Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:15])=[O:13])=[CH:8][CH:7]=1.[C:25]([C:27]1[CH:28]=[C:29]([CH:44]=[CH:45][CH:46]=1)[O:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([O:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:32]=1)#[CH:26].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CCCCCC>[O:37]([C:33]1[CH:32]=[C:31]([CH:36]=[CH:35][CH:34]=1)[O:30][C:29]1[CH:28]=[C:27]([C:25]#[C:26][C:2]2[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=2)[O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:15])=[O:13])=[CH:8][CH:7]=2)[CH:46]=[CH:45][CH:44]=1)[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: C#Cc1cccc(Oc2cccc(Oc3ccccc3)c2)c1
Reactant: O=C(C(=O)c1ccc(Oc2cccc(Br)c2)cc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: O=C(C(=O)c1ccc(Oc2cccc(C#Cc3cccc(Oc4cccc(Oc5ccccc5)c4)c3)c2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 44.1 %

Procedure:
To a 250 ml flask fitted with a reflux condenser, nitrogen inlet and thermometer were added 4(3-bromophenoxy)benzil (11.08 g, 29.08 mmol), 1-(3-ethynylphenoxy)-3-phenoxybenzene (21.64 g, 75.66 mmol), triethylamine (150 ml), and triphenylphosphine (0.40 g). After stirring at room temperature under a nitrogen atmosphere for 10 minutes, cuprous iodide (Alfa 98%, 0.20 g) and dichlorobis (triphenylphosphine) palladium (II) (0.20 g) were added. The flask was heated to an internal temperature of 90° C. and maintained by oil bath heating under nitrogen until TLC indicated reaction completion (4 hr). The triethylamine was distilled from the residue and the residue was suspended in toluene. The toluene was washed with 15% HCl (560 ml) twice and separated. The organic layer was washed with ethylenediamine (20 ml) by adding the ethylenediamine at room temperature, heating to 60° C. for 0.5 h and cooling. Water (250 ml) was added and the toluene was separated from the aqueous layer. The ethylenediamine wash was repeated once more. After washing with water (3×500 ml), the organic layer was dried over anhydrous magnesium sulfate (3.00 g) and the toluene distilled by rotary evaporation at reduced pressure to give a dark brown oil. The oil was dissolved in 4:1 hexane:methylene chloride and chromatographed on a silica gel column (Woelm DCC, 230 g, 5 cm dia×25 cm H) using 4:1 hexane:methylene chloride as the eluent. The product was dried in a 70° C. oven under reduced pressure to afford a light brown tacky oil (7.52 g, 44%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O-:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:12]OC(OC)OC>CO>[CH3:12][O:10][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=1
Reactant: COC(OC)OC
Reactant: O=C([O-])Cc1cccc(O)c1
Solvent: CO
Product: COC(=O)Cc1cccc(O)c1

Procedure:
To a solution of 3-hydroxyphenylacetate (2.0 g) in methanol (10 ml), 250 mg of tosic acid monohydrate and 2.9 ml of trimethoxymethane were added, and the reaction solution was heated to reflux for 5 hours. The reaction solution was cooled, and then the solvent was distilled off under reduced pressure. The residual residue was diluted with diethyl ether, washed with a saturated aqueous sodium bicarbonate solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: ethyl acetate/hexane (0:100-50:50)) to afford the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:21](N1C=CN=C1)(N1C=CN=C1)=[S:22]>CN(C)C=O>[N:1]([C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1)=[C:21]=[S:22]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2)CC1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N=C=S)cc2)CC1
Reaction time: 1 h
Yield: 104.2 %

Procedure:
A solution of 4-(4-aminophenyl)-1-piperazinecarboxylic acid, 1,1-dimethylethyl ester (15 g, 54.1 mmol) (from Step B above) in N,N-dimethyl-formamide (120 mL) was added dropwise to a cooled (−15° C.) solution of 1,1′-thiocarbonyldiimidazole (9.66 g, 54.2 mmol) (Aldrich) in N,N-dimethylformamide (40 mL). After the addition was complete, the cooling bath was removed and the solution was stirred for 1 h. The mixture was poured into ice-water (1 L), stirred for 30 minutes, and extracted with diethyl ether. The combined extracts were dried over Na2SO4, and evaporated in vacuo to provide 4-(4-isothio-cyanatophenyl)-1-piperazinecarboxylic acid, 1,1-dimethylethyl ester (18 g, 94%).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]([O:9]CC)=O)=[N:4][N:3]=1.C(O)C.[CH3:15][NH2:16]>CO>[NH2:1][C:2]1[S:6][C:5]([C:7]([NH:16][CH3:15])=[O:9])=[N:4][N:3]=1
Reactant: CCOC(=O)c1nnc(N)s1
Reactant: CN
Solvent: CO
Solvent: CCO
Product: CNC(=O)c1nnc(N)s1
Temperature: 25 °C
Reaction time: 6 h
Yield: 102.3 %

Procedure:
To a suspension of ethyl 5-amino-1,3,4-thiadiazole-2-carboxylate (106 mg, 0.612 mmol) in methanol (1.5 mL) was added 33 wt % ethanol solution of methylamine (0.5 mL, 4.00 mmol). The mixture was stirred at room temperature for 6 h, heated to 70° C. and cooled. The mixture was concentrated, mixed with water and lyophilized to give 5-amino-N-methyl-1,3,4-thiadiazole-2-carboxamide as a white solid (99 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.69 (q, J=4.8 Hz, 1H), 7.70 (s, 2H) 2.73 (d, J=4.78 Hz, 3H); MS (ES+) m/z: 159 (M+H); LC retention time: 0.44 min (analytical HPLC Method A).
Reaction SMILES: C([O:4][CH:5](OC(=O)C)[C:6]([CH3:13])=[CH:7][CH2:8][O:9][C:10](=[O:12])[CH3:11])(=O)C.C(O)=O>O>[C:10]([O:9][CH2:8]/[CH:7]=[C:6](\[CH3:13])/[CH:5]=[O:4])(=[O:12])[CH3:11]
Reactant: CC(=O)OCC=C(C)C(OC(C)=O)OC(C)=O
Solvent: O
Solvent: O=CO
Product: CC(=O)OC/C=C(\C)C=O
Reaction time: 3 h
Yield: 75.6 %

Procedure:
48.8 parts of 1,1,4-triacetoxy-2-methyl-but-2-ene, having the isomer composition stated in Example 1, 400 parts of formic acid and 10.8 parts of water are boiled for 3 hours. After stripping off the formic acid and water on a rotary evaporator, fractional distillation of the residue gives 21.5 parts of 4-acetoxy-2-methylcrotonaldehyde (75.6% of theory) of boiling point 102°-105° C./21 mbar (nD20 =1.4642). According to NMR analysis, the aldehyde obtained consists of 98.3% (E)- and 1.7% (Z)-4-acetoxy-2-methylcrotonaldehyde.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].N1C=CN=C1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>CN(C)C=O>[Si:14]([O:2][C:1]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: Oc1ccccc1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccccc1O
Reaction time: 3 h
Yield: 66 %

Procedure:
To a stirred solution of catechol (5.5 g; 50 mmol) in 20 mL of dimethylformamide was added imidazole (7.14 g; 105 mmol) and t-butyldimethylsilylchloride (7.53 g; 50 mmol). The reaction mixture was stirred for 3 hours after which time TLC showed the reaction to be complete. The reaction mixture was chromatographed directly onto silica gel and eluted with 5% ethyl acetate in hexane to give 7.4 g (66%) of the monosilyl catechol 16. NMR (CDCl3) δ6.963 (dd, J=8.0, 1.6 Hz, 1H, ArH), 6.891 (dt, J=8.0, 2.0 Hz, 1H, ArH), 6.847 (dd, J=8.0, 1.6 Hz, 1H, ArH), 6.773 (dt, J=7.6, 1.6 Hz, 1H, ArH), 5.518 (s, 1H, OH), 0.996 (s, 9H, CCH3), 0.252 (s, 6H, SiCH3); 13C NMR (CDCl3) δ147.250, 142.550, 122.143, 119.989, 117.835, 114.870, 25.730, 18.193, -4.322.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[C:18]4[C:17]5[CH:19]=[C:20]([NH:23][C:24](=[O:33])[C:25]6[C:30]([Cl:31])=[CH:29][N:28]=[C:27](Cl)[CH:26]=6)[CH:21]=[CH:22][C:16]=5[CH2:15][CH2:14][C:13]=4[C:12]([C:34]([NH2:36])=[O:35])=[N:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[C:18]4[C:17]5[CH:19]=[C:20]([NH:23][C:24](=[O:33])[C:25]6[C:30]([Cl:31])=[CH:29][N:28]=[C:27]([N:41]7[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]7)[CH:26]=6)[CH:21]=[CH:22][C:16]=5[CH2:15][CH2:14][C:13]=4[C:12]([C:34]([NH2:36])=[O:35])=[N:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CN1CCNCC1
Reactant: NC(=O)c1nn(-c2ccc3c(c2)OCO3)c2c1CCc1ccc(NC(=O)c3cc(Cl)ncc3Cl)cc1-2
Product: CN1CCN(c2cc(C(=O)Nc3ccc4c(c3)-c3c(c(C(N)=O)nn3-c3ccc5c(c3)OCO5)CC4)c(Cl)cn2)CC1
Temperature: 100 °C
Yield: 46 %

Procedure:
A mixture of the title compound of Example 211 (1.2 g, 0.0023 mol) and N-methylpiperazine (4.6 mL, 0.046 mol) was heated at 100° C. in a sealed tube for 24 h. The completion of the reaction was checked by HPLC. After removal of the volatiles under vacuum, the residue was partitioned between water and CH2Cl2. The organic layer was washed an additional time with water and dried over MgSO4. The crude product mixture was purified by chromatography on silica gel using CH2Cl2/MeOH: 12/1 to 10/2 to give 0.62 g of the title product, yield: 46%. Mp: 305–307° C. 1H NMR (400 MHz, d6-DMSO): δ 2.18 (s, 3H), 2.34–2.35 (d, 2H, J=5 Hz), 2.89–2.91 (m, 4H), 3.49 (d, 2H, J=5 Hz), 6.08 (s, 2H), 6.91–7.03 (m, 3H), 7.1 (d, 1H, J=2 Hz), 7.24–7.3 (m, 3H), 7.38–7.41 (dd, 1H, J=8.3 Hz, 2 Hz), 7.49 (s, 1H), 8.13 (s, 1H), 10.33 (s, 1H). M+1=587.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[CH:7]=1)[CH:3]=[O:4].C(O)(C)C.[BH4-].[Na+].Cl>C(OCC)C>[CH3:1][C:2]([CH3:13])([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[CH:7]=1)[CH2:3][OH:4]
Reactant: Cc1cccc(CC(C)(C)C=O)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCOCC
Product: Cc1cccc(CC(C)(C)CO)c1
Temperature: 20 °C
Reaction time: 24 h

Procedure:
44 g of 2,2-dimethyl-3-(3-methylphenyl)-propionaldehyde (according to Example 3) were added in small portions under argon and at 20° C. to a pre-mix of 150 ml of isopropanol and 3.8 g of sodium borohydride. The entire mixture was stirred for 24 hours at 20° C. Excess sodium borohydride was then decomposed by the dropwise addition of 2N HCl. The reaction mixture was then taken up in 150 ml of diethyl ether and extracted with water, 2N NaOH and, again, with water.
Reaction SMILES: [H-].[Na+].[CH:3]1([OH:8])[CH2:7][CH2:6][CH2:5][CH2:4]1.[NH2:9][C:10]1[N:18]=[C:17]2[C:13]([N:14]=[CH:15][N:16]2[C@H:19]2[CH2:23][C@H:22]([OH:24])[C@@H:21]([CH2:25][OH:26])[CH2:20]2)=[C:12](Cl)[N:11]=1.Cl>>[NH2:9][C:10]1[N:18]=[C:17]2[C:13]([N:14]=[CH:15][N:16]2[C@H:19]2[CH2:23][C@H:22]([OH:24])[C@@H:21]([CH2:25][OH:26])[CH2:20]2)=[C:12]([O:8][CH:3]2[CH2:7][CH2:6][CH2:5][CH2:4]2)[N:11]=1
Reactant: OC1CCCC1
Reactant: Nc1nc(Cl)c2ncn([C@@H]3C[C@H](CO)[C@@H](O)C3)c2n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: Nc1nc(OC2CCCC2)c2ncn([C@@H]3C[C@H](CO)[C@@H](O)C3)c2n1
Temperature: 25 °C

Procedure:
Sodium hydride (60% oil dispersion, 113 mg)was added to cydopentanol (7mL). To the resulting solution, after effervescence had ceased, was added (+)-(1S-2R4R)-4-(2-amino-6-chloro-9H-purin-yl)-2-(hydroxymethyl)cyclopentanol (400 mg, 1.4 mmol). The solution was maintained at 8° for 40 minutes, cooled to room temperature, and neutralized with 1N hydrochloric acid. Volatiles were removed and the residue chromatographed on silica gel. Title compound was eluted with methanol: chloroform/15:85 as a white solid foam which solidified form acetonitrile: methanol/20:1 as a white powder (223 mg, 48%), m.p. 181°-182°; mass spectrum (Cl, CH4): 334(M+1); 1H-NMR(DMSO-d6)δ: 7.97 (s, 1, H8), 6.32 (brs, 2, NH2), 5.60 (m, 1, CHO of cydopentyl) 5.0-4.8 (m, 1, CHN), 4.78 (d. J=4.1 Hz, 1, OH), 4.66 (t,J=5.1 Hz, 1, CH2OH), 4.1 (m, 1, CHOH), 3.6-3.4 (m, 2, CH2O), 2.4-1.9 (m, 6 methylene), 1.9-1.5 (m, 7, methylene); [α]20589 +9.34°, [α]20578 +9.85°, [α]20546 +11.1°, [α]20430 +18.2°, [α]20365 +26.6° (c=0.782, methanol).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([I:15])=[CH:9][CH:8]=3.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[I:15][C:10]1[CH:9]=[CH:8][C:7]2[N:6]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28])[C:5]3[C:13]([C:12]=2[CH:11]=1)=[CH:14][C:2]([I:1])=[CH:3][CH:4]=3
Reactant: OCCCCCCCCCCCBr
Reactant: Ic1ccc2[nH]c3ccc(I)cc3c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: OCCCCCCCCCCCn1c2ccc(I)cc2c2cc(I)ccc21
Reaction time: 24 h
Yield: 88.2 %

Procedure:
To a solution of 3,6-diiodocarbazole (10.0 g, 23.87 mmol) and 11-bromo-1-undecanol (7.0 g, 27.87 mmol) in DMF (100.0 ml) was added K2CO3 (32.0 g, 231.33 mmol). The reaction was carried out at room temperature for 24 h. Water (300 ml) was added. The precipitate was filtered. The crude product was purified by silica gel column using Hexane/ethyl acetate (7:3) as solvent. 12.4 g (87.9%) of pure product as white solid was obtained. 1H-NMR (CDCl3, TMS, 500 MHZ): δ=8.32 (d, 2Harom, J=1.5 Hz), 7.71 (dd, 2Harom, J1=1.5 Hz, J2=8.5 Hz), 7.16 (dd, 2Harom, J1=1.5 Hz, J2=8.5 Hz), 4.21 (t, 2H, NCH2), 3.64 (m, 2H, OCH2), 3.41 (t, 1H, OH), 1.81 (m, 4H, 2×CH2), 1.54 (m, 4H, 2×CH2), 1.30 (m, 10H, 5×CH2) ppm.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([O-:28])=[O:27])=[C:15]([CH2:18][O:19][C:20](=[O:25])[CH2:21][C:22]([CH3:24])=[O:23])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[C:32](=[O:44])([O:37][CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1)[O:33][CH:34](I)[CH3:35].C(OCC)(=O)C>CN(C)C=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([O:28][CH:34]([O:33][C:32]([O:37][CH:38]4[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]4)=[O:44])[CH3:35])=[O:27])=[C:15]([CH2:18][O:19][C:20](=[O:25])[CH2:21][C:22]([CH3:24])=[O:23])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(I)OC(=O)OC1CCCCC1
Reactant: CC(=O)CC(=O)OCC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)Cc3csc(N)n3)[C@H]2SC1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)CC(=O)OCC1=C(C(=O)OC(C)OC(=O)OC2CCCCC2)N2C(=O)[C@@H](NC(=O)Cc3csc(N)n3)[C@H]2SC1
Temperature: -5 °C
Yield: 52.9 %

Procedure:
In 30 ml of N,N-dimethylformamide is dissolved 4.76 g of sodium 7β-[2-(2-aminothiazol-4-yl]acetamido]-3-acetoacetoxymethylceph-3-em-4-carboxylate and the solution is cooled to -5° C. With stirring, to the solution is added dropwise 5.0 g of 1-iodoethyl cyclohexyl carbonate, followed by stirring for further 5 minutes. The reaction mixture is poured into a mixture of 300 ml of ethyl acetate and 200 ml of ice water and the organic layer is separated. The aqueous layer is extracted with 200 ml of ethyl acetate. The organic layers are combined and washed with 150 ml each portion of ice water (three times) and saturated aqueous sodium chloride (three times) and then dried over anhydrous magnesium sulfate. The solution is then distilled off under reduced pressure and isopropyl ether is added to the residue. The resultant white powder is collected by filtration, washed with isopropyl ether and dried to obtain 3.3 g of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@:12]([CH2:19][CH:20]([CH3:22])[CH3:21])([CH3:18])[CH2:13][C:14]([O:16][CH3:17])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[CH3:24][CH:25]([N-]C(C)C)[CH3:26].C(Br)C=C>C1COCC1>[CH2:26]([C@@H:13]([C@@:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])([CH2:19][CH:20]([CH3:22])[CH3:21])[CH3:18])[C:14]([O:16][CH3:17])=[O:15])[CH:25]=[CH2:24]
Reactant: COC(=O)C[C@](C)(CC(C)C)NC(=O)OCc1ccccc1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CC[C@H](C(=O)OC)[C@](C)(CC(C)C)NC(=O)OCc1ccccc1
Temperature: -80 °C
Reaction time: 0.33 h

Procedure:
500 mg (1.71 mmol) of methyl(S)-3-benzyloxycarbonylamino-3-isobutyl-butanoate, prepared according to the procedure described in Liebigs Ann., pp 1217-1228 (1995), is dissolved in 10 mL of dry THF and cooled under Argon to -80° C. 1.881 mL (3.762 mmol) of 2M LDA is added, and the mixture is stirred at -40° C. for 20 minutes. The reaction is cooled to -78° C., and 828 mg (6.84 mmol) of allyl bromide are added. The mixture is stirred at -78° C. for 5 hours and at room temperature overnight. The reaction is quenched with 20 mL of 1M pH 7 phosphate buffer. The pH is lowered to 2 with 1N HCl. The water layer is extracted with EtOAc. The combined organic layers are dried over MgSO4, and concentrated to provide the crude product, which is purified by chromatography using 70% hexanes/30% EtOAc as eluant to give the title compound.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]([N:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)=[O:30])[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[Cl:37][C:38]1[CH:43]=[C:42](B(O)O)[CH:41]=[CH:40][N:39]=1>>[Cl:37][C:38]1[CH:43]=[C:42]([N:17]2[C:18]3[C:14](=[CH:13][C:12]([C:10]([N:7]4[CH2:6][CH2:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:9][CH2:8]4)=[O:11])=[CH:20][CH:19]=3)[CH:15]=[C:16]2[C:21]([N:23]2[CH2:24][CH2:25][N:26]([C:29]([N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:30])[CH2:27][CH2:28]2)=[O:22])[CH:41]=[CH:40][N:39]=1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(C(=O)N5CCCCC5)CC4)cc3c2)CC1
Reactant: OB(O)c1ccnc(Cl)c1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCN(C(=O)N4CCCCC4)CC2)n3-c2ccnc(Cl)c2)CC1
Yield: 62 %

Procedure:
The title compound was synthesized in analogy to example 5, after stirring for 3.5 days at 35° C., from {4-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carbonyl]-piperazin-1-yl}-piperidin-1-yl-methanone (example 14) and 2-chloropyridine-4-boronic acid to afford the desired product as a light-brown foam (62%). MS (ISP): 606.1 (M+H)+.
Reaction SMILES: CC1(C)[O:13][C@@H:12]2[C@@H:4]([CH2:5][N:6]3[C@@H:11]2[C@H:10]([OH:14])[CH2:9][CH2:8][CH2:7]3)[O:3]1.Cl>C1COCC1>[CH2:8]1[CH2:7][N:6]2[C@@H:11]([C@H:12]([OH:13])[C@H:4]([OH:3])[CH2:5]2)[C@H:10]([OH:14])[CH2:9]1
Reactant: CC1(C)O[C@H]2[C@H]3[C@H](O)CCCN3C[C@H]2O1
Agent: Cl
Solvent: C1CCOC1
Product: O[C@H]1[C@H]2[C@H](O)CCCN2C[C@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
To a solution of swainsonine acetonide (104 mg, 0.49 mmol) in THF (6.5 ml) was added 6.0 ml of 6M HCl. The colorless solution was stirred overnight at room temperature. The solvent was removed in vacuo, leaving a colorless, viscous oil. The oil was then purified by an ion exchange chromatography (Dowex-1×8). Fractions (visualized with iodine or ninhydrin) were collected and concentrated in vacuo to furnish 68.5 mg(81% yield) of swainsonine as a white solid: mp and mixed mp 140-142 C; [α]D25 =-75.71 (c 2.33, MeOH); Rf=0.36 in 1-butanol:chloroform:ethanol:concentrated ammonium hydroxide (4:4:4:1); 1H NMR (D2O, ref. DSS, 300MHz) 4.34 (m, 1H, H-2), 4.24 (dd, J1,8a =3.7 Hz, J1,2 =6.1 Hz, 1H, H-1), 3.78 (dd, J=3.9, 9.3 & 10.7 Hz, 1H, H-8), 2.89 (m, 1H), 2.86 (dd, J=2.6 & 11.0 Hz, 1H, H-3), 2.53 (dd, J=7.8 & 11.0 Hz, 1H, H-3'), 2.04 (m, 1H), 1.96 (m, 1H), 1.89 (dd, J8a,8 =9.3 Hz, J8a,1 =3.7 Hz, H-8a), 1.70 (m, 1H), 1.49 (m, 1H), 1.22 (m, 1H); 13C NMR (D2O, ref: CH3CN, 100MHz) δ23.21, 32.51, 51.72, 60.65, 66.37, 69.08, 69.72, 72.87; HRMS(M+) 173.1052 calcd for C8H15NO3, found 173.1041.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[CH3:10][O:11]C(Cl)Cl>[Ti](Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([CH:3]=1)[CH:10]=[O:11]
Reactant: COc1ccc(Br)cc1
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(Br)cc1C=O
Reaction time: 1.5 h
Yield: 95.3 %

Procedure:
p-Bromoanisole (15 g., 0.08 mole) in 350 ml. of methylene chloride was cooled to 0° C. Titanium tetrachloride (30 g., 17.4 ml., 0.16 mole) was added dropwise. After 10 minutes 1,1-dichloromethyl methyl ether (12.7 g., 0.088 mole) was added dropwise and the reaction stirred for 90 minutes at 0°-10° C., then quenched into excess saturated sodium bicarbonate and methylene chloride. The organic layer was separated and combined with a further methylene chloride extract of the aqueous phase. The combined organic layers were back washed with saturated sodium chloride, dried over anhydrous magnesium sulfate, filtered, and evaporated in vacuo to yield 5-bromo-2-methoxybenzaldehyde (16.4 g., m.p. 107°-110° C.).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][CH:11]=1)[NH2:8])([CH3:3])[CH3:2].[C:12](Cl)(Cl)=[S:13].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([N:8]=[C:12]=[S:13])[CH:9]=[CH:10][CH:11]=1)([CH3:3])[CH3:2]
Reactant: S=C(Cl)Cl
Reactant: CC(C)Oc1cccc(N)c1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)Oc1cccc(N=C=S)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-isopropoxy aniline (6.0 g, 40 mmol), in 150 mL of CHCl3 was added dropwise thiophosgene (2.81 mL, 44 mmol) at 0° C. After the addition of thiophosgene, triethylamine (7.0 mL, 48 mmol) was added slowly and the reaction mixture was stirred for 2 hours at room temperature. It was then concentrated and diluted with 200 mL of ethyl acetate. The triethylamine hydrochloride salt was filtered off and the filtrate was concentrated to yield crude 3-isopropoxyphenyl isothiocyanate. The crude 3-isopropoxyphenyl isothiocyanate was dissolved in 150 mL of acetic acid, and anthranilic acid (6.04 g, 44 mmol) was added. The resulting reaction mixture was refluxed for 16 hours and then cooled to room temperature. The white solid was separated which was filtered to yield 9.0 g of the title compound (72.1%), mp 288°-290° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](=[O:23])[CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([N+:20]([O-])=O)[CH:14]=2)=[CH:4][C:3]=1[N+:24]([O-])=O>CO.C(OCC)(=O)C.[Pd]>[NH2:20][C:15]1[CH:14]=[C:13]([CH2:12][CH2:11][C:10](=[O:23])[CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([NH2:24])[CH:4]=2)[CH:18]=[CH:17][C:16]=1[OH:19]
Reactant: O=C(CCc1ccc(O)c([N+](=O)[O-])c1)CCc1ccc(O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1cc(CCC(=O)CCc2ccc(O)c(N)c2)ccc1O
Yield: 98 %

Procedure:
A solution of 8.2 g of 1,5-bis(4-hydroxy-3-nitrophenyl)pentan-3-one in 50 ml of methanol and 150 ml of ethyl acetate was placed in a Parr hydrogenator with 300 mg of 10% Pd/C. After 3 hours the solution was filtered and evaporated to dryness to give 6.7 g of product of m.p. 131°-133° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[NH:12][CH2:11][CH:10]([CH2:13][CH3:14])[O:9]2)[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[C:21](Cl)(=[O:26])[CH2:22][CH:23]([CH3:25])[CH3:24]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[N:12]([C:21](=[O:26])[CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:11][CH:10]([CH2:13][CH3:14])[O:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCC1CNC(c2cccc(Cl)c2)O1
Reactant: CC(C)CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC1CN(C(=O)CC(C)C)C(c2cccc(Cl)c2)O1

Procedure:
Four and two-tenths grams of 2-(m-chlorophenyl)-5-ethyl-1,3-oxazolidine was combined with 1.7 g of pyridine in 25 ml of methylene chloride and 2.4 g of isovaleroyl chloride was added dropwise with stirring and the mixture was stirred overnight. The mixture was washed with 50 ml of 5% NaOH and 200 ml of water, dried with MgSO4 and stripped under vacuum. The yield was 2.4 g, nD30 1.5490. The structure was confirmed by NMR and infrared spectroscopy.