Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[O:9][CH:8]=[N:7][C:6]=1[CH:10]=[C:11](O)[C:12]([NH:14][C@H:15]([C:23](=[O:25])[NH2:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:13])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:1]([C:5]1[O:9][CH:8]=[N:7][C:6]=1/[CH:10]=[C:11]1/[C:12](=[O:13])[NH:14][C@@H:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:23](=[O:25])[NH:24]/1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ocnc1C=C(O)C(=O)N[C@@H](Cc1ccccc1)C(N)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ocnc1/C=C1\NC(=O)[C@H](Cc2ccccc2)NC1=O

Procedure:
Using a Deanstark trap, a solution of compound 4 (50 mg, 0.14 mmol) in toluene was refluxed in the presence of p-toluenesulfonic acid (0.8 mg, 3 mol %) for 18 h. After solvent was removed in vacuo, the residue was purified by preparative HPLC (μBondasphere 5C18 100 A, 19×150 mm) and eluted using a linear gradient from 40 to 60% CH3CN in 0.1% TFA aq over 40 min at a flow rate of 5 mL/min, and the desired fraction was collected and lyophilized to obtain KPU-245; yield 11 mg (23%); m.p. 52-56° C., 1H HMR (300 MHz, DMSO-d6)δ 10.65 (s, 1H), 8.60 (s, 1H), 8.47 (s, 1H), 7.24-7.13 (m, 5H), 6.37 (s, 1H), 4.52 (br s, 1H), 3.20 (dd, J=3.7, 13.6 Hz, 1H), 2.95 (dd, J=5.0, 13.6 Hz, 1H), 1.31 (s, 9H), HRMS (EI): m/z 339.1584 (M+) (calcd for C19H21N3O3: 339.1583).
Reaction SMILES: O.[O:2]=[C:3]1[CH:8]=[C:7]([CH2:9][OH:10])O[CH:5]=[C:4]1[O:11][CH2:12][C:13]([O:15]CC)=[O:14].[NH3:18]>>[O:2]=[C:3]1[CH:8]=[C:7]([CH2:9][OH:10])[NH:18][CH:5]=[C:4]1[O:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: CCOC(=O)COc1coc(CO)cc1=O
Reactant: N
Solvent: O
Product: O=C(O)COc1c[nH]c(CO)cc1=O
Temperature: 120 °C

Procedure:
A mixture of ethyl 2-(4-oxo-6-hydroxymethyl-4H-pyran-3-yloxy)acetate monohydrate (10 g) in conc. ammonia was heated at 120° C. for 10 hours in a sealed vessel and the reaction mixture was concentrated. To the residue was added water and the resultant solution was adjusted to pH 1 to 2 with 10% hydrochloric acid. The resultant precipitates were washed with water and dried to give crystals (6 g) of 2-(4-oxo-6-hydroxymethyl-1,4-dihydropyridin-3-yloxy)acetic acid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH:5]([C:16]1[CH:24]=[CH:23][C:19]2[O:20][CH2:21][O:22][C:18]=2[CH:17]=1)[C:6]([N:8]([CH3:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:7].C1C=C[NH+]=CC=1.C1C=C[NH+]=CC=1.[O-][Cr](O[Cr]([O-])(=O)=O)(=O)=O>C(Cl)Cl>[O:1]=[CH:2][CH2:3][CH2:4][CH:5]([C:16]1[CH:24]=[CH:23][C:19]2[O:20][CH2:21][O:22][C:18]=2[CH:17]=1)[C:6]([N:8]([CH3:15])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:7]
Reactant: CN(C(=O)C(CCCO)c1ccc2c(c1)OCO2)c1ccccc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CN(C(=O)C(CCC=O)c1ccc2c(c1)OCO2)c1ccccc1
Reaction time: 2 h
Yield: 75.3 %

Procedure:
A solution of β-(2-hydroxyethyl)-N-methyl-N-phenyl-1,3-benzodioxol-5-yl-propanamide (500 mg) in CH2Cl2 (10 mL) was treated with PDC (570 mg) and molecular sieves (4A, 570 mg) and stirred at room temperture for 2 hours. The reaction mixture was filtered through a pad of silica gel rinsed with EtOAc (100 mL) and concentrated under reduced pressure to yield an oil. Silica gel chromatography eluting with 50-75% EtOAc/Hexanes gave the desired title compound (374 mg).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:36][C:37]1[CH:38]=[C:39]([CH:64]=[CH:65][CH:66]=1)[CH2:40][CH:41]1[CH2:45][C:44](=[O:46])[O:43][CH:42]1[C:47]1[O:48][C:49]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)=[C:50]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[N:51]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>O1CCCC1>[C:52]1([C:50]2[N:51]=[C:47]([CH:42]3[CH:41]([CH2:40][C:39]4[CH:64]=[CH:65][CH:66]=[C:37]([OH:36])[CH:38]=4)[CH2:45][C:44](=[O:46])[O:43]3)[O:48][C:49]=2[C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1
Reactant: CC(C)(C)[Si](Oc1cccc(CC2CC(=O)OC2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C1CC(Cc2cccc(O)c2)C(c2nc(-c3ccccc3)c(-c3ccccc3)o2)O1
Reaction time: 5 h
Yield: 80.8 %

Procedure:
A 1.0 M solution of tetrabutylammonium fluoride in tetrahydrofuran (THF) (0.75 ml) was added to a solution of 3-[3-(tert-butyldiphenylsilyloxy)benzyl]-2-(4,5-diphenyl-2-oxazolyl)-5-oxotetrahydrofuran (0.26 g) in THF (0.75 ml) at room temperature. The resulting mixture was stirred at the same temperature for 5 hours and partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried over MgSO4, and evaporated in vacuo. The residue was chromatographed over silica gel to afford 2-(4,5-diphenyl-2-oxazolyl)-3-(3-hydroxybenzyl)-5-oxotetrahydrofuran (133 mg) as a colorless oil. (+) APCI-MS (m/z): 412 (M+ +1) IR (Nujol): 3340, 1770, 1590 cm-1NMR (CDCl3, δ): 2.30-3.26 (4H, m), 3.35-3.47 (1H, m), 5.22 and 5.31 (1H, each d, J=18.2 and 6.1 Hz, respectively), 6.53-6.68 (2H, m), 7.12-7.65 (13H, m)
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>CS(C)=O>[N+:8]([C:4]1[CH:3]=[C:2]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:7]=[CH:6][CH:5]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccc(F)c1
Reactant: C1COCCN1
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cccc(N2CCOCC2)c1
Temperature: 110 °C

Procedure:
3-Fluoronitrobenzene (10 g) was added to a solution of morpholine (34 ml) in DMSO (120 ml) and heated at 110° C. for 60 h. The reaction mixture was cooled and poured onto water (800 ml). The precipitate was collected by filtration and the orange solid was dried under vacuum and used in subsequent reactions without further purification (13.7 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][CH:8]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][Si](C(C)(C)C)(C)C)=[CH:13][CH:12]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CO.O1CCCC1.C(OCC)C>[C:1]([O:5][C:6](=[O:32])[NH:7][CH:8]([C:25]1[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(C(=O)c1ccc(O[Si](C)(C)C(C)(C)C)cc1)c1ccc(Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOCC
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(O)cc1)c1ccc(Cl)cc1

Procedure:
To a solution of 1.37 g (2.88 mmol) rac-[2-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-1-(4-chloro-phenyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester in 30 ml methanol were added at ambient temperature 3.45 ml (3.45 mmol) 1M tetrabutylammonium fluoride in tetrahydrofuran. After 10 min the reaction mixture was diluted with diethyl ether, the solution washed twice with sodium bicarbonate solution and once with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by flash-chromatography over silica gel with a heptane/ethyl acetate gradient of 0 to 80% ethyl acetate. The purified title compound was triturated in di-isopropyl ether, filtered, dried and obtained as colorless solid: MS (ISN): 360.2 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[NH2:5].CCN(C(C)C)C(C)C.[C:20](OC(=O)C)(=[O:22])[CH3:21]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:20](=[O:22])[CH3:21])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(N)cc1F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(NC(C)=O)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.3 %

Procedure:
To a solution of 3-fluoro-4-methoxyaniline (1.15 g, 8.15 mmol) in dry CH2Cl2 (81 mL) in a 250 mL round-bottomed flask equipped with a magnetic stirrer were added DIEA (5.4 mL, 32.7 mmol), DMAP (221 mg, 1.81 mmol) and acetic anhydride (4.4 mL, 46.5 mmol) and the mixture was stirred overnight at RT. The solution was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent cyclohexane:EtOAc=100:0 to 50:50) gave N-(3-fluoro-4-methoxyphenyl)acetamide SMA 44032 as a brown solid (1.08 g, 72% yield).
Reaction SMILES: Cl[CH2:2][C:3]([C:6]1[N:10]([CH3:11])[C:9]2[CH:12]=[C:13]([Cl:17])[C:14]([Cl:16])=[CH:15][C:8]=2[N:7]=1)([OH:5])[CH3:4].[CH3:18][CH:19]([CH3:22])[CH2:20][SH:21].C[O-].[Na+]>CO>[Cl:16][C:14]1[C:13]([Cl:17])=[CH:12][C:9]2[N:10]([CH3:11])[C:6]([C:3]([OH:5])([CH3:4])[CH2:2][S:21][CH2:20][CH:19]([CH3:22])[CH3:18])=[N:7][C:8]=2[CH:15]=1
Reactant: CC(C)CS
Reactant: Cn1c(C(C)(O)CCl)nc2cc(Cl)c(Cl)cc21
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)CSCC(C)(O)c1nc2cc(Cl)c(Cl)cc2n1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 1-chloro-2-(5,6-dichloro-1-methyl-1H-benzoimidazol-2-yl)-propan-2-ol (408 mg) in methanol (10 mL) at room temperature was added a solution of 2-methyl-1-propanethiol (150 mg) and sodium methoxide (0.381 mls of 25 wt % in MeOH). The resulting mixture was stirred at room temperature overnight. The reaction mixture was then concentrated. The crude product was purified by flash chromatography (10%-40% EtOAc/hexanes) to yield the title compound as a light orange solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12](O)=[O:13])[CH:11]=1)[NH:8][CH:7]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])[CH2:23][CH2:22]3)[CH:16]=1)[CH2:6][C:5]2([CH3:35])[CH3:34].[CH:36]1([S:39]([NH2:42])(=[O:41])=[O:40])[CH2:38][CH2:37]1>CN(C)C1C=CN=CC=1.ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]([NH:42][S:39]([CH:36]3[CH2:38][CH2:37]3)(=[O:41])=[O:40])=[O:13])[CH:11]=1)[NH:8][CH:7]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])[CH2:23][CH2:22]3)[CH:16]=1)[CH2:6][C:5]2([CH3:35])[CH3:34]
Reactant: Cc1ccccc1N1CCN(c2cccc(C3CC(C)(C)c4cc(F)cc(C(=O)O)c4N3)c2)CC1
Reactant: NS(=O)(=O)C1CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccccc1N1CCN(c2cccc(C3CC(C)(C)c4cc(F)cc(C(=O)NS(=O)(=O)C5CC5)c4N3)c2)CC1
Yield: 29.7 %

Procedure:
A mixture of 6-fluoro-4,4-dimethyl-2-[3-(4-o-tolyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (100 mg, 0.21 mmol), 1-3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (60 mg, 0.31 mmol), 4-dimethylaminopyridine (38 mg, 0.31 mmol), cyclopropane sulfonic acid amide (76 mg, 0.63 mmol) in dichloromethane (10 mL) was refluxed for 12 h. Removal of the solvent to afford the oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded cyclopropanesulfonic acid {6-fluoro-4,4-dimethyl-2-[3-(4-o-tolyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-8-carbonyl}-amide (36 mg, 30%) as a light yellow solid: MS (ESI) M+1=577.3.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8](OC)=[O:9])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]3[CH2:22][CH2:21][CH2:20]3)[N:14]=2)[CH:3]=1.CO.[NH3:25]>>[Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:25])=[O:9])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]3[CH2:22][CH2:21][CH2:20]3)[N:14]=2)[CH:3]=1
Reactant: COC(=O)c1nnc(Cl)cc1Nc1cccc(C2CCC2)n1
Reactant: N
Solvent: CO
Product: NC(=O)c1nnc(Cl)cc1Nc1cccc(C2CCC2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.3 %

Procedure:
In a 100 mL round bottom flask, methyl 6-chloro-4-(6-cyclobutylpyridin-2-ylamino)pyridazine-3-carboxylate (350 mg, 1.1 mmol) was suspended in ammonia 7M in methanol (7.87 g, 10.0 mL, 70.0 mmol). The flask was sealed and stirred at room temperature for 18 h. The solid formed was separated by filtration and dried in high vacuum to give 6-chloro-4-(6-cyclobutylpyridin-2-ylamino)pyridazine-3-carboxamide (281 mg, 84.3% yield) as a white solid. 1H NMR (DMSO-d6) δ: 11.95 (s, 1H), 9.34 (s, 1H), 8.85 (s, 1H), 8.20 (s, 1H), 7.69 (t, J=7.7 Hz, 1H), 6.91 (dd, J=7.7, 3.6 Hz, 2H), 3.66 (quin, J=8.6 Hz, 1H), 2.19-2.40 (m, 4H), 1.78-2.15 (m, 2H); LC-MS 304.1 [M+H]+.
Reaction SMILES: C([BH3-])#N.[Na+].[NH2:5][C:6]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:7]=1[C:8]([NH:10][CH2:11][C:12]([NH:14][CH2:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)=[O:13])=[O:9].[CH2:27]([O:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1)[CH3:28].C(O)(=O)C>CO>[NH2:5][C:6]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:7]=1[C:8]([NH:10][CH2:11][C:12]([NH:14][CH2:15][CH:16]1[CH2:17][CH2:18][N:19]([CH2:34][C:33]2[CH:36]=[CH:37][C:30]([O:29][CH2:27][CH3:28])=[CH:31][CH:32]=2)[CH2:20][CH2:21]1)=[O:13])=[O:9]
Reactant: CCOc1ccc(C=O)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)NCC(=O)NCC1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOc1ccc(CN2CCC(CNC(=O)CNC(=O)c3cc(Cl)ccc3N)CC2)cc1
Temperature: 60 °C
Reaction time: 14 h

Procedure:
Sodium cyanoborohydride (140 mmol) in methanol (0.4 mL) was added to a mixture of 4-[(N-(2-amino-5-chlorobenzoyl)glycyl)aminomethyl]piperidine (0.10 mmol), 4-ethoxybenzaldehyde (0.10 mmol), acetic acid (0.050 mL), and methanol (1.6 mL). The reaction mixture was stirred at 60° C. for 14 h. The reaction mixture was loaded onto Varian™ SCX column and washed with CH3OH (20 mL). Product was eluted using 2 N NH3 in CH3OH (6 mL) and concentrated. Preparative TLC (SiO2, AcOEt/CH3OH 5:1) afforded 4-[{N-(2-amino-5-chlorobenzoyl)glycyl}aminomethyl]-1-(4-ethoxybenzyl)piperidine (Compound No. 1429) and 1-(4-ethoxybenzyl)-4-[{N-(2-(4-ethoxybenzyl)amino-5-chlorobenzoyl)glycyl)aminomethyl]piperidine (Compound No. 1433).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11]([N:14]([CH2:19][C@H:20]3[O:24][C:23]([CH3:26])([CH3:25])[N:22]([C:27]([O:29][C@@H:30]4[C@H:37]5[C@H:33]([O:34][CH2:35][CH2:36]5)[O:32][CH2:31]4)=[O:28])[C@H:21]3[CH2:38][C:39]3[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=3)[CH2:15][CH:16]([CH3:18])[CH3:17])(=[O:13])=[O:12])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.Cl.[N:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1[CH2:53]Cl.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11]([N:14]([CH2:19][C@H:20]3[O:24][C:23]([CH3:26])([CH3:25])[N:22]([C:27]([O:29][C@@H:30]4[C@H:37]5[C@H:33]([O:34][CH2:35][CH2:36]5)[O:32][CH2:31]4)=[O:28])[C@H:21]3[CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][CH2:53][C:48]4[CH:49]=[CH:50][CH:51]=[CH:52][N:47]=4)=[CH:41][CH:40]=3)[CH2:15][CH:16]([CH3:17])[CH3:18])(=[O:12])=[O:13])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(C)CN(C[C@H]1OC(C)(C)N(C(=O)O[C@H]2CO[C@H]3OCC[C@H]32)[C@H]1Cc1ccc(O)cc1)S(=O)(=O)c1ccc2c(c1)OCCO2
Reactant: ClCc1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)CN(C[C@H]1OC(C)(C)N(C(=O)O[C@H]2CO[C@H]3OCC[C@H]32)[C@H]1Cc1ccc(OCc2ccccn2)cc1)S(=O)(=O)c1ccc2c(c1)OCCO2
Yield: 63.1 %

Procedure:
0.1 g of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (4S,5R)-5-{[(2,3-dihydro-1,4-benzodioxin-6-ylsulfonyl)(isobutyl)amino]methyl}-4-(4-hydroxybenzyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate, 0.03 g of o-picolylchloride-hydrochloride and 0.15 g of cesium carbonate were suspended in 0.5 mL of dimethyl formamide and heated to 60 degrees for 3 h. The mixture was diluted with ethyl acetate and washed with water. Chromatography on silica gel (9:1 ethyl acetate/hexanes) gave 72 mg of the desired material
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[C:6](=[N:7][C:8](SC)=[N:9][CH:10]=2)[N:5]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[CH:2]=[CH2:3].[NH2:22][C:23]1[CH:24]=[CH:25][C:26]([N:31]2[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]2)=[C:27]([CH2:29][OH:30])[CH:28]=1>>[OH:30][CH2:29][C:27]1[CH:28]=[C:23]([NH:22][C:8]2[N:7]=[C:6]3[N:5]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=4)[N:4]([CH2:1][C:2]#[CH:3])[C:12](=[O:13])[C:11]3=[CH:10][N:9]=2)[CH:24]=[CH:25][C:26]=1[N:31]1[CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH2:36]1
Reactant: C=CCn1c(=O)c2cnc(SC)nc2n1-c1ccccn1
Reactant: CN1CCN(c2ccc(N)cc2CO)CC1
Product: C#CCn1c(=O)c2cnc(Nc3ccc(N4CCN(C)CC4)c(CO)c3)nc2n1-c1ccccn1

Procedure:
10 mg of the entitled compound was obtained as a yellow solid in the same manner as in Example 113-1 to 113-2, for which, however, 2-allyl-6-(methylthio)-1-pyridin-2-yl-3H-pyrazolo[3,4-d]pyrimidin-3-one obtained in Example 29-1 was used in place of 2-allyl-1-[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one used in Example 113-1, and [5-amino-2-(4-methylpiperazin-1-yl)phenyl]methanol was used in place of 4-(4-methylpiperazin-1-yl)aniline used in Example 113-2.
Reaction SMILES: C[C:2]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][C:9]2[C:4](=[C:5]([Cl:16])[C:6]([Cl:15])=[C:7]([OH:14])[C:8]=2[CH2:11][CH:12]=[CH2:13])[C:3]1=[O:17].C([O-])(=[O:26])C.[Na+].C(OO)(=O)C>ClCCl>[Cl:15][C:6]1[C:7]2[O:14][CH:12]([CH2:13][OH:26])[CH2:11][C:8]=2[C:9]2[CH2:10][CH:2]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:3](=[O:17])[C:4]=2[C:5]=1[Cl:16]
Reactant: C=CCc1c(O)c(Cl)c(Cl)c2c1CC(C)(c1ccccc1)C2=O
Reactant: CC(=O)[O-]
Agent: CC(=O)OO
Agent: [Na+]
Solvent: ClCCl
Product: O=C1c2c(Cl)c(Cl)c3c(c2CC1c1ccccc1)CC(CO)O3
Temperature: 120 °C

Procedure:
To a solution of 2-methyl-2-phenyl-4-allyl-5-hydroxy-6,7-dichloro-1-indanone (8.2 g., 0.024 mole) in dichloromethane (80 ml.) is added sodium acetate (150 mg.) and 40% peracetic acid (6 ml.). The reaction is stirred at 25°C. for 12 days during which time two 1 ml. portions of 40% peracetic acid are added at four day intervals. The reaction mixture is washed with water, aqueous sodium bicarbonate and brine. The solvent is distilled at reduced pressure and the residual oil is heated at 120°C. for 20 minutes affording 4,5-dichloro-2-hydroxymethyl-6-oxo-7-phenyl-1,2,7,8-tetrahydro-6H-indeno-[5,4-b]-furan (α-isomer) which is used in the next step without further purification.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1([CH:22]([F:24])[F:23])[CH2:8][N:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[C:6]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:5]=2[O:4]1.C(=O)(O)[O-:27].[Na+].C(C1C(CO)=C(SC2C=CC=C(CCCC)C=2CO)C=CC=1)CCC.ClC1C=CC=C(C(OO)=O)C=1>ClCCl.O.ClCCCl>[F:25][CH:2]([F:1])[C:3]1([CH:22]([F:24])[F:23])[CH2:8][N:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N+:10]=2[O-:27])[C:6]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:5]=2[O:4]1
Reactant: O=[N+]([O-])c1ccc2c(c1)N(c1ccccn1)CC(C(F)F)(C(F)F)O2
Reactant: O=C([O-])O
Agent: CCCCc1cccc(Sc2cccc(CCCC)c2CO)c1CO
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: ClCCCl
Product: O=[N+]([O-])c1ccc2c(c1)N(c1cccc[n+]1[O-])CC(C(F)F)(C(F)F)O2
Reaction time: 8 h
Yield: 34.4 %

Procedure:
2- (2,2-bis(difluoromethyl)-6-nitro-3,4-dihydro-2H-1,4-benzoxazine-4-yl)pyridine (1.32 g) 50% m-chloroperbenzoic acid (2.56 g), sodium bicarbonate (1.26 g), 1,2-dichloroethane (12 mL), water (12 mL), and butylhydroxymethylphenylsulfide (0.1 g) were stirred at reflux under nitrogen for 2 hours. Additional m-chloroperbenzoic acid (1.28 g), and Sodium bicarbonate (0.063 g) were added and reflux was continued overnight. The reaction mixture was cooled, diluted with dichloromethane and washed with sodium bicarbonate solution. The organic layer was separated, washed (water), dried and concentrated. Chromatography, eluting with dichloromethane followed by ethyl acetate, gave the title compound as a yellow amorphous solid (0.475 g); mp 138°-140 ° C.; NMR: 4.12 (s,2), 6.61 (t,2), 7.12 (s,1), 7.33 (d,1), 7.49 (m,2) 7.62 (d,1), 7.79 (d,1), 8.42 (d,1); MS: m/z=374(M+1). Analysis for C15H11 F4N3O4 : Calculated: C, 48.27; H, 2.97; N, 11.26; Found: C, 48.30; H, 2.97; N, 11.25.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([CH2:14][NH2:15])[CH2:12][C@H:11]2[C@@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:16]1[C:20]2=[CH:21][CH:22]=[CH:23][C:24]([C:25](O)=[O:26])=[C:19]2[CH:18]=[CH:17]1>>[C:1]([O:5][C:6]([N:8]1[C@H:13]([CH2:14][NH:15][C:25]([C:24]2[CH:23]=[CH:22][CH:21]=[C:20]3[O:16][CH:17]=[CH:18][C:19]=23)=[O:26])[CH2:12][C@H:11]2[C@@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)c1cccc2occc12
Reactant: CC(C)(C)OC(=O)N1[C@H](CN)C[C@@H]2C[C@@H]21
Product: CC(C)(C)OC(=O)N1[C@H](CNC(=O)c2cccc3occc23)C[C@@H]2C[C@@H]21

Procedure:
prepared by reaction of (1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester with benzofuran-4-carboxylic acid (M. A. Eissenstat et al. J. Med. Chem. 1995, 38, 3094-3105). LC-MS (acidic): tR=1.00 min; [M+H]+=357.1. 1H-NMR (CDCl3): δ=0.58 (bs, 1H); 0.80-0.86 (m, 1H); 1.52 (s, 9H); 1.52-1.59 (m, 1H); 1.79 (bd, J=13.3 Hz, 1H); 2.51-2.60 (m, 1H); 3.24-3.30 (m, 1H); 3.60-3.64 (m, 2H); 4.45-4.52 (m, 1H); 7.32 (t, J=7.9 Hz, 1H); 7.47 (bs, 1H); 7.61 (d, J=8.2 Hz, 1H); 7.65 (d, J=7.5 Hz, 1H); 7.70 (bs, 1H); 8.43 (bs, 1H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][N:6]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:5][C@@H:4]([C:18]([OH:20])=[O:19])[CH2:3]1.CCN(CC)CC.[Si:28](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]>C(Cl)(Cl)Cl>[CH3:32][C:31]([Si:28]([CH3:30])([CH3:29])[O:1][C@H:2]1[CH2:7][N:6]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:5][C@@H:4]([C:18]([OH:20])=[O:19])[CH2:3]1)([CH3:34])[CH3:33]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(O)[C@H]1C[C@@H](O)CN(C(=O)OCc2ccccc2)C1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@H](C(=O)O)CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 14 h
Yield: 72.6 %

Procedure:
To cis-(3RS,5RS)-5-hydroxy-1-{[(phenylmethyl)oxy]carbonyl}-3-piperidinecarboxylic acid (0.78 g; 2.8 mmol) in CHCl3 was added Et3N (2.0 ml; 15 mmol), and tert-butyldimethylsilyl chloride (1.06 g; 7.0 mmol). The reaction was allowed to stir for 14 hours under N2 at room temperature. The reaction was diluted with 200 ml of CHCl3 and washed with saturated aqueous NaHCO3, 0.1 N aqueous HCl, saturated aqueous NH4Cl, and brine. The organic layer was dried with Na2SO4, and the solvents were removed to provide the desired compound (0.80 g; 73%) as a colorless oil.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1)=[CH2:2].Br[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[Cu]I.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(#N)C>[N:22]1[CH:23]=[CH:24][CH:25]=[C:20](/[CH:2]=[CH:1]/[C:3]2[CH:4]=[C:5]([NH:9][C:10]3[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[CH:12][N:11]=3)[CH:6]=[CH:7][CH:8]=2)[CH:21]=1
Reactant: C=Cc1cccc(Nc2ncccc2[N+](=O)[O-])c1
Reactant: Brc1cccnc1
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cccnc1Nc1cccc(/C=C/c2cccnc2)c1
Yield: 67.6 %

Procedure:
A mixture of 2-(3-vinylphenylamino)-3-nitropyridine (12.9 g), 3-bromopyridine (12.7 g), palladium(II) acetate (0.24 g), copper(I) iodide (0.10 g), tri-o-tolylphosphine (0.65 g), triethylamine (25 ml) and acetonitrile (150 ml) was stirred under reflux under nitrogen overnight. After removal of the solvents, crude residue was chromatographed on silica gel (450 g, chloroform as eluent) to give 2-[3-[(E)-2-(3-pyridyl)vinyl]phenylamino]-3-nitropyridine as a reddish orange crystals (11.5 g).