Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NN.[CH2:3]([O:28][C:29]1[CH:34]=[C:33]([O:35][CH3:36])[C:32]([C:37]([N:39]2[CH2:43][C:42](=[CH2:44])[CH2:41][C@H:40]2[CH2:45][OH:46])=[O:38])=[CH:31][C:30]=1[N+:47]([O-])=O)[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([C:15]([N:17]2[CH2:21][C:20](=[CH2:22])[CH2:19][CH:18]2[CH2:23][OH:24])=[O:16])=[CH:9][C:8]=1[N+:25]([O-])=O.C(Cl)(Cl)Cl.CO>CO.[Ni]>[CH2:5]([O:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([C:15]([N:17]2[CH2:21][C@@H:20]([CH3:22])[CH2:19][C@H:18]2[CH2:23][OH:24])=[O:16])=[CH:9][C:8]=1[NH2:25])[CH2:4][CH2:3][O:28][C:29]1[CH:34]=[C:33]([O:35][CH3:36])[C:32]([C:37]([N:39]2[CH2:43][CH:42]([CH3:44])[CH2:41][CH:40]2[CH2:45][OH:46])=[O:38])=[CH:31][C:30]=1[NH2:47]
Reactant: C=C1CC(CO)N(C(=O)c2cc([N+](=O)[O-])c(OCCCOc3cc(OC)c(C(=O)N4CC(=C)C[C@H]4CO)cc3[N+](=O)[O-])cc2OC)C1
Agent: [Ni]
Agent: NN
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cc(OCCCOc2cc(OC)c(C(=O)N3C[C@@H](C)C[C@H]3CO)cc2N)c(N)cc1C(=O)N1CC(C)CC1CO
Temperature: 25 °C
Yield: 62 %

Procedure:
A solution of hydrazine (23 mg, 23 μL, 0.72 mmol) in MeOH (5 mL) was added dropwise to a solution of the diol 76 (95 mg, 0.145 mmol) and Raney Ni (20 mg) in MeOH (15 mL) heated at reflux. After 1 hour at reflux TLC (90% CHCl3/MeOH) revealed some amine formation. The reaction mixture was treated with further Raney Ni (20 mg) and hydrazine (23 mg, 23 μL, 0.72 mmol) in MeOH (5 mL) and was heated at reflux for an additional 30 minutes at which point TLC revealed complete reaction. The reaction mixture was then treated with enough Raney Ni to decompose any remaining hydrazine and heated at reflux for a further 1.5 hours. Following cooling to room temperature the mixture was filtered through a sinter and the resulting filtrate evaporated in vacuo. The resulting residue was then treated with CH2Cl3 (30 mL), dried (MgSO4), filtered and evaporated in vacuo to provide the bis-amine (77) as a yellow oil (54 mg, 63%): 1H NMR (270 MHz, CDCl3) (diastereoisomers) δ 6.73 (S, 2Harom) 6.32 (s, 2Harom), 4.60-4.30 (m, 2H, NCHCH2OH) 4.19 (t, 4H, J=5.87 Hz, OCH2CH2CH2O), 3.78-3.50 (m, 14H, NCHCH2OH, NCH2CHCH3 and OCH3), 2.40-1.55 (m, 8H, NCH2CHCH3); OCH2CH2CH2O and NCH2CHCH2CH2), 1.00-0.95 (m, 6H, NCH2CHCH3); MS (EI), m/z (relative intensity) 600 (M+., 16), 459 (46), 345 (16), 206 (13), 186 (17), 180 (31), 166 (37), 149 (6), 142 (76), 100 (6), 98 (13), 97 (29), 84 (81), 69 (7), 55 (100).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C@@H:5]([CH2:7][C:8](O)=[O:9])[C:4](=[O:11])[O:3]1.B.C1COCC1.Cl>O1CCCC1>[OH:9][CH2:8][CH2:7][C@@H:5]1[O:6][C:2]([CH3:1])([CH3:12])[O:3][C:4]1=[O:11]
Reactant: CC1(C)OC(=O)[C@H](CC(=O)O)O1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: CC1(C)OC(=O)[C@H](CCO)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.2 %

Procedure:
Step B To the solution of ((S)-2,2-dimethyl-5-oxo-[1,3]dioxolan-4-yl)-acetic acid (10.1 g, 58 mmol) in anhydrous tetrahydrofuran (20 mL) at 0° C. was added a solution of BH3.THF (1 M, 70 mL, 70 mmol). The reaction mixture was stirred at room temperature for 2 h. Aqueous HCl solution was added, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous NaHCO3 solution, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (EtOAc) to give (S)-5-(2-hydroxy-ethyl)-2,2-dimethyl-[1,3]dioxolan-4-one as a colorless oil (6.8 g, 72%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]1[CH:14]=[N:15][N:16]=[C:9]1[C:8](=[O:17])[NH:7]2)([O-:3])=[O:2].[N+:18]([O-])([O-:20])=[O:19].[K+]>OS(O)(=O)=O>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[N+:18]([O-:20])=[O:19])[N:10]1[CH:14]=[N:15][N:16]=[C:9]1[C:8](=[O:17])[NH:7]2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])[O-]
Reactant: O=c1[nH]c2cc([N+](=O)[O-])ccc2n2cnnc12
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=c1[nH]c2cc([N+](=O)[O-])c([N+](=O)[O-])cc2n2cnnc12
Temperature: 50 °C
Reaction time: 2 h

Procedure:
This product (17) was dissolved in H2SO4 and cooled in an ice/H2O bath. KNO3 was added and the ice bath removed. The solution was stirred an additional 2 hours and then heated at 50° C. for 40 hours, yielding 7,8-dinitro-1,2,4-triazolo[4,3-a]quinoxalin-4(5H)-one (18).
Reaction SMILES: [C:1]1([N:7]2[C:16]([OH:17])=[C:10]3[N:11]=[CH:12][N:13]=[C:14]([SH:15])[C:9]3=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])O.[K+].Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>C(O)C>[C:1]1([N:7]2[C:16]([OH:17])=[C:10]3[N:11]=[CH:12][N:13]=[C:14]([S:15][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:9]3=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1c2ncnc(S)c2nn1-c1ccccc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)CSc1ncnc2c(O)n(-c3ccccc3)nc12
Temperature: 80 °C
Reaction time: 2 h

Procedure:
1.22 g of 2-phenyl-3-hydroxy-7-mercapto-pyrazolo [4,3-d]pyrimidine was suspended in 100 ml of ethanol, and 0.5 g of potassium hydrogen carbonate was added. While heating the mixture at 80° C., 1 g of ethyl bromoacetate was dropwise added, and the heating and reaction were continued for further 2 hours. Then, the solvent was distilled off. Water was added to the residue, and the residue was dissolved. The solution was acidified with hydrochloric acid, and the precipitated crystals were extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The remaining solid was recrystallized from acetone-chloroform.
Reaction SMILES: [NH:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3].C(O[C@@H:14]1[C:18]([F:20])([CH3:19])[C@@:17]([O:22][C:23](=[O:25])[CH3:24])([CH3:21])[CH:16]([CH2:26][O:27][C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:15]1)(=O)C.Cl[Sn](Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>C(#N)C>[C:28]([O:27][CH2:26][C@@H:16]1[C:17]([O:22][C:23](=[O:25])[CH3:24])([CH3:21])[C@:18]([F:20])([CH3:19])[CH:14]([N:1]2[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]2=[O:3])[O:15]1)(=[O:35])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC(=O)O[C@H]1OC(COC(=O)c2ccccc2)[C@@](C)(OC(C)=O)C1(C)F
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cc(C)c(=O)[nH]c2=O)[C@]1(C)F
Yield: 34 %

Procedure:
To a stirred solution of thymine (about 0.68 g, 5.43 mmol) in acetonitrile (about 15 ml) was added compound N,O-Bis-trimethylsilylacetamide (7.90 ml, 32.6 mmol) at room temperature and refluxed for about 2 hours. To this added (2R,4R)-5-(benzoyloxymethyl)-3-fluoro-3,4-dimethyltetrahydrofuran-2,4-diyl diacetate (about 1.00 g, 2.71 mmol) in acetonitrile (about 15 ml) drop wise at about 0° C. and SnCl4 (about 0.47 ml, 4.00 mmol) then refluxed for about 15 hours. Completion of the reaction monitored by thin-layer chromatography, neutralized the reaction mixture with saturated sodium bicarbonate, aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine and dried over sodium sulphate. Concentrated under reduced pressure and purified by silica gel column chromatography using 3% methanol in dichloromethane as eluent furnished title compound (0.40 g) as a colorless solid. Yield: 34%; 1H NMR (300 MHz, CDCl3): δ 8.07 (s, 1H), 8.05-8.04 (m, 2H), 7.60-7.58 (m, 1H), 7.49-7.44 (m, 2H), 7.15-7.13 (m, 1H), 6.38 (d, 1H, J=23.1 Hz), 4.74-4.65 (m, 2H), 4.49-4.41 (m, 1H), 2.12 (s, 3H), 1.94 (d, 3H, J=0.9 Hz), 1.83 (d, 3H, J=2.4 Hz), 1.48 (d, 3H, J=23.4 Hz); ES Mass: [M+1] 435 (30%), [M+Na] 457 (100%); IR cm−: 3432, 2926, 1753, 1692, 1602, 1547, 1384, 1276, 1115, 954, 833; HPLC:. 92%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[C:20]4[C:24](=[C:25]([F:27])[CH:26]=3)[NH:23][C:22]([CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[CH:21]4)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].[OH-].[Na+].Cl>C(O)(C)C>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[C:20]4[C:24](=[C:25]([F:27])[CH:26]=3)[NH:23][C:22]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:21]4)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2]
Reactant: CCOC(=O)CCc1cc2cc(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)cc(F)c2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CC(C)Oc1ccc(-c2nc(-c3cc(F)c4[nH]c(CCC(=O)O)cc4c3)no2)cc1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.8 %

Procedure:
To a suspension of ethyl 3-[5-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-7-fluoro-1H-indol-2-yl]propanoate (D165) (310 mg) in isopropanol (20 mL) was added 20% sodium hydroxide (670 mg) solution. Then the reaction mixture was stirred at room temperature overnight. The mixture was acidified with HCl (2 M) to pH 4. The solvent of the reaction was removed by evaporation. The residue was dissolved in DMF (5 mL), the precipitation was filtered then the filtrate was purified by Mass Directed Auto Prep to afford 3-[5-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-7-fluoro-1H-indol-2-yl]propanoic acid (E113) (54.6 mg) as a white solid. δH (DMSO-d6, 400 MHz): 1.38 (6H, d), 2.70 (2H, t), 2.99 (2H, t), 4.97 (1H, m), 6.44 (1H, s), 7.49 (1H, d), 7.54 (1H, d), 8.07 (1H, s), 8.39 (1H, dd), 8.50 (1H, d), 11.82 (1H, s). δF (DMSO-d6, 376 MHz): −132.6; MS (ES): C23H19FN4O4 requires 434; found 435.2 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])[CH:6]=[CH:5]2.[OH:22][CH2:23][CH2:24][C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28]>>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][NH:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:28][C:27]3[CH:26]=[C:25]([CH2:24][CH2:23][OH:22])[CH:31]=[CH:30][CH:29]=3)[CH:3]=2)[N:8]=1
Reactant: COc1ccccc1CNc1ccc2cc(Br)ccc2n1
Reactant: Nc1cccc(CCO)c1
Product: COc1ccccc1CNc1ccc2cc(Nc3cccc(CCO)c3)ccc2n1

Procedure:
The title compound, yellow oil, MS: m/e=400.3 (M+H+), was prepared in accordance with the general method of example 84 from (6-bromo-quinolin-2-yl)-(2-methoxy-benzyl)-amine (see example 2, step A) and commercially available 3-(2-hydroxyethyl)-aniline.
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[CH:31]1(B(O)O)[CH2:33][CH2:32]1.N1C=CC=CC=1>C(Cl)(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:31]1([N:11]2[C:12]3[C:17](=[CH:16][C:15]([C:19]([N:21]4[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]4)=[O:20])=[CH:14][CH:13]=3)[CH:18]=[C:10]2[C:8]([N:5]2[CH2:6][CH2:7][C:2]([F:1])([F:30])[CH2:3][CH2:4]2)=[O:9])[CH2:33][CH2:32]1
Reactant: OB(O)C1CC1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3C2CC2)CC1
Temperature: 50 °C
Reaction time: 96 h
Yield: 12 %

Procedure:
The title compound was synthesized in analogy to example 66, from (4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 32), cyclopropylboronic acid (commercially available), copper(II) acetate and pyridine using chloroform as solvent and stirring at 50° C. for 4 days, to give the desired product as a light brown foam (12%).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:16])/[CH:9]=[CH:10]/[C:11]1[CH:15]=[CH:14][NH:13][CH:12]=1)([CH3:6])([CH3:5])[CH3:4].[CH3:17][N:18]([CH3:29])[C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[C:3]([O:7][C:8](=[O:16])/[CH:9]=[CH:10]/[C:11]1[CH:15]=[CH:14][N:13]([S:25]([C:22]2[CH:21]=[CH:20][C:19]([N:18]([CH3:29])[CH3:17])=[CH:24][CH:23]=2)(=[O:27])=[O:26])[CH:12]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)/C=C/c1cc[nH]c1
Reactant: CN(C)c1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Product: CN(C)c1ccc(S(=O)(=O)n2ccc(/C=C/C(=O)OC(C)(C)C)c2)cc1

Procedure:
Starting materials: sodium hydride 60% (0.031 g), (E)-3-(1H-pyrrol-3-yl)-acrylic acid tert-butyl ester (compound D1) (0.100 g), 4-dimethylamino-benzenesulfonyl chloride (0.145 g). Reaction conditions: 30° C., 45 min; −30° C., 2.5 hours.
Reaction SMILES: Cl[C:2]([F:9])([F:8])C(OCC)=O.[Br:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][C:20]=1[OH:21])[C:14]([O:16][CH3:17])=[O:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][C:20]=1[O:21][CH:2]([F:9])[F:8])[C:14]([O:16][CH3:17])=[O:15]
Reactant: CCOC(=O)C(F)(F)Cl
Reactant: COC(=O)c1ccc(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC(F)F)c(Br)c1
Temperature: 65 °C
Yield: 49.1 %

Procedure:
Ethyl chlorodifluoroacetate (1.12 ml, 8.7 mmol) was added to a mixture of methyl 3-bromo-4-hydroxybenzoate (Description 64, 2.0 g, 8.7 mmol) and potassium carbonate (1.2 g, 8.7 mmol) in N,N-dimethylformamide (20 ml) and the mixture was heated at 65° C. for 16 h. The mixture was cooled, water (100 ml) was added and the mixture was extracted with ethyl acetate (2×100 ml). The combined organic fractions were dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with hexane/EtOAc (95:5) to give the title compound as a colorless solid (1.20 g, 49%). 1H NMR (250 MHz, CDCl3) δ8.31 (1 H, d, J 2.0 Hz), 8.22 (1 H, dd, J 8.5, 2.0 Hz), 7.05 (1 H, m), 6.61 (1 H, t, J 73 Hz), and 3.93 (3 H, s).
Reaction SMILES: [Si:1]([O:8][C:9]1([C:12]2[N:17]=[C:16]([C:18]#[N:19])[CH:15]=[CH:14][CH:13]=2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[O-]CC.[Na+].Cl.Cl.N[C:27]1[CH:28]=[CH:29][C:30]([N:34]2[CH2:39][CH2:38][CH2:37][C@@H:36]([C:40]([N:42]3[CH2:46][CH2:45][CH2:44][CH2:43]3)=[O:41])[CH2:35]2)=[N:31][C:32]=1[NH2:33].C(N(CC)CC)C>C(O)C.C(O)(=O)C>[Si:1]([O:8][C:9]1([C:12]2[N:17]=[C:16]([C:18]3[NH:33][C:32]4=[N:31][C:30]([N:34]5[CH2:39][CH2:38][CH2:37][C@@H:36]([C:40]([N:42]6[CH2:43][CH2:44][CH2:45][CH2:46]6)=[O:41])[CH2:35]5)=[CH:29][CH:28]=[C:27]4[N:19]=3)[CH:15]=[CH:14][CH:13]=2)[CH2:10][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC1(c2cccc(C#N)n2)CC1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CC(C)(C)[Si](C)(C)OC1(c2cccc(-c3nc4ccc(N5CCC[C@@H](C(=O)N6CCCC6)C5)nc4[nH]3)n2)CC1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
To a solution of 6-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)picolinonitrile (45.0 mg, 0.164 mmol) in ethanol (0.3 mL) was added dropwise a solution of sodium ethoxide in ethanol (0.1 mL, 21 wt %, 0.2 mmol). The reaction mixture was stirred at room temperature for 50 min and then heated to 35° C. for 1.5 h. To the mixture was added (R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone dihydrochloride (77.2 mg, 0.2 mmol), triethylamine (47 μL, 0.3 mmol) and acetic acid (47 μL). The reaction mixture was heated to 110° C. for 50 min. The solution was transferred to a microwave vial and it was heated to 145° C. for 20 min. The solvent was removed under reduced pressure to afford (R)-(1-(2-(6-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)pyridin-2-yl)-3H-imidazo[4,5-b]pyridin-5-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone. The material was used without further purification.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([N:15]([C:22](=[O:24])[CH3:23])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:11]=1)C)(C)(C)C.C(OCC)(=O)C.Cl>C(OCC)(=O)C.C(O)C>[CH3:6][NH:7][CH2:9][C:10]1[CH:14]=[C:13]([N:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:22](=[O:24])[CH3:23])[N:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:11]=1
Reactant: CC(=O)N(c1ccccc1)c1cc(CN(C)C(=O)OC(C)(C)C)nn1-c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNCc1cc(N(C(C)=O)c2ccccc2)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.6 %

Procedure:
tert-Butyl({5-[acetyl(phenyl)amino]-1-phenyl-1H-pyrazol-3-yl}methyl)methylcarbamate (83 mg) was dissolved in ethyl acetate (2 mL) and ethanol (1 mL), a 4 mol/L hydrogen chloride-ethyl acetate solution (3 mL) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (3 mL), and the mixture was added to a solution of fumaric acid (23 mg) in ethanol (5 mL). The solvent was evaporated under reduced pressure, and the residue was recrystallized from a mixed solvent of ethyl acetate and ethanol to give the title compound as colorless crystals (yield 32 mg, yield 43%).
Reaction SMILES: [CH2:1]([CH:8]1[CH:12]([C:13](O)=[O:14])[O:11][C:10](=[O:16])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.C[O-].[Na+].[BH4-].[Na+].Cl>CO.O>[CH2:1]([C@H:8]1[C@@H:12]([CH2:13][OH:14])[O:11][C:10](=[O:16])[NH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(Cc2ccccc2)C(C(=O)O)O1
Agent: C[O-]
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: O=C1N[C@@H](Cc2ccccc2)[C@@H](CO)O1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 50 g of a 97.2:2.8 mixture of the (4S,5S):(4S,5R) isomers of 4-benzyl-2-oxo-oxazolidine-5-carboxylic acid in 300 ml of methanol was combined with 1 ml of sulphuric acid and refluxed for 3.5 hours. The solution was cooled to 0° C. and adjusted to pH 7 with a solution of 30% sodium methoxide in methanol. 10.26 g of sodium borohydride were added to the solution at 0-3° C. After 1 hour's stirring at 0° C., the suspension is adjusted to pH 1 at 0-20° C. with 25% hydrochloric acid. After the addition of water and stirring at -10° C., the suspension is filtered. 41.5 g (89%) of 99% (4S,5S)-4-benzyl-5-hydroxymethyl-oxazolidin-2-one, melting point 168-171° C., [α]D20 : -79.1° (1% in methanol), were obtained.
Reaction SMILES: O1C2=CN=CC=C2C(=O)C1.C(OC([C:16]1[O:28][C:19]2=[N:20][CH:21]=[CH:22][C:23]([C:24]([F:27])([F:26])[F:25])=[C:18]2[C:17]=1[OH:29])=O)C>>[F:26][C:24]([F:25])([F:27])[C:23]1[CH:22]=[CH:21][N:20]=[C:19]2[O:28][CH2:16][C:17](=[O:29])[C:18]=12
Reactant: CCOC(=O)c1oc2nccc(C(F)(F)F)c2c1O
Agent: O=C1COc2cnccc21
Product: O=C1COc2nccc(C(F)(F)F)c21

Procedure:
This compound was prepared using a method analogous to that of furo[2,3-c]pyridin-3(2H)-one (A.2.4.3), 3-hydroxy-4-(trifluoromethyl)furo[2,3-b]pyridine-2-carboxylic acid ethyl ester replacing 3-hydroxyfuro[2,3-c]pyridine-2-carboxylic acid ethyl ester;
Reaction SMILES: [N+:1]([C:4]1[C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].S(Cl)(Cl)=O.[CH:17]1C=CC=CC=1>>[CH3:17][O:11][C:10](=[O:12])[C:9]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: c1ccccc1
Reactant: O=C(O)c1ccccc1[N+](=O)[O-]
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccccc1[N+](=O)[O-]

Procedure:
A solution of 6-nitro-benzoic acid in benzene was treated with thionyl chloride (2.5 eq) and stirred at reflux for 8 h. After evaporation, the residue was dissolved in chloroform and then treated with methanol. After stirring at reflux for 3 h, the mixture was evaporated to afford compound 3.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:19]=[CH:18][C:7]([NH:8][C:9](=[O:17])[CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:6][C:5]=1[N+:20]([O-])=O)[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH2:34]([N:41]1[C:45](=[O:46])[C:44](=[C:47]2[N:51]([CH3:52])[C:50]3[CH:53]=[CH:54][CH:55]=[CH:56][C:49]=3[S:48]2)[S:43][CH2+:42]1SC)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH2:34]([N:41]1[C:45](=[O:46])[C:44](=[C:47]2[N:51]([CH3:52])[C:50]3[CH:53]=[CH:54][CH:55]=[CH:56][C:49]=3[S:48]2)[S:43][C:42]1=[N:20][C:5]1[CH:6]=[C:7]([NH:8][C:9](=[O:17])[CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:18]=[CH:19][C:4]=1[NH:3][CH2:1][CH3:2])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CCNc1ccc(NC(=O)CN2CCOCC2)cc1[N+](=O)[O-]
Reactant: CS[CH2+]1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCNc1ccc(NC(=O)CN2CCOCC2)cc1N=C1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1

Procedure:
In a manner similar to Example 30, intermediate 4′-ethylamino-2-(morpholin-4-yl)-3′-nitroacetanilide was hydrogenated and then condensed with 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazolium p-toluenesulfonate to afford the title compound. 1H-NMR (CDCl3): δ 8.87 (1H, s), 7.49-7.53 (3H, m), 7.28-7.37 (5H, m), 7.19 (1H, t), 7.12 (1H, dd), 7.04 (1H, d), 6.57 (1H, d), 5.19 (2H, s), 3.79 (8H, br s), 3.16 (2H, s), 3.01 (2H, q), 2.66 (4H, br s), 1.06 (3H, t); MS(ESI): 615 (MH+).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([CH3:8])=[CH:4][C:5](O)=[O:6].[CH3:11][CH:12]([CH3:30])[CH2:13][CH2:14][NH:15][C:16]([C:18]1[N:19]=[N:20][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:22][CH:23]=1)=[O:17]>>[CH3:11][CH:12]([CH3:30])[CH2:13][CH2:14][NH:15][C:16]([C:18]1[N:19]=[N:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:5](=[O:6])[CH:4]=[C:3]([CH3:8])[C:2]([F:10])([F:9])[F:1])[CH2:26][CH2:25]2)=[CH:22][CH:23]=1)=[O:17]
Reactant: CC(C)CCNC(=O)c1ccc(N2CCNCC2)nn1
Reactant: CC(=CC(=O)O)C(F)(F)F
Product: CC(=CC(=O)N1CCN(c2ccc(C(=O)NCCC(C)C)nn2)CC1)C(F)(F)F

Procedure:
Following the procedure of Example 9, making variations only as required to use to use 4,4,4-trifluoro-3-methylbut-2-enoic acid in place of 2,5-dichlorobenzoic acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl)amide, the title compound was obtained as a white powder (62% yield). 1H NMR (300 MHz, CDCl3) δ 8.05, 7.83, 7.00, 6.55, 3.86-3.83, 3.80-3.73, 3.62-3.60, 3.48, 2.01, 1.75-1.62, 1.49, 0.92. MS (ES+) m/z 414.4 (M+1).
Reaction SMILES: [C:1]1([NH:7][CH2:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:49][CH2:50][C:51]1[C:52]([OH:59])=[N:53][C:54]([CH3:58])=[CH:55][C:56]=1[CH3:57]>ClCCl.O>[OH:59][C:52]1[C:51]([CH2:50][NH:49][C:13](=[O:15])[C:12]2[CH:11]=[CH:10][C:9]([CH2:8][NH:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:17][CH:16]=2)=[C:56]([CH3:57])[CH:55]=[C:54]([CH3:58])[N:53]=1
Reactant: O=C(O)c1ccc(CNc2ccccc2)cc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2ccc(CNc3ccccc3)cc2)c(O)n1
Reaction time: 0.5 h
Yield: 41.9 %

Procedure:
4-((Phenylamino)methyl)benzoic acid (150 mg, 0.66 mmol), 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (301 mg, 0.79 mmol) and triethylamine (2 mL) were dissolved in dichloromethane (20 mL). The mixture was stirred for 0.5 hour. And then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (100 mg, 0.66 mmol) was added to the mixture. The mixture was stirred at 25° C. for 12 hours. To the mixture, water (10 mL) was added and the mixture was extracted with dichloromethane (10 mL×3). The combined organic phase was dried by sodium sulfate and then filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-((phenylamino)methyl)benzamide (100 mg, 42%). LRMS (M+H+) m/z: calcd 361.18. found 361. HPLC purity (214 nm): 99%. 1H NMR (300 MHz, CD3OD): δ 7.75 (d, J=8.1 Hz, 2H), 7.44 (d, J=8.1 Hz, 2H), 7.06-7.04 (m, 2H), 6.60-6.58 (m, 3H), 6.11 (s, 1H), 4.49 (s, 2H), 4.37 (s, 2H), 2.36 (s, 3H), 2.24 (s, 3H).