Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH:7]([C:11]1[S:12][CH:13]=[C:14]([C:16](OCC)=[O:17])[N:15]=1)[C:8]([NH2:10])=[NH:9].C(OCC)(=O)C.O>O1CCCC1>[NH:7]([C:11]1[S:12][CH:13]=[C:14]([CH2:16][OH:17])[N:15]=1)[C:8]([NH2:10])=[NH:9]
Reactant: CCOC(=O)c1csc(NC(=N)N)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: N=C(N)Nc1nc(CO)cs1
Yield: 62.2 %

Procedure:
To a suspension of lithium aluminum hydride (0.5 g) in dry tetrahydrofuran (260 ml) is portionwise added 2-guanidino-4-ethoxycarbonylthiazole (3.6 g) at 0° C. with stirring in half an hour, and the resultant mixture is refluxed under stirring for 4 hours. Ethyl acetate and water are added to the reaction mixture for decomposing excess lithium aluminum hydride. The organic layer is separated and the residual layer is extracted with methanol. The methanolic extract is combined with the organic layer, dried over anhydrous sodium sulfate and concentrated in vacuum. The residue is chromatographed on a column of silica gel, which is eluted with ethyl acetate:methanol (4:1, v/v). The eluate is concentrated in vacuum to give 2-guanidino-4-hydroxymethylthiazole (1.8 g) as crystals melting at 163°-165° C. The yield is 62.2%.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][CH:9]([O:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[C:19]([O:23][CH3:24])[NH:20]2)=[C:16]([NH2:25])[N:15]=1)[CH2:10][CH2:11][CH3:12].C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][CH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>CN(C=O)C.CCOC(C)=O>[CH3:8][CH:9]([O:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]2[CH2:33][CH:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[C:16]([NH2:25])[N:15]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CCCC(C)Oc1nc(N)c2nc(OC)[nH]c2n1
Reactant: BrCC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCCC(C)Oc1nc(N)c2nc(OC)n(CC3CCOCC3)c2n1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 44.1 %

Procedure:
To a solution of 2-[(1-methylbutyl)oxy]-8-methoxy-9H-purin-6-amine trifluoroacetic acid salt (218 mg) in dry DMF (3.71 mL) was added potassium carbonate (330 mg). The mixture was stirred at 60° C. for 90 mins. The reaction was cooled and 4-(bromomethyl)tetrahydro-2H-pyran (118 mg) was added. The reaction was stirred at 50° C. for 6 h and was cooled to room temperature. The mixture was taken up in EtOAc (40 mL) and washed with water (2×20 mL). The organics were separated, dried over MgSO4 and concentrated in vacuo to give a viscous yellow oil. The material was purified by C18 reverse phase chromatography (ISCO) using water (0.1% formic acid)-acetonitrile (0.05% formic acid) as eluent (20-60%) to afford the title compound as a clear oil (92 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([NH:10][C:11](=[O:27])[C:12]2[CH:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=3)[CH:15]=[C:14]([CH:25]=O)[CH:13]=2)[CH3:9])=[N:6][CH:7]=1.O1CCOCC1.N1C=CC=CC=1.[Cl-].[NH4+:41].[OH2:42]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([NH:10][C:11](=[O:27])[C:12]2[CH:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=3)[CH:15]=[C:14](/[CH:25]=[N:41]/[OH:42])[CH:13]=2)[CH3:9])=[N:6][CH:7]=1
Reactant: O
Reactant: [NH4+]
Reactant: Cc1ccc(-c2cc(C=O)cc(C(=O)N[C@H](C)c3ccc(F)cn3)c2)nc1
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: Cc1ccc(-c2cc(/C=N/O)cc(C(=O)N[C@H](C)c3ccc(F)cn3)c2)nc1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
To a solution of N-[(1R)-1-(5-fluoro-2-pyridinyl)ethyl]-3-formyl-5-(5-methyl-2-pyridinyl)benzamide (1.10 g, 3.01 mmol) in dioxane (15 mL) hydroxylamine hydrochloride salt (0.314 g, 4.52 mmol) and pyridine (0.73 mL, 9.04 mmol). The reaction mixture was stirred at 70° C. for 18 h. The mixture was cooled to ambient temperature. Saturated aqueous ammonium chloride and water were added. The mixture was extracted with dichloromethane (3×). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (95% dichloromethane/methanol→85% dichloromethane/methanol) gave the title compound (0.91 g). MS 379.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:36]=[C:37]([F:39])[CH:38]=1)[CH2:5][C@H:6]1[C@@H:10]([C@H:11]2[CH2:20][C:19]3[C:14](=[C:15]([OH:21])[CH:16]=[CH:17][CH:18]=3)[CH2:13][N:12]2[CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:9][C:8](=[O:35])[NH:7]1.[CH3:40][Si](C=[N+]=[N-])(C)C>C(OCC)C.CO>[CH:22]([N:12]1[C@@H:11]([C@H:10]2[O:9][C:8](=[O:35])[NH:7][C@H:6]2[CH2:5][C:4]2[CH:3]=[C:2]([F:1])[CH:38]=[C:37]([F:39])[CH:36]=2)[CH2:20][C:19]2[C:14](=[C:15]([O:21][CH3:40])[CH:16]=[CH:17][CH:18]=2)[CH2:13]1)([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C1N[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2Cc3cccc(O)c3CN2C(c2ccccc2)c2ccccc2)O1
Solvent: CCOCC
Solvent: CO
Product: COc1cccc2c1CN(C(c1ccccc1)c1ccccc1)[C@@H]([C@H]1OC(=O)N[C@H]1Cc1cc(F)cc(F)c1)C2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A 60 mg (0.11 mmol) portion of (4S,5S)-4-(3,5-difluorobenzyl)-5-((R)-2-benzhydryl-8-hydroxy-1,2,3,4-tetrahydroisoquinolin-3-yl)oxazolidin-2-one from Step F (14) was dissolved in 2.5 mL of a 4:1 solution of diethyl ether and methanol. A 0.5 mL portion of 2M trimethylsilyldiazomethane was added and the solution was stirred at rt for 16 h. The excess diazomethane was quenched with the addition of several drops of acetic acid and the solvents were removed in vacuo to provide the desired product. 1H NMR (500 MHz, CDCl3) δ ppm 2.45-2.59 (m, 1H) 3.16-3.22 (m, 1H) 3.25 (dd, J=10.07, 5.49 Hz, 1H) 3.67 (s, 3H) 3.76 (s, 1H) 3.80 (d, J=2.14 Hz, 1H) 3.83 (d, J=2.44 Hz, 1H) 3.97-4.03 (m, 1H) 4.08 (d, J=18.62 Hz, 1H) 4.70 (dd, J=10.22, 6.56 Hz, 1H) 4.85 (s, 1H) 4.92 (s, 1H) 6.66 (d, J=7.93 Hz, 1H) 6.78 (d, J=7.63 Hz, 3H) 7.14-7.19 (m, 1H) 7.20-7.29 (m, 5H) 7.32 (t, J=7.63 Hz, 2H) 7.35 (d, J=7.02 Hz, 2H) 7.42 (d, J=7.32 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C@H:9]1[CH2:15][NH:14][C:13](=S)[C@H:12]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:11][CH2:10]1.[Cl-].[F:26][C:27]([F:34])([F:33])[CH2:28][CH:29]([OH:32])[CH2:30][NH3+:31].C(N(CC)CC)C>C(O)C.[Hg](Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C@H:9]1[CH2:15][NH:14]/[C:13](=[N:31]\[CH2:30][CH:29]([OH:32])[CH2:28][C:27]([F:34])([F:33])[F:26])/[C@H:12]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:11][CH2:10]1
Reactant: [NH3+]CC(O)CC(F)(F)F
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2c(F)cccc2F)CNC1=S
Agent: Cl[Hg]Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2c(F)cccc2F)CN/C1=N\CC(O)CC(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Mercury(II) chloride (538 mg, 1.98 mmol) was added to a solution of tert-butyl [(3R,6S)-6-(2,6-difluorophenyl)-2-thioxoazepan-3-yl]carbamate (353 mg, 0.99 mmol), 4,4,4-trifluoro-2-hydroxybutan-1-aminium chloride (498 mg, 2.77 mmol), and triethylamine (0.61 mL, 4.36 mmol) in ethanol (10 mL) at 55° C. After 2 h, the reaction was allowed to cool to ambient temperature. The mixture was filtered and concentrated. Saturated aqueous sodium bicarbonate was added and the mixture was extracted with dichloromethane (2×). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated to give the title compound. MS 466.2 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:18])[C:13]([C:19]([NH:21][CH3:22])=O)=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CNC(C1N(C)C2C(C=1)=CC=CC=2)=O>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:18])[C:13]([CH2:19][NH:21][CH3:22])=[CH:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNC(=O)c1cc2cc(OCc3ccccc3)ccc2n1C
Agent: CNC(=O)c1cc2ccccc2n1C
Product: CNCc1cc2cc(OCc3ccccc3)ccc2n1C
Yield: 69 %

Procedure:
According to the procedure of Preparation 1(b), except substituting 5-benzyloxy-N,1-dimethylindole-2-carboxamide (37.4 g, 126.7 mmole) for the N,1-dimethylindole-2-carboxamide, the title compound (24.5 g, 69%) was prepared as a white solid: MS (ES) m/e 281 (M+H)+.
Reaction SMILES: [OH-].[Na+].OO.[CH3:5][C:6]1([CH3:34])[CH2:11][O:10][CH:9]([CH:12]([C@@H:14]2[C@:31]3([CH3:32])[C@H:17]([C@H:18]4[C@H:28]([CH2:29][CH2:30]3)[C@:26]3([CH3:27])[C:21](=[CH:22][C:23](=[O:33])[CH:24]=[CH:25]3)[CH:20]=[CH:19]4)[CH2:16][CH2:15]2)[CH3:13])[O:8][CH2:7]1.C(OCC)(=[O:37])C.CCCCCC>CO.O>[CH3:34][C:6]1([CH3:5])[CH2:7][O:8][CH:9]([CH:12]([C@@H:14]2[C@:31]3([CH3:32])[C@H:17]([C@H:18]4[C@H:28]([CH2:29][CH2:30]3)[C@:26]3([CH3:27])[C:21](=[CH:22][C:23](=[O:33])[C@@H:24]5[O:37][C@@H:25]53)[CH:20]=[CH:19]4)[CH2:16][CH2:15]2)[CH3:13])[O:10][CH2:11]1
Reactant: CC(C1OCC(C)(C)CO1)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Reactant: CCOC(C)=O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCCCCC
Solvent: CO
Product: CC(C1OCC(C)(C)CO1)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 16 h
Yield: 77 %

Procedure:
A 10 weight % solution of sodium hydroxide in methanol (1.16 ml) and 6.36 ml of a 30 weight % solution of hydrogen peroxide in water (containing 62.3 mmoles of hydrogen peroxide) were added to a solution of 4.66 g (11.3 mmoles) of 20-(5,5-dimethyl-1,3-dioxan-2-yl)pregna-1,4,6-trien-3-one in 150 ml of methanol and the mixture was stirred at room temperature for 16 hours. The reaction mixture thus obtained was diluted with water and after the methanol was partially distilled off under reduced pressure at room temperature, the residue was extracted with ether. The extract was washed successively with aqueous potassium iodide solution and aqueous sodium chloride solution and the organic layer was dried over magnesium sulfate. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel chromatography (eluent: ethyl acetate/hexane=1:10, v/v) to recover 3.72 g of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxypregna-4,6-dien-3-one (yield: 77%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:39])[C@H:10]([CH:36]([CH3:38])[CH3:37])[NH:11][C:12](=[O:35])[C@@H:13]([CH2:31][CH:32]([CH3:34])[CH3:33])[NH:14][C:15](=[O:30])[CH:16]([OH:29])[CH:17]1[CH2:21][CH2:20][CH2:19][N:18]1C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:40].O1CCOCC1>ClCCl>[ClH:40].[CH2:1]([O:8][C:9](=[O:39])[C@H:10]([CH:36]([CH3:38])[CH3:37])[NH:11][C:12](=[O:35])[C@@H:13]([CH2:31][CH:32]([CH3:33])[CH3:34])[NH:14][C:15](=[O:30])[CH:16]([OH:29])[CH:17]1[CH2:21][CH2:20][CH2:19][NH:18]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C[C@@H](NC(=O)C(O)C1CCCN1C(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)OCc1ccccc1)C(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)C[C@@H](NC(=O)C(O)C1CCCN1)C(=O)N[C@H](C(=O)OCc1ccccc1)C(C)C

Procedure:
[2-Hydroxy-2-(N-t-butyloxycarbonylpyrrolidin-2-yl)acetyl]-D-leucylvaline benzyl ester (100 mg) was dissolved in dichloromethane (1 ml) and 1 ml of a 4N hydrochloric acid/dioxane solution was added to the solution under cooling with ice to conduct a reaction at room temperature for 2 h. The reaction liquid was concentrated under reduced pressure and the residue was washed with n-hexane several times and concentrated to give [2-hydroxy-2-(pyrrolidin-2-yl)acetyl]-D-leucylvaline benzyl ester hydrochloride.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16]([Cl:19])(=[O:18])=[O:17])=[CH:12][CH:11]=1>>[CH3:20][C:10]1[CH:15]=[CH:14][C:13]([S:16]([Cl:19])(=[O:18])=[O:17])=[CH:12][C:11]=1[N+:1]([O-:4])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1ccc(S(=O)(=O)Cl)cc1[N+](=O)[O-]
Yield: 88 %

Procedure:
To a mixed solution of fuming nitric acid (3.5 ml) and conc. sulfuric acid (5.4 ml) was added p-toluenesulfonyl chloride (5.00 g, 26.2 mmol) in several portions under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr. To the reaction mixture was added ice, and the mixture was extracted with diethyl ether. The organic layer was successively washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to give 4-methyl-3-nitrobenzenesulfonyl chloride (5.43 g, yield 88.0%).
Reaction SMILES: N1(C[C:8]([CH:12]2[CH2:17]O[CH2:15][CH2:14][N:13]2C)=CC#N)CCOCC1.[C:19](Cl)(=O)[CH2:20][CH3:21]>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH3:15][CH2:14][N:13]([CH:12]([CH3:17])[CH3:8])[CH:20]([CH3:21])[CH3:19]
Reactant: CN1CCOCC1C(=CC#N)CN1CCOCC1
Reactant: CCC(=O)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCN(C(C)C)C(C)C
Yield: 78 %

Procedure:
Prepared according to General Procedure A using 4-(-N-morpholinyl)-3(-N methyl-morpholinyl)-but-2-enenitrile (45.0 mg, 0.179 mmol), TiCl4.(THF)2 (120 mg, 0.359 mmol), i-Pr2NEt (125 μL, 0.716 mmol), and propionyl chloride (0.54 mL 1M solution HC2Cl2, 054 mmol) in 1.8 mL of CH2Cl2 at −20° C. to provide the pure product in 78% yield 5.7 mg, 0.139 mmol) as a white solid; mp 92-94 ° C.; 95:5 syn-anti:syn-syn by 1H NMR. Syn-anti isomer: IR (film)2974, 2920, 2858, 1637, 1444, 1359; 1112, 1074, 911, 850, 734 cm−1; 1H NMR (400 MHZ, CDCl3) δ 5.11 (s, 1H, CH2═C), 4.95 (s, 1H, CH2═C) 3.75 (d, J=9.2 Hz, 1H, CHCN) 3.47-3.67 (m, 16H, O(CH2CH2,)2N) 3.10 (dq, J=7.5, 15.3 Hz, 1H, (CHCHCN) 2.92 (m, 1H, (OC)CHCH2), 2.54 (dd, J=8.6, 15.0 Hz, 1H, CH2C═CH2) 2.14 (dd, J=5.6, 15.2 Hz, 1H, CH2C═CH2) 1.30 (d, J=6.8 Hz, 3H, CH3), 1.10 (d, J=6.8 Hz, 3H, CH3), 13C NMR (100 MHZ) δ; 173.7, 171.0, 140.8, 116.1, 112.2, 66.8, 66.7, 66.6, 46.0, 45.9, 42.2, 42.0, 40.5, 37.8, 37.2, 33.6, 17.9, 16.4; LRMS (CI) m/z 363 (M)+; HRMS (CI) exact mass calcd for (C19H29N3O4)+ requires m/z 363.2158, found m/z 363.2162.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].Br[C:17]1[CH:18]=[C:19]([S:23]([C:26]2[CH:27]=[N:28][C:29]3[C:34]([CH:35]=2)=[CH:33][CH:32]=[CH:31][C:30]=3I)(=[O:25])=[O:24])[CH:20]=[CH:21][CH:22]=1>>[C:12]([O:11][C:9]([N:2]1[CH2:3][CH:4]2[CH2:8][N:7]([C:17]3[CH:18]=[C:19]([S:23]([C:26]4[CH:27]=[N:28][C:29]5[C:34]([CH:35]=4)=[CH:33][CH:32]=[CH:31][C:30]=5[N:7]4[CH2:6][CH:5]5[CH2:1][N:2]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3][CH:4]5[CH2:8]4)(=[O:25])=[O:24])[CH:20]=[CH:21][CH:22]=3)[CH2:6][CH:5]2[CH2:1]1)=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Reactant: O=S(=O)(c1cccc(Br)c1)c1cnc2c(I)cccc2c1
Product: CC(C)(C)OC(=O)N1CC2CN(c3cccc(S(=O)(=O)c4cnc5c(N6CC7CN(C(=O)OC(C)(C)C)CC7C6)cccc5c4)c3)CC2C1
Yield: 12 %

Procedure:
The title compound was prepared by analogy to the procedure of 1.3, except using tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate and 3-(3-bromophenylsulfonyl)-8-iodoquinoline. 18 mg (12%) of the title compound were obtained as a pale yellow solid
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:11]([CH2:45][CH:46]([CH3:48])[CH3:47])=[N:12][C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)=[CH:17][C:16]([NH:27]C(=O)OCC1C3C=CC=CC=3C3C1=CC=CC=3)=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1CCCCC1.O>CN(C)C=O>[NH2:27][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([CH2:45][CH:46]([CH3:48])[CH3:47])[C:10]([CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[C:19]2[C:20]1[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=1
Reactant: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(NC(=O)OCC4c5ccccc5-c5ccccc54)cc23)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCNCC1
Product: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(N)cc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
To a solution of 9H-fluoren-9-ylmethyl 3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-4-(4-methylphenyl)-6-quinolinylcarbamate (1.28 g, 2.0 mmol) in N,N-dimethylformamide (20 ml) was added piperidine (1 ml), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium-sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give tert-butyl [6-amino-2-isobutyl-4-(4-methylphenyl)-3-quinolinyl]methylcarbamate (0.81 g, yield 96.4%).
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[C:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(O)[CH2:5][CH2:6]2.S(=O)(=O)(O)O.[OH-:22].[Na+].[C:24](#[N:26])[CH3:25]>>[CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[C:4]([NH:26][C:24](=[O:22])[CH3:25])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][CH2:6]2
Reactant: [OH-]
Reactant: CC#N
Reactant: CN1C2CCC1C(O)(c1ccccc1)CC2
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(=O)NC1(c2ccccc2)CCC2CCC1N2C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of 210 mg (0.966 mmol) 8-methyl-2-phenyl-8-aza-bicyclo[3.2.1]octan-2-ol in 1.6 ml acetonitrile under nitrogen at 0° C., was added drop-wise 560 ul (10.43 mmol) sulfuric acid (98%) over a period of 10 minutes. The colorless solution was then stirred at room temperature for 48 hours. The solution was poured onto ice. The mixture was basified with NaOH 5N and extracted 3 times with dichloromethane. The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude colorless oil (209 mg) was purified with flash column chromatography on silica (20 g) eluting with a gradient formed from n-heptane and ethyl acetate (0 to 100%) to provide 180 mg (y: 72.1%) of the title compound as a colorless oil. MS (m/e): 259.2 (M+H+).
Reaction SMILES: [C:1]([O:7][CH2:8][CH2:9][O:10][CH2:11]/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:16][CH:15]=1)(=[O:6])[CH2:2][C:3]([CH3:5])=O.[NH2:27]/[C:28](/[CH3:34])=[CH:29]\[C:30]([O:32][CH3:33])=[O:31].[N+:35]([C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][CH:45]=1)[CH:41]=O)([O-:37])=[O:36]>C(O)C>[CH3:5][C:3]1[NH:27][C:28]([CH3:34])=[C:29]([C:30]([O:32][CH3:33])=[O:31])[CH:41]([C:40]2[CH:43]=[CH:44][CH:45]=[C:38]([N+:35]([O-:37])=[O:36])[CH:39]=2)[C:2]=1[C:1]([O:7][CH2:8][CH2:9][O:10][CH2:11]/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:16][CH:15]=1)=[O:6]
Reactant: CC(=O)CC(=O)OCCOC/C=C/c1ccc(Cc2cccnc2)cc1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: COC(=O)/C=C(/C)N
Solvent: CCO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCOC/C=C/c2ccc(Cc3cccnc3)cc2)C1c1cccc([N+](=O)[O-])c1
Yield: 60.6 %

Procedure:
In 10 ml of ethanol were dissolved 1.0 g of 2-[(E)-3-[4-(pyridin-3-ylmethyl)phenyl]allyloxy]ethyl acetoacetate, 330 mg of methyl 3-aminocrotonate and 430 mg of 3-nitrobenzaldehyde, and the resulting solution was subjected to reaction under reflux for 9 hours. Subsequently, the solvent was removed by distillation under reduced pressure, and the residue thus obtained was purified by a column chromatography [Wako Silica Gel C-200, eluant: toluene:ethyl acetate (1:1 by volume)] to obtain 1.0 g (yield 60.6%) of yellow, oily 3-[2-[(E)-3-[4-(pyridin-3-ylmethyl)phenyl]allyloxy]ethyl] 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8]O)=[C:6]([CH3:10])[CH:5]=[CH:4][N:3]=1.BrP(Br)Br.[CH3:15][C:16]1[N:21]=[C:20]([SH:22])[N:19]=[C:18]([OH:23])[CH:17]=1.C(N(CC)CC)C>ClCCl>[CH3:1][C:2]1[C:7]([CH2:8][S:22][C:20]2[N:19]=[C:18]([OH:23])[CH:17]=[C:16]([CH3:15])[N:21]=2)=[C:6]([CH3:10])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: Cc1ccnc(C)c1CO
Agent: BrP(Br)Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(O)nc(SCc2c(C)ccnc2C)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
(2,4-dimethylpyridin-3-yl)methanol was dissolved in dichloromethane (100 mL). Tribromophosphane (1.5 mL, 16 mmol) was added slowly. After 2 hours, the mixture was evaporated to dryness. The crude solid was dissolved in cold ethanol (100 mL), and 6-methyl-2-sulfanylpyrimidin-4-ol (1.13 g, 8.0 mmol) and triethylamine (4.5 mL, 32 mmol) were added. The resulting mixture was stirred at room temperature for 3 hours. The solvent was evaporated, and the crude solid was washed with THF (200 mL). After evaporation of solvent, the crude was purified by CombiFlash (0-6% MeOH in DCM) to provide 2-{[(2,4-dimethylpyridin-3-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (2.5 g, 64% yield); 1H NMR (500 MHz, DMSO-d6): δ 2.23 (s, 3H), 2.68 (s, 3H), 2.84 (s, 3H), 4.62 (s, 2H), 6.05 (br, 1H), 7.71 (s, 1H), 8.62 (s, 1H); M+ 232.
Reaction SMILES: [CH3:1][C:2](C)([O-])[CH3:3].[K+].[OH:7][C:8]1[C:12]2[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:11]=2[O:10][C:9]=1[C:19]([O:21][CH3:22])=[O:20].BrC(C)C.Cl>CS(C)=O.O>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]2[O:10][C:9]([C:19]([O:21][CH3:22])=[O:20])=[C:8]([O:7][CH:2]([CH3:3])[CH3:1])[C:12]=2[CH:13]=1
Reactant: COC(=O)c1oc2ccc(OC)cc2c1O
Reactant: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Solvent: CC(C)Br
Solvent: O
Product: COC(=O)c1oc2ccc(OC)cc2c1OC(C)C
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A solution of potassium tert-butoxide (12.0 g, 107 mmol) in 50 mL of methyl sulfoxide is cooled in a cold water bath while a solution of methyl 3-hydroxy-5-methoxy-2-benzofurancarboxylate (16.2 g, 73 mmol) [Connor D. T., et al., J. Med, Chem. 35, 958 (1992)] in 150 mL of methyl sulfoxide is added dropwise. The mixture is stirred for 45 minutes and 2-bromopropane (12.0 mL, 15.7 g, 128 mmol) is added in one portion. After stirring at room temperature for 48 hours, the mixture is added to 1.2 kg of ice and water and acidified with 6.0N HCl . The mixture is extracted with dichloromethane, and the combined organic layers are washed with water, 5% aqueous Na2CO3, and water again, then dried (anhydrous sodium sulfate) and evaporated to an oil residue. The oil is purified by bulb-to-bulb vacuum distillation to provide 14.2 g (74%) to methyl 5-methoxy-3 -(1-methylethoxy)-2-benzofurancarboxylate, suitable for further synthesis; mp=55°-63° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][C:3]=1[O:13][CH3:14].CCN(CC)CC.[CH3:22][C:23]([Si:26](Cl)([CH3:28])[CH3:27])([CH3:25])[CH3:24]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:23]([Si:26]([CH3:28])([CH3:27])[O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][C:3]=1[O:13][CH3:14])([CH3:25])([CH3:24])[CH3:22]
Reactant: COc1cc2c(cc1O)C(=O)CCC2
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1O[Si](C)(C)C(C)(C)C)C(=O)CCC2
Reaction time: 2 h
Yield: 95.2 %

Procedure:
To a well-stirred solution of 7-Hydroxy-6-methoxy-1-tetralone (80.0 mg, 0.42 mmol) in CH2Cl2, was added Et3N (47 mg, 0.46 mmol), followed by DMAP (5.1 mg, 0.042 mmol) and TBSCl (69 mg, 0.46 mmol) at 0° C. under dry nitogen. After 2 h (at rt), the mixture was partitioned between CH2Cl2 and water. The organic layer was dried over anhydrous sodium sulfate, and after filtration, the organic layer was concentrated in vacuo to provide a yellow oil. 7-[(tertButyldimethylsilyl)oxy]-6-methoxy-1-tetralone (122 mg, 0.40 mmol, 95%) was obtained following purification by column chromatography. 1H-NMR (CDCl3, 300 MHz) 0.15 (s, 6H), 0.99 (s, 9H),2.11 (m, 2H), 2.58 (t, J=6.1 Hz, 2H), 2.88 (t, J=6.0 Hz, 2H), 3.86 (s, 3H), 6.63 (s, 1H), 7.56 (s, 1H).