CC=O)COS(=O)(=O)c1ccccc1C
Temperature: 37 °C
Reaction time: 1 h

Procedure:
A suspension of the product of Example 61 c) (4573 g, 7.47 mol) in acetonitrile (4 L) was added to a 50 L reactor equipped with a thermocouple and nitrogen inlet. An additional 13 L of acetonitrile was added and the suspension was heated to 37° C. with steam. A solution of triflic acid (1253 mL, 14.16 mol) in water (7.6 L) was added over 20 minutes. Then the mixture was stirred at 39–42° C. for 1 hour. The reaction mixture was quenched by adding it to 20 L of 23% aqueous sodium bicarbonate solution and 35 L of methyl t-butyl ether. The reaction flask was rinsed with 5 L of methyl t-butyl ether and an additional 20 L of 23% aqueous sodium bicarbonate was addded. This mixture was stirred for 10 minutes and the layers were separated. The organic layer was washed with a mixture of 25 L of 23% aqueous sodium bicarbonate solution and 15 L of 7% NaCl solution. Then the organic layer was washed with 25 L of 7% NaCl solution. The solvents were removed on a batch concentrator to provide a thick slurry. Heptane (32 L) was added to the slurry and then evaporated. Additional heptane (12 L) was added and evaporated. A further amount of heptane (40 L) was added and the suspensin was heated to 44° C. in 60 minutes, causing complete dissolution. The reaction flask was cooled to 40° C. in 10 minutes by running cold water over the surface of the flask. The solution was then allowed to slowly cool to 35° C., where cyrstallization occurs. The resulting thick mixture was stirred for 14 hours. The precipitate was filtered and rinsed twice with 4 L of heptane and then dried on the filter funnel for 2 hours and then in a vacuum oven with nitrogen purge for 60 hours at room temperature. The resulting solid (3200 g), heptane (30 L) and methyl t-butyl ether (1.6 L) were combined and heated with stirring to dissolution. The resulting solution was cooled over 1 hour to 42° C. and the resulting suspension was stirred for 20 hours while cooling to room temperature. The precipitate was filtered and dried in a vacuum oven with nitrogen purge for 20 hours at room temperature to give the desired product (2860 g).
Reaction SMILES: [CH2:1]([N:8]1[C:13]2=[N:14][C:15]3[N:16]([CH3:24])[C:17](=O)[N:18]([CH3:22])[C:19](=[O:21])[C:20]=3[N:12]2[C:11]([OH:25])=[CH:10][C:9]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Li+].C(Cl)(Cl)Cl.Cl>O1CCOCC1.O>[CH2:1]([N:8]1[C:13]2=[N:14][C:15]3[N:16]([CH3:24])[CH2:17][N:18]([CH3:22])[C:19](=[O:21])[C:20]=3[N:12]2[C:11]([OH:25])=[CH:10][C:9]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c(=O)c2c(nc3n(Cc4ccccc4)c(=O)cc(O)n23)n(C)c1=O
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: C1COCCO1
Product: CN1CN(C)c2nc3n(Cc4ccccc4)c(=O)cc(O)n3c2C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 395 g. (1.12 moles) of 9-benzyl-1,3-dimethyl-6-(hydroxy)pyrimido[2,1-f]purine-2,4,8(1H,3H,9H)-trione in 10.5 liters of dry 1,4-dioxane, add 68.1 g. (3.14 moles) of lithium borohydride in portions. Maintain the reaction temperature at 20°-25° C. by controlling the rate of addition and by use of a cooling bath as needed. Stir the mixture at room temperature for 0.5 hour, then reflux for 18 hours. Remove solvent under reduced pressure. Allow the residue to cool; then add 4.5 liters of chloroform. To the resultant mixture, cautiously add dropwise 1.1 liters of water. Stir the mixture at room temperature until two clear phases result. Add 3N hydrochloric acid portionwise to bring the pH to 4-5. Separate the layers, and extract the aqueous phase with two 1.1-liter portions of chloroform. Wash the combined extracts with three 1.1-liter volumes of water, and dry over anhydrous sodium sulfate. Filter the drying agent, and remove volatiles from the filtrate under reduced pressure. Crystallize the residue from methanol-ethyl acetate to obtain title compound (I) as a solid with m.p. 176°-182° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([C:14]([F:17])([F:16])[F:15])([OH:13])[CH2:11][OH:12])[CH:7]=1.C(N(CC)CC)C.[NH4+].[Cl-]>CS(C)=O.C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([OH:13])([C:14]([F:17])([F:16])[F:15])[CH:11]=[O:12])[CH:7]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CO)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(F)cc1C(C)(C)CC(O)(C=O)C(F)(F)F
Reaction time: 3 h

Procedure:
1.5 g (4.8 mmol) of 4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-trifluoromethylpentane-1,2-diol and 3.4 ml (24.4 mmol) of triethylamine in 17 ml of DMSO and 53 ml of CH2Cl2 are mixed at 10° C. in portions with 3 g (18.9 mmol) of pyridine-sulfur trioxide complex. After 3 hours at 12-18° C., it is hydrolyzed while being cooled with ice with saturated NH4Cl solution, and it is extracted with ethyl acetate. The combined extracts are dried (Na2SO4) and concentrated by evaporation: 1.57 g of the product as a light yellow oil.
Reaction SMILES: [OH:1][C:2]([CH:4]([C:6]1[CH:15]=[CH:14][C:9]([CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:8][CH:7]=1)[CH3:5])=[O:3].[NH2:16][C@H:17]([C:23]([OH:25])=[O:24])[CH2:18][CH2:19][CH2:20][CH2:21][NH2:22].O>C(O)C>[OH:3][C:2]([C@H:4]([C:6]1[CH:7]=[CH:8][C:9]([CH2:10][CH:11]([CH3:12])[CH3:13])=[CH:14][CH:15]=1)[CH3:5])=[O:1].[NH2:16][C@H:17]([C:23]([OH:25])=[O:24])[CH2:18][CH2:19][CH2:20][CH2:21][NH2:22]
Reactant: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Agent: NCCCC[C@H](N)C(=O)O
Solvent: O
Solvent: CCO
Product: CC(C)Cc1ccc([C@H](C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 50.6 %

Procedure:
167 grams of racemic ibuprofen and 118 grams of (S)-lysine were charged into 180 cc of water and 5.82 liters of ethanol were added. The resulting slurry was agitated and aged at 30° C. for 24 hours. A clear liquor was drawn off through a filter and the liquor cooled to 25° C. The resulting supersaturated liquor was then added to a slurry of 50 grams of 99.4% (S)-ibuprofen-(S)-lysine. The precipitated solid was separated by filtration and the mother liquor recycled to the slurry mixture of racemic ibuprofen and (S)-lysine. The procedure was continued until essentially all the (S)-ibuprofen in the original charge was depleted. This procedure resulted in the formation of 144 grams of 98.1-98.8% pure (S)-ibuprofen-(S)-lysine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.Cl[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]([O:35][CH3:36])[CH:28]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(O)CCC.CCCCCC.C(OCC)(=O)C>[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:9]2[CH2:14][CH2:13][N:12]([CH2:23][CH2:24][CH2:25][O:26][C:27]3[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]([O:35][CH3:36])[CH:28]=3)[CH2:11][CH2:10]2)=[CH:20][CH:19]=1
Reactant: COc1cc(OC)cc(OCCCCl)c1
Reactant: Fc1ccc(C(c2ccc(F)cc2)C2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCCCO
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1cc(OC)cc(OCCCN2CCC(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c1

Procedure:
A mixture of 5.51 g (0.019 mole) of 4-[bis(4-fluorophenyl)methyl]piperidine, 4.42 g (0.019 mole) of 1-(3-chloropropoxy)-3,5-dimethoxybenzene and potassium carbonate (5.53 g, 0.04 mole) was heated overnight at reflux in 350 ml of 1-butanol containing potassium iodide (0.3 g). The reaction mixture was concentrated to dryness and the residue partitioned between chloroform-5% sodium hydroxide and chloroform-water. Removal of chloroform gave a brown oil. The oil was subjected to chromatography on a silica gel column using a gradient elution series of hexane-ethyl acetate and ethyl acetatedimethoxyethane. After combining proper fractions eluted from the column and removing solvent, the residue oil was dried in vacuo overnight at 80° C. This produced 2.61 g (28.5%) of brown oil.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([NH:12][NH2:13])=O)=[CH:9][C:4]=2[NH:3][CH:2]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH2:24][CH2:25][C:26](Cl)=O)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:38])=CC=1>>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:24][CH2:25][C:26]1[S:38][C:10]([C:8]2[CH:7]=[CH:6][C:5]3[NH:1][CH:2]=[N:3][C:4]=3[CH:9]=2)=[N:12][N:13]=1
Reactant: COc1ccc(CCC(=O)Cl)cc1OC
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: NNC(=O)c1ccc2nc[nH]c2c1
Product: COc1ccc(CCc2nnc(-c3ccc4[nH]cnc4c3)s2)cc1OC

Procedure:
The compound was synthesized starting from benzimidazol-5-carbohydrazide (176 mg; 1 mmol), TEA (0.153 ml; 1.1 mmol), 3,4-dimethoxyphenylpropionylchloride (228 mg, 1.1 mmol) and Lawesson's reagent (606 mg; 1.5 mmol) as described in method 1; yield: 0.017 g (4.6%); MS m/z: 367.2 [M+H]+; 1H-NMR (DMSO d6, 400 MHz): δ 3.00 (t, 2H, 3J=7.5 Hz); 3.40 (t, 2H, 3J=7.5 Hz); 3.68 (s, 3H); 3.70 (s, 3H); 6.75-6.77 (m, 1H); 6.81-6.83 (m, 1H); 6.89 (br s, 1H); 7.67-7.69 (m, 1H); 7.73-7.75 (m, 1H); 8.09 (br s, 1H); 8.34 (s, 1H; HPLC (METHOD [A]): rt 10.82 min (100%)
Reaction SMILES: C([O:4][C@H:5]1[CH2:8][C@H:7]([C:9]([N:11]2[CH2:17][CH2:16][CH2:15][N:14]([CH:18]3[CH2:21][CH2:20][CH2:19]3)[CH2:13][CH2:12]2)=[O:10])[CH2:6]1)(=O)C.C1COCC1.O.O[Li].O>O>[CH:18]1([N:14]2[CH2:15][CH2:16][CH2:17][N:11]([C:9]([C@H:7]3[CH2:8][C@H:5]([OH:4])[CH2:6]3)=[O:10])[CH2:12][CH2:13]2)[CH2:21][CH2:20][CH2:19]1
Reactant: CC(=O)O[C@H]1C[C@H](C(=O)N2CCCN(C3CCC3)CC2)C1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C([C@H]1C[C@H](O)C1)N1CCCN(C2CCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.2 %

Procedure:
To a stirred solution trans-3-[(4-cyclobutyl-1,4-diazepan-1-yl)carbonyl]cyclobutyl acetate (50 mg, 0.17 mmol) in 5:1 THF/H2O (93 ml) at RT was added LiOH.H2O (8.5 mg, 0.2 mmol). The mixture was stirred at RT overnight, diluted with H2O and extracted with DCM. The organic layer was then dried (Na2SO4), filtered and concentrated at reduced pressure to yield the title compound as pale yellow oil (40 mg, 93%).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12]3[N:17]=[C:16]([N:18]4[CH:22]=[C:21]([CH:23]=O)[C:20]([CH3:25])=[N:19]4)[CH:15]=[CH:14][N:13]=3)[CH:9]=2)[N:4]([CH3:26])[C:3]=1[CH3:27].Cl.C([N:31]([CH2:34][CH3:35])[CH2:32]C)C.[BH-](OC(C)=O)(OC(C)=O)[O:37]C(C)=O.[Na+]>ClCCl>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12]3[N:17]=[C:16]([N:18]4[CH:22]=[C:21]([CH2:23][N:31]5[CH2:32][CH:35]([OH:37])[CH2:34]5)[C:20]([CH3:25])=[N:19]4)[CH:15]=[CH:14][N:13]=3)[CH:9]=2)[N:4]([CH3:26])[C:3]=1[CH3:27]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cc1nn(-c2ccnc(Nc3ccc4c(c3)c(Cl)c(C)n4C)n2)cc1C=O
Reactant: CCN(CC)CC
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: Cc1nn(-c2ccnc(Nc3ccc4c(c3)c(Cl)c(C)n4C)n2)cc1CN1CC(O)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a slurry of Intermediate No. 9 (642 mg, 1.68 mmol), 3-azetidinole hydrochloride (370 mg, 2 equiv.) and triethylamine (1.4 mL, 6 equiv.) in 100 mL of dichloromethane, was added NaBH(OAc)3 (1.07 g, 3 equiv.) at room temperature. The reaction was stirred for 12 hour at room temperature and then quenched with 1N—NaOH. It was extracted with ethyl acetate and washed twice with brine. The collected organic layer was dried over anhydrous sodium sulfate and then concentrated in vacuo. The resulting residue was purified by silica gel chromatography (DCM/MeOH) to afford desired Compound No. 141 as a pale yellow solid (540 mg, 73%); MS (ESI) m/z 438 [M+H]+; 1H NMR (300 MHz, DMSO-d3) δ 9.72 (s, 1H), 8.59 (s, 1H), 8.52 (d, 1H, J=5.4 Hz), 7.95 (s, 1H), 7.45 (s, 2H), 7.14 (s, 1H, J=5.4 Hz), 4.41 (m, 1H), 4.05 (m, 4H), 3.70 (s, 3H), 3.35 (m, 2H), 2.42 (s, 3H), 2.34 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[O:7][CH2:6][C:5]([CH2:20][CH2:21][N:22]2[CH:26]=[CH:25][N:24]=[C:23]2[N+:27]([O-:29])=[O:28])([CH2:8]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:4][O:3]1.C1N2CCOCCOCCN(CCOCCOCC2)CCOCCOC1.[F-:57].[K+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[CH3:1][C:2]1([CH3:30])[O:7][CH2:6][C:5]([CH2:8][F:57])([CH2:20][CH2:21][N:22]2[CH:26]=[CH:25][N:24]=[C:23]2[N+:27]([O-:29])=[O:28])[CH2:4][O:3]1
Reactant: [F-]
Reactant: Cc1ccc(S(=O)(=O)OCC2(CCn3ccnc3[N+](=O)[O-])COC(C)(C)OC2)cc1
Agent: C1COCCN2CCOCCOCCN(CCO1)CCOCCOCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC1(C)OCC(CF)(CCn2ccnc2[N+](=O)[O-])CO1

Procedure:
5 mg (11.4 μmol equivalents) of 2,2-dimethyl-5-[2-(2-nitro-1H-imidazol-1-yl)ethyl]-5-(p-toluenesulfonyloxymethyl)-1,3-dioxane was dissolved in 1 mL of acetonitrile, 14 mg (34.5 μmol equivalents) of Kryptofix 222 (trade name, Merck), 0.82 g (14.1 μmol equivalents) of potassium fluoride, and 0.4 mg (2.9 μmol equivalents) of potassium carbonate were added thereto, and the mixture was refluxed while heating for 5 hours. After completion of the reaction, water was added and the mixture was extracted three times with chloroform. The combined chloroform layers were dried with anhydrous magnesium sulfate and subsequently concentrated under vacuum. The obtained crude product was purified by silica gel column chromatography to give a trace amount of 2,2-dimethyl-5-fluoromethyl-5-[2-(2-nitro-1H-imidazol-1-yl)ethyl]-1,3-dioxane.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]=[O:8])=[CH:5][N:4]=[CH:3]1.[OH2:9].[C:10]1([CH3:20])C=CC(S(O)(=O)=O)=CC=1>C(O)CO>[CH3:1][N:2]1[C:6]([CH:7]2[O:9][CH2:10][CH2:20][O:8]2)=[CH:5][N:4]=[CH:3]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O
Reactant: Cn1cncc1C=O
Solvent: OCCO
Product: Cn1cncc1C1OCCO1

Procedure:
1-Methyl-5-formyl imidazole (0.64 g) was treated with ethylene glycol (0.3 ml), p-toluenesulphonic acid monohydrate (0.0015 g) and powdered 4A molecular seives under N2 for 18 hours at reflux. Subsequent cooling and filtration was followed by washing of the organic phase with aqueous sodium carbonate solution (2N), drying and concentration to give the title compound; δH (CDCl3) 7.43 (1H,s), 7.12 (1H,s), 5.91 (1H,s), 4.10(4H,m), 3.70(3H,s).
Reaction SMILES: C(O)(=O)[C@@:2]1([CH2:12][CH2:11][C@H:7]([C:8](O)=O)[C:4]1([CH3:6])C)C.[CH2:15]([N:18]1[CH2:23][C@@H:22]([CH3:24])[NH:21][CH2:20][C@@H:19]1[CH3:25])[CH:16]=[CH2:17].C(=O)C1C=CC=CC=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.C(O)(=O)C>[CH2:15]([N:18]1[CH2:23][C@@H:22]([CH3:24])[N:21]([CH2:8][C:7]2[CH:4]=[CH:6][CH:2]=[CH:12][CH:11]=2)[CH2:20][C@@H:19]1[CH3:25])[CH:16]=[CH2:17]
Reactant: CC1(C)[C@@H](C(=O)O)CC[C@@]1(C)C(=O)O
Reactant: C=CCN1C[C@@H](C)NC[C@@H]1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=Cc1ccccc1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C=CCN1C[C@@H](C)N(Cc2ccccc2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of the (+)-(1R,3S)-camphoric acid salt of (+)-(2S,5R)-1-allyl-2,5-dimethylpiperazine from Preparation 1 (78.2 g) and benzaldehyde (26.5 g) in tetrahydrofuran (500 ml) containing glacial acetic acid (2 ml) was added sodium triacetoxyborohydride (93.3 g) portionwise over 10 minutes. The resulting mixture was stirred at room temperature for 4 hours. The reaction was partitioned between ethyl acetate (1500 ml) and aqueous sodium hydroxide (750 ml of 2N solution). The layers were separated and the organic phase was washed with 10% sodium metabisulphite solution (200 ml) and saturated brine solution. The organic layer was dried (MgSO4) and evaporated to dryness in vacuo to give the title compound, 52.1 g.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[C:15]([N:18]1[CH:23]([CH3:24])[CH2:22][N:21]([C:25]2[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=2)[CH2:20][CH:19]1[CH3:33])(=[O:17])[CH3:16].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.S(=O)(O)[O-].[Na+]>CN(C)C(=O)C>[C:15]([N:18]1[C@@H:23]([CH3:24])[CH2:22][N:21]([C:25]2[CH:26]=[CH:27][C:28]([C:29]3[NH:6][C:4](=[O:5])[C:3]4[C:7]([O:13][CH3:14])=[CH:8][C:9]([O:11][CH3:12])=[N:10][C:2]=4[N:1]=3)=[CH:31][CH:32]=2)[CH2:20][C@H:19]1[CH3:33])(=[O:17])[CH3:16]
Reactant: COc1cc(OC)c(C(N)=O)c(N)n1
Reactant: CC(=O)N1C(C)CN(c2ccc(C=O)cc2)CC1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4C[C@@H](C)N(C(C)=O)[C@@H](C)C4)cc3)nc2n1
Temperature: 135 °C
Reaction time: 16 h

Procedure:
A mixture of 2-amino-4,6-dimethoxy-nicotinamide (0.25 g, 1.26 mmol), 4-(4-acetyl-3,5-dimethyl-piperazin-1-yl)-benzaldehyde (0.43 g, 1.64 mmol), p-toluenesulfonic acid monohydrate (0.53 mg, 2.77 mmol) and sodium bisulfite (0.45 g, 2.52 mmol) in N,N-dimethylacetamide (5.0 mL) was stirred at 135° C. under N2 for 16 hours and then cooled to room temperature. The mixture was concentrated to dryness under reduced pressure. Water (40 mL) was added to the residue and stirred for 0.5 hours. The precipitate was filtered and the solid was rinsed with water and dried over Na2SO4. The crude solid was purified by column chromatography (silica gel 230-400 mesh; eluting with 2.5% methanol in dichloromethane) to afford the title compound as yellow solid. Yield: 90 mg (16.3%). MP 279-279.8° C. 1H NMR (400 MHz, CDCl3): δ 10.18 (s, 1H), 8.14 (d, J=8.8 Hz, 2H), 6.99 (d, J=8.8 Hz, 2H), 6.20 (s, 1H), 4.78 (bs, 1H), 4.12 (s, 3H), 4.02 (s, 3H), 3.70 (d, J=12.0 Hz, 2H) 3.11 (d, J=10 Hz, 2H), 2.18 (s, 3H), 1.40 (bs, 6H).
Reaction SMILES: [CH:1]([S:3]([F:6])(=[O:5])=[O:4])=[CH2:2].[CH:7]1[CH2:11][CH:10]=[CH:9]C=1.[CH3:12]COCC>>[C:1]12([S:3]([F:6])(=[O:5])=[O:4])[CH2:12][CH:10]([CH2:11][CH2:7]1)[CH:9]=[CH:2]2
Reactant: C1=CCC=C1
Reactant: CCOCC
Reactant: C=CS(=O)(=O)F
Product: O=S(=O)(F)C12C=CC(CC1)C2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 92 %

Procedure:
To 20.00 g (0.018 mol) of vinylsulfonyl fluoride in 40 ml of anhydrous ether was added 16.00 g (0.24 mol) of freshly prepared cyclopentadiene. The reaction was carried out for 20 min at 0° C. and then allowed to warm up to room temperature. After 24 hours., ether was distilled out at a normal pressure and the residue was distilled under reduced pressure to give a colorless oil (bp=97-99° C./15 torr) in 92% yield. The product was identified by 1H and 13C NMR and IR spectroscopy.