Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [K+].[N:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[C:18]([O-:20])=[O:19])=[CH:4][CH:3]=1.CN(C=O)C.Cl[CH2:27][N:28]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[S:29]([C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=1)(=[O:31])=[O:30].O>C1COCC1>[C:39]1([N:28]([CH2:27][O:19][C:18]([C:10]2[NH:11][C:12]3[C:17]([C:9]=2[NH:8][C:5]2[CH:6]=[CH:7][N:2]=[CH:3][CH:4]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:20])[S:29]([C:32]2[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=2)(=[O:31])=[O:30])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=C([O-])c1[nH]c2ccccc2c1Nc1ccncc1
Reactant: Cc1ccc(S(=O)(=O)N(CCl)c2ccccc2)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N(COC(=O)c2[nH]c3ccccc3c2Nc2ccncc2)c2ccccc2)cc1
Temperature: 0 °C
Yield: 10.1 %

Procedure:
Under N2, at 60° C. dissolve 3-(4-pyridinylamino)-1H-indole-2-carboxylic acid potassium salt (2.2 g, 7.5 mmol) in a mixture of anhydrous THF and DMF (90:10 mL). Cool to 0° C. and add a solution of N-chloromethyl-N-phenyl-4-methylbenzenesulfonamide (2.6 g, 8.80 mmol) in anhydrous THF (5 mL) dropwise. After 20 min add water (100 mL) and then extract with ethyl acetate (4×50 mL). Combine the organic layers, wash with NaHCO3 (sat), water, brine, dry with Na2SO4 and then concentrate. Purify the residue on an ISCO RediSep 35 gram silicagel cartridge, eluting with ethyl acetate and then 30% methanol/ethyl acetate. Combine product containing fractions and concentrate to a solid. Dissolve the solid in methanol and precipitate with ether to give the title compound as a yellow solid (390 mg): ESI/MS 313 (M+H, 1H NMR (CD3OD) δ 8.05 (2H, 2br d, J=6.5 Hz, J=6.8 Hz), 7.38 (14H, m), 6.61 (2H, br d, J=7.0 Hz), 5.93 (2H, s), 2.44 (3H, s).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[CH2:3].[NH2:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[N:11][C:12]([Cl:18])=[CH:13][CH:14]=2)[N:9]=1.C(N(CC)CC)C.CO>C(Cl)Cl>[Cl:18][C:12]1[N:11]=[C:10]2[C:15]([CH:16]=[CH:17][C:8]([NH:7][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3])=[N:9]2)=[CH:14][CH:13]=1
Reactant: C=C(C)C(=O)Cl
Reactant: Nc1ccc2ccc(Cl)nc2n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: C=C(C)C(=O)Nc1ccc2ccc(Cl)nc2n1
Temperature: 4 °C
Reaction time: 1 h
Yield: 43.5 %

Procedure:
Methacryloyl chloride (9 g) dissolved in methylene chloride (30 cc) is added in the course of 20 minutes to a solution of 2-amino-7-chloro-1,8-naphthyridine (9 g) and triethylamine (19 g) in methylene chloride (300 cc). After 30 minutes' heating under reflux, the solution obtained is washed with 0.5 N hydrochloric acid (150 cc) and distilled water (2×150 cc) and then concentrated to dryness under reduced pressure (4 kPa). The solid obtained (13.5 g) is dissolved in boiling methanol (350 cc). After 3 hours' cooling at 4° C., the crystallized solid is separated by filtration, washed with methanol (2×30 cc) and dried in the air. The isolated product (9 g; m.p. 195° C.) is then added in the course of 5 minutes to concentrated sulphuric acid (d=1.83; 19 cc). The reaction mixture is heated for 10 minutes to 60° C., stirred for 1 hour at 25° C. and then poured into distilled water (200 cc). The precipitate formed is separated by filtration, washed with distilled water (5×20 cc) and recrystallized in acetonitrile (70 cc). N-(7-Chloro-1,8-naphthyridin-2-yl)methacrylamide (5.4 g), m.p. 182° C., is thereby obtained.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10]([C:12]1([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11])[CH2:2]2.[Br:25][CH2:26][C:27]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=1)=[O:28]>C(#N)C>[Br-:25].[C:19]1([C:12]2([C:10]([O:9][C@@H:3]3[CH:4]4[CH2:7][CH2:8][N+:1]([CH2:26][C:27](=[O:28])[NH:29][C:30]5[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=5)([CH2:6][CH2:5]4)[CH2:2]3)=[O:11])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C1(c2ccccc2)CCCCCC1
Reactant: Cc1ccc(NC(=O)CBr)cc1
Solvent: CC#N
Product: Cc1ccc(NC(=O)C[N+]23CCC(CC2)[C@@H](OC(=O)C2(c4ccccc4)CCCCCC2)C3)cc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.5 %

Procedure:
To 1-phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (Example 14e) (51 mg) in acetonitrile (1 mL) was added 2-bromo-N-p-tolyl-acetamide (Example 46a) (39 mg). The reaction was stirred at room temperature overnight and the acetonitrile was removed under reduced pressure. The material was recrystallised from acetonitrile/ethyl acetate to afford the title compound as a colourless solid (16 mg).
Reaction SMILES: N[C@H](C(O)=O)COC[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-].C[N+](C)(C)C[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O[N:31]1C(=O)CCC1=O)(C)=O.CN1CCOCC1>>[CH2:22]1[CH2:23][CH2:24][CH:19]([NH:31][CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]2)[CH2:20][CH2:21]1
Reactant: CC(=O)ON1C(=O)CCC1=O
Reactant: N[C@@H](COCc1ccccc1)C(=O)O
Reactant: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CN1CCOCC1
Product: C1CCC(NC2CCCCC2)CC1

Procedure:
H-Ser(Bzl)-OH (18.6 g, 95.4 mmol) was dissolved in 45 ml of Triton B (40% methanolic solution of Trimethylbenzylammonium Hydroxide), evaporated to dryness and the residue re-evaporated twice with DMF (250 ml each). The oily residue was taken up in DMF (250 ml) and stirred with Ac-OSu (16.5 g, 95.4 mmol) for 5 hr. A few ml (~5 ml) of NMM was added to bring the reaction to slightly basic conditions during this period of time. Acidic acid (~5 ml) was then added and the solvents removed by evaporation, leaving an oily residue which was partitioned between 5% HOAc and EtOAc. The aqueous layer was extracted once more with EtOAc and the combined EtOAc solution washed twice with small volumes of H2O, dried over Na2SO4, and evaporated to approximately 300 ml (one-third of original volume). Crystalline product formed immediately when DCHA was added to a slightly basic condition (~35 ml). The crude material (32.5 g, mp 135°-145° ) was recrystallized from EtOH (150 ml) and ether (900 ml): Yield, 17.8 g (44.7%); mp 166°-168°; [α]D25 = +34.18° (c l, MeOH).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[NH:10]=[C:11]=[NH:12].C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[Br:2][C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:11]([NH2:12])=[NH:10])=[CH:5][CH:4]=1
Reactant: Nc1ccc(Br)cc1
Reactant: N=C=N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N=C(N)Nc1ccc(Br)cc1
Yield: 76.3 %

Procedure:
Hydrochloric acid (1.503 mL, 9.07 mmol) was added to 4-bromoaniline (2 g, 11.63 mmol) and carbodiimide (0.538 g, 12.79 mmol) in ethanol (10 mL) heated to reflux for 90 min. The solvent was removed under reduced pressure and potassium carbonate (0.964 g, 6.98 mmol) in water (10.00 mL) was added. Crystals were filtered off and washed with several portions of DCM to give the title compound (1.9 g, 60%).
Reaction SMILES: ClCl.[Cl:3][C:4]1[S:5][C:6]2[C:12]([N:13]3[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]3=[O:25])=[C:11]([F:26])[CH:10]=[CH:9][C:7]=2[N:8]=1.[Cl:27]N1C(=O)CCC1=O>>[Cl:3][C:4]1[S:5][C:6]2[C:12]([N:13]3[C:18](=[O:19])[C:17]([Cl:27])=[C:16]([C:20]([F:22])([F:23])[F:21])[N:15]([CH3:24])[C:14]3=[O:25])=[C:11]([F:26])[CH:10]=[CH:9][C:7]=2[N:8]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)ccc3nc(Cl)sc23)c1=O
Agent: ClCl
Product: Cn1c(C(F)(F)F)c(Cl)c(=O)n(-c2c(F)ccc3nc(Cl)sc23)c1=O

Procedure:
Once the pyrimidinedione ring (VIII) is formed, additional substituents may be optionally added. For example, a chlorine moiety is added to the 3-(2-chloro-6-fluorobenzothiazol-7-yl)-1-methyl-6-trifluoromethyl-2,4-(1H,3H)-pyrimidinedione molecule by treating it with N-chlorosuccinimide under acidic conditions, affording 3-(2-chloro-6-fluorobenzothiazol-7-yl)-1-methyl-5-chloro-6-trifluoromethyl-2,4-(1H,3H)-pyrimidinedione (IX). Example 8 provides the detailed procedure for this method. ##STR3##
Reaction SMILES: C(=O)([O-])OC.COC(O[C@H:11]1[CH2:16][CH2:15][C@H:14]2[C@H:17]3[C@H:27]([CH2:28][CH2:29][C@:12]12[CH3:13])[C@:25]1([CH3:26])[C@H:20]([CH2:21][C:22](=[O:30])[CH2:23][CH2:24]1)[CH2:19][CH2:18]3)=O.N#N>C1(C)C=CC=CC=1>[CH3:13][C@:12]12[CH2:29][CH2:28][C@H:27]3[C@@H:17]([CH2:18][CH2:19][C@@H:20]4[C@:25]3([CH3:26])[CH2:24][CH2:23][C:22](=[O:30])[CH2:21]4)[C@@H:14]1[CH2:15][CH:16]=[CH:11]2
Reactant: COC(=O)O[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: COC(=O)[O-]
Agent: N#N
Solvent: Cc1ccccc1
Product: C[C@]12CCC(=O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C=CC[C@@H]12
Yield: 85.4 %

Procedure:
This synthesis is depicted in FIG. 1. A solution of the methyl carbonate, 17β-methoxycarbonyloxy-5α-androstan-3-one (II) (9.6 g, 27.6 mmol) in toluene (200 ml) was pyrolyzed (b) in a Pyrex glass column (1=10 m, φ=9 mm) at 480° (N2 stream ca. 11 ml/min) at a rate of ca. 1 g/h. The crude product (collected in two liquid N2 -cooled traps) was washed with sat. aq. NaHCO3 - and NaCl-solution, dried (Na2SO4) and evaporated. The residue (7.24 g, 97%) was recrystallized from PE at 0° to give 6.42 g (87%) of 1. An analytical sample was recrystallized from acetonitrile at RT. M.p. 142°-144°, [a]D =+35.6° (c=1.15) ([2]: m.p. 140°-141°, [a]D17 =+38° (c=2.08)). --IR. (CDCl3): 1710s, 1595w. --1H-NMR. (360 MHz): 0.79 (s, 3 H); 1.05 (s, 3 H); 5.70 (m, 1 H); 5.84 (m, 1 H).
Reaction SMILES: C1(C)C=CC(C2C=CC=CN=2)=CC=1.O.C1(S(O)(=O)=O)C=CC=CC=1.[Br:25]Br.[Br:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)=[CH:31][CH:30]=1>ClC1C=CC=CC=1.O>[Br:27][CH:28]([Br:25])[C:29]1[CH:30]=[CH:31][C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)=[CH:33][CH:34]=1
Reactant: BrCc1ccc(-c2ccccn2)cc1
Reactant: BrBr
Agent: Cc1ccc(-c2ccccn2)cc1
Agent: O=S(=O)(O)c1ccccc1
Solvent: O
Solvent: Clc1ccccc1
Product: BrC(Br)c1ccc(-c2ccccn2)cc1
Yield: 68.89 %

Procedure:
In a 300 ml four neck flask equipped with a water separator were placed 2-(4-tolyl)pyridine (20.0 g, 0.118 mol), chlorobenzene (100 ml) and benzenesulfonic acid monohydrate (20.82 g, 0.118 mol), and the mixture was heated. At around 90° C., water was azeotropically distilled into the water separator. The mixture was further heated while distilling water until the temperature of the distillate reached 131° C. Bromine (26.4 g, 0.165 mol) was added dropwise to this reaction mass at 120-130° C. over 8 hours. The reaction mixture was stirred with heating at a temperature in the above-mentioned range for 4 hours and analyzed by HPLC. As a result, 2-(4-bromomethylphenyl)pyridine was confirmed to have been produced in a 68.89% yield and 2-(4-dibromomethylphenyl)pyridine was confirmed to have been produced in a 19.49% yield. This reaction mass was used as it was in the next reaction. From the 1H-NMR analysis, production of 2-(4-bromomethylphenyl)pyridine benzenesulfonate and 2-(4-dibromomethylphenyl)pyridine benzenesulfonate was confirmed.
Reaction SMILES: [CH:1]([Si:4]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[O:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]2[N:11]([C:13]([C:16]([O:18]CC)=[O:17])=[CH:14][N:15]=2)[CH:12]=1)([CH3:3])[CH3:2].[Li+].[OH-]>C1COCC1.CO.O>[CH:24]([Si:4]([CH:1]([CH3:3])[CH3:2])([CH:21]([CH3:23])[CH3:22])[O:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]2[N:11]([C:13]([C:16]([OH:18])=[O:17])=[CH:14][N:15]=2)[CH:12]=1)([CH3:26])[CH3:25]
Reactant: CCOC(=O)c1cnc2ccc(CO[Si](C(C)C)(C(C)C)C(C)C)cn12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)[Si](OCc1ccc2ncc(C(=O)O)n2c1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The crude ethyl 6-(((triisopropylsilyl)oxy)methyl)imidazo[1,2-a]pyridine-3-carboxylate (60) obtained above was dissolved in THF/MeOH/H2O (3:2:1, 5 mL). 6N LiOH (2.27 mL, 13.6 mmol) was added and the reaction mixture was stirred at room temperature for 2 hours. All solvents were removed and 6N HCl was added until pH 5-6. EtOAc (5 mL) was added and the mixture was stirred for 1 hour. The precipitate was filtered and dried to give 6-(((triisopropylsilyl)oxy)methyl)imidazo[1,2-a]pyridine-3-carboxylic acid (61). 1H NMR (400 MHz, d6-DMSO) δ 9.37 (s, 1H), 8.21 (s, 1H), 7.76 (dd, J=1.2, 9.2 Hz, 1H), 7.46 (dd, J=2.0, 9.2 Hz, 1H), 4.94 (s, 2H), 1.20 (m, 3H), 1.08 (d, J=6.8 Hz, 18H). MS m/z 349.2 (M+1)+.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].Cl.[CH:7]1([NH:10][C:11]([C@@H:13]2[CH2:17][CH2:16][CH2:15][NH:14]2)=[O:12])[CH2:9][CH2:8]1.C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[CH:7]1([NH:10][C:11]([C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[C:3](=[O:4])[CH2:2][Br:1])=[O:12])[CH2:9][CH2:8]1
Reactant: O=C(Br)CBr
Reactant: O=C(NC1CC1)[C@@H]1CCCN1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(NC1CC1)[C@@H]1CCCN1C(=O)CBr

Procedure:
To a solution of 1.2 g of bromo-acetyl bromide in 30 ml of DCM a solution of 1 g of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride, 0.6 g of triethylamine and 7 mg of DMAP in 10 ml of DCM was added drop-wise at 0° C. After 1 h the reaction mixture was diluted with ethyl acetate and the solids were filtered off. The organic phase was evaporated under reduced pressure and the residue was filtered over silica gel eluting with ethyl acetate/heptane (8/2). After evaporation of the solvent the obtained product was pure enough for the subsequent reaction step. Yield: 1.3 g.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[C:11]([C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12].[CH3:24][NH2:25]>>[CH3:24][NH:25][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[NH:1][C:19](=[O:20])[C:18]1[CH:22]=[CH:23][C:15]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:16][CH:17]=1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: CN
Reactant: Nc1ccccc1C(=O)O
Product: CNC(=O)c1ccccc1NC(=O)c1ccc(C(C)(C)C)cc1
Yield: 59.9 %

Procedure:
The 2-aminobenzoic acid (137 mg, 1.0 mmol) was reacted with 4-tert-butyl benzoyl chloride (196 mg, 1.0 mmol) as described in general procedure M. The resulting compound was coupled with methylamine (62 mg, 2.0 mmol) as described in general procedure A to afford the title product (186 mg) as a pure white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:26]3[CH:31]=[C:30]([CH3:32])[C:29]([O:33][CH3:34])=[C:28]([CH3:35])[CH:27]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:9]2=[O:25])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:45](Cl)(=[O:47])[CH3:46]>C(Cl)Cl>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:45](=[O:47])[CH3:46])=[CH:3][CH:4]=2)([C:26]2[CH:27]=[C:28]([CH3:35])[C:29]([O:33][CH3:34])=[C:30]([CH3:32])[CH:31]=2)[C:9]1=[O:25]
Reactant: CC(=O)Cl
Reactant: COc1c(C)cc(C2(c3ccc(N)cc3)C(=O)N(Cc3ccccc3Cl)c3ccccc32)cc1C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(C)cc(C2(c3ccc(NC(C)=O)cc3)C(=O)N(Cc3ccccc3Cl)c3ccccc32)cc1C
Yield: 94.5 %

Procedure:
Combine 3-(4-amino-phenyl)-1-(2-chloro-benzyl)-3-(4-methoxy-3,5-dimethyl-phenyl)-1,3-dihydro-indol-2-one (126 mg, 0.26 mmol), N,N-diisopropylethylamine (0.068 mL, 0.39 mmol) and acetyl chloride (0.020 mL, 0.29 mmol) in CH2Cl2 (1 mL) and stirred at room temperature for 48 h. Dilute with CH2Cl2 and wash with water. Backwash water with CH2Cl2 and ethyl acetate. Combine all organics, dilute with more CH2Cl2 and wash with 1N HCl and brine. Dry (MgSO4), filter and concentrate in vacuo to give a residual foam. Purify by flash chromatography (gradient of 33% EtOAc/hexanes to 66% EtOAc/hexanes) to give 129 mg (67%) of the title compound as a white foam. MS (ES): m/z=525 (M+1), 523 (M−1); 1H NMR(DMSO-d6): δ9.99 (s, 1H), 7.53 (m, 3H), 7.41-7.26 (m, 4H), 7.12 (m, 3H), 6.98 (m, 2H), 6.82 (s, 2H), 5.08 (s, 2H), 3.64 (s, 3H), 2.15 (s, 6H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:24]([O:26][CH3:27])=[O:25])=[N:11][N:12]2[C:17]([CH3:21])([C:18](O)=[O:19])[CH2:16][N:15]([CH3:22])[C:14](=[O:23])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][NH:29][CH3:30]>C1COCC1>[CH2:1]([O:8][C:9]1[C:10]([C:24]([O:26][CH3:27])=[O:25])=[N:11][N:12]2[C:17]([CH3:21])([C:18]([N:29]([CH3:30])[CH3:28])=[O:19])[CH2:16][N:15]([CH3:22])[C:14](=[O:23])[C:13]=12)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1nn2c(c1OCc1ccccc1)C(=O)N(C)CC2(C)C(=O)O
Reactant: CNC
Solvent: C1CCOC1
Product: COC(=O)c1nn2c(c1OCc1ccccc1)C(=O)N(C)CC2(C)C(=O)N(C)C
Reaction time: 96 h

Procedure:
The title compound was prepared from 3-benzyloxy-5,7-dimethyl-2-methoxycarbonyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-7-carboxylic acid using a procedure similar to that described in Example 2, Step 5 except that 2N dimethylamine in THF was used in place of 4-fluorobenzylamine, and the reaction time totaled 4 days. 1H NMR (400 MHz, d6-DMSO) δ 7.47-7.45 (m, 2H), 7.38-7.32 (m, 3H), 5.23 (dd, J=10.8, 16.0 Hz, 2H), 4.16 (d, J=13.6 Hz, 1H), 3.81-3.76 (m, 4H), 3.00 (s, 3H), 2.72 (br s, 6H), 1.78 (s, 3H); ES MS (M+H)=401.
Reaction SMILES: C(O)[C@H]1O[C@H](O[C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O.O.[CH3:25][C:26]1([CH3:40])[O:31][C:30](=[O:32])[CH:29]=[C:28]([CH2:33][C:34](=[O:39])[CH2:35][N:36]=[N+:37]=[N-:38])[O:27]1>C(OCC)(=O)C>[CH3:25][C:26]1([CH3:40])[O:31][C:30](=[O:32])[CH:29]=[C:28]([CH2:33][CH:34]([OH:39])[CH2:35][N:36]=[N+:37]=[N-:38])[O:27]1
Reactant: CC1(C)OC(=O)C=C(CC(=O)CN=[N+]=[N-])O1
Agent: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Solvent: CCOC(C)=O
Solvent: O
Product: CC1(C)OC(=O)C=C(CC(O)CN=[N+]=[N-])O1
Temperature: 32 °C
Reaction time: 0.5 h
Yield: 22.1 %

Procedure:
30 g of baker's yeast (made by Oriental Yeast Co., Ltd.) and 15 g of saccharose were added in 30 ml of tap water, and the solution was then stirred at 32° C. for 30 minutes. Afterward, 300 mg of 2,2-dimethyl-6-(3-azido-2-oxopropyl)-1,3-dioxin-4-one were added thereto, and the solution was then stirred overnight at the same temperature. 7.5 g of saccharose were further added thereto, followed by stirring overnight. Water of the reaction solution was then distilled off under reduced pressure, and the residue was extracted with dichloromethane and then dried over anhydrous sodium sulfate. Afterward, the solvent was distilled off, and the resultant residue was then subjected to column chromatography (an eluent of hexane:ethyl acetate=4:1), thereby obtaining 67 mg (yield 22%) of (+)-2,2-dimethyl-6-(3-azido-2-hydroxypropyl)-1,3-dioxin-4-one [a compound having the formula (1) in which n is 1, X is N3, Y is a hydrogen atom, and a substituent is present at the 6-position].
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:34]([C:37]1[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]2[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=2)=[CH:39][C:38]=1[OH:51])(=[O:36])[CH3:35].O[C@H:53]([C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][C:64]=1[CH3:69])[CH2:54][CH2:55][C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57]>C1COCC1>[C:34]([C:37]1[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]2[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=2)=[CH:39][C:38]=1[O:51][C@@H:53]([C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][C:64]=1[CH3:69])[CH2:54][CH2:55][C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])(=[O:36])[CH3:35]
Reactant: CC(=O)c1ccc(OCc2cccnc2)cc1O
Reactant: Cc1ccccc1[C@@H](O)CCC(=O)OC(C)(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)c1ccc(OCc2cccnc2)cc1O[C@H](CCC(=O)OC(C)(C)C)c1ccccc1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 22.7 %

Procedure:
Diisopropyl azodicarboxylate (8 g) is added portionwise to a stirred solution of triphenylphosphine (10.5 g) in THF (100 mL) at 0° C. under nitrogen. Stirring is continued at 0° C. for 15 minutes. A solution of 2-acetyl-5-(3-pyridylmethoxy)phenol (4.5 g) and tert-butyl (S)-4-hydroxy-4-(2-methylphenyl)butanoate (4.9 g) in THF (100 mL) is added at such a rate that the temperature does not exceed 5° C. The reaction is allowed to warm to ambient temperature stirred for 16 hours, then concentrated in vacuo. The residue is partitioned between ethyl acetate (200 mL) and water (200 mL) and the organic phase dried over magnesium sulphate, filtered and concentrated in vacuo.The residue is purified by flash chromatography on silica eluting initially with a mixture of ethyl acetate and cyclohexane (1:1 v/v) then with ethyl acetate. Fractions homogeneous in the required product are combined and evaporated to give t-butyl (R)-4-(2-acetyl-5-(3-pyridylmethoxy)phenoxy)-4-(2-methylphenyl)butanoate (2 g).
Reaction SMILES: FC1C=CC(C[N:7]2C(=O)N(C3SC(C(O)=O)=C(C)N=3)C=N2)=CC=1.[CH3:24][C:25]1[N:26]=[C:27]([N:33]2[CH2:37][C@@H:36]([CH3:38])[N:35]([CH2:39][C:40]3[CH:45]=[CH:44][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:42][CH:41]=3)[C:34]2=[O:50])[S:28][C:29]=1[C:30]([OH:32])=O>>[CH3:24][C:25]1[N:26]=[C:27]([N:33]2[CH2:37][C@@H:36]([CH3:38])[N:35]([CH2:39][C:40]3[CH:41]=[CH:42][C:43]([C:46]([F:48])([F:49])[F:47])=[CH:44][CH:45]=3)[C:34]2=[O:50])[S:28][C:29]=1[C:30]([NH2:7])=[O:32]
Reactant: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Reactant: Cc1nc(N2C[C@@H](C)N(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1C(=O)O
Product: Cc1nc(N2C[C@@H](C)N(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1C(N)=O

Procedure:
Following the procedure as described in Example 1, making variations as required to replace 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methyl-thiazole-5-carboxylic acid with (R)-4-methyl-2-(4-methyl-2-oxo-3-(4-(trifluoromethyl)-benzyl)imidazolidin-1-yl)thiazole-5-carboxylic acid, the title compound was obtained as a colorless solid: mp 110-112° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.73 (d, J=8.2 Hz, 2H), 7.56 (d, J=8.2 Hz, 2H), 7.32 (br, 2H), 4.66 (d, J=16.0 Hz, 1H), 4.45 (d, J=16.0 Hz, 1H), 4.21 (t, J=9.6 Hz, 1H), 3.83-3.76 (m, 1H), 3.57 (dd, J=10.2, 6.8 Hz, 1H), 2.46 (s, 3H), 1.22 (d, J=6.2 Hz, 3H); MS (ES+) m/z 399.0 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[Li+].[Li+].[Br-].[Li+].[N+:9]([C:12]1[CH:24]=[CH:23][C:15]2[CH2:16][CH2:17][CH2:18][CH:19](Br)[C:20](=[O:21])[C:14]=2[CH:13]=1)([O-:11])=[O:10].O>CN(C)C=O.CCOCC>[N+:9]([C:12]1[CH:24]=[CH:23][C:15]2[CH2:16][CH2:17][CH:18]=[CH:19][C:20](=[O:21])[C:14]=2[CH:13]=1)([O-:11])=[O:10]
Reactant: O=C1c2cc([N+](=O)[O-])ccc2CCCC1Br
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: O=C1C=CCCc2ccc([N+](=O)[O-])cc21
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 73.2 %

Procedure:
A mixture of 548 g of lithium carbonate and 548 of lithium bromide in 5.480 liters of dimethylformamide was heated to 100° C. and 548 g of 3-nitro-6-bromo-6,7,8,9-tetrahydro [5H] benzocycloheptene-5-one were added thereto over 5 minutes. The mixture was held at 100° C. for 45 minutes and was then poured into 25 liters of a mixture of water and ice. The mixture was vacuum filterd and the insolubles were extracted 8 times with 1 liter of methylene chloride. The organic phase was washed with water, dried over sodium sulfate and was evaporated to dryness under reduced pressure to obtain a red crystalline mass. The latter was empasted successively 3 times with 400 ml of ether, once with 400 ml of ethanol and once with 400 ml of ether and was dried at 40° C. to obtain 286.7 g of 3-nitro-8,9-dihydro [5H] benzocycloheptene-5-one in the form of orange-red crystals melting at 128° C.