Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[C:8]([OH:18])=[CH:7][N:6]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3)([O:3]C)=[O:2].[OH-].[Na+]>CO>[C:1]([C:5]1[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[C:8]([OH:18])=[CH:7][N:6]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3)([OH:3])=[O:2]
Reactant: COC(=O)c1ncc(O)c2c1[nH]c1ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ncc(O)c2c1[nH]c1ccccc12
Yield: 66.9 %

Procedure:
In 30 ml of methanol was dissolved 1.0 g of the product of Example 2 followed by addition of 2 ml of 10% aqueous sodium hydroxide. The mixture was refluxed at water bath temperature for 6 hours and the methanol then removed by distillation. The residue was neutralized with a 10% aqueous hydrochloric acid and the resultant crystals were recovered by filtration and recrystallized from methanoltetrahydrofuran to yield 630 mg of the title compound as colorless needles, m.p. 158°-159° C. (decomp.). Mol. wt. (based on mass spectrum) 228. Elemental analysis found: C, 63.32%; H, 3.28%; N, 12.05%; calculated for C12H8N2O3 : C, 63.16%; H, 3.53%; N, 12.28%. The IR absorption spectrum shows the absorption at 1680 cm-1 in starting compound has disappeared with absorption observed at 1610 cm-1 (carbonyl).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]([NH:15][CH2:16][C:17]([OH:19])=[O:18])=[O:14])[N:3]=1.[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([SH:27])=[CH:23][CH:22]=1>>[OH:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([S:27][C:24]2[CH:25]=[CH:26][C:21]([CH3:20])=[CH:22][CH:23]=2)=[N:3][C:4]=1[C:13]([NH:15][CH2:16][C:17]([OH:19])=[O:18])=[O:14]
Reactant: Cc1ccc(S)cc1
Reactant: O=C(O)CNC(=O)c1nc(Cl)c2ccccc2c1O
Product: Cc1ccc(Sc2nc(C(=O)NCC(=O)O)c(O)c3ccccc23)cc1

Procedure:
The title compound was prepared from [(1-chloro-4-hydroxy-isoquinoline-3-carbonyl)-amino]-acetic acid (U.S. Pat. No. 6,093,730) and 4-methylbenzenethiol under conditions analogous to Example D-110; MS (−) m/z 367.09 (M−1)
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].C1COCC1.[C:14]([C:16]1[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=1)#[CH:15]>CCN(CC)CC>[C:14]([C:16]1[CH:17]=[C:18]([NH:22][C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[O:7])[CH:19]=[CH:20][CH:21]=1)#[CH:15]
Reactant: O=C(Cl)c1cccs1
Reactant: C#Cc1cccc(N)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C#Cc1cccc(NC(=O)c2cccs2)c1
Temperature: 55 °C
Yield: 85 %

Procedure:
A dry 25 mL flask was charged with thiophene-2-carbonyl chloride and THF (5 mL) was added. 3-Ethynyl-phenylamine (0.905 g, 3.59 mmol) was added to the THF solution of the acid chloride followed by NEt3, and the mixture was allowed to stir at 55° C. The reaction mixture was then allowed to cool to room temperature and extracted with EtOAc (˜10 mL), 1M HCl (˜10 mL), followed by brine (˜10 mL). The combined organic extracts were combined and dried over anhydrous Na2SO4(s) and the concentrated. The crude residue was purified by chromatography (silica gel, gradient elution EtOAc/Hexanes 0 to 50%). The product containing fractions were concentrated to give the title compound as a tan solid (0.33 mg, 1.45 mmol, 85%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:15][CH3:16])[C:12]=1[O:13][CH3:14])[C:6]([O:8][CH3:9])=[O:7].[N+:17]([O-])([OH:19])=[O:18]>C(OC(=O)C)(=O)C>[N+:17]([C:10]1[C:11]([O:15][CH3:16])=[C:12]([O:13][CH3:14])[C:3]([O:2][CH3:1])=[CH:4][C:5]=1[C:6]([O:8][CH3:9])=[O:7])([O-:19])=[O:18]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1cc(OC)c(OC)c(OC)c1
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1cc(OC)c(OC)c(OC)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Methyl 3,4,5-trimethoxybenzoate (13.0 g) was dissolved in acetic anhydride (60 mL), a 1:20 mixed liquid (9 mL) of fuming nitric acid and concentrated nitric acid was slowly added dropwise at −10° C. to the solution, and the resultant mixture was stirred for 3 hours under ice cooling. Acetic anhydride was distilled off, water and an aqueous solution of potassium carbonate were added to the residue, and the mixture was stirred at room temperature for 40 minutes and then extracted with ethyl acetate. The resultant organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:2) to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[C:4]([CH3:15])[C:3]=1[C:16](=[O:18])[CH3:17].[Br-:19].[Br-:20].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C>[Br:19][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6]2[CH:5]=[C:4]([CH3:15])[C:3]([C:16](=[O:18])[CH2:17][Br:20])=[C:2]([CH3:1])[CH:7]=2)=[CH:10][CH:11]=1
Reactant: CC(=O)c1c(C)cc(Nc2ccccc2)cc1C
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Product: Cc1cc(Nc2ccc(Br)cc2)cc(C)c1C(=O)CBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.6 %

Procedure:
To a solution of 1-(2,6-dimethyl-4-(phenylamino)phenyl)ethanone (2.10 g, 8.78 mmol) in acetonitrile (50 mL) was added tetrabutylammoniumtribromide (TBABr3, 4.24 g, 8.78 mmol). The reaction was stirred at room temperature for 60 min. The solution was concentrated under reduced pressure, added with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure to give 1-(4-(4-bromophenylamino)-2,6-dimethylphenyl)-2-bromoethanone (2.01 g), which was used directly for the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:10])[CH2:5][C:6]=1[C:7]([NH2:9])=O.P(Cl)(Cl)(Cl)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][C:2]1[NH:3][C:4](=[O:10])[CH2:5][C:6]=1[C:7]#[N:9]
Reactant: CC1=C(C(N)=O)CC(=O)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC(C)=O
Product: CC1=C(C#N)CC(=O)N1

Procedure:
A mixture of 0.9 g (4.6 mmol) of 2-methyl-5-oxo-4,5-dihydropyrrole-3-carboxamide, 1.4 g (9.2 mmol) of phosphorus oxychloride and 0.9 g (6.4 mmol) of potassium carbonate in 50 ml of acetone was refluxed for 6 h. The mixture was then concentrated and the resulting residue was chromatographed over silica gel (mobile phase: cyclohexane:ethyl acetate 10:1 to 1:1). This gave 0.15 g (19% of theory) of the desired product (IR: 2220 cm−1).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH3:8])=[C:6]([CH:9]([NH2:11])C)[CH:5]=[N:4]1)[CH3:2].[F:12][C:13]([F:31])([F:30])[C:14]([C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:27](O)=[O:28])[CH:23]=2)[N:18]=1)([CH3:16])[CH3:15].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[CH2:1]([N:3]1[C:7]([CH3:8])=[C:6]([CH2:9][NH:11][C:27]([C:22]2[CH:23]=[C:24]3[C:19](=[CH:20][CH:21]=2)[N:18]=[C:17]([C:14]([CH3:16])([CH3:15])[C:13]([F:31])([F:30])[F:12])[CH:26]=[CH:25]3)=[O:28])[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncc(C(C)N)c1C
Reactant: CC(C)(c1ccc2cc(C(=O)O)ccc2n1)C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCn1ncc(CNC(=O)c2ccc3nc(C(C)(C)C(F)(F)F)ccc3c2)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 12.4 %

Procedure:
To a DMF (3 ml) solution of 1-(1-ethyl-5-methyl-1H-pyrazol-4-yl)ethanamine (95 mg, 0.62 mmol), (2,2,2-trifluoro-1,1-dimethylethyl)quinoline-6-carboxylic acid (176 mg, 0.62 mmol), HBTU (284 mg, 0.748 mmol) and triethylamine (0.434 ml, 3.12 mmol) were added and the mixture was stirred for 3 hours at room temperature. The reaction was quenched with sat. NaHCO3 aq and water, and the product was extracted with EtOAc/hexane (4:1) (3×20 ml). The combined organic extracts were dried over Na2SO4, and concentrated in vacuo. The crude material was purified by silica gel chromatography, using EtOAc/hexane (2:1) to give the title product (31 mg, 12%) as a white solid. 1H NMR (300 MHz, DMSO-d6) 1.27 (3H, t) 1.49 (3H, d), 1.71 (6H, s), 2.25 (3H, s), 4.01 (1H, q), 5.19 (1H, m), 7.44 (1H, s), 7.86 (1H, d), 8.06 (1H, d), 8.20 (1H, d), 8.51 (1H, d), 8.53 (1H, bs) 8.86 (1H, d). LCMS (ESI) RT=3.11 mins, m/z 417 (M−H)−, 419 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.Br[C:15]1[C:16]([NH2:33])=[N:17][CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH:30]([CH3:32])[CH3:31])(=[O:29])=[O:28])=[CH:23][CH:22]=2)[N:20]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[NH2:33][C:16]1[C:15]([N:1]2[CH2:5][CH2:4][CH:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:2]2)=[N:20][C:19]([C:21]2[CH:22]=[CH:23][C:24]([S:27]([CH:30]([CH3:32])[CH3:31])(=[O:29])=[O:28])=[CH:25][CH:26]=2)=[CH:18][N:17]=1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(Br)n2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(N3CCC(NC(=O)OC(C)(C)C)C3)n2)cc1
Temperature: 100 °C
Yield: 47.3 %

Procedure:
tert-Butyl N-pyrrolidin-3-ylcarbamate (43.14 mg, 0.2316 mmol) was added to a stirred solution of 3-bromo-5-(4-(isopropylsulfonyl)phenyl)pyrazin-2-amine (75 mg, 0.2105 mmol) and DIPEA (29.93 mg, 40.34 μL, 0.2316 mmol) in NMP (1 mL) and the reaction mixture heated to 100° C. under microwave conditions for 90 minutes. The reaction mixture was partitioned between EtOAc/water and the layers separated. The aqueous layer was extracted with EtOAc (×3) and the combined organic extracts washed with brine (×2), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion™, 12 g column, eluting with 0 to 100% EtOAc/Petroleum Ether). The fractions were collected concentrated in vacuo and freeze-dried to give the title compound as a yellow solid (46 mg, 48% Yield). 1H NMR (400.0 MHz, DMSO) δ 1.17 (d, 6H), 1.40 (s, 9H), 1.79-1.82 (m, 1H), 2.08-2.17 (m, 1H), 3.30-3.38 (m, 1H), 3.42-3.44 (m, 2H), 3.60-3.71 (m, 2H), 4.06-4.12 (m, 1H), 6.22 (s, 2H), 7.16 (d, 1H), 7.83 (d, 2H), 8.18 (d, 2H) and 8.20 (s, 1H) ppm; (ES+) 462.3.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:14]=[CH:13][C:7]2[N:8]=[C:9]([O:11]C)[S:10][C:6]=2[CH:5]=1.[BrH:15]>>[BrH:15].[NH2:1][CH2:2][CH2:3][C:4]1[CH:14]=[CH:13][C:7]2[NH:8][C:9](=[O:11])[S:10][C:6]=2[CH:5]=1
Reactant: COc1nc2ccc(CCN)cc2s1
Agent: Br
Product: NCCc1ccc2[nH]c(=O)sc2c1

Procedure:
The resultant 6-(2-aminoethyl)-2-methoxy-1,3-benzothiazole (1.3 g) was dissolved in 48% HBr (9 ml) and the reaction mixture was stirred under reflux for 1 hour.
Reaction SMILES: C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C.I[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[C:37]1([CH3:64])[CH:42]=[CH:41][C:40]([S:43]([N:46]2[CH2:51][CH2:50][N:49]([S:52]([C:55]3[CH:60]=[CH:59][C:58]([CH3:61])=[CH:57][CH:56]=3)(=[O:54])=[O:53])[CH2:48][CH:47]2[CH:62]=[CH2:63])(=[O:45])=[O:44])=[CH:39][CH:38]=1>C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[CH:62]([CH:47]1[CH2:48][N:49]([S:52]([C:55]2[CH:56]=[CH:57][C:58]([CH3:61])=[CH:59][CH:60]=2)(=[O:53])=[O:54])[CH2:50][CH2:51][N:46]1[S:43]([C:40]1[CH:39]=[CH:38][C:37]([CH3:64])=[CH:42][CH:41]=1)(=[O:44])=[O:45])=[CH:63][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[C:37]1([CH3:64])[CH:42]=[CH:41][C:40]([S:43]([N:46]2[CH2:51][CH2:50][N:49]([S:52]([C:55]3[CH:60]=[CH:59][C:58]([CH3:61])=[CH:57][CH:56]=3)(=[O:54])=[O:53])[CH2:48][CH:47]2[CH:62]=[CH2:63])(=[O:44])=[O:45])=[CH:39][CH:38]=1
Reactant: Ic1ccccc1
Agent: [Pd+2]
Agent: C=CC1CN(S(=O)(=O)c2ccc(C)cc2)CCN1S(=O)(=O)c1ccc(C)cc1
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)N2CCN(S(=O)(=O)c3ccc(C)cc3)C(C=Cc3ccccc3)C2)cc1
Temperature: 110 °C
Reaction time: 0.75 h

Procedure:
Combine tri-o-tolylphosphine (72 mg, 0.24 mmol), palladium acetate (12 mg, 0.05 mmol), triethylamine (0.22 mL, 1.6 mmol), iodobenzene (0.20 mL, 1.83 mmol), 1,4-bis-(toluene-4-sulfonyl)-2-vinyl-piperazine (320 mg, 0.76 mmol) and acetonitrile (8 mL) in a sealable vessel and purge with nitrogen. Seal the vessel and heat at 110° C. After 21 hours 45 minutes, cool to ambient temperature and dilute with ethyl acetate. Filter and discard the solids. Concentrate the filtrate and purify by silica gel chromatography using ethyl acetate-hexanes (0–30%) as the eluent to give a 8:1 ratio of the title compound to 1,4-bis-(toluene-4-sulfonyl)-2-vinyl-piperazine: mass spectrum (ion spray): m/z=497 (M+1); 1H NMR(DMSO-d6): δ7.59 (d, 2H), 7.53 (d, 2H), 7.42 (d, 2H), 7.19–7.36 (m, 7H), 6.48 (d, 1H), 6.08 (dd, 1H), 4.62 (m, 1H), 3.70 (br d, 1H), 3.52 (m, 2H), 3.29 (dd, 1H), 2.41 (s, 3H), 2.29–2.32 (m, 1H), 2.26 (s, 3H), 2.12 (dd, 1H).
Reaction SMILES: [CH3:1][CH2:2][CH:3]([CH:5]1[NH:27][C:25](=[O:26])[CH2:24][NH:23][C:21](=[O:22])[CH:20]2[NH:28][C:29]([CH:31]([CH:51]([CH:53]([OH:56])[CH2:54][OH:55])[CH3:52])[NH:32][C:33]([CH:35]3[N:39]([C:40]([CH:42]([CH2:46][C:47]([OH:49])=[O:48])[NH:43][C:44](=[O:45])[CH:13]([CH2:14][S:15]([C:17]4[NH:59][C:58]5[CH:60]=[C:61]([OH:64])[CH:62]=[CH:63][C:57]=5[C:18]=4[CH2:19]2)=[O:16])[NH:12][C:10](=[O:11])[CH2:9][NH:8][C:6]1=[O:7])=[O:41])[CH2:38][CH:37]([OH:50])[CH2:36]3)=[O:34])=[O:30])[CH3:4].C(N(CC)CC)C.ClC(C([O-])=O)C(C)C.Cl.[C:81]([O:85][C:86]([NH:88][CH2:89][CH2:90][CH2:91][CH2:92][CH2:93][CH2:94][NH2:95])=[O:87])([CH3:84])([CH3:83])[CH3:82]>CN(C)C=O>[CH3:1][CH2:2][CH:3]([CH:5]1[NH:27][C:25](=[O:26])[CH2:24][NH:23][C:21](=[O:22])[CH:20]2[NH:28][C:29]([CH:31]([CH:51]([CH:53]([OH:56])[CH2:54][OH:55])[CH3:52])[NH:32][C:33]([CH:35]3[N:39]([C:40]([CH:42]([CH2:46][C:47]([OH:49])=[O:48])[NH:43][C:44](=[O:45])[CH:13]([CH2:14][S:15]([C:17]4[NH:59][C:58]5[CH:60]=[C:61]([OH:64])[CH:62]=[CH:63][C:57]=5[C:18]=4[CH2:19]2)=[O:16])[NH:12][C:10](=[O:11])[CH2:9][NH:8][C:6]1=[O:7])=[O:41])[CH2:38][CH:37]([OH:50])[CH2:36]3)=[O:34])=[O:30])[CH3:4].[C:81]([O:85][C:86]([N-:88][CH2:89][CH2:90][CH2:91][CH2:92][CH2:93][CH2:94][NH-:95])=[O:87])([CH3:84])([CH3:83])[CH3:82]
Reactant: CC(C)(C)OC(=O)NCCCCCCN
Agent: CC(C)C(Cl)C(=O)[O-]
Agent: CCC(C)C1NC(=O)CNC(=O)C2Cc3c([nH]c4cc(O)ccc34)S(=O)CC(NC(=O)CNC1=O)C(=O)NC(CC(=O)O)C(=O)N1CC(O)CC1C(=O)NC(C(C)C(O)CO)C(=O)N2
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)[N-]CCCCCC[NH-]
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
20 mg of dried β-amanitin (22 μmol) was dissolved in 0.3 ml of dried dimethylform-amide (DMF), and 0.005 ml of triethylamine was added. Under magnetic stirring, the reaction mixture was cooled to −18° C. (ice/NaCl) and after 10 min 0.164 ml of a mixture of 0.1 ml of chloroisobutylformate and 1.0 ml of DMF (110 μmol, 5 eq.) was added. The reaction was allowed to proceed for 20 min at −18° C. Fifty-five mg (220 μmol, 10 eq.) of t-butyloxy-carbonyl-hexamethylenediamine hydrochloride and 0.005 ml of triethylamine were dissolved in 0.3 ml of DMF, added to the reaction and stirred for 1 h at RT.
Reaction SMILES: C(O[C:4]([NH:6][NH:7][C:8]([NH:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[O:9])=[O:5])C.Cl>[OH-].[K+]>[O:9]=[C:8]1[N:10]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[C:4](=[O:5])[NH:6][NH:7]1
Reactant: CCOC(=O)NNC(=O)NCC(=O)OC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: COC(=O)Cn1c(=O)[nH][nH]c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.7 %

Procedure:
27.47 g (0.125 mol) of 1-ethoxycarbonyl-4-methoxycarbonylmethyl-semicarbazide were dissolved in 95 ml (0.38 mol) of 4-M potassium hydroxide solution and heated on a steam-bath for 1.5 hours. The resulting solution was cooled to room temperature, acidified to pH 1 with concentrated hydrochloric acid and evaporated in vacuo to give a colourless solid. This solid was extracted with three 90 ml portions of boiling methanol. The extracts were filtered, combined and added to 400 ml of methanolic hydrogen chloride. The mixture was left to stand at room temperature overnight and then evaporated in vacuo to give a colourless solid. This solid was recrystallized from methanol to give 7.50 g (35%) of methyl 3,5-dioxo-1,2,4-triazolidine-4-acetate of melting point 215°-218° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([CH2:14][C:15]([O:17]C)=O)[CH:11]=[CH:10][N:9]=2)[CH2:4][CH2:3]1.[NH3:19]>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([CH2:14][C:15]([NH2:19])=[O:17])[CH:11]=[CH:10][N:9]=2)[CH2:4][CH2:3]1
Reactant: COC(=O)Cc1ccnc(N2CCN(C)CC2)c1
Reactant: N
Product: CN1CCN(c2cc(CC(N)=O)ccn2)CC1
Temperature: 25 °C
Yield: 31 %

Procedure:
A solution of methyl 2-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)acetate (750 mg, 2.81 mmol) in methanolic ammonia (10 ml) was heated in a steel bomb at 90° C. for 72 h. The reaction mixture was cooled to room temperature, concentrated and dried in vacuum to afford the crude product. Purification by triturating with diethyl ether afforded 370 mg (31%) of 2-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)acetamide as a light brown color solid.
Reaction SMILES: FC1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:12][CH:11]=[N:10][C@H:9]2C([O-])=O)=[CH:4]C=1.[K+].Cl.C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CC1CCNCC1>C(Cl)(Cl)Cl>[CH3:4][CH:5]1[CH2:8][CH2:9][N:10]([CH:11]=[O:12])[CH2:7][CH2:6]1
Reactant: O=C([O-])[C@@H]1N=CO[C@H]1c1ccc(F)cc1
Agent: CC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC1CCN(C=O)CC1
Temperature: 4 °C
Reaction time: 0.17 h

Procedure:
To a solution of potassium (±)-threo-5-(4-fluorophenyl)-4,5-dihydrooxazole-4-carboxylate, ANP 20162 (500 mg, 2.02 mmol), and triethylamine hydrochloride (278.3 mg, 2.02 mmol) in 50 mL of anhydrous CHCl3 at 4° C., was added HOBT (300.5 mg, 2.22 mmol) and EDCI (426.3 mg, 2.22 mmol). The reaction mixture was stirred at 4° C. for 10 min under nitrogen and 4-methylpiperidine (477.5 μL, 4.04 mmol) was added dropwise. The reaction mixture was stirred at 4° C. to RT for 15 h under nitrogen. The solvent was evaporated and the obtained residue was partitioned between EtOAc (150 mL) and 1N NaOH (50 mL). The organic layer was washed with brine (20 mL), dried over MgSO4, filtered and evaporated to give (±)-trans-5-(4-fluorophenyl)-4,5-dihydrooxazol-4-yl)(4-methylpiperidin-1-yl)methanone, LPO 26074 as a red oil (590 mg, 100% crude yield).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:12][CH2:13][C@@H:14]2[CH2:18][S:17][C:16]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[CH:25][C:24]([Cl:28])=[CH:23][C:22]=4[NH:29][CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[N:15]2)[CH:8]=[N:9][C:10]=1[CH3:11])=[O:5])C.CO.O.[OH-].[Li+].Cl>O1CCCC1.O>[Cl:28][C:24]1[CH:25]=[C:26]2[C:21](=[C:22]([NH:29][CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[CH:23]=1)[NH:20][C:19]([C:16]1[S:17][CH2:18][C@@H:14]([CH2:13][CH2:12][N:7]3[C:6]([C:4]([OH:5])=[O:3])=[C:10]([CH3:11])[N:9]=[CH:8]3)[N:15]=1)=[CH:27]2
Reactant: CCOC(=O)c1c(C)ncn1CC[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)=N1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ncn(CC[C@@H]2CSC(c3cc4cc(Cl)cc(NC5CCCC5)c4[nH]3)=N2)c1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.5 %

Procedure:
The compound (35 mg, 0.07 mmol) prepared in Example 109 was dissolved in tetrahydrofuran (10 ml), methanol (10 ml) and water (10 ml). Lithium hydroxide monohydrate (29 mg, 0.70 mmol) was added thereto, and the mixture was stirred for 8 h at room temperature. After completion of the reaction, 1N hydrochloric acid solution was added. The mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and purified by column chromatography to give the title compound (17 mg, Yield 52%).
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5](=[O:8])[O:6][CH:7]=1.[N+:9]([C:12]1[CH:17]=[CH:16][C:15]([SH:18])=[CH:14][CH:13]=1)([O-:11])=[O:10].C(N(CC)CC)C>ClCCl>[N+:9]([C:12]1[CH:17]=[CH:16][C:15]([S:18][CH2:2][C:3]2[O:4][C:5](=[O:8])[O:6][CH:7]=2)=[CH:14][CH:13]=1)([O-:11])=[O:10]
Reactant: O=c1occ(CBr)o1
Reactant: O=[N+]([O-])c1ccc(S)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1occ(CSc2ccc([N+](=O)[O-])cc2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.3 %

Procedure:
In 30 ml of dichloromethane was dissolved 1.0 g of 4-bromomethyl-1,3-dioxol-2-one, and 0.9 g of 4-nitrobenzenethiol was added. Then, 0.6 g of triethylamine was added, and the mixture was stirred at room temperature for 1 hour. After the reaction, the solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate. The insoluble materials were separated by filtration, and the solvent was evaporated under reduced pressure. The residue was subjected to medium-pressure silica gel column chromatography as in Example 1 [except that the column was eluted with a mixture of chloroform and n-hexane (2/1, v/v)]. The eluate was evaporated under reduced pressure, and the residue was recrystallized from a mixed solvent of chloroform and n-hexane to give 0.5 g of the captioned compound as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27]CC)=[O:26].Cl>C(O)(=O)C>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26]
Reactant: CCOC(=O)CCCCCOc1cc2c(c(Cl)c1Cl)C(=O)C(C)(C1CCCC1)C2
Agent: Cl
Solvent: CC(=O)O
Product: CC1(C2CCCC2)Cc2cc(OCCCCCC(=O)O)c(Cl)c(Cl)c2C1=O
Temperature: 0 °C

Procedure:
A mixture of ethyl 6-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]hexanoate (16 g., 0.036 mole), acetic acid (100 ml.) and 6N hydrochloric acid (50 ml.) is stirred and refluxed for 6 hours. The mixture is poured into ice water (500 g.), extracted with ether, dried over Na2SO4, filtered and concentrated to a volume of 100 ml., and chilled. A total of 11.5 of 6-[6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]hexanoic acid separates, m.p. 127°-129° C.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1([Li])C=CC=CC=1.[Cl:31][C:32]1[CH:37]=[CH:36][N:35]=[C:34]([C:38]([CH:40]2[CH2:42][CH2:41]2)=O)[C:33]=1[CH3:43]>CCOCC>[Cl:31][C:32]1[CH:37]=[CH:36][N:35]=[C:34]([C:38]([CH:40]2[CH2:42][CH2:41]2)=[CH:2][O:3][CH3:4])[C:33]=1[CH3:43]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1c(Cl)ccnc1C(=O)C1CC1
Agent: [Cl-]
Agent: [Li]c1ccccc1
Solvent: CCOCC
Product: COC=C(c1nccc(Cl)c1C)C1CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 48.2 %

Procedure:
5.54 g of (methoxymethyl) triphenyl phosphonium chloride is suspended in 53 ml of anhydrous ether and 18.4 ml of phenyllithium (0.88 M) was dropped thereto and the resulting mixture was stirred at a room temperature for 15 minutes. 35 ml of ether solution of 3.01 g of (4-chloro-3-methyl-2-pyridyl)cyclopropylketone (X) was dropped thereto and the resulting mixture was stirred at a room temperature for 2 hours. The resulting residue was separated by filtering and washed with ether, and thereafter, the ether filtrate and ether used for washing were collected together and the collected solution was washed with water, and thereafter, dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=4:1) to obtain 1.66 g of 2-(4-chloro-3-methyl-2-pyridyl)-2-cyclopropyl-1-methoxyethene.