Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].Cl[C:15]1[CH:25]=[C:19]2[N:20]([CH3:24])[CH2:21][CH2:22][CH2:23][N:18]2[C:17](=[O:26])[N:16]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:15]2[CH:25]=[C:19]3[N:20]([CH3:24])[CH2:21][CH2:22][CH2:23][N:18]3[C:17](=[O:26])[N:16]=2)=[CH:4][C:3]=1[C:10]([F:11])([F:12])[F:13]
Reactant: OCc1ccc(F)c(C(F)(F)F)c1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Product: CN1CCCn2c1cc(OCc1ccc(F)c(C(F)(F)F)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from (4-fluoro-3-(trifluoromethyl)phenyl)methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9]2[N:10]=[CH:11][C:12]([C:15]([NH2:17])=O)=[N:13][CH:14]=2)[CH2:6]1.C(N(CC)CC)C.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>C1COCC1>[Br:1][C:2]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9]2[N:10]=[CH:11][C:12]([C:15]#[N:17])=[N:13][CH:14]=2)[CH2:6]1
Reactant: NC(=O)c1cnc(N2CC(Oc3cc(F)ccc3Br)C2)cn1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: N#Cc1cnc(N2CC(Oc3cc(F)ccc3Br)C2)cn1
Reaction time: 0.25 h

Procedure:
To 5-[3-(2-bromo-5-fluorophenoxy)azetidin-1-yl]pyrazine-2-carboxamide (0.66 g, 1.8 mmol) in THF (30 mL) at 0° C. was added triethylamine (0.46 g, 4.5 mmol) followed by TFAA (0.57 g, 2.7 mmol). After 15 min at room temperature, the reaction mixture was partitioned between ethyl acetate and saturated sodium bicarbonate. The organic phase was separated, dried over sodium sulfate and filtered. The residue was purified by flash chromatography to provide the title compound as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][NH:5][C:6](=[O:18])[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[C:9]([O:16][CH3:17])[CH:8]=1>CO.[Pd]>[NH2:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]([NH:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:19])=[O:18])=[CH:8][C:9]=1[O:16][CH3:17]
Reactant: COc1cc(C(=O)NCCN(C)C)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COc1cc(C(=O)NCCN(C)C)ccc1N
Reaction time: 4 h

Procedure:
To a suspension of the product of Example 31A (5.4 g, 20.2 mmol) in methanol (200 mL) was added 10% palladium on carbon (540 mg) and the mixture was stirred under hydrogen for 4 hours. The catalyst was filtered off and the filtrate was concentrated to give the title compound. MS: 238 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:50]=[CH:49][CH:48]=[CH:47][C:10]=1[CH2:11][C:12]1[C:13]([O:23][C@@H:24]2[O:41][C@H:40]([CH2:42][O:43]C(=O)C)[C@@H:35]([O:36]C(=O)C)[C@H:30]([O:31]C(=O)C)[C@H:25]2[O:26]C(=O)C)=[N:14][N:15]([CH2:20][CH2:21][OH:22])[C:16]=1[CH:17]([CH3:19])[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+]>CO>[CH2:1]([O:8][C:9]1[CH:50]=[CH:49][CH:48]=[CH:47][C:10]=1[CH2:11][C:12]1[C:13]([O:23][C@@H:24]2[O:41][C@H:40]([CH2:42][OH:43])[C@@H:35]([OH:36])[C@H:30]([OH:31])[C@H:25]2[OH:26])=[N:14][N:15]([CH2:20][CH2:21][OH:22])[C:16]=1[CH:17]([CH3:19])[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2nn(CCO)c(C(C)C)c2Cc2ccccc2OCc2ccccc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)c1c(Cc2ccccc2OCc2ccccc2)c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)nn1CCO
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.9 %

Procedure:
To a solution of 4-(2-hydroxybenzyl)-1-(2-hydroxyethyl)-5-isopropyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole (35 mg) in N,N-dimethylformamide (3 mL) were added benzyl bromide (20 mg) and potassium carbonate (18 mg), and the mixture was stirred at room temperature for 14 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=1/3—ethyl acetate) to give 4-(2-benzyloxybenzyl)-1-(2-hydroxyethyl)-5-isopropyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole (33 mg). To a solution of 4-(2-benzyloxybenzyl)-1-(2-hydroxyethyl)-5-isopropyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole (33 mg) in methanol (3 mL) was added sodium methoxide (28% methanol solution, 9 μL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol) to give the title compound (20 mg).
Reaction SMILES: C(OC([N:11]1C[C@H](O)C[C@H]1C(O)=O)=O)C1C=CC=CC=1.C(O[C:28]1[C:47]([O:48][CH3:49])=[CH:46][C:31]([C:32]([N:34]2[CH:38]=[C:37](CC(OC)=O)[CH2:36][C@H:35]2[CH2:44]O)=[O:33])=[C:30]([N+]([O-])=O)[CH:29]=1)C1C=CC=CC=1.NO.[N+](O)([O-])=O>C(Cl)(Cl)Cl>[CH3:49][O:48][C:47]1[C:46]2[N:11]=[CH:44][C@@H:35]3[CH2:36][CH2:37][CH2:38][N:34]3[C:32](=[O:33])[C:31]=2[CH:30]=[CH:29][CH:28]=1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Reactant: COC(=O)CC1=CN(C(=O)c2cc(OC)c(OCc3ccccc3)cc2[N+](=O)[O-])[C@H](CO)C1
Agent: NO
Solvent: O=[N+]([O-])O
Solvent: ClC(Cl)Cl
Product: COc1cccc2c1N=C[C@@H]1CCCN1C2=O

Procedure:
Finely ground Cd/Pb couple (1.02 g). was added in small portions to a stirred solution of 100 (0.64 g, 1.51 mmol) in THF (10 mL) and 1M NH4OAc (10 mL). The reaction was followed by TLC (EtOAc), when no more starting material was observed, the mixture was poured into ethyl acetate (200 mL). The organic phase was dried over MgSO4 and evaporated to yield the product as a pale yellow oil (0.28 g, 80%): 1H NMR (270 MHz, CDCl3) δ2.15 (m, 4H); 3.52 (m, 2H); 3.87 (s, 3H); 5.15 (m, 1H); 6.8-7.2 (m, 3H); 7.8 (d, J=4.7 Hz, 1H, imine H11). IR (Nujol): cm−1 3373, 2975, 1621, 1576, 1440, 1419, 1250, 1075, 750. MS: m/e (relative intensity) 230 (M+., 100), 215 (45), 201 (20), 187 (5), 160 (5), 146 (4), 133 (20), 105 (10), 76 (25), 70 (45), 63 (3), 51 (3). HRMS Calculated for C13H14N2O2: 230.1055. Found: 230.1055. [α]25D=+455.3° (c=0.6, CHCl3).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]2[CH:15]=[C:14]([CH2:16][O:17][CH3:18])[O:13][N:12]=2)=[C:9]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:23]1(=O)[CH2:28][CH2:27][CH2:26][CH2:25][C:24]1=[O:29].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[Cl:1][C:2]1[C:10]([C:11]2[CH:15]=[C:14]([CH2:16][O:17][CH3:18])[O:13][N:12]=2)=[C:9]([S:19]([CH3:22])(=[O:20])=[O:21])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][C:28]1[CH2:27][CH2:26][CH2:25][C:24](=[O:29])[CH:23]=1)=[O:5]
Reactant: COCc1cc(-c2c(S(C)(=O)=O)ccc(C(=O)O)c2Cl)no1
Reactant: O=C1CCCCC1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COCc1cc(-c2c(S(C)(=O)=O)ccc(C(=O)OC3=CC(=O)CCC3)c2Cl)no1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1.04 g (3.0 mmol) of 2-chloro-3-(5-methoxymethylisoxazol-3-yl)-4-methylsulfonylbenzoic acid are introduced into 50 ml of dichloromethane together with 0.37 g (3.3 mmol) of cyclohexanedione and treated with 0.68 g (3.3 mmol) of dicyclohexylcarbodiimide. After stirring at room temperature for 16 hours, the precipitate is filtered off with suction and the filtrate is washed with water. After the removal of the solvent, 1.22 g (92% of theory) of 3-oxo-1-cyclohexenyl 2-chloro-3-(5-methoxymethylisoxazol-3 yl)-4-methyl-sulfonylbenzoate are obtained as a yellowish, partly crystalline oil.
Reaction SMILES: CC(CC(O[C@@H:8]1[C@@:12]2([O:14][CH2:13]2)[C@H:11]2[C@H:15](OC(CC(C)C)=O)[O:16][CH:17]=[C:18]([CH2:19][O:20][C:21]([CH3:23])=[O:22])[C:10]2=[CH:9]1)=O)C>C(Cl)(Cl)Cl.FC(F)(F)C(O)=O>[CH3:23][C:21]([O:20][CH2:19][C:18]1[C:10]2=[CH:9][CH:8]=[C:12]([CH:13]=[O:14])[C:11]2=[CH:15][O:16][CH:17]=1)=[O:22]
Reactant: CC(=O)OCC1=CO[C@@H](OC(=O)CC(C)C)[C@H]2C1=C[C@H](OC(=O)CC(C)C)[C@]21CO1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OCc1cocc2c(C=O)ccc1-2
Reaction time: 0.08 h

Procedure:
Valtrate (1) (9.2 g) was dissolved in 20 ml of chloroform at room temperature. In another flask, 20 g of trifluoroacetic acid was dissolved in 40 ml of chloroform. This second solution then was added to the first solution. The clear solution became dark green/blue after stirring for 5 minutes. Chloroform (60 ml) was added to the reaction mixture, and the reaction mixture was washed with water until a pH of 4 was reached. Sodium chloride with 0.5% NaHCO3 (125 mL) was added to neutralize the mixture. Baldrinal (2, 1.1 g) was collected as a yellow liquid using column chromatography with 8:2 hexanes:ethyl acetate as solvent.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[C:7]([C:17]([O:19]C)=[O:18])=[CH:8][C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:10][C:4]=2[N:3]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Li+]>CN(C)C=O.O1CCCC1.O>[Cl:29][C:25]1[CH:24]=[C:23]([CH2:22][N:3]2[C:4]3[CH:10]=[C:9]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)[CH:8]=[C:7]([C:17]([OH:19])=[O:18])[C:5]=3[N:6]=[C:2]2[CH3:1])[CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)c1cc(N2CCOCC2)cc2nc(C)[nH]c12
Reactant: Clc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1nc2c(C(=O)O)cc(N3CCOCC3)cc2n1Cc1cccc(Cl)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 13.38 %

Procedure:
To a solution of methyl 2-methyl-5-(4-morpholinyl)-1H-benzimidazole-7-carboxylate, prepared as described in Example 26, step d (0.2 g, 0.726 mmol) in N,N-Dimethylformamide (DMF) (10 mL) was added 1-(bromomethyl)-3-chlorobenzene (0.190 mL, 1.453 mmol) and potassium carbonate (0.301 g, 2.179 mmol). The resulting reaction mixture was stirred for 3 h at 80° C. The solution was cooled to room temperature and poured into water and was extracted with EtOAc. The combined organic phase was washed with Brine and concentrated. The residue was purified on Biotage Isolera purification system using a Biotage 10 g SNAP silica gel cartridge and eluted with a gradient of DCM to 5% MeOH/DCM over 10 column volumes. The expected compound was collected and evaporated to yield a tan solid. The tan solid was dissolved in tetrahydrofuran (THF) (10.00 mL) followed by the addition of 1M lithium hydroxide solution (10 mL, 10 mmol). The reaction was stirred at 50° C. for 2 h. The reaction was cooled to room temperature and the organic solvent was removed in vacuo. The solution was diluted with water (20 mL) and acidified with 1 N HCl. The mixture was then filtered and a gray solid was isolated. The aqueous layer was found to contain a significant amount of product and was evaporated. Both solid and residue were purified by reversed phase HPLC with a gradient of acetonitrile (0.1% TFA) and water (0.1% TFA v/v) (5-50%) over 10 minutes. The appropriate fractions were collected and evaporated to procide the desired product (37.5 mg, 0.097 mmol, 13.38% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.93 (br. s., 3H) 3.05 (br. s., 4H) 3.77-3.85 (m, 4H) 5.55 (br. s., 2H) 6.88 (s, 1H) 7.09 (br. s., 1H) 7.20 (s, 1H) 7.31-7.39 (m, 3H). MS (ES+) m/e 385.8 [M+H]+.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.[O:11]([C:13]#[N:14])[K]>O>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH:10][C:13]([NH2:14])=[O:11])=[CH:5][CH:4]=1
Reactant: NNc1ccc(Br)cc1
Reactant: N#CO[K]
Agent: Cl
Solvent: O
Product: NC(=O)NNc1ccc(Br)cc1
Temperature: 25 °C

Procedure:
A solution of 1-(4-bromophenyl)hydrazine hydrochloride (25 g, 110 mmol) and KOCN (0.73 g, 9.0 mmol) in water (500 mL) was stirred overnight at 40° C., and allowed to cool to rt. The solids formed were collected by filtration to obtain compound 52a as a grey solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C7H8BrN3O: 230.0 (M+H). Found 230.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:9])[NH:5][CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH2:18][CH2:19][CH2:20][Cl:21]>CN(C)C=O>[Cl:21][CH2:20][CH2:19][CH2:18][CH2:17][N:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]1=[O:9]
Reactant: ClCCCCBr
Reactant: COc1ccc[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccn(CCCCCl)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
A mixture of 3-methoxy-2(1H)-pyridone (0.54 g, 4.31 mmol) and potassium carbonate (0.71 g, 5.14 mmol) in anhydrous N,N-dimethylformamide (20 mL) was stirred at room temperature for 1 h. 1-Bromo-4-chlorobutane (0.50 mL, 4.33 mmol) was then added and the resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with water (20 mL) and extracted with dichloromethane (3×30 mL). The organic layers were collected, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel, eluting with 100% dichloromethane and 5% methanol in dichloromethane to afford the title compound as a pale yellow oil (0.39 g, 42%). 1H NMR (400 MHz, CDCl3) δ ppm 6.87 (dd, 1H) 6.59 (dd, 1H) 6.10 (t, 1H) 4.02 (t, 2H) 3.81 (s, 3H) 3.57 (t, 2H) 2.01-1.87 (m, 2H) 1.87-1.73 (m, 2H).
Reaction SMILES: N1C=CC=CC=1.Cl.[CH3:8][NH:9][O:10][CH3:11].[Cl:12][CH2:13][CH2:14][CH2:15][C:16](Cl)=[O:17]>C(Cl)Cl>[Cl:12][CH2:13][CH2:14][CH2:15][C:16]([N:9]([O:10][CH3:11])[CH3:8])=[O:17]
Reactant: CNOC
Reactant: O=C(Cl)CCCCl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CON(C)C(=O)CCCCl
Reaction time: 0.25 h
Yield: 93 %

Procedure:
Pyridine (101.28 g, 106.6 mL, 1281.79 mmol) was added to a solution of N,O-dimethylhydroxylamine hydrochloride (50 g, 512.72 mmol) in DCM (800 mL) at 0° C. and stirring was continued for 15 min. Chlorobutyrylchloride (72.29 g, 512.72 mmol) was then added to this mixture and was stirred continuously at 0° C. for 2 h. The reaction mixture was diluted with DCM and the organic layer was washed with water followed by brine. The organic layer was separated, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 79 g of the title compound as a pale brown liquid. MS (ESI): m/z 166.1 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[N:7]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Br:17][CH2:18][CH2:19][CH2:20][CH:21](Br)[CH3:22]>>[C:1]([O:5][C:6](=[O:16])[N:7]([C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][Br:17])=[CH:13][CH:14]=1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(O)cc1
Reactant: CC(Br)CCCBr
Product: CN(C(=O)OC(C)(C)C)c1ccc(OCCCCCBr)cc1

Procedure:
In analogy to example 1.4, reaction of (4-Hydroxy-phenyl)-methyl-carbamic acid tert-butyl ester with 1,4-dibromopentane yielded [4-(5-Bromo-pentyloxy)-phenyl]-methyl-carbamic acid tert-butyl ester, MS: 372 (MH+, 1Br).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([CH3:11])=[CH:9][CH:10]=1)=[O:5])[CH3:2].S(Cl)([Cl:15])(=O)=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([CH3:11])=[C:9]([Cl:15])[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(C)s1
Reactant: O=S(=O)(Cl)Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1cc(Cl)c(C)s1
Reaction time: 1.5 h

Procedure:
5-Methyl-2-thiophenecarboxylic acid (2.84 g) was dissolved in N,N-dimethylformamide (30 ml), and iodoethane (1.68 ml) and potassium carbonate (2.76 g) were added. The mixture was stirred at room temperature for 15 hours, poured into water and extracted with diethyl ether. The extract was washed with 5% aqueous potassium hydrogen sulfate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 2-methyl-3-thiophenecarboxylic acid ethyl ester (1.84 g). 5-Methyl-2-thiophenecarboxylic acid ethyl ester (1.84 g) was dissolved in acetonitrile (30 ml), and sulfuryl chloride (1.31 ml) in acetonitrile (20 ml) was added dropwise. The mixture was stirred for 1.5 hour over a water bath, and 10% aqueous sodium thiosulfate (100 ml) was added. The mixture was stirred at room temperature for 2 hours and extracted with diethyl ether. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and the desired fractions were concentrated under reduced pressure to give 4-chloro-5-methyl-2-thiophenecarboxylic acid ethyl ester (1.67 g). 4-Chloro-5-methyl-2-thiophenecarboxylic acid ethyl ester (1.67 g) was dissolved in a mixture of ethanol (10 ml) and tetrahydrofuran (10 ml), and 1N aqueous sodium hydroxide (16 ml) was added. The mixture was stirred at 60° C. for 2 hours and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 4-chloro-5-methyl-2-thiophenecarboxylic acid (0.98 g) as crystals.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)=[CH:10][CH:9]=1>N1C=CC=CC=1>[CH2:5]([O:4][C:2]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)=[CH:12][CH:13]=1)=[O:3])[CH3:6]
Reactant: Nc1ccc(-n2cccc2)cc1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccc(-n2cccc2)cc1
Reaction time: 1.5 h

Procedure:
Ethyl chloroforrnate (0.38 ml) was added dropwisc to a stirred solution of 1-(4-aminophenyl)pyrrole (0.56 g, 3.54 mmol , Corelli et al., Farmaco. Ed. Sci., 1983, 38, 219) in pyridine (5 ml) at 5-10° C. for 15 minutes. The cooling bath was removed and stirring continued for 1.5 hours. The mixture was evaporated and the residue was purified by flash column chromatography on silica gel, eluting with a gradient of 1-4% MeOH in dichloromethane to give the title product (0.43 g) as a solid.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:25][C@@H:26]1[CH2:30][O:29][C:28](=[O:31])[NH:27]1>>[CH2:23]([C:19]1[CH:20]=[C:21]([CH3:22])[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([N:27]4[C@H:26]([CH3:25])[CH2:30][O:29][C:28]4=[O:31])=[N:7][CH:6]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=1)[CH3:24]
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Reactant: C[C@@H]1COC(=O)N1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4C)nc3)CC2)c(C)c1
Yield: 61.9 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (6-bromopyridin-3-yl)[4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (1.37 g) described in Preparation Example 115 and (R)-4-methyloxazolidin-2-one (0.53 g) described in Preparation Example 25, the title compound (892 mg) was obtained.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[CH:14]([N:27]1[CH2:30][CH:29](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:28]1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[CH:14]([N:27]1[CH2:30][CH:29]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])[CH2:28]1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1ccc(S(=O)(=O)OC2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)C1CN(C(c2ccccc2)c2ccccc2)C1
Reaction time: 2 h

Procedure:
To 17.90 g (111.80 mmol) of diethyl malonate dissolved in 250 ml of tetrahydrofuran was added 4.07 g (101.75 mmol) of 60% sodium hydride at room temperature, followed by 2 hours of stirring. Thereafter, thereto was added 20 g (50.82 mmol) of 1-benzhydryl-3-(p-toluenesulfonyloxy)azetidine which has been dissolved in 90 ml of tetrahydrofuran, followed by 1 week of heating under reflux. The reaction solution was mixed with 10% citric acid aqueous solution and then tetrahydrofuran was evaporated. The resulting residue was mixed with saturated sodium bicarbonate aqueous solution, extracted with chloroform (200 ml×3) and dried over anhydrous sodium sulfate. After evaporation of the solvent, the resulting residue was purified by a silica gel column chromatography (230-400 mesh silica gel 450 ml, ethyl acetate:hexane 1:3) to yield quantitative amount of the title compound.
Reaction SMILES: [F:1][C:2]1[C:3]([N+:24]([O-])=O)=[C:4]2[C:9]3=[C:10]([O:13][CH2:14][C:15]4([CH2:19][CH2:18][CH2:17][CH2:16]4)[N:8]3[CH:7]=[C:6]([C:20]([NH2:22])=[O:21])[C:5]2=[O:23])[C:11]=1[F:12].S(S([O-])=O)([O-])=O.[Na+].[Na+].O>O.CO>[NH2:24][C:3]1[C:2]([F:1])=[C:11]([F:12])[C:10]2[O:13][CH2:14][C:15]3([CH2:16][CH2:17][CH2:18][CH2:19]3)[N:8]3[C:9]=2[C:4]=1[C:5](=[O:23])[C:6]([C:20]([NH2:22])=[O:21])=[CH:7]3
Reactant: NC(=O)c1cn2c3c(c(F)c(F)c([N+](=O)[O-])c3c1=O)OCC21CCCC1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: NC(=O)c1cn2c3c(c(F)c(F)c(N)c3c1=O)OCC21CCCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 72.9 %

Procedure:
To a suspension of 9,10-difluoro-8-nitro-7-oxo-2,7-dihydrospiro[[1,4]oxazino[2,3,4-ij]quinoline-3,1′-cyclopentane]-6-carboxamide (1 g, 2.7 mmol) in a mixture of water/methanol (1:1 v/v, 30 mL) was added sodium hydrosulfite (Na2S2O4, 3.75 g, 22 mmol). The suspension was refluxed for 5 h until all starting material had disappeared. Upon completion, the reaction mixture was cooled to room temperature and 50 ml of water were added. After 20 minutes, a light yellow solid was collected by filtration and washed with water. The solid was dried under vacuo to give 660 mg (73% yield) of the title compound that was used without further purification in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][N:9]=[C:8]2[CH2:14][OH:15])=[O:4].ClCCl.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[O:36]1[CH:41]=[CH:40][CH2:39][CH2:38][CH2:37]1>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][N:9]=[C:8]2[CH2:14][O:15][CH:37]1[CH2:38][CH2:39][CH2:40][CH2:41][O:36]1)=[O:4]
Reactant: COC(=O)c1ccc2[nH]nc(CO)c2c1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)c1ccc2[nH]nc(COC3CCCCO3)c2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-hydroxymethyl-1H-indazole-5-carboxylic acid methyl ester (0.32 g, 1.55 mmol) in a mixture of anhydrous dichloromethane and THF (2:1, 60 mL) was added pyridinium p-toluene sulfonate (0.08 g, 0.31 mmol) and then 3,4-dihydro-2H-pyran (0.19 g, 2.32 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours under nitrogen. Solvent was evaporated; water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL). The organic phase was washed with brine (100 mL) and dried over anhydrous Na2SO4. Removal of solvent gave 3-(tetrahydro-pyran-2-yloxymethyl)-1H-indazole-5-carboxylic acid methyl ester as a yellow gummy material. Yield: 0.55 g (crude). This product was used in next step without further purification.