Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][P:5]([CH2:8][CH2:9][CH:10]=[CH2:11])(=[O:7])[OH:6].[H][H]>O.[Pd]>[NH2:1][CH2:2][CH2:3][CH2:4][P:5]([CH2:8][CH2:9][CH2:10][CH3:11])(=[O:6])[OH:7]
Reactant: C=CCCP(=O)(O)CCCN
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Product: CCCCP(=O)(O)CCCN

Procedure:
A solution of 1 g of 3-aminopropyl(but-3-enyl)phosphinic acid in 25 ml of water is treated with 0.1 g of 5% palladium on charcoal and hydrogenated at room temperature until hydrogen uptake ceases. The catalyst is removed by filtration of the reaction mixture through celite and the filtrate evaporated to dryness, to afford 3-aminopropyl(butyl)phosphinic acid, m.p. 231-234° (dec.) 31 --NMR (D2O): δ+44.6 ppm.
Reaction SMILES: [Na+].[C:2]1([CH3:11])[CH:7]=[CH:6][C:5]([S:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH2:12](Br)[C:13]([CH3:16])([CH3:15])[CH3:14]>CN(C=O)C.O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:12][C:13]([CH3:16])([CH3:15])[CH2:14][S:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:11])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: CC(C)(C)CBr
Reactant: Cc1ccc(S(=O)[O-])cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)CC(C)(C)C)cc1
Yield: 45.4 %

Procedure:
In a sealed tube, dissolve p-toluenesulfinic acid sodium salt (5.71 g, 32.1 mmol) in DMF (20 mL) and water (10 mL). Add neo-pentyl bromide (6.3 mL, 48 mmol) and tetrabutylammonium iodide (592 mg, 1.60 mmol) and heat the mixture at 145° C. overnight. Cool the reaction to ambient temperature, dilute with water and extract 3 times with EtOAc. Dry over anhydrous Na2SO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1) to give the desired intermediate as a colorless oil (3.3 g, 45%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].S(=O)(=O)(O)O.[CH:17](O)([CH3:19])[CH3:18]>>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH:17]([CH3:19])[CH3:18])=[O:10]
Reactant: O=C(O)Cc1ccccc1O
Reactant: CC(C)O
Agent: O=S(=O)(O)O
Product: CC(C)OC(=O)Cc1ccccc1O
Temperature: 0 °C

Procedure:
Isopropyl 2-hydroxyphenylacetate was prepared using the procedure described in J. Amer. Chem. Soc., 70, 1948, 1930. To a flask were added 10 g of 2-hydroxy phenylacetic acid, 99 mL of isopropanol and 9.9 mL of concentrated sulfuric acid. The mixture was refluxed for 5.5 hrs, poured into 400 mL of ice and extracted with 3×100 mL of ether. The organic layer was washed with 100 mL of aqueous solution of sodium bicarbonate (saturated). The organic fraction was dried over sodium sulfate and the solvent removed by rotary evaporation. The residue was flash chromatographed on silica gel eluted with 10% ethyl acetate/hexane to give 9.227 g of the desired product as a white solid. 1H NMR (300 Mhz, δ, CDCl3): 7.16 (m, 1H), 7.08 (dd, 1H), 6.92 (dd, 1H), 6.80 (m, 1H), 5.04 (septet, J=6.2 Hz, 1H), 3.60 (s, 2H), 1.25 (d, 6.2 Hz, 6H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:13](O)[CH2:14][CH2:15]C.C(OC(C)C)(C)C>[Zn]>[C:1]1([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CCc1ccccc1
Reactant: CCCCO
Agent: [Zn]
Solvent: CC(C)OC(C)C
Product: CCCCOC(=O)CCc1ccccc1

Procedure:
Under a nitrogen atmosphere, a mixture of methyl 3-phenylpropionate (3.0 mmol), n-butanol (3.6 mmol), the zinc cluster obtained in the above-described Example 1 (0.0375 mmol), and diisopropyl ether (5.0 ml) was refluxed for 18 hours. As a result, butyl 3-phenylpropionate was obtained quantitatively.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[C:5]([OH:13])=[CH:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH:20]1(Br)[CH2:22][CH2:21]1>CN(C=O)C.O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[C:5]([O:13][CH:20]2[CH2:22][CH2:21]2)=[CH:4][N:3]=1
Reactant: Oc1cnc(Cl)c2cc(F)ccc12
Reactant: BrC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc2c(OC3CC3)cnc(Cl)c2c1
Temperature: 145 °C
Yield: 20 %

Procedure:
To a solution of 1-chloro-7-fluoroisoquinolin-4-ol (1 g, 5.06 mmol) in DMF (5 mL) was added Cs2CO3 (4.95 g, 15.18 mmol) followed by cyclopropyl bromide (1.2 mL, 15.18 mmol) at room temperature. The reaction vessel (Pressure tube) was sealed and heated at 145° C. for 18 h. The reaction mass was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography to get desired compound (0.24 g, 20%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:32]=[CH:31][C:30]([Br:33])=[CH:29][C:10]=1[CH2:11][CH2:12][N:13]([C:16]1[CH:21]=[CH:20][C:19]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][N:17]=1)[CH2:14][CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:8][C:9]1[CH:32]=[CH:31][C:30]([Br:33])=[CH:29][C:10]=1[CH2:11][CH2:12][N:13]([C:16]1[CH:21]=[CH:20][C:19]([C:22]([OH:24])=[O:23])=[CH:18][N:17]=1)[CH2:14][CH3:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CCc1cc(Br)ccc1OCc1ccccc1)c1ccc(C(=O)OC(C)(C)C)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN(CCc1cc(Br)ccc1OCc1ccccc1)c1ccc(C(=O)O)cn1
Yield: 84.2 %

Procedure:
tert-Butyl 2-[N-(2-benzyloxy-5-bromophenethyl)-N-ethylamino]-5-pyridinecarboxylate (800 mg) and trifluoroacetic acid (20 ml) in dichloromethane (20 ml) was heated at reflux for 30 minutes. The solvent was evaporated and the residue crystallised from a mixture of dichloromethane and diethyl ether (1:2) to give the title compound (600 mg) mpt 214° C. (decomp).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])#[N:5].[OH-].[Na+].[C:14]1(C)C=CC=CC=1>>[CH3:1][N:2]([CH:14]=[C:6]([C:4]#[N:5])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:3]
Reactant: CCOC(=O)CC#N
Reactant: CNC
Reactant: Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)C(C#N)=CN(C)C
Temperature: 20 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
5.5 g of dimethylamine were condensed with 20.9 g of methoxymethyleneiminium methylsulphate at 0° C. After stirring for 1 hour at 20° C., excess dimethylamine and 70% of the resulting methanol were removed in vacuo. Analogously to Example 1, the salt obtained was reacted with 11.4 g of ethyl cyanoacetate and 4.0 g of NaOH in 140 ml of toluene. 93% of ethyl dimethylaminomethylenecyano-acetate were obtained, together with 1.2% of the corresponding methyl ester.
Reaction SMILES: [Cl:1][CH2:2][CH:3]([OH:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]([CH3:18])([CH3:17])[C:13]([O:15][CH3:16])=[O:14].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.S(=O)(=O)(O)O.O>CC(C)=O.C(O)(C)C>[Cl:1][CH2:2][C:3](=[O:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]([CH3:17])([CH3:18])[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)C(C)(C)OCCCCCCCC(O)CCl
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: CC(C)O
Solvent: O
Product: COC(=O)C(C)(C)OCCCCCCCC(=O)CCl
Yield: 59 %

Procedure:
Methyl 2-(9-chloro-8-hydroxynonyloxy)-2-methylpropionate (31 g) was dissolved in 465 ml of acetone, and 46 ml of Jones reagent prepared by adding 10.2 ml of conc. sulfuric acid and 12 g of chromic (VI) oxide to 45 ml of water was added dropwise with stirring under ice-cooling. After 3-hour-stirring at room temperature, an excess amount of Jones reagent was decomposed by adding isopropyl alcohol, The reaction mixture was poured into ice-cold water, extracted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (Wakogel® C-200, n-hexane:ethyl acetate=7.5:1) to provide 18.16 g of the objective compound as oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[CH:12]=[C:13]([CH:17]=[C:18]([NH:20][C:21]3[CH:26]=[N:25][CH:24]=[CH:23][N:22]=3)[N:19]=2)[C:14]([OH:16])=O)[CH3:9])=[CH:4][CH:3]=1.Cl.[CH3:28][NH:29][CH3:30].Cl.C(N=C=NCCCN(C)C)C.ON1C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[CH:12]=[C:13]([CH:17]=[C:18]([NH:20][C:21]3[CH:26]=[N:25][CH:24]=[CH:23][N:22]=3)[N:19]=2)[C:14]([N:29]([CH3:30])[CH3:28])=[O:16])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@H](Nc1cc(C(=O)O)cc(Nc2cnccn2)n1)c1ccc(F)cc1
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@H](Nc1cc(C(=O)N(C)C)cc(Nc2cnccn2)n1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.7 %

Procedure:
70 mg of (S)-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino) isonicotinic acid (Example 141) was dissolved in 0.5 ml of dimethylformamide, 81 mg of dimethylamine hydrochloride, 37 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 32 mg of 1-hydroxy-7-azabenzotriazole, and 0.18 ml of diisopropylethylamine were added thereto, and the mixture was stirred at room temperature for 4 hours. The reaction solution was diluted with ethyl acetate, and the organic layer was washed in turn with water and brine, and then dried over magnesium sulfate. The solvent was distilled off, and then the obtained residue was purified by silica gel column chromatography to obtain 45 mg of the objective compound as pale yellow powder.
Reaction SMILES: [CH3:1][O:2]C1C=C2C(=CC=1OC)N=CN=C2N1CCC(N2C(=O)C3C(=CC=C(O)C=3)NC2=O)CC1.[CH3:34][O:35][C:36]1[CH:37]=[C:38]2[C:43](=[CH:44][C:45]=1[O:46][CH3:47])[N:42]=[CH:41][N:40]=[C:39]2[N:48]1[CH2:53][CH2:52][CH:51]([N:54]2[C:63](=[O:64])[C:62]3[C:57](=[CH:58][CH:59]=[C:60]([N+]([O-])=O)[CH:61]=3)[NH:56][C:55]2=[O:68])[CH2:50][CH2:49]1.[CH3:69]I.[H-].[Na+]>>[CH3:34][O:35][C:36]1[CH:37]=[C:38]2[C:43](=[CH:44][C:45]=1[O:46][CH3:47])[N:42]=[CH:41][N:40]=[C:39]2[N:48]1[CH2:53][CH2:52][CH:51]([N:54]2[C:63](=[O:64])[C:62]3[C:57](=[CH:58][CH:59]=[C:60]([O:2][CH3:1])[CH:61]=3)[N:56]([CH3:69])[C:55]2=[O:68])[CH2:50][CH2:49]1
Reactant: COc1cc2ncnc(N3CCC(n4c(=O)[nH]c5ccc([N+](=O)[O-])cc5c4=O)CC3)c2cc1OC
Reactant: COc1cc2ncnc(N3CCC(n4c(=O)[nH]c5ccc(O)cc5c4=O)CC3)c2cc1OC
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: COc1ccc2c(c1)c(=O)n(C1CCN(c3ncnc4cc(OC)c(OC)cc34)CC1)c(=O)n2C
Yield: 74 %

Procedure:
The procedure similar to that described in Example 1 was repeated, except that 251.0 mg (0.56 mmol) of 3-[1-(6,7-dimethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-6-hydroxy-2,4-dioxoquinazoline (Compound 102) obtained in Reference Example 13 was used in place of Compound 24 and 3 equivalents of methyl iodide and 3 equivalents of sodium hydride were used. As a result, 197.2 mg (yield: 74%) of Compound 69 was obtained as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[NH2:10])=[CH:5][C:4]=1[CH3:16].[O-:17][C:18]#[N:19].[Na+].FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[NH2:19][C:18]([NH:10][N:9]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH3:16])[CH:5]=1)=[O:17]
Reactant: N#C[O-]
Reactant: COC(=O)CN(N)c1ccc(OC)c(C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CN(NC(N)=O)c1ccc(OC)c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.2 %

Procedure:
A mixture of methyl [1-[4-methoxy-3-methylphenyl]hydrazino]acetate (Intermediate 97, 380 mg, 0.0017 mol), sodium cyanate (380 mg, 0.0058 mol) and trifluoroacetic acid (0.4 ml, 0.0052 mol) in dry toluene (10 ml) was stirred under nitrogen and at room temperature for 31/2 hours. It was poured into 8% sodium bicarbonate solution (20 ml) and extracted with ethyl acetate (2×20 ml). The organic extract was dried (MgSO4) and evaporated to give a yellow solid which was triturated with ether and filtered to give the title compound as a yellow solid (237 mg, 52%) m.p. 174°-176° C.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([CH3:21])[CH2:6][C:7]1[N:11]([CH:12]2[CH2:14][CH2:13]2)[C:10]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[N:9][N:8]=1)C.O.[NH2:24][NH2:25]>C(O)C>[CH:12]1([N:11]2[C:10]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[N:9][N:8]=[C:7]2[CH2:6][CH:5]([CH3:21])[C:4]([NH:24][NH2:25])=[O:3])[CH2:14][CH2:13]1
Reactant: NN
Reactant: CCOC(=O)C(C)Cc1nnc(-c2ccncc2)n1C1CC1
Solvent: O
Solvent: CCO
Product: CC(Cc1nnc(-c2ccncc2)n1C1CC1)C(=O)NN

Procedure:
3-(4-cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-2-methyl-propionic acid ethyl ester (2.14 g, 7.1 mmol) was mixed with hydrazine monohydrate in ethanol at 120° C. in a sealed flask for 2 hours. The reaction mixture was concentrated and triturated with ether to give 3-(4-cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-2-methyl-propionic acid hydrazide. This compound was mixed with 3-Chloro-benzimidic acid ethyl ester hydrochloride (0.722 g, 7.8 mmol) in ethanol at 130° C. o.n. The reaction mixture was concentrated, quenched with saturated sodium carbonate, extracted with DCM. The organic layer was dried and purified by column chromatograph with 5% methanol (2M NH3) in DCM to racemic 4-(5-{2-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propyl}-4-cyclopropyl-4H[1,2,4] triazol-3-yl)-pyridine 1.19 g (41.1%). This material (70 mg) was separated on Chiralpak AD using ethanol as eluent to give the title compound. 1H-NMR: 8.77(d, 2H), 8.02 (s, 1H), 7.92 (d, 1H), 7.72 (d, 2H), 7.51 (d, 1H), 7.47(t, 1H), 4.12 (m, 1H), 3.69 (dd, 1H), 3.44 (m, 1H), 3.26 (dd, 1H), 1.66 (d, 3H), 1.24 (m, 2H) and 0.79 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH:5]=O.[C:13]([OH:19])(=[O:18])[CH2:14]C(O)=O.C([O-])(=O)C.[NH4+:24]>C(O)C>[NH2:24][CH:5]([C:4]1[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:3]=1[O:2][CH3:1])[CH2:14][C:13]([OH:19])=[O:18]
Reactant: O=C(O)CC(=O)O
Reactant: COc1ccc(C=O)c(OC)c1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCO
Product: COc1ccc(C(N)CC(=O)O)c(OC)c1
Temperature: 40 °C
Yield: 36.3 %

Procedure:
A mixture of 2,4-dimethoxybenzaldehyde (21 g, 0.126 mol), malonic acid (20 g, 0.192 mol), ammonium acetate (30 g, 0.39 mol) and ethanol (40 ml) was stirred and heated on a water bath. After refluxing for 4 h the mixture was cooled to 40° C. and the precipitated salt was filtered off and washed with cold ethanol (40 ml). By additional cooling on ice a further crystalline material precipitated, which was isolated and washed with cold ethanol (40 ml) and ether (40 ml). Recrystallisation from ethanol/water 60:40 gave 3-amino-3-(2,4-dimethoxyphenyl)propanoic acid (10.3 g, 38%).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:3]1[NH2:13].C([C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1)C.[OH-].[Na+].[CH2:28](O)[CH3:29]>O>[CH3:1][C:2]1([CH3:14])[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:3]1[NH:13][C:21](=[O:22])[C:20]1[CH:19]=[CH:18][CH:17]=[C:25]([CH2:28][CH3:29])[CH:24]=1
Reactant: CCO
Reactant: CC1(C)ON=C(c2ccccc2)N1N
Reactant: CCc1ccc(C(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCc1cccc(C(=O)NN2C(c3ccccc3)=NOC2(C)C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice-cold stirred solution of the 5,5-dimethyl-3-phenyl-[1,2,4]oxadiazol-4-ylamine (0.5 g, 2.6 mmol) in 6 mL of ethanol, was added an excess of 4-ethylbenzoyl chloride (4 mL), followed by aqueous NaOH (8%, 7 mL). The solution was stirred overnight and allowed to warm to room temperature. The mixture was diluted with water and extracted with CH2Cl2. The combined CH2Cl2 extracts were dried over MgSO4, and the solvent was removed in vacuo. The product, N-(5,5-dimethyl-3-phenyl-[1,2,4]oxadiazol-4-yl)-3-ethyl-benzamide, was isolated by silica gel chromatography. 1H-NMR (300 MHz, CDCl3) δ (ppm): 7.8 (m, 3H), 7.6 (d, 2H), 7.4 (m, 2H), 7.2 (d, 2H), 2.7 (q, 2H), 1.65 (s, 6H), 1.2 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:10])[O:4][C:5]([CH3:9])=[CH:6][C:7]=1[OH:8].CN(C=O)C.C([O-])([O-])=O.[K+].[K+].Cl[CH2:23][N:24]1[C:34](=[O:35])[C:33]2[C:28](=[CH:29][C:30]([O:39][CH3:40])=[CH:31][C:32]=2[CH:36]([CH3:38])[CH3:37])[S:25]1(=[O:27])=[O:26]>O>[Cl:1][C:2]1[C:3](=[O:10])[O:4][C:5]([CH3:9])=[CH:6][C:7]=1[O:8][CH2:23][N:24]1[C:34](=[O:35])[C:33]2[C:28](=[CH:29][C:30]([O:39][CH3:40])=[CH:31][C:32]=2[CH:36]([CH3:38])[CH3:37])[S:25]1(=[O:26])=[O:27]
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CCl)C2=O
Reactant: Cc1cc(O)c(Cl)c(=O)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(COc1cc(C)oc(=O)c1Cl)C2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19 %

Procedure:
A mixture of 3-chloro-4-hydroxy-6-methyl-2H-pyran-2-one (0.493 g, 3.07 mmol), DMF and K2CO3 (0.467 g, 3.38 mmol) was stirred at room temperature under N2 for 0.5 hours then 2-chloromethyl-4-isopropyl-6-methoxysaccharin (0.978 g, 3.22 mmol) was added in one portion. The mixture was stirred at room temperature for 3 hours, and then at 75° C. for 3 hours. The mixture was poured into water, extracted with ethyl acetate and the organic layer was washed with brine and dried. The solvent was removed in vacuo and the residue was purified by column chromatography on silica eluting with 30% ethyl acetate/hexane to afford 0.25 g (18.1% ) of 2-(3-chloro-6-methyl-2-oxo-2H-pyran-4-yl)oxymethyl-4-isopropyl-6-methoxysaccharin, m.p. 182.5°-183.5° C. after recrystallization from ether/hexane.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[C:16](OC)(=[O:27])[C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=1.CC(C)([O-])C.[K+].Cl>CO.CN(C)C=O>[CH3:24][O:23][C:21]([C:20]1[CH:25]=[CH:26][C:17]([C:16](=[O:27])[CH2:14][C:13]([C:10]2[CH:9]=[CH:8][C:7]([O:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:12][CH:11]=2)=[O:15])=[CH:18][CH:19]=1)=[O:22]
Reactant: CCCCCOc1ccc(C(C)=O)cc1
Reactant: COC(=O)c1ccc(C(=O)OC)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: CCCCCOc1ccc(C(=O)CC(=O)c2ccc(C(=O)OC)cc2)cc1
Reaction time: 3.5 h
Yield: 91.7 %

Procedure:
Dimethylformamide (485 l), p-pentyloxyacetophenone (30.3 kg) and dimethyl terephthalate (45.6 kg) were charged in 2000-liter reactor and stirred. To this mixture was added potassium tert-butoxide (24.7 kg) in several portions and, after that, a reaction was carried out at the inner temperature of 20 to 25° C. for 3.5 hours. After completion of the reaction, methanol (1210 l) was added to the reaction solution at 20 to 30° C. and then 6N hydrochloric acid (49 l) at 5 to 15° C. The mixture was stirred at room temperature for 1 hour, and the resulting appeared crystals were filtered and washed with methanol (152 l) and then water (152 l). The crystals were dried overnight in vacuo to give 1-(4-methoxycarbonylphenyl)-3-(4-pentyloxyphenyl)propane-1,3-dione (49.6 kg).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[C:10]([Cl:11])=[CH:9][C:8]([Cl:12])=[CH:7][N:6]=1)=[O:4].[N:13]12[CH2:22][N:17]3[CH2:18][N:19]([CH2:21][N:15]([CH2:16]3)[CH2:14]1)[CH2:20]2>C(Cl)(Cl)Cl>[Br-:1].[Cl:11][C:10]1[C:5]([C:3](=[O:4])[CH2:2][N+:13]23[CH2:22][N:17]4[CH2:18][N:19]([CH2:21][N:15]([CH2:16]4)[CH2:14]2)[CH2:20]3)=[N:6][CH:7]=[C:8]([Cl:12])[CH:9]=1
Reactant: O=C(CBr)c1ncc(Cl)cc1Cl
Reactant: C1N2CN3CN1CN(C2)C3
Solvent: ClC(Cl)Cl
Product: O=C(C[N+]12CN3CN(CN(C3)C1)C2)c1ncc(Cl)cc1Cl
Product: [Br-]
Temperature: 25 °C
Yield: 97.3 %

Procedure:
5.00 g of the 2-bromo-1-(3,5-dichloropyridin-2-yl)ethanone prepared in Step 2 in Synthetic Example 2 in 30 ml of chloroform was added dropwise to 2.61 g of 1,3,5,7-tetraazatricyclo[3,3,1,13,7]decane in 50 ml of chloroform with stirring at room temperature, and the mixture was stirred at the same temperature for 2 hours. After completion of the reaction, the precipitated crystals were collected by filtration and washed with 30 ml of chloroform to obtain 7.40 g of the desired product as white crystals.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:16]3=[CH:17][C:18]4[O:22][CH2:21][O:20][C:19]=4[CH:23]=[C:15]3[O:14][CH2:13]1)[C:5](=[O:12])[N:6]2[CH3:11].BrC1C=CC=C2C=1C1(COC3C=C4C(=CC1=3)CCO4)C(=O)N2C[C:35]1[O:36][C:37](C(F)(F)F)=[CH:38][CH:39]=1.O1C=CC(B(O)O)=C1.N1C=C(B(O)O)C=NC=1>>[O:36]1[CH:37]=[CH:38][C:39]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[C:4]2([C:16]4=[CH:17][C:18]5[O:22][CH2:21][O:20][C:19]=5[CH:23]=[C:15]4[O:14][CH2:13]2)[C:5](=[O:12])[N:6]3[CH3:11])=[CH:35]1
Reactant: CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2c(Br)cccc21
Reactant: O=C1N(Cc2ccc(C(F)(F)F)o2)c2cccc(Br)c2C12COc1cc3c(cc12)CCO3
Agent: OB(O)c1ccoc1
Agent: OB(O)c1cncnc1
Product: CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2c(-c3ccoc3)cccc21

Procedure:
Following the procedure as described in EXAMPLE 4.14, and making non-critical variations using 4′-bromo-1′-methylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 4′-bromo-1′-{[5-(trifluoromethyl)-2-furyl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and 3-furanboronic acid to replace pyrimidine-5-boronic acid, the title compound was obtained (81%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 7.40-7.28 (m, 2H), 7.05-6.95 (m, 1H), 6.90-6.78 (m, 2H), 6.45-6.38 (m, 1H), 6.23-6.16 (m, 1H), 6.07-5.97 (m, 1H), 5.97-5.80 (m, 2H), 4.75-4.50 (m, 2H), 3.30-3.22 (m, 3H); MS (ES+) m/z 362.4 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[NH:10][C@H:11]([C:15](=[O:21])[NH:16][CH2:17][CH2:18][CH:19]=O)[C@@H:12]([OH:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:23][C@H:24]([C@@H:30]([OH:52])[C@H:31]1[C@@H:35]([O:36][C:37](=[O:39])[CH3:38])[C@@H:34]([O:40][C:41](=[O:43])[CH3:42])[C@H:33]([N:44]2[CH:49]=[CH:48][C:47](=[O:50])[NH:46][C:45]2=[O:51])[O:32]1)[C:25]([O:27][CH2:28][CH3:29])=[O:26].N[C@H]([C@@H](O)[C@H]1[C@@H](OC(=O)C)[C@@H](OC(=O)C)[C@@H](N2C=CC(=O)NC2=O)O1)C(OCC)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.C(O)(=O)C>[C:37]([O:36][C@H:35]1[C@@H:34]([O:40][C:41](=[O:43])[CH3:42])[C@@H:33]([N:44]2[CH:49]=[CH:48][C:47](=[O:50])[NH:46][C:45]2=[O:51])[O:32][C@@H:31]1[C@H:30]([OH:52])[CH:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[NH:23][CH2:19][CH2:18][CH2:17][NH:16][C:15](=[O:21])[C@H:11]([C@@H:12]([OH:14])[CH3:13])[NH:10][C:9](=[O:22])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:39])[CH3:38]
Reactant: CCOC(=O)[C@H](N)[C@@H](O)[C@@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: C[C@H](O)[C@H](NC(=O)OCc1ccccc1)C(=O)NCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CCOC(=O)[C@H](N)[C@@H](O)[C@@H]1O[C@H](n2ccc(=O)[nH]c2=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)C(NCCCNC(=O)[C@@H](NC(=O)OCc1ccccc1)[C@H](C)O)[C@@H](O)[C@H]1O[C@H](n2ccc(=O)[nH]c2=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 46 %

Procedure:
A solution of [(1S,2S)-2-hydroxy-1-(3-oxo-propylcarbamoyl)-propyl]-carbamic acid benzyl ester (215 mg, 0.699 mmol, obtained from Reference Example 18) and a mixture of ethyl (2R,3R)-2-amino-3-hydroxy-3-[(2S,3R,4R,5R)-3,4-bis(acetyloxy)-5-(2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl]propanoate and ethyl (2R,3R)-2-amino-3-hydroxy-3-[(2S,3R,4R,5S)-3,4-bis(acetyloxy)-5-(2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl]propanoate (300 mg, 0.699 mmol) in anhydrous tetrahydrofuran (3 ml) were stirred at room temperature under a nitrogen atmosphere for 15 minutes. Acetic acid (40 μl) and sodium triacetoxyborohydride (0.296 mg, 1.4 mmole) were added and the resulting solution was stirred under nitrogen for an additional 2.5 hours. The reaction mixture was partitioned between ethyl acetate and aqueous sodium bicarbonate solution, and the aqueous layer was separated and extracted with ethyl acetate (2×75 ml). The combined extracts were washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was chromatographed (flash column, silica gel, 5% methanol in methylene chloride) to provide ethyl (5S)-12-[(R)-[(2R,3R,4R,5S)-3,4-bis(acetyloxy)-5-(2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl](hydroxy)methyl]-5-[(1S)-1-hydroxyethyl]-3,6-dioxo-1-phenyl-2-oxa-4,7,11-triazatridecan-13-oate (230 mg, 46%) as a white solid.