Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OC)(OC)(OC)[CH2:2][CH2:3][CH3:4].[CH2:11]([O:18][C:19]1[CH:28]=[C:27]2[C:22]([C:23]([NH:30][CH2:31][CH:32]([CH3:34])[CH3:33])=[C:24]([NH2:29])[CH:25]=[N:26]2)=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:11]([O:18][C:19]1[CH:20]=[CH:21][C:22]2[C:23]3[N:30]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:1]([CH2:2][CH2:3][CH3:4])=[N:29][C:24]=3[CH:25]=[N:26][C:27]=2[CH:28]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)CNc1c(N)cnc2cc(OCc3ccccc3)ccc12
Reactant: CCCC(OC)(OC)OC
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC(C)C
Temperature: 105 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
Trimethyl orthobutyrate (29.75 mL, 0.1859 mol) was added in three portions to a solution of 7-benzyloxy-N4-(2-methylpropyl)quinoline-3,4-diamine (54.6 g, 0.170 mol) in toluene (795 mL). Pyridine hydrochloride (1.96 g) was then added, and the reaction was heated at 105° C. and stirred for four hours. Additional trimethyl orthobutyrate (7 mL, 40 mmol) was then added, and the reaction was stirred for three hours. The reaction was allowed to cool to ambient temperature, and the solvent was removed under reduced pressure. The oily residue was treated with chloroform, which was removed under reduced pressure to remove residual toluene, and then again diluted with chloroform (1.2 L). The resulting solution was washed sequentially with 5% aqueous sodium bicarbonate, water, and brine; dried over magnesium sulfate; filtered; and concentrated under reduced pressure to yield 60.3 g of 7-benzyloxy-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinoline as an oily brown solid, containing a small amount of toluene (0.93 equivalents).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].F[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: Fc1ccccn1
Reactant: Oc1cc(F)ccc1Br
Product: Fc1ccc(Br)c(Oc2ccccn2)c1

Procedure:
2-Bromo-5-fluoro-phenol was reacted with 2-fluoro-pyridine according to the method of Example 101A to provide the title compound. MS (DCI/NH3) m/z 268 (M)+, 270 (M+2)+.
Reaction SMILES: [CH:1](/[C:9]1[C:17]2[C:12](=[CH:13][C:14]([CH:18]=O)=[CH:15][CH:16]=2)[NH:11][N:10]=1)=[CH:2]\[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][C:21]1=[O:29].N1CCCCC1>CO>[CH:1](/[C:9]1[C:17]2[C:12](=[CH:13][C:14](/[CH:18]=[C:22]3/[C:21](=[O:29])[NH:20][C:28]4[C:23]/3=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:15][CH:16]=2)[NH:11][N:10]=1)=[CH:2]\[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=Cc1ccc2c(/C=C/c3ccccc3)n[nH]c2c1
Reactant: O=C1Cc2ccccc2N1
Solvent: C1CCNCC1
Solvent: CO
Product: O=C1Nc2ccccc2/C1=C\c1ccc2c(/C=C/c3ccccc3)n[nH]c2c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 11.9 %

Procedure:
A solution of (E)-3-styryl-1H-indazole-6-carbaldehyde (27 mg, 0.109 mmol) and oxindole (15 mg, 0.109 mmol) in MeOH (1.0 mL) was treated with piperidine (1 uL. 0.011 mmol) and the reaction stirred at 60° C. for 4 hours. The MeOH was removed and the residue purified by prep-HPLC to give 4.7 mg, 12% of a yellow powder. 1H NMR (400 MHz, CD3OD) δ 8.26 (d, J=8.38 Hz, 2H), 7.91-7.86 (m, 2H), 7.71-7.64 (m, 3H), 7.60-7.49 (m, 2H), 7.42 (t, J=7.41 Hz, 2H), 7.31 (t, J=7.49 Hz, 1H), 7.26 (t, J=7.89 Hz, 1H), 6.94 (d, J=7.75 Hz, 1H), 6.89 (t, J=6.86 Hz, 1H); MS ESI 364.2 [M+H]+, calcd for [C24H17N3O+H]+ 364.14.
Reaction SMILES: [CH:1]([Si:4]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[O:5][CH2:6][CH2:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=O)([CH3:3])[CH3:2].[CH2:22]1[C:27](=[O:28])[CH2:26][C:24](=[O:25])[CH2:23]1.N1CCC[C@H]1C(O)=O.CC1NC(C)=C(C(OCC)=O)CC=1C(OCC)=O>ClCCl>[OH:25][C:24]1[CH2:23][CH2:22][C:27](=[O:28])[C:26]=1[CH2:11][C:10]1[CH:13]=[CH:14][CH:15]=[C:8]([CH2:7][CH2:6][O:5][Si:4]([CH:19]([CH3:21])[CH3:20])([CH:1]([CH3:3])[CH3:2])[CH:16]([CH3:18])[CH3:17])[CH:9]=1
Reactant: O=C1CCC(=O)C1
Reactant: CC(C)[Si](OCCc1cccc(C=O)c1)(C(C)C)C(C)C
Agent: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1
Agent: O=C(O)[C@@H]1CCCN1
Solvent: ClCCl
Product: CC(C)[Si](OCCc1cccc(CC2=C(O)CCC2=O)c1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 76 %

Procedure:
To a solution of 14 (0.920 g, 3.0 mmol), 1,3-cyclopentadione (0.098 g, 1.0 mmol), and L-proline (0.005 mg) in dichloromethane (5 mL), diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (0.253 g, 1.0 mmol) was added, and the resulting mixture was allowed to stir at rt for 12 h. The reaction mixture was directly purified by silica gel column chromatography using a gradient of ethyl acetate in hexanes as eluent, obtaining the title compound. Yield: 76%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[C@H:5]([CH3:7])[NH2:6])[CH3:2].[CH2:9]1[CH2:15][S:12](=[O:14])(=[O:13])[O:11][CH2:10]1>O1CCCC1>[CH2:1]([O:3][C:4](=[O:8])[C@@H:5]([NH:6][CH2:10][CH2:9][CH2:15][S:12]([OH:14])(=[O:13])=[O:11])[CH3:7])[CH3:2]
Reactant: CCOC(=O)[C@H](C)N
Reactant: O=S1(=O)CCCO1
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](C)NCCCS(=O)(=O)O
Temperature: 25 °C
Yield: 41.8 %

Procedure:
To a solution of L-alanine ethyl ester (1.67 g, 14.3 mmol) in tetrahydrofuran (25 mL) was slowly added 1,3-propanesultone (1.42 g, 11.9 mmol). The solution was stirred at reflux for 2 hours. The reaction was cooled to room temperature. The solid was collected by filtration, washed with acetone (2×25 mL) and dried in vacuo, affording the title compound (1.19 g, 42%). 1H NMR (D2O, 500 MHz) δ ppm 4.16 (m, 2H), 4.01 (m, 1H), 3.12 (m, 2H), 2.87 (t, 2H, J=7.3 Hz), 2.01 (m, 2H), 1.43 (d, 3H, J=7.3 Hz), 1.14 (t, 3H, J=6.8 Hz). 13C (D2O, 125 MHz) δ ppm 170.22, 63.84, 55.69, 47.94, 44.73, 21.51, 14.05, 13.25. [α]D=−2.4° (c=0.0022 in water), ES-MS 240 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[O:18][C:17](=[O:19])[N:16]([CH3:20])[N:15]=3)[CH2:10][CH2:9]2)=[C:4]([F:21])[CH:3]=1.[N+:22]([C:25]1[O:29][C:28]([CH:30]=O)=[CH:27][CH:26]=1)([O-:24])=[O:23]>CC(O)=O.CO>[F:21][C:4]1[CH:3]=[C:2](/[N:1]=[CH:30]/[C:28]2[O:29][C:25]([N+:22]([O-:24])=[O:23])=[CH:26][CH:27]=2)[CH:7]=[CH:6][C:5]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:18][C:17](=[O:19])[N:16]([CH3:20])[N:15]=2)[CH2:10][CH2:9]1
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Reactant: Cn1nc(C2CCN(c3ccc(N)cc3F)CC2)oc1=O
Solvent: CC(=O)O
Solvent: CO
Product: Cn1nc(C2CCN(c3ccc(/N=C/c4ccc([N+](=O)[O-])o4)cc3F)CC2)oc1=O
Yield: 85 %

Procedure:
5-[1-(4-Amino-2-fluorophenyl)-4-piperidyl]-3-methyl-2,3-dihydro-1,3,4-oxadiazol-2-one (7f, 0.29 g, 1 mmol) on reacting with 5-nitro2-furaldehyde in the presence of catalytic amount of CH3COOH (3 drops) in methanol at 0° C. for 10 h and the obtained solid is filtered, washed with water and recrystallized in ethanol to obtain product 5-[1-(2-fluoro-4-[(E)-1-(5-nitro-2-furyl)methylidene]aminophenyl)-4-piperidyl]-3-methyl-2,3-dihydro-1,3,4-oxadiazol-2-one (9f, 352 mg, 85%).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14](=[O:15])[C:13]2[N:12]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[C:11]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]([F:35])([F:34])[F:33])[CH:26]=3)=[N:10][C:9]=2[N:8]([CH3:36])[C:7]1=[O:37].[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C1COCC1.O>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:12]2[C:13]3[C:14](=[O:15])[N:6]([CH2:5][CH2:4][CH2:3][NH:2][S:39]([CH3:38])(=[O:41])=[O:40])[C:7](=[O:37])[N:8]([CH3:36])[C:9]=3[N:10]=[C:11]2[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]([F:34])([F:33])[F:35])[CH:26]=2)=[CH:18][CH:19]=1
Reactant: Cn1c(=O)n(CCCN)c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(=O)n(CCCNS(C)(=O)=O)c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.3 %

Procedure:
1-(3-Aminopropyl)-7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (0.10 g, 0.19 mmol, example 357) and TEA (0.80 mL, 0.57 mmol) were combined in THF (1 mL). Methanesulfonyl chloride (0.30 mL, 0.38 mmol) was added and the reaction was stirred at room temperature for 3 h. The reaction was diluted with water (100 mL) and extracted with ethyl acetate (3×75 mL). The combined extracts were dried with magnesium sulfate, filtered and evaporated under reduced pressure to an oil. The oil was purified using a 2000 micron preparative TLC plate eluted with 5% methanol/DCM. Target band was scraped off plate and eluted off silica gel with eluent to give N-(3-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)propyl)methanesulfonamide (0.045 g, 39% yield) as a tan solid. LCMS retention time=4.048 minutes and 99% purity, LCMS MH+ 602. 1H NMR (DMSO-d6) δ 7.59 (t, 1H, J=8 Hz), 7.45-7.48 (m, 1H), 7.39-7.43 (m, 5H), 7.31 (d, 1H, J=8 Hz), 6.96 (t, 1H), 5.43 (s, 2H), 3.91 (t, 2H, J=8 Hz), 3.29 (s, 3H), 2.96 (dd, 2H, J=4 Hz and 12 Hz), 2.87 (s, 3H), 1.69-1.79 (m, 2H).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:3]=1.C([N:14](CC)CC)C.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]([NH2:14])=[O:11])[CH:3]=1
Reactant: O=C(O)Cc1cccnc1
Reactant: CCN(CC)CC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: NC(=O)Cc1cccnc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 156.4 %

Procedure:
A solution of 3-pyridylacetic acid hydrochloride (2.6 g), triethylamine (1.52 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (3.16 g) and N-hydroxybenzotriazole (2.52 g) in N,N-dimethylformamide (40 ml) was stirred at 0° C. for 15 minutes. (2E,4E)- and (2Z,4E)-4-Methyl-2,4-heptadien-1-ylamine (2.69 g) was added to the solution. The solution was stirred at 0° C. for 2 hours and then at room temperature overnight. The reaction mixture was evaporated in vacuo and the residue was diluted with ethyl acetate and washed with aqueous sodium hydrogen carbonate solution. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel (4% methanol-chloroform) to give N-[(2E,4E)- and (2Z,4E)-4-methyl-2,4-heptadien-1-yl]-3-pyridylacetamide (3.19 g) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:25](=[O:37])[NH:26][CH2:27][C:28]2[C:29](=[O:36])[NH:30][C:31]([CH3:35])=[CH:32][C:33]=2[CH3:34])[C:5]([CH3:24])=[C:6]([N:8]([CH3:23])[C@H:9]2[CH2:14][CH2:13][C@H:12]([NH:15]C(=O)OC(C)(C)C)[CH2:11][CH2:10]2)[CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:15][C@H:12]1[CH2:11][CH2:10][C@H:9]([N:8]([CH3:23])[C:6]2[C:5]([CH3:24])=[C:4]([CH:3]=[C:2]([Br:1])[CH:7]=2)[C:25]([NH:26][CH2:27][C:28]2[C:29](=[O:36])[NH:30][C:31]([CH3:35])=[CH:32][C:33]=2[CH3:34])=[O:37])[CH2:14][CH2:13]1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(C)[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)c2C)c(=O)[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(C)[C@H]3CC[C@H](N)CC3)c2C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A stirred solution of trans-tert-butyl (4-((5-bromo-3-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-2-methylphenyl)(methyl)amino)cyclohexyl)carbamate (0.7 g, 1.21 mmol) in DCM (8 mL) was cooled to 0° C. and TFA (2.5 mL) was added to it. Reaction mass was stirred at room temperature for 1 h. On completion, reaction was concentrated to dryness. Residue was basified with aqueous sodium bicarbonate till pH 8 and aqueous layer extracted with 20% MeOH/DCM. The combined organic layers were dried over sodium sulfate, filtered and concentrated to afford crude material which was then purified by solvent washings giving desired compound (0.5 g, 86%). LCMS: 475.20 (M+1)+; HPLC % 92.35 (@ 254 nm) (Rt; 4.416; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 8.21 (t, 1H), 7.18 (s, 1H), 7.01 (s, 1H), 5.85 (s, 1H), 4.23 (d, 2H), 2.63-2.66 (m, 2H), 2.55 (s, 3H), 2.17 (s, 3H), 2.10 (s, 6H), 1.79-1.82 (m, 2H), 1.60 (m, 2H), 1.46-1.49 (m, 2H), 1.06-1.09 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:4]=2[S:5][C:6]=1[C:7](Cl)=[O:8].[NH2:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=1.C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[C:3]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:4]=2[S:5][C:6]=1[C:7]([NH:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:25][CH:26]=1)=[O:8]
Reactant: COc1ccc2sc(C(=O)Cl)c(Cl)c2c1
Reactant: COC(=O)c1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NC(=O)c2sc3ccc(OC)cc3c2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.5 %

Procedure:
To a 0° C. solution of 3-chloro-5-methoxybenzo[b]thiophene-2-carbonyl chloride (500 mg, 1.9 mmol) in 20 mL of THF is added methyl p-aminobenzoate (318 mg, 2.1 mmol) followed by triethylamine (293 μL, 2.1 mmol). The reaction mixture is allowed to warm to room temperature and stirring is continued overnight. The mixture is partitioned between ethyl acetate and 1N HCl, then washed with 1N NaOH, saturated NaHCO3, and brine. The organic layer is dried over MgSO4. Filtration followed by concentration in vacuo and recrystallization from ethyl acetate:hexane provides 225 mg of methyl 4-[[[3-chloro-5-methoxybenzo[b]thien-2yl]carbonyl]amino]benzoate; mp=205°-206° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][NH:10][C:3]=12.[F:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[OH:21].C([O-])([O-])=O.[K+].[K+]>O(C1C=CC=CC=1)C1C=CC=CC=1>[F:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[O:21][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][NH:10][C:3]=12
Reactant: Clc1ccnc2cc[nH]c12
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=[N+]([O-])c1ccc(Oc2ccnc3cc[nH]c23)c(F)c1
Temperature: 170 °C
Yield: 26.1 %

Procedure:
A mixture of 266 (180 mg, 1.18 mmol), 2-fluoro-4-nitrophenol (558 mg, 3.55 mmol) and K2CO3 (981 mg, 7.10 mmol) in Ph2O (4 mL) was heated at 170° C. for 8 hours, cooled to room temperature and partitioned between EtOAc and water. Organic phase was collected, dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash column chromatography with gradient elution of hexane, to hexane/EtOAc (1:1), to afford the title compound 267 (84 mg, 26% yield) as a yellowish solid. MS (m/z): 274.1(M+H) (found).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH2:11])=[S:10].Br[C:13]1([C:17](OCC)=[O:18])[CH2:16][CH2:15][CH2:14]1>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[S:10][C:13]2([C:17](=[O:18])[N:11]=1)[CH2:16][CH2:15][CH2:14]2
Reactant: Cc1ccccc1NC(N)=S
Reactant: CCOC(=O)C1(Br)CCC1
Product: Cc1ccccc1NC1=NC(=O)C2(CCC2)S1

Procedure:
Synthesis was performed from N-(2-methylphenyl)thiourea and ethyl 1-bromocyclobutanecarboxylate according to Method D.
Reaction SMILES: [CH3:1][C:2]([N+:15]([O-:17])=[O:16])([CH3:14])[CH2:3][C:4]1[N:8]2[CH:9]=[CH:10][CH:11]=[C:12]([OH:13])[C:7]2=[N:6][CH:5]=1.Cl[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(=O)CC>[CH3:14][C:2]([N+:15]([O-:17])=[O:16])([CH3:1])[CH2:3][C:4]1[N:8]2[CH:9]=[CH:10][CH:11]=[C:12]([O:13][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:7]2=[N:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)CCl
Reactant: CC(C)(Cc1cnc2c(O)cccn12)[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)(C)OC(=O)COc1cccn2c(CC(C)(C)[N+](=O)[O-])cnc12
Yield: 80.8 %

Procedure:
3-(2-Methyl-2-nitropropyl)imidazo[1,2-a]pyridin-8-ol (1.0 g, 4.25 mmol), tert-butyl chloroacetate (964 mg, 6.4 mmol), potassium carbonate (590 mg, 4.27 mmol), and a small amount of potassium iodide in 2-butanone (30 ml) are reacted as described in Amine 9. The crude product residue is chromatographed on silica gel with dichloromethane/ethanol 9:1 to give 1.2 g of tert-butyl [3-(2-methyl-2-nitropropyl)imidazo[1,2-a]pyridin-8-yloxy]-acetate (81%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:4]=1[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Br:17][CH2:18][C:19](Br)=[O:20]>C(OCC)(=O)C>[CH3:1][N:2]([C:19](=[O:20])[CH2:18][Br:17])[C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:4]=1[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Br)CBr
Reactant: CNc1ccc(Cl)cc1Cc1ccccc1
Solvent: CCOC(C)=O
Product: CN(C(=O)CBr)c1ccc(Cl)cc1Cc1ccccc1
Reaction time: 1 h

Procedure:
The N-methyl 2-benzyl-4-chloroaniline (10.8 g) in solution in ethyl acetate is treated at 5° C. with 4.9 ml of bromoacetyl bromide. After 1 hour at room temperature, decantation and washing with water, the solution is concentrated. Upon crystallization, N-methyl 2'-benzyl-4'-chloro-bromoacetanilide is obtained (12.21 g). MP=78° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH2:10][CH:11]([C:13]([O:15][CH3:16])=[O:14])[N:12]=2)=[CH:4][CH:3]=1.BrN1C(=O)CCC1=O>C1C=CC=CC=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[N:12]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)C1COC(c2ccc(F)cc2)=N1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: c1ccccc1
Product: COC(=O)c1coc(-c2ccc(F)cc2)n1
Yield: 67.3 %

Procedure:
Benzoyl peroxide (0.49 g, 2.0 mmol) was added to a solution of methyl 2-(4-fluorophenyl)-4,5-dihydrooxazole-4-carboxylate (9.0 g, 40.3 mmol) in dry benzene (180 mL) and the mixture was refluxed for 15 min. N-bromosuccinimide (8.6 g, 48.3 mmol) was then added and the reaction mixture was refluxed for 2 h. The reaction mixture was quenched with ice-cold water and the crude product was extracted with EtOAc. The combined extracts were washed with 10% aqueous NaHCO3 solution, H2O and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica 60-120 mesh, eluant 10-15% EtOAc in petroleum ether) to get methyl 2-(4-fluorophenyl)oxazole-4-carboxylate (6 g, yield 67%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.29 (s, 1H), 8.14-8.10 (m, 2H), 7.19-7.15 (t, J=8.5 Hz, 2H), 3.96 (s, 3H). MS (ESI) m/z: Calculated for C11H8FNO3: 221.05. found: 221.8 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[O:9][C:10]([CH:13]3[CH2:15][CH2:14]3)=[N:11][N:12]=2)=[CH:6][N:5]=[C:4]([S:16][CH3:17])[N:3]=1.C([N:20](CC)CC)C.C(Cl)(Cl)Cl>C1COCC1>[NH2:20][C:2]1[C:7]([C:8]2[O:9][C:10]([CH:13]3[CH2:15][CH2:14]3)=[N:11][N:12]=2)=[CH:6][N:5]=[C:4]([S:16][CH3:17])[N:3]=1
Reactant: CSc1ncc(-c2nnc(C3CC3)o2)c(Cl)n1
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CSc1ncc(-c2nnc(C3CC3)o2)c(N)n1
Temperature: 60 °C
Reaction time: 12 h

Procedure:
4-Chloro-5-(5-cyclopropyl[1,3,4]oxadiazol-2-yl)-2-methylthiopyrimidine (13 mg, 0.050 mmol) [Compound (AC) in which Q is a chlorine atom, R2B is methylthio, and —X—Y—Z— is —O—C(c-C3H5)═N—] obtained in Reference Example 3 was dissolved in THF (0.50 mL), then triethylamine (0.007 mL) and a chloroform solution (1.0 mol/L, 0.10 mL) of R1—H [wherein R1 is the same as that defined above: Compound (B)] were added thereto, followed by stirring at 60° C. for 12 hours with hermetic sealing. After completion of the reaction was confirmed by thin-layer chromatography, the reaction mixture was concentrated and dried. The residue was dissolved in chloroform (0.60 mL), then benzoyl chloride polymer-bound [about 2.5 mmol/g, 23 mg, Canadian Journal of Chemistry, vol. 55, p. 3351 (1977)], and poly(4-vinylpyridine) (23 mg) were added thereto, followed by further stirring at room temperature for 12 hours. The resin was filtered off from the reaction mixture, and the filtrate was concentrated and dried to give 4-amino-5-(5-cyclopropyl[1,3,4]oxadiazol-2-yl)-2-methylthiopyrimidine [Compound (AD) in which —X—Y—Z— is —O—C(c-C3H5)═N—].
Reaction SMILES: F[B-](F)(F)F.[O:6]=[N+:7]=[O:8].N1C(C)=CC(C)=CC=1C.[OH:18][CH2:19][CH2:20][NH:21][C:22]([C@@H:24]1[CH2:28][S:27][C:26](=[O:29])[NH:25]1)=[O:23]>C(#N)C>[N+:7]([O:18][CH2:19][CH2:20][NH:21][C:22]([C@@H:24]1[CH2:28][S:27][C:26](=[O:29])[NH:25]1)=[O:23])([O-:8])=[O:6]
Reactant: O=C1N[C@H](C(=O)NCCO)CS1
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: Cc1cc(C)nc(C)c1
Product: O=C1N[C@H](C(=O)NCCO[N+](=O)[O-])CS1
Reaction time: 0.5 h
Yield: 13.9 %

Procedure:
0.44 g of nitronium tetrafluoroborate and a solution of 0.41 g of 2,4,6-collidine in 20 ml of acetonitrile were added at a temperature of from -10° C. to 0° C. to 30 ml of acetonitrile, and the resulting mixture was stirred at the same temperature for 30 minutes. At the end of this time, 0.50 g of (4R)-N-(2-hydroxyethyl)-2-oxothiazolidine-4-carboxamide was added to the mixture, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was then freed from the solvent by distillation under reduced pressure. The residue was mixed with ethyl acetate and insoluble materials were filtered off. The filtrate was concentrated by evaporation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using ethyl acetate as the eluent. The pale yellow crystals thus obtained were recrystallized from ethyl acetate, to give 86 mg of the title compound as colorless crystals. The melting point and nuclear magnetic resonance spectrum of the product were identical with those of the compound produced as described in Example 1.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([CH2:10][O:11][C:12]2[CH:13]=[C:14]([CH:44]=[CH:45][CH:46]=2)[C:15]([NH:17][C:18]2[CH:30]=[C:29]([CH2:31][CH2:32][CH2:33][S:34]([C:37]3[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=3)(=[O:36])=[O:35])[CH:28]=[CH:27][C:19]=2[O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:16])[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:49]N(C)C=O.CI>O>[C:1]([C:5]1[N:6]=[C:7]([CH2:10][O:11][C:12]2[CH:13]=[C:14]([CH:44]=[CH:45][CH:46]=2)[C:15]([N:17]([C:18]2[CH:30]=[C:29]([CH2:31][CH2:32][CH2:33][S:34]([C:37]3[CH:38]=[CH:39][C:40]([Cl:43])=[CH:41][CH:42]=3)(=[O:36])=[O:35])[CH:28]=[CH:27][C:19]=2[O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH3:49])=[O:16])[S:8][CH:9]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)COc1ccc(CCCS(=O)(=O)c2ccc(Cl)cc2)cc1NC(=O)c1cccc(OCc2nc(C(C)(C)C)cs2)c1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CCOC(=O)COc1ccc(CCCS(=O)(=O)c2ccc(Cl)cc2)cc1N(C)C(=O)c1cccc(OCc2nc(C(C)(C)C)cs2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
Under ice-cooling, ethyl 2-[3-[(4-tert-butyl-2-thiazolyl)methoxy]benzoylamino]-4-[3-(4-chlorophenylsulfonyl)propyl]phenoxyacetate (266 mg, 0.39 mmol) was added to a mixture of 60% sodium hydride (19 mg, 0.48 mmol) and dimethylformamide (2 ml), and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was again cooled with ice, methyl iodide (29 μl, 0.47 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution and the product formed was extracted with toluene. The extract was washed with water and brine in that order, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. Thereafter, the resulting residue was purified by silica gel column chromatography (eluent=chloroform:methanol=50:1) to give ethyl 2-[N-[3-[(4-tert-butyl-2-thiazolyl)methoxy]benzoyl]-N-methylamino]-4-[3-(4-chlorophenylsulfonyl)propyl]phenoxyacetate (213 mg, 0.31 mmol, 78%).