Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]([OH:13])[CH2:11][NH2:12].[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22](=O)[CH3:23])=[CH:17][CH:16]=1.O>C1C=CC=CC=1>[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([NH:12][CH2:11][CH:10]([C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH:3]=2)[OH:13])[CH3:23])=[CH:17][CH:16]=1
Reactant: NCC(O)c1cc2ccccc2o1
Reactant: CC(=O)Cc1ccc(C)cc1
Solvent: c1ccccc1
Solvent: O
Product: Cc1ccc(CC(C)NCC(O)c2cc3ccccc3o2)cc1

Procedure:
A mixture of 2-(2-benzofuranyl)-2-hydroxy ethanamine (1.0 g) and 4-methylphenylacetone (0.76 g) in benzene (50 ml) was heated under reflux using a Dean and Stark head until the required amount of water had been collected. The solvent was evaporated, replaced with ethanol (50 ml) and the solution hydrogenated at atmospheric pressure over platinum oxide until the theoretical amount of hydrogen had been taken up. The reaction mixture was filtered through diatomaceous earth, the filtrate evaporated and the residue chromatographed on Kieselgel 60. Elution with 2% methanolchloroform gave N-[2-(4-methylphenyl)-1-methylethyl]-2-(2-benzofuranyl)-2-hydroxy ethanamine, as an 80:20 mixture of diastereoisomers, m.p. 92-98 (cyclohexane).
Reaction SMILES: [CH:1]1[C:6]([NH:7]N)=[CH:5][CH:4]=[C:3]([N:9]2[CH:13]=[N:12][N:11]=[CH:10]2)[CH:2]=1.[O:14]1[CH:19]=[CH:18][CH2:17][CH2:16][CH2:15]1.Cl>O1CCOCC1>[N:12]1[N:11]=[CH:10][N:9]([C:3]2[CH:2]=[C:1]3[C:6](=[CH:5][CH:4]=2)[NH:7][CH:19]=[C:18]3[CH2:17][CH2:16][CH2:15][OH:14])[CH:13]=1
Reactant: C1=COCCC1
Reactant: NNc1ccc(-n2cnnc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: OCCCc1c[nH]c2ccc(-n3cnnc3)cc12
Yield: 29.6 %

Procedure:
A solution of 4'-(1,2,4-triazol-4-yl)phenylhydrazine (25 g, 143 mmol) in dioxan (250 ml) was treated with dihydropyran (24 g, 286 mmol) followed by 1M hydrochloric acid (150 ml) and heated at reflux for 18 hours. The reaction mixture was evaporated with toluene then reevaporated. Inorganic solids were removed by treating the residue with a mixture of methanol and acetonitrile. The mother liquors were purified by column chromatography on silica using dichloromethane:methanol (9:1→4:1) as the eluant. The compound was recrystallised from acetonitrile to afford the title compound as a white solid (10.24 g, 30%), mp 205°-207° C. δ (360 MHz, d6 -DMSO) 1.81 (2H, quintet, J=7Hz, CH2), 2.75 (2H, t, J=8Hz, CH2), 3.46 (2H, dt, J1 =6Hz, J2 =5Hz, CH2), 4.43 (1H, t, J=5Hz, OH), 7.26 (1H, d, J=2Hz, Ar-H), 7.29 (1H, dd, J1 =9Hz, J2 =2Hz, Ar-H), 7.47 (1H, d, J=9Hz, Ar-H), 7.77 (1H, d, J=2Hz, Ar-H), 9.01 (2H, s, Triazole-H), 11.05 (1H, br s, indole NH). MS, CI+, m/z for (M+H)+ =243.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH2:10][O:9][CH2:8][CH2:7][C:5]=2[N:6]=1.C([O-])(=O)C.[Na+].[H][H]>CO.[Pd]>[N:6]1[C:5]2[CH2:7][CH2:8][O:9][CH2:10][C:4]=2[S:3][CH:2]=1
Reactant: Clc1nc2c(s1)COCC2
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: c1nc2c(s1)COCC2
Yield: 79.7 %

Procedure:
2-Chloro-6,7-dihydro-4H-pyrano[4,3-d]thiazole (1.78 g) was dissolved in methanol (30 ml), and to the solution 10% palladium on carbon (300 mg) and sodium acetate (830 mg) were added. The mixture was stirred for 5 days in a hydrogen stream of 5 atm. After the catalyst was separated by filtration, the filtrate was concentrated, and the residue was subjected to column chromatography on silica gel (hexane:ethyl acetate=2:1) to obtain 6,7-dihydro-4H-pyrano[4,3-d]thiazole (1.14 g) as a colorless oil.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:5]=1[CH:6]=O)[CH3:2].C1(P(=[CH:35][C:36]([O:38][CH3:39])=[O:37])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[CH3:39][O:38][C:36](=[O:37])[CH:35]=[CH:6][C:5]1[CH:8]=[CH:9][C:10]([C:12]([F:15])([F:14])[F:13])=[CH:11][C:4]=1[NH:3][CH2:1][CH3:2]
Reactant: CCNc1cc(C(F)(F)F)ccc1C=O
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCNc1cc(C(F)(F)F)ccc1C=CC(=O)OC

Procedure:
2-Ethylamino-4-trifluoromethyl-benzaldehyde (22 mg) was reacted with methyl (triphenylphosphoranylidene)acetate (49 mg, 0.14 mmol) at 110° C. overnight as described above to yield 3-(2-ethylamino-4-trifluoromethyl-phenyl)-acrylic acid methyl ester. 3-(2-Ethylamino-4-trifluoromethyl-phenyl)-acrylic acid methyl ester was reacted with 1N LiOH (5 ml) as described above to yield the title compound (20.2 mg)
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N+:2]=1[O-].P(Cl)(Cl)([Cl:14])=O>ClCCl>[Cl:14][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: [O-][n+]1ccc2ccccc2c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: Clc1nccc2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of isoquinoline-N-oxide (5.52 g, 38 mmol) in dichloromethane (50 ml) was added over 15 minutes to a solution of phosphorus oxychloride (40 ml) in dichloromethane (50 ml) at room temperature. The mixture was stirred for 1 hour, then heated to reflux for 2 hours. After cooling to room temperature, the mixture was poured into ice water (500 ml). The mixture was then extracted with dichloromethane (2×250 ml) and the combined organic layers were washed with 10% aqueous potassium carbonate solution (200 ml), brine (200 ml) then dried (Na2SO4) and evaporated to give the title compound (5.0 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[CH2:14][O:15][Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:33](O)(=[O:35])[CH3:34].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:33]([O:13][C@@H:11]1[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C@H:9]([CH2:14][O:15][Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:10]1)(=[O:35])[CH3:34]
Reactant: CC(=O)O
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)O[C@H]1C[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)N(C(=O)OC(C)(C)C)C1
Temperature: 50 °C
Reaction time: 2 h
Yield: 98.4 %

Procedure:
To a stirred mixture of (2S,4R)-1-tert-butoxycarbonyl-2-tert-butyldiphenylsilyloxymethy-4-hydroxypyrrolidine (21.7 g, 47.6 mmol), acetic acid (3.0 ml, 52.4 mmol) and PPh3 (12.5 g, 52.4 mmol) in THF (330 ml) was added DIAD (9.4 ml, 47.6 mmol) at room temperature under an atmosphere of nitrogen. After 2 h stirring the same temperature, the mixture was heated at 50° C. for 2 h. After cooling to room temperature, the reaction mixture was concentrated in vacuo. The resulting residue was chromatographed on silica gel [1 Kg, n-hexane/EtOAc(5/1)], to give (2S,4S)-4-acetoxy-1-tert-butoxycarbonyl-2-tert-butyldiphenylsilyloxymethypyrrolidine (23.3 g, 99%) as a colorless oil. 1H-NMR (CDCl3) δ1.06 (s, 9H), 1.35 and 1.43 (s, 9H, amide isomers), 1.92 (br, 3H), 2.20-2.45 (m, 2H), 3.31-4.07 (m, 5H), 5.17-5.30 (m, 1H), 7.36-7.44 (m, 6H), 7.65-7.71 (m, 4H).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN([C:23]([O:27][N:28]1N=NC2C=CC(=C[C:29]1=2)Cl)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:23][O:27][N:28]([CH3:29])[C:17](=[O:19])[C@@H:9]([NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[CH2:10][C:11]1[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccncc1)C(=O)O
Reactant: CN(C)C(On1nnc2ccc(Cl)cc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)[C@H](Cc1ccncc1)NC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
To a mixture of Boc-β-(4-pyridyl)-L-alanine (75, 300 mg, 1.08 mmol) and NH(Me) OMe.HCl (1.2 eq., 1.30 mmol, 129 mg) in DCM (10 mL) was added HCTU (1.2 eq., 1.30 mmol, 536 mg) and DiPEA (3.5 eq., 3.78 mmol, 625 μL) and the mixture was stirred for 1 hour after which TLC analysis indicated complete conversion of starting material. The solvent was evaporated under reduced pressure en the residue was taken up in EtOAc, extracted with sat. aq. NaHCO3 (2×) and brine, dried over MgSO4 and concentrated in vacuo. The title compound was obtained after purification by column chromatography (EtOAc->2% MeOH/EtOAc) as a pale yellow solid (yield: 334 mg, 1.08 mmol, quant.). 1H NMR (400 MHz, CD3OD): δ=8.40 (d, J=4.59 Hz, 2H), 7.29 (d, J=4.88 Hz, 2H), 6.97 (d, J=7.26 Hz, 1H), 4.77-4.68 (m, 1H), 3.76 (s, 3H), 3.15 (s, 3H), 3.02 (dd, J=13.59, 4.85 Hz, 1H), 2.83-2.77 (m, 1H), 1.32 (s, 9H) ppm. 13C NMR (100 MHz, CD3OD): δ=173.49, 157.58, 149.88, 149.50, 126.48, 80.55, 62.25, 52.71, 38.03, 32.49, 28.66 ppm. [α]D23=−2.9 (c=1, MeOH). HRMS: calcd. for C15H43N3O4 [M+H]+310.17613. found 310.17615.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)=[CH:5][CH:4]=1.Cl.[NH2:20][OH:21]>>[F:1][C:2]([F:18])([F:17])[C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][C:11](=[N:20][OH:21])[CH2:10][CH2:9]2)=[CH:5][CH:4]=1
Reactant: O=C1CCN(Cc2ccc(C(F)(F)F)cc2)CC1
Reactant: NO
Agent: Cl
Product: ON=C1CCN(Cc2ccc(C(F)(F)F)cc2)CC1

Procedure:
1-(4-Trifluoromethylbenzyl)-4-piperidone oxime is prepared from 1-(4-trifluoromethylbenzyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=1)([O-:3])=[O:2].[O:17]=[C:18]1[C:23]([CH:24]=O)=[CH:22][CH:21]=[CH:20][NH:19]1.C(Cl)Cl>CO>[N+:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[CH:24][C:23]3[C:18](=[O:17])[NH:19][CH:20]=[CH:21][CH:22]=3)[C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccc[nH]c1=O
Reactant: O=[N+]([O-])c1ccc2c(c1)Cc1ccccc1-2
Solvent: CO
Solvent: ClCCl
Product: O=c1[nH]cccc1C=C1c2ccccc2-c2ccc([N+](=O)[O-])cc21
Temperature: 85 °C
Reaction time: 24 h

Procedure:
To a solution of 2-nitrofluorene (326 mg, 1.54 mmol) and 2-oxo-1,2-dihydro-pyridine-3-carbaldehyde (19 mg, 1.54 mmol) in 10 mL of methanol was added KF—Al2O3 (224 mg, 1.38 mmol). The resulting mixture was stirred at 85° C. After 24 hrs, TLC indicated that a new product was produced and lots of starting material was still remained. 40 mL of CH2Cl2 was added into the reaction mixture. The insoluble solid was filtrated, and the filtrate was concentrated under vacuum to give a yellow solid, which was purified by silica gel column; eluting with 60% EtOAc in hexane afforded 26 mg of CYD-1-93 as a yellow solid. 1H-NMR (600 MHz, d6-DMSO) δ 12.18 (br s, 2H), 8.77 (d, 1H, J=1.8 Hz), 8.52 (d, 1H, J=1.8 Hz), 8.28 (m, 2H), 8.15 (m, 2H), 8.10 (d, 1H, J=7.8 Hz), 8.06 (m, 2H), 7.97 (m, 2H), 7.86 (m, 2H), 7.80 (s, 1H), 7.63 (m, 1H), 7.59 (m, 1H), 7.49 (m, 3H), 7.37 (m, 1H), 6.40 (m, 2H). 13C-NMR (150 MHz, CDCl3) δ 161.2, 161.1, 146.9, 146.2, 146.1, 143.6, 142.1, 141.7, 140.5, 139.6, 138.3, 137.3, 136.1, 136.0, 133.6, 133.4, 129.3, 129.1, 129.0, 128.8, 127.9, 127.4, 126.1, 125.9, 124.0, 123.9, 123.5, 121.9, 121.5, 121.1, 120.7, 120.5, 119.0, 105.1, 105.0.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:15]=1[N:21]([CH2:26][CH:27](OS(C)(=O)=O)[CH3:28])[S:22]([CH3:25])(=[O:24])=[O:23]>CN(C)C=O>[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:15]=1[N:21]([CH2:26][CH:27]([N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6])[CH3:28])[S:22]([CH3:25])(=[O:23])=[O:24]
Reactant: Cc1cccc(C)c1N(CC(C)OS(C)(=O)=O)S(C)(=O)=O
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1N(CC(C)N1C(=O)c2ccccc2C1=O)S(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
33.3 g/0.19 moles of potassium phthalimide are added to a solution of 30 g (89 mmoles) of 1-[N-(2,6-dimethylphenyl)-methane-sulfonamido]-2-methanesulfonyloxy-propane in 300 ml of dry dimethyl formamide, and the mixture is stirred at 145°-150° C. for one hour. The mixture is cooled, poured onto 800 ml of ice water, and the aqueous mixture is extracted thrice with 200 ml of chloroform, each. The chloroform solution is washed thrice with 50 ml of n sodium hydroxide solution and then thrice with 100 ml of water, each, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The oily residue is triturated with 35 ml of isopropanol, the separated crystalline substance is filtered off, washed with ice-cold isopropanol and dried. 22 g (64.1%) of 1-[N-(2,6-dimethylphenyl)-methanesulfonamido]-2-phthalimido-propane are obtained as a colourless, crystalline substance; m.p.: 124°-127° C.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)[N:7]=[C:6]([CH3:19])[C:5]=2[C:20]([OH:22])=O)[CH2:3][CH2:2]1.Cl.Cl.[CH3:25][C@H:26]1[CH2:31][C@H:30]([N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[CH2:29][CH2:28][NH:27]1>>[CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:17])([F:16])[F:18])[CH:10]=3)[N:7]=[C:6]([CH3:19])[C:5]=2[C:20]([N:27]2[CH2:28][CH2:29][C@@H:30]([N:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)[CH2:31][C@@H:26]2[CH3:25])=[O:22])[CH2:2][CH2:3]1
Reactant: Cc1nn(-c2cccc(C(F)(F)F)c2)c(C2CC2)c1C(=O)O
Reactant: C[C@H]1C[C@H](N2CCCC2)CCN1
Agent: Cl
Product: Cc1nn(-c2cccc(C(F)(F)F)c2)c(C2CC2)c1C(=O)N1CC[C@@H](N2CCCC2)C[C@@H]1C

Procedure:
The title compound was prepared from 5-cyclopropyl-3-methyl-1-(3-trifluoromethyl-phenyl)-1H-pyrazole-4-carboxylic acid (Example 181A) and (trans)-2-methyl-4-pyrrolidin-1-yl-piperidine dihydrochloride (example 199B) in direct analogy to the general procedure used in example 150. MS: 461.2 (MH+).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:14]1([CH2:20][C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]=2[OH:31])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>C(Cl)Cl>[C:5]([C:29]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([OH:31])=[C:21]([CH2:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:30]=1)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Oc1c(Cc2ccccc2)ccc2ccccc12
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1ccccc1)c1cc(Cc2ccccc2)c(O)c2ccccc12
Reaction time: 3 h
Yield: 40 %

Procedure:
A mixture of aluminum chloride (1.25 g, 9.4 mmole) in methylene chloride (25 mL) was stirred at 0° and treated dropwise with benzoyl chloride (1.1 mL, 9.4 mmole) and stirred for 5 minutes. A solution of 2-(phenylmethyl)-1-naphthol (2.0 g, 8.5 mmole) in methylene chloride (6 mL) was added dropwise over 15 minutes, and stirring was continued at 0° for 3 hours. The mixture was poured into 1.0N hydrochloric acid, and the crude product was isolated by extraction with methylene chloride. Recrystallization from toluene provided the title compound (1.15 g, 40%) as pale yellow crystals, mp 152°-155°.
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][C@@H:13]2[C@@H:18]([OH:19])[C@H:17]([OH:20])[C@@H:16]([OH:21])[C@@:15]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]4[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH:40]=[CH2:41])=[CH:34][CH:33]=4)[CH:25]=3)([O:22][CH3:23])[O:14]2)(=O)=O)=CC=1.N1C(C)=CC(C)=CC=1C>CS(C)=O>[CH2:39]([O:38][C:35]1[CH:36]=[CH:37][C:32]([CH2:31][C:26]2[CH:25]=[C:24]([C@:15]3([O:22][CH3:23])[O:14][C@H:13]([CH:12]=[O:11])[C@@H:18]([OH:19])[C@H:17]([OH:20])[C@H:16]3[OH:21])[CH:29]=[CH:28][C:27]=2[Cl:30])=[CH:33][CH:34]=1)[CH:40]=[CH2:41]
Reactant: C=CCOc1ccc(Cc2cc([C@]3(OC)O[C@H](COS(=O)(=O)c4ccc(C)cc4)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Solvent: Cc1cc(C)nc(C)c1
Solvent: CS(C)=O
Product: C=CCOc1ccc(Cc2cc([C@]3(OC)O[C@H](C=O)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Temperature: 150 °C

Procedure:
To a solution of ((2R,3S,4S,5R,6S)-6-(3-(4-(allyloxy)benzyl)-4-chlorophenyl)-3,4,5-trihydroxy-6-methoxytetrahydro-2H-pyran-2-yl)methyl 4-methylbenzenesulfonate (4.5 g, 7.49 mmol) in dry DMSO (30 mL), was added collidine (6.95 mL, 52.44 mmol) and the mixture was heated at 150° C. for 45 min. After the completion of the reaction as monitored by TLC, the reaction mixture was used as such for the next step.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1.Cl[CH2:15][CH:16]1[O:21][CH2:20][CH2:19][N:18]([CH3:22])[CH2:17]1>>[CH3:22][N:18]1[CH2:19][CH2:20][O:21][CH:16]([CH2:15][N:1]2[CH:5]=[C:4]([C:6]3[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=3)[N:3]=[CH:2]2)[CH2:17]1
Reactant: CN1CCOC(CCl)C1
Reactant: N#Cc1ccnc(-c2c[nH]cn2)c1
Product: CN1CCOC(Cn2cnc(-c3cc(C#N)ccn3)c2)C1

Procedure:
The title compound was prepared from 2-(1H-imidazol-4-yl)pyridine-4-carbonitrile and 2-(chloromethyl)-4-methylmorpholine according to the procedure for the preparation of Example 43, part A (heating to 120°). [M+H] Calc'd for C15H17N5O, 284. Found, 284.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH:3]1[CH2:15][C:7]2[C:8]3[CH:9]=[CH:10][NH:11][C:12]=3[CH:13]=[CH:14][C:6]=2[CH2:5][CH2:4]1.[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CC([O-])(C)C.[K+]>C1COCC1>[CH3:1][N:2]([CH3:16])[CH:3]1[CH2:15][C:7]2[C:8]3[CH:9]=[CH:10][N:11]([S:23]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)(=[O:25])=[O:24])[C:12]=3[CH:13]=[CH:14][C:6]=2[CH2:5][CH2:4]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CN(C)C1CCc2ccc3[nH]ccc3c2C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN(C)C1CCc2ccc3c(ccn3S(=O)(=O)c3ccccc3)c2C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of N,N-dimethyl-6,7,8,9-tetrahydro-3H-benzo[e]indol-8-amine (32 mg, 0.2 mmol) in THF is treated with benzenesulfonyl chloride (29.1 mg, 0.22 mmol) followed by KOtBu (19.8 mg, 0.22 mmol), stirred at room temperature for 18 h and concentrated in vacuo. The resultant residue is dissolved in a mixture of DMSO, methanol and water and purified by Gilson preparative HPLC1 to give the title compound, [M+H] 369, retention time (RT) 2.067 minutes. 1Gilson Preparative HPLC conditions: Gilson Preparative HPLC system; YMC Pro C18, 20 mm×50 mm ID, 5 uM column; 2 mL injection; Solvent A: 0.02% TFA/water; Solvent B:0.02% TFA/acetonitrile; Gradient: Time 0: 95% A; 2 min: 95% A; 14 min: 10% A, 15 min: 10% A, 16 min: 95% A; Flow rate 22.5 mL/min; Detection: 254 nm DAD.
Reaction SMILES: B(Br)(Br)Br.[C:5]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18]C)=[CH:15][CH:16]=2)[C:11]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([CH3:20])[CH2:10][C:9]1([CH3:28])[CH3:27])(=[O:7])[CH3:6].O>ClCCl>[C:5]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=2)[C:11]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([CH3:20])[CH2:10][C:9]1([CH3:28])[CH3:27])(=[O:7])[CH3:6]
Reactant: COc1ccc2c(c1)C(C)(c1ccccc1)CC(C)(C)N2C(C)=O
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CC(=O)N1c2ccc(O)cc2C(C)(c2ccccc2)CC1(C)C
Reaction time: 18 h

Procedure:
Boron tribromide (1.30 ml) was added dropwise to a cooled (0° C.) solution of 1-acetyl-6-methoxy-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (0.9 g) in dichloromethane (75 ml). After stirring for 18 h, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, 5% aq. NaHCO3 and water, dried (MgSO4) and concentrated in vacuo.
Reaction SMILES: C[O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][C:9]2[O:19][C:13]3([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[N:12]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:11](=[O:27])[C:10]=2[CH:28]=1.[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.Cl>CC(O)=O>[CH2:30]([N:16]1[CH2:17][CH2:18][C:13]2([N:12]([CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:11](=[O:27])[C:10]3[CH:28]=[C:6](/[CH:5]=[CH:4]/[C:3]([OH:29])=[O:2])[CH:7]=[CH:8][C:9]=3[O:19]2)[CH2:14][CH2:15]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)N(Cc1ccccc1)C1(CCNCC1)O2
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)/C=C/c1ccc2c(c1)C(=O)N(Cc1ccccc1)C1(CCN(Cc3ccccc3)CC1)O2
Yield: 95 %

Procedure:
(E)-3-{1′-Benzyl-3,4-dihydro-3-benzyl-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-acrylic acid methyl ester was obtained by reacting (E)-3-{3,4-dihydro-3-benzyl-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-acrylic acid methyl ester (485 mg, 1.13 mmol, Intermediate 6) with benzyl bromide, according to the procedure described in Example 2, Step A, giving a white solid (544 mg, quantitative). The methyl ester (500 mg, 1.03 mmol) was hydrolyzed with HCl 20% and AcOH following the procedure described Example 55, Step B, giving (E)-3-{1′-benzyl-3,4-dihydro-3-benzyl-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-acrylic acid as a white solid (500 mg, 95%). The resulting product was treated with NH2OTHP according to the procedure described in Example 1, Step B, giving (E)-3-{1-benzyl-3,4-dihydro-3-benzyl-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide as a yellow solid (228 mg, 40%). Finally, removal of the THP protecting group (177 mg, 0.312 mmol) following the procedure described in Example 1, Step C gave (E)-3-{1′-benzyl-3,4-dihydro-3-benzyl-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-N-hydroxy-acrylamide (150 mg, trifluoroacetate salt) after purification by preparative HPLC.
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:11][C:12]([C:14]1[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=1)=O>>[C:2]1([C:1]2[O:8][CH:11]=[C:12]([C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)[N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccccc1
Reactant: CCOC(=O)c1ccc(C(=O)CBr)cc1
Product: CCOC(=O)c1ccc(-c2coc(-c3ccccc3)n2)cc1
Yield: 29 %

Procedure:
In the same manner as in Example 1, benzamide was reacted with ethyl 4-bromoacetylbenzoate to obtain ethyl 4-(2-phenyl-4-oxazolyl)benzoate. The product was recrystallized from ethanol. Yield: 29%. Pale yellow prisms. Melting Point: 110 to 112° C.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][C:12](=[O:13])[C:7]=3[CH:6]=[CH:5][C:4]=2[NH:3][N:2]=1.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C)C=O>[CH2:14]([N:2]1[CH:1]=[C:9]2[C:4]([CH:5]=[CH:6][C:7]3[C:12](=[O:13])[CH2:11][CH2:10][C:8]=32)=[N:3]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C1CCc2c1ccc1[nH]ncc21
Reactant: BrCc1ccccc1
Solvent: CN(C)C=O
Product: O=C1CCc2c1ccc1nn(Cc3ccccc3)cc21
Temperature: 100 °C
Reaction time: 15 h

Procedure:
To a suspension of 7,8-dihydrocyclopenta[e]indazol-6(3H)-one (6.00 g, 34.8 mmol) in 60 mL of dimethylformamide was added benzyl bromide (5.40 mL, 45.5 mmol) and the mixture was heated to 100° C. After 15 hours, the solution was cooled to room temperature and partitioned between chloroform and saturated aqueous NaHCO3. The organic phase was washed with water (3×) and brine and dried over Na2SO4. The solution was concentrated to low volume under vacuum and flash chromatographed on silica gel eluting with EtOAc/dichloroethane (0:100 to 20:80) which removed a minor amount (˜10%) of the faster eluting regioisomer 3-benzyl-7,8-dihydrocyclopenta-[e]indazol-6(3H)-one and gave 2-benzyl-7,8-dihydrocyclopenta[e]indazol-6(2H)-one as a pale yellow solid.