Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH:18]=[CH2:19])[CH:13](O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1C=CC(P([N:66]=[N+:67]=[N-:68])(C2C=CC=CC=2)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH:18]=[CH2:19])[CH:13]([N:66]=[N+:67]=[N-:68])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCC1CCN(C(=O)OCc2ccccc2)CC1O
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=CCC1CCN(C(=O)OCc2ccccc2)CC1N=[N+]=[N-]
Reaction time: 4 h

Procedure:
To a stirred solution of 4-Allyl-3-hydroxy-piperidine-1-carboxylic acid benzyl ester (293 mg, 1.06 mmol) were added triphenyl phosphine(362 mg, 1.38 mmol), a solution of diethyl azodicarboxylate in toluene (0.6 ml, 1.38 immol; 40% solution) and DPPA (297 μL, 1.38 mmol). After stirring for 4 h, the mixture was evaporated and the residue was purified by column chromatography (15% AcOEt-hexane)to give 4-Allyl-3-azido-piperidine-1-carboxylic acid benzyl ester.
Reaction SMILES: [CH2:1]([C:4]1([S:7]([O-:10])(=O)=[O:8])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[K+].S(Cl)([Cl:14])=O>CN(C=O)C>[CH2:1]([C:4]1([S:7]([Cl:14])(=[O:10])=[O:8])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: O=S(Cl)Cl
Reactant: C=CCC1(S(=O)(=O)[O-])CC1
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCC1(S(=O)(=O)Cl)CC1

Procedure:
A solution of potassium 1-allylcyclopropane-1-sulfonate (3.44 g, 17.2 mmol), thionyl chloride (10 ml) and DMF (5 drops) was refluxed at 60° C. for 16 h. The volatiles evaporated under reduced pressure and the residue extracted with CH2Cl2 (50 ml). The extract was washed with water, dried (MgSO4) and evaporated to obtain the crude product as yellow gummy oil which was washed with hexane and used in the next reaction without further purification (2.7 g, 15 mmol, 87%). 1HNMR (300 MHz, CDCl3): δ 5.728 (m, 1H), 5.191 (t, 2H), 2.9 (d, 2H), 0.756 (m, 2H), 0.322 (m, 2H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5][C:6]1[C:15]2[O:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:12]([CH3:22])[C:11](=[O:23])[C:10]=2[CH:9]=[CH:8][CH:7]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:37][CH2:36][N:35]([CH2:2][CH2:3][CH2:4][S:5][C:6]2[C:15]3[O:14][C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[C:12]([CH3:22])[C:11](=[O:23])[C:10]=3[CH:9]=[CH:8][CH:7]=2)[CH2:34][CH2:33]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: Cc1c(-c2ccccc2)oc2c(SCCCCl)cccc2c1=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1N1CCN(CCCSc2cccc3c(=O)c(C)c(-c4ccccc4)oc23)CC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 61.1 %

Procedure:
A mixture of 4.4 g of Intermediate XXXIV, 2.5 g of 1-(2-methoxyphenyl)-piperazine, 1 g of potassium iodide and 1.8 g of anhydrous potassium carbonate in 40 ml of dimethylformamide was stirred at 100° C. for 3 hours. After cooling to 20°-25° C., the reaction mixture was poured into 350 ml of water and extracted with dichloromethane. The organic extracts were washed with water and dried on anhydrous sodium sulfate, and the solvent was then evaporated off in vacuo. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate: petroleum ether 3:2, and by crystallization from ethanol, yielding 3.9 g of the title compound, m.p. (70) 96°-99° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12][Si](C=[N+]=[N-])(C)C>C1(C)C=CC=CC=1.CO>[CH3:12][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:2]=1[OH:1]
Reactant: Cc1ccc(C(=O)O)c(O)c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)c1ccc(C)cc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-hydroxy-4-methylbenzoic acid (1.52 g, 10 mmol) in toluene (6 mL) and methanol (2 mL) at 0° C. is added trimethylsilyldiazomethane (2 M in hexane, 6 mL, 12 mmol) dropwise. The mixture is then warmed up to ambient temperature and it is stirred for 2 h. The solvent is removed under reduced pressure and the residue is purified by flash chromatography to give the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C@H:3]([OH:10])[CH2:4][C:5](OCC)=[O:6].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[F:1][C:2]([F:12])([F:11])[C@H:3]([OH:10])[CH2:4][CH2:5][OH:6]
Reactant: CCOC(=O)C[C@@H](O)C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCC[C@@H](O)C(F)(F)F
Temperature: 25 °C
Reaction time: 20 h
Yield: 96.7 %

Procedure:
A solution of ethyl (R)-(+)-4,4,4trifluoro-3-hydroxybutyrate (3.12 g, 16.8 mmol) in diethyl ether (8 mL) was added to a 0–5° C. suspension of lithium aluminium hydride (1.01 g, 26.6 mmol) in diethyl ether (17 mL) over 25 minutes. Upon complete addition, the mixture was stirred at ambient temperature for 20 h. The mixture was cooled to 0–5° C. and quenched by dropwise addition of 3N HCl (17 mL), followed by stirring at ambient temperature for 3 h. The liquid portion was decanted away and the salts were washed with additional diethyl ether. The combined organic portions were washed (brine), dried, and evaporated to give the product as a cloudy, colourless oil (2.34 g, 96%).
Reaction SMILES: [C:1]([C:5]12[CH2:11][CH:9]([CH2:10]1)[CH2:8][CH:7]([C:12]([O:14]C)=[O:13])[CH2:6]2)([O:3]C)=[O:2].O.[OH-].[Li+]>O1CCCC1.C(O)(C)C.O>[C:1]([C:5]12[CH2:11][CH:9]([CH2:10]1)[CH2:8][CH:7]([C:12]([OH:14])=[O:13])[CH2:6]2)([OH:3])=[O:2]
Reactant: COC(=O)C1CC2CC(C(=O)OC)(C2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: O=C(O)C1CC2CC(C(=O)O)(C2)C1
Yield: 379.1 %

Procedure:
A stirred solution of 1,3-dicarbomethoxybicyclo[3.1.1]heptane (1.90 g, 8.95 mmol) in tetrahydrofuran (25 mL) and isopropanol (8 mL) was treated with a solution of lithium hydroxide hydrate (2.1 g, 50 mmol) in water (25 mL), and the mixture was heated to 60°-70° C. for 3 h with stirring. The organic solvents were removed in vacuo, and the alkaline aqueous solution was cooled on an ice bath and acidified with 6N hydrochloric acid (10 mL). The solid was filtered, rinsed with cold water, and partially air dried overnight, then further dried under vacuum to afford 6.25 g (86%) of subject material as a white solid. No MS could be obtained. 1H NMR (CDCl3) δ 2.40-2.50 (m, 2H), 1.90-2.00 (m, 4H), 1.80-1.90 (m, 2H), 1.70-1.80 (m, 2H).
Reaction SMILES: P([O-])(O)(O)=O.[K+].N(S([O-])(=O)=O)(S([O-])(=O)=[O:10])[O].[K+].[K+].[OH:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([O:30][CH:31]([CH3:35])[C:32]([OH:34])=[O:33])=[CH:22][CH:21]=1>O.C(O)C>[C:32]([CH:31]([O:30][C:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:20](=[O:19])[C:21](=[O:10])[CH:22]=1)[CH3:35])([OH:34])=[O:33]
Reactant: CC(Oc1ccc(O)c2ccccc12)C(=O)O
Reactant: [O]N(S(=O)(=O)[O-])S(=O)(=O)[O-]
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(OC1=CC(=O)C(=O)c2ccccc21)C(=O)O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 38.0 g potassium dihydrogen phosphate in 7.5 liters of distilled water (pH 4.0) was added 89.4 g (0.33 mole) of potassium nitrosodisulfonate (Fremy's reagent). To this solution was added immediately a solution of 34.8 g (0.15 mole) of 2-(4-hydroxy-1-naphthoxy)propionic acid in 125 ml ethanol. The mixture was stirred for 2.5 hours under nitrogen at room temperature. The yellow-brown solid was collected, washed with a little water and dried (under nitrogen). The yield was 30.0 g (81 percent). The crude product melted at 182° to 184° C.
Reaction SMILES: Cl[CH2:2][C@@H:3]1[O:12][CH2:11][C@@H:6]2[CH2:7][O:8][CH2:9][CH2:10][N:5]2[CH2:4]1.[C:13]([O-:16])(=[O:15])[CH3:14].[K+]>CN(C=O)C>[C:13]([O:16][CH2:2][CH:3]1[O:12][CH2:11][CH:6]2[CH2:7][O:8][CH2:9][CH2:10][N:5]2[CH2:4]1)(=[O:15])[CH3:14]
Reactant: CC(=O)[O-]
Reactant: ClC[C@H]1CN2CCOC[C@H]2CO1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OCC1CN2CCOCC2CO1
Temperature: 140 °C
Reaction time: 16 h
Yield: 41.5 %

Procedure:
A suspension of (3R,9aS)-3-(chloromethyl)hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazine (1.97 g, 10.3 mmol) and potassium acetate (10.1 g, 102 mmol) in DMF (20.0 mL) was stirred at 140° C. for 16 h, and then at 150° C. for another 12 h. The reaction mixture was partitioned between water (250 mL) and ethyl acetate (250 mL), the organic layer was washed with 5% lithium chloride (2×100 mL) and brine (100 mL) then dried over anhydrous sodium sulfate and concentrated in vacuo. Column chromatography (SiO2, 1:1 hexane:ethyl acetate, then 100% ethyl acetate) afforded 0.92 g (42%) of hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl acetate as a yellow oil. Distinct diastereomers as described above were converted in this step to give: (3R,9aS)-hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl acetate: 1H NMR (400 MHz, CDCl3): 4.18 (dd, 1H), 4.00 (m, 1H), 3.80 (dd, 1H), 3.68 (dt, 1H), 3.60 (dd, 1H), 3.46 (m, 2H), 3.22 (t, 1H), 2.64 (dd, 1H), 2.53 (m, 2H), 2.43-2.35 (m, 2H), 2.10 (s, 3H), and (3S,9aS)-hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl acetate: 1H NMR (400 MHz, CDCl3): 4.09 (d, 2M), 3.90-3.82 (m, 2H), 3.75-3.64 (m, 3H), 3.27 (t, 1H), 3.18 (t, 1H), 2.69 (dd, 1H), 2.63 (m, 1H), 2.46-2.33 (m, 2H), 2.16 (t, 1H), 2.10 (s, 3H).
Reaction SMILES: [NH3:1].[CH:2]1([C:5]2[N:10]=[C:9]([O:11][CH3:12])[N:8]=[C:7](C(Cl)(Cl)Cl)[N:6]=2)[CH2:4][CH2:3]1>O1CCCC1>[NH2:1][C:7]1[N:6]=[C:5]([CH:2]2[CH2:4][CH2:3]2)[N:10]=[C:9]([O:11][CH3:12])[N:8]=1
Reactant: N
Reactant: COc1nc(C2CC2)nc(C(Cl)(Cl)Cl)n1
Solvent: C1CCOC1
Product: COc1nc(N)nc(C2CC2)n1
Temperature: 80 °C

Procedure:
5 ml of concentrated aqueous ammonia are added to a solution of 1 g of 2-cyclopropyl-4-methoxy-6-trichloromethyl-1,3,5-triazine in 3 ml of tetrahydrofuran; the whole is placed into a bomb tube and heated at 80° C. for 30 minutes. The mixture is cooled and then filtered; the filter residue is dissolved in 30 ml of methylene chloride, and the solution is dried over magnesium sulfate, and concentrated by evaporation. The residue crystallises to leave 0.4 g of white crystals, m.p. 157°-158° C.
Reaction SMILES: [OH:1][C@H:2]([C@@H:8]([OH:20])[CH:9]1[CH2:11][N@@:10]1[C@@H:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13])[C:3]([O:5][CH2:6][CH3:7])=O.[Li+].[Cl-].[BH4-].[Na+].[H-].[Na+].[CH:27]1[CH:32]=[CH:31][C:30]([CH2:33]Br)=[CH:29][CH:28]=1>CCO.CN(C=O)C.C(OCC)(=O)C>[C:14]1([C@H:12]([N@:10]2[CH2:11][CH:9]2[C@H:8]([O:20][CH2:12][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C@@H:2]([O:1][CH2:33][C:30]2[CH:31]=[CH:32][CH:27]=[CH:28][CH:29]=2)[CH2:3][O:5][CH2:6][C:7]2[CH:3]=[CH:2][CH:8]=[CH:9][CH:11]=2)[CH3:13])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)[C@H](O)[C@@H](O)C1C[N@@]1[C@H](C)c1ccccc1
Agent: CCOC(=O)[C@H](O)[C@@H](O)C1C[N@]1[C@H](C)c1ccccc1
Agent: [BH4-]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: C[C@H](c1ccccc1)[N@]1CC1[C@H](OCc1ccccc1)[C@H](COCc1ccccc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
To a solution of (2R,3S)-ethyl 2,3-dihydroxy-3-((R)-1-((R)-1-phenylethyl)aziridin-2-yl)propanoate (1 g, 3.57 mmol) in EtOH was added LiCl (756 mg, 17.85 mmol, 5 equiv) and NaBH4 (680 mg, 17.85 mmol, 5 equiv) at 0° C. The reaction mixture was stirred for 20 hrs at 0° C. and quenched with water. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over MgSO4, filtered through a pad of celite and concentrated in vacuo. The resulting alcohol was used without further purification. To a slurry of NaH (471 mg, 11.78 mmol, 60% dispersion in mineral oil, 3.3 equiv) in DMF (6 mL, 2 M) was added a solution of the resulting alcohol in DMF (7 mL, 0.5 M) at 0° C. After 30 min, BnBr (1.4 mL, 11.78 mmol, 3.3 equiv) was added. The reaction mixture was stirred for 6 hrs at room temperature, diluted with ethyl acetate and quenched with water. The mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The resulting crude product was purified by silica gel flash chromatography with ethyl acetate/hexane (1/9 to 1/6) to afford the title product. Yield: 1.29 g (71% over 2 steps); yellow oil.
Reaction SMILES: [F:1][CH:2]([CH3:11])[C:3](=O)[CH2:4][C:5]([O:7]CC)=O.Cl.[C:13](=[NH:18])([NH2:17])[CH2:14][CH2:15][CH3:16].C[O-].[Na+]>CO.C(OCC)(=O)C>[F:1][CH:2]([C:3]1[N:17]=[C:13]([CH2:14][CH2:15][CH3:16])[NH:18][C:5](=[O:7])[CH:4]=1)[CH3:11]
Reactant: CCOC(=O)CC(=O)C(C)F
Reactant: CCCC(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCc1nc(C(C)F)cc(=O)[nH]1
Reaction time: 8 h
Yield: 100.4 %

Procedure:
A mixture of ethyl 4-fluoro-3-oxopentanoate (5.0 g), butanimidamide hydrochloride (4.6 g) and sodium methoxide (28% methanol solution, 16 mL) in methanol (50 mL) was stirred overnight. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale yellow oil (5.7 g, 100%).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2([CH:15]=[C:16]([F:19])[CH2:17][OH:18])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1.O>C1C=CC=CC=1.N1C=CC=CC=1>[C:1]([O:18][CH2:17][C:16]([F:19])=[CH:15][C:12]1([C:9]2[CH:8]=[CH:7][C:6]([Cl:5])=[CH:11][CH:10]=2)[CH2:13][CH2:14]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: OCC(F)=CC1(c2ccc(Cl)cc2)CC1
Solvent: c1ccncc1
Solvent: O
Solvent: c1ccccc1
Product: CC(=O)OCC(F)=CC1(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 87 %

Procedure:
Acetyl chloride (0.72 ml) was slowly added to a stirred solution of 1-(4-chlorophenyl)-1-(2-fluoro-3-hydroxyprop-1-enyl)cyclopropane (Example 9) (0.36 g) in benzene (20 ml) and pyridine (0.14 ml) at 0° C., and stirring was continued for 24 h while the mixture warmed to room temperature. After addition of water (10 ml), the mixture was extracted with diethyl ether (3×20 ml) and the combined organic layers were washed with water (3×10 ml) and evaporated under reduced pressure. The residue was chromatographed on silica using diethyl ether/hexane (1:9) to yield 1-(3-acetoxy-2-fluoroprop-1-enyl)-1-(4-chlorophenyl)cyclopropane (0.37 g, 87%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][C:3]=12.[NH2:19][NH2:20].CO>>[NH:19]([C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][C:3]=12)[NH2:20]
Reactant: NN
Reactant: C[Si](C)(C)CCOCn1ccc2c(Br)ccnc21
Solvent: CO
Product: C[Si](C)(C)CCOCn1ccc2c(NN)ccnc21
Temperature: 97 °C
Yield: 92 %

Procedure:
To 4-bromo-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine (1.98 g, 0.00605 mol) was added hydrazine (11.0 mL, 0.350 mol) followed by addition of methanol (1.0 mL, 0.025 mol) (to improve solubility). The reaction mixture was heated in a sealed tube at 97° C. (an oil bath) for 18 h. The reaction mixture was cooled to rt and formed an off-white solid precipitate. The solid was filtered off and rinsed with cold water and dried to give 4-hydrazino-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine (1.55 gm) as a light yellow solid, LC/MS (M+H)+:279, 1H NMR (DMSO-d6) δ 7.98(d, 1H), 7.91(s, 1H), 7.28(d, 1H), 6.69(s, 1H), 6.61(d, 1H), 5.58(s, 2H), 4.37(s, 2H), 3.56(t, 2H), 0.90(t, 2H), 0.0(s, 9H).
Reaction SMILES: [C:1]([NH:4][C:5]([NH2:7])=[S:6])(=[NH:3])[NH2:2].N1CC[CH2:11][CH2:10][CH2:9]1>CC(C)=O>[NH2:3][C:1]1[NH:2][C:10]([CH3:11])([CH3:9])[N:7]=[C:5]([SH:6])[N:4]=1
Reactant: N=C(N)NC(N)=S
Reactant: C1CCNCC1
Solvent: CC(C)=O
Product: CC1(C)N=C(S)N=C(N)N1
Yield: 80 %

Procedure:
In the 200 ml of acetone was refluxed for 3 hours 7.1 g (0.06 mole) of amidinothiourea in the presence of 6 ml of piperidine. After having been allowed to cool, the reaction mixture was filtered to collect 7.6 g (in 80% yield) of colorless powder as deposited. Recrystallization from alcohol gave 7.0 g (in 74% yield) of colorless branch-like crystals, m.p. 186.5°-187.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.C(O)(=O)C.[CH3:14][C:15]([CH3:17])=O.C([BH3-])#N.[Na+].C1COCC1.Cl>CO>[CH:15]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)([CH3:17])[CH3:14]
Reactant: COc1ccc(N)cc1
Reactant: CC(C)=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(NC(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a stirred solution of 4-methoxyphenylamine (1.24 g, 6.22 mmol) in methanol (15 mL) at ambient temperature was added successively, glacial acetic acid (415 mg, 6.91 mmol), acetone (669 mg, 11.5 mmol), and 1M sodium cyanoborohydride in THF (12.7 mL, 12.6 mmol). The reaction mixture was stirred overnight at room temperature. The pH was adjusted to 2 with 6N HCl and stirred for 30 minutes to quench excess sodium cyanoborohydride. The pH was then adjusted to 8.5 with 1N NaOH and the resultant solution extracted with diethyl ether (2×50 mL) and ethyl acetate (50 mL). The organic extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (1.42 g, 5.91 mmol) as a yellow oil. 1H NMR (300 MHz, CDCl3): δ 6.78(d, J=8.8 Hz, 2H), 6.57(d, J=9.1 Hz, 2H), 3.75(s, 3H), 3.55(m, 1H), 2.92(br s, 1H), 1.18(d, J=6.1 Hz, 6H); TLC (EtOAc/Hex (2:3)): Rf =0.72
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][CH2:9][NH2:10].I.CS[C:14]1[C:22]2[CH:23]=[CH:24][CH:25]=[C:20]3[C:21]=2[C:16](=[CH:17][CH:18]=[CH:19]3)[N:15]=1.C(O)C.[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33]>CC(C)=O>[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][CH2:9][NH:10][C:14]1[C:22]2[CH:23]=[CH:24][CH:25]=[C:20]3[C:21]=2[C:16](=[CH:17][CH:18]=[CH:19]3)[N:15]=1
Reactant: CSC1=Nc2cccc3cccc1c23
Reactant: NCCOc1ccccn1
Agent: I
Agent: O=C(O)/C=C/C(=O)O
Solvent: CC(C)=O
Solvent: CCO
Product: c1ccc(OCCNC2=Nc3cccc4cccc2c34)nc1

Procedure:
A mixture consisting of 3.0 grams of 2-(2-pyridinyloxy) ethylamine, 6.5 grams of 2-methylthiobenz(cd)indole hydriodide, and 150 ml of ethanol was stirred and heated under reflux, utilizing the conditions of Example 16. The crude free base (weight, 7.1 grams) was dissolved in 20 ml of acetone and added to a stirred boiling solution of 5.5 grams of fumaric acid in 1200 ml of acetone. After cooling the precipitate of the title compound was collected, washed with acetone, and dried; yield, 7.6 grams; mp 184° C.-185° C. with decomposition.
Reaction SMILES: [Br:1][CH:2]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][NH:4][C:3]1=[O:11].I[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].[H-].[Na+].[NH4+].[Cl-]>C1COCC1>[Br:1][CH:2]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][N:4]([CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:3]1=[O:11]
Reactant: O=C1NCCCCCCC1Br
Reactant: CC(C)(C)OC(=O)CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CN1CCCCCCC(Br)C1=O
Reaction time: 2 h

Procedure:
Add a solution of 7.35 g. 3-bromoperhydroazonin-2-one [Nagasawa et al., J. Med. Chem., 14, 501 (1971)]and 8.47 g t-butyl iodoacetate in 70 ml THF to a suspension of 0.881 g sodium hydride in 35 ml THF. After 2 hours at room temperature, add 15 ml saturated NH4Cl solution, filter and concentrate the filtrate in vacuo. Partition the residue between ether and H2O and wash the organic phase with H2O and brine. Dry the ether solution and filter. Decolorize the filtrate with charcoal, filter and concentrate the filtrate in vacuo to isolate 3-bromo-1-t-butoxycarbonylmethylperhydroazonin-2-one. Purify a sample for characterization by silica gel chromatography. Anal. C14H24BrNO3). Calc: C, 50.31; H, 7.24; N, 4.18; Br, 23.91. Found: C, 49.86; H, 7.33; N, 4.30; Br, 23.51. Mass spectrum: M+ at 334; m/e: 278 (M+ --C 4 H8); 261 (M+ --C4H9O); 232 (M+ --C4H9CO2 --H, base).
Reaction SMILES: [C:1]1([CH:7]2[O:12][CH2:11][CH:10]([OH:13])[CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:21]12([C:31](Cl)=[O:32])[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]3)[CH2:22]1)[CH2:28]2>CN(C)C1C=CN=CC=1.ClCCl>[C:21]12([C:31]([O:13][CH:10]3[CH2:11][O:12][CH:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[O:8][CH2:9]3)=[O:32])[CH2:28][CH:27]3[CH2:26][CH:25]([CH2:24][CH:23]([CH2:29]3)[CH2:22]1)[CH2:30]2
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: OC1COC(c2ccccc2)OC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OC1COC(c2ccccc2)OC1)C12CC3CC(CC(C3)C1)C2
Reaction time: 15 h
Yield: 80 %

Procedure:
1.00 g (5.55 mmol) of 2-phenyl[1.3]dioxan-5-ol, 1.16 ml (8.32 mmol) of triethylamine and 68 mg (0.56 mmol) of 4-dimethylaminopyridine were dissolved in 20 ml of dichloromethane, and 1.28 g (6.10 mmol) of 1-adamantanecarbonyl chloride was added thereto with stirring under ice-cooling, followed by stirring for 30 minutes at the same temperature, and then further for 15 hours at room temperature. Dichloromethane was distilled off under reduced pressure, and to the residue was added aqueous sodium hydrogencarbonate and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane:ethyl acetate=9:1) to give 1.52 g of the title compound as a pale yellow powder (yield: 80%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Br[C:9]1[CH:10]=[CH:11][C:12]([O:29][CH2:30][CH3:31])=[C:13]([C:15]2[NH:16][C:17](=[O:28])[C:18]3[N:23]([CH3:24])[N:22]=[C:21]([CH2:25][CH2:26][CH3:27])[C:19]=3[N:20]=2)[CH:14]=1>>[CH2:30]([O:29][C:12]1[CH:11]=[CH:10][C:9]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:14][C:13]=1[C:15]1[NH:16][C:17](=[O:28])[C:18]2[N:23]([CH3:24])[N:22]=[C:21]([CH2:25][CH2:26][CH3:27])[C:19]=2[N:20]=1)[CH3:31]
Reactant: Brc1ccccn1
Reactant: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(Br)ccc3OCC)nc12
Product: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(-c4ccccn4)ccc3OCC)nc12

Procedure:
The title compound was prepared form 2-bromopyridine and 5-(5-bromo-2-ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-one, following the procedure described in Example 32, and was obtained as an off-white solid (33%), m.p. 216°-218° C. Found C,67.61; H,5.81; N,17.63. C22H23N5O2 requires C,67.85; H,5.95; N,17.98%.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][N:14]([C:27]1[CH:28]=[C:29]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:30]=[CH:31][CH:32]=1)[C:15](=[O:26])[C:16]1[CH:21]=[CH:20][C:19]([O:22]C)=[C:18]([O:24][CH3:25])[CH:17]=1)=O)(C)(C)C.F[C:40]([F:45])([F:44])C(O)=O.ClCCl>C(#N)C>[C:29]1([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:30]=[CH:31][CH:32]=[C:27]([N:14]([CH2:13][C@@H:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)[C:15](=[O:26])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH:40]([F:44])[F:45])=[C:18]([O:24][CH3:25])[CH:17]=2)[CH:28]=1
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc(C(=O)N(C[C@@H]2CCCN2C(=O)OC(C)(C)C)c2cccc(-c3ccccc3)c2)cc1OC
Solvent: CC#N
Solvent: ClCCl
Product: COc1cc(C(=O)N(C[C@@H]2CCCN2)c2cccc(-c3ccccc3)c2)ccc1OC(F)F

Procedure:
Experimental condition analogous to Example 1, from 1 g (1.94 mmol) of 2-(S)-{[biphenyl-3-yl-(3,4-dimethoxy-benzoyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester, 25 mL of trifluoroacetic acid and 100 mL of dichloromethane. Gave 0.75 gram of white semi solid: LC-MSD, m/z for: C26H26F2N2O3 [M+H]: 452.2. LC retention time on HPLC, C18 column gradient 20-95% acetonitrile with 0.1% TFA in 7 minutes: 3.54.