Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([NH:7][CH:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][S:11][C:10]2[CH:19]=[CH:20][C:21]([CH3:23])=[CH:22][C:9]1=2)=[O:6].[F:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:27][CH:26]=1.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:24][C:25]1[CH:26]=[CH:27][C:28]([N:31]2[CH2:36][CH2:35][N:34]([CH2:2][CH2:3][CH2:4][C:5]([NH:7][CH:8]3[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[CH2:12][S:11][C:10]4[CH:19]=[CH:20][C:21]([CH3:23])=[CH:22][C:9]3=4)=[O:6])[CH2:33][CH2:32]2)=[CH:29][CH:30]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: Cc1ccc2c(c1)C(NC(=O)CCCCl)c1ccccc1CS2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)C(NC(=O)CCCN1CCN(c3ccc(F)cc3)CC1)c1ccccc1CS2
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 65 %

Procedure:
A mixture of 10 g of 11-(4-chlorobutyrylamino)-2-methyl-6,11-dihydrodibenzo[b,e]thiepin, 10 g of 1-(4-fluorophenyl)piperazine, 10 g of sodium iodide and 100 ml of dimethylformamide is stirred at 100° C. for 1.5 hours. After the reaction mixture is cooled to room temperature, 100 ml of 10% aqueous potassium carbonate solution is added and the solution is extracted with three 300-ml portions of chloroform. The combined extracts are treated in substantially the same manner as in Example 1(1) to give 9.2 g of the title compound. m.p. 205°-207° C. (recrystallized from ethyl acetate);
Reaction SMILES: C(O[C:4](=O)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)C.ClC1C=CC(C2[C:24]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][N:41]([CH2:44][CH3:45])[CH2:42][CH3:43])=[CH:34][CH:33]=4)[N:26]=3)=[CH:23][NH:22][N:21]=2)=CC=1>>[Cl:11][C:7]1[CH:6]=[C:5]([C:4]2[C:24]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][N:41]([CH2:42][CH3:43])[CH2:44][CH3:45])=[CH:34][CH:33]=4)[N:26]=3)=[CH:23][NH:22][N:21]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(=O)c1cccc(Cl)c1
Reactant: CCN(CC)CCOc1ccc(Nc2nccc(-c3c[nH]nc3-c3ccc(Cl)cc3)n2)cc1
Product: CCN(CC)CCOc1ccc(Nc2nccc(-c3c[nH]nc3-c3cccc(Cl)c3)n2)cc1

Procedure:
The title compound is prepared as described in Example 1 using 3-chloro-benzoic acid ethyl ester (see Example 5) and 4-(2-diethylamino-ethoxy)-phenylamine (see Example 3).
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([C@H:12]1[N:15]([CH:16]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:14](=[O:35])[C@@H:13]1[C@H:36]([O:38][C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40])[CH3:37])[CH3:11])(C(C)(C)C)(C)C.Cl>CO.C(OCC)(=O)C>[OH:8][CH2:9][C@@H:10]([C@H:12]1[N:15]([CH:16]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)[C:14](=[O:35])[C@@H:13]1[C@H:36]([O:38][C:39]([O:41][CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)=[O:40])[CH3:37])[CH3:11]
Reactant: COc1ccc(CC(Cc2ccc(OC)cc2)N2C(=O)[C@H]([C@@H](C)OC(=O)OCc3ccccc3)[C@H]2[C@@H](C)CO[Si](C)(C)C(C)(C)C)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(CC(Cc2ccc(OC)cc2)N2C(=O)[C@H]([C@@H](C)OC(=O)OCc3ccccc3)[C@H]2[C@@H](C)CO)cc1

Procedure:
A solution of (3S,4R)-4-(1-(R)-t-butyldimethylsilyloxymethylethyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-1-di(p-anisyl)methyl-2-azetidinone (0.40 g) in methanol (40 ml) was treated with 6N hydrochloric acid (10 ml) with ice-cooling for 20 minutes. The reaction mixture was diluted with ethyl acetate (200 ml), washed with brine and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate in vacuo gave an oily residue, which was purified by silica gel chromatography to yield (3S,4R)- 4-(1-(R)-hydroxymethylethyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-1-di(p-anisyl)methyl-2-azetidinone.
Reaction SMILES: C(OC(N1CCC(C([O:20][C:21]2[CH:43]=[CH:42][C:24]3[C:25]4[N:29]([CH2:30][CH2:31][O:32][C:23]=3[CH:22]=2)[CH:28]=[C:27]([C:33]2[N:34]([CH:39]([CH3:41])[CH3:40])[N:35]=[C:36]([CH3:38])[N:37]=2)[N:26]=4)CC)CC1)=O)C1C=CC=CC=1.[H-].[Na+].[CH2:46]([O:48][C:49](=[O:61])[C:50](Br)([CH2:56][CH:57]([CH3:59])[CH3:58])[C:51]([O:53][CH2:54][CH3:55])=[O:52])[CH3:47]>CN(C=O)C>[CH2:46]([O:48][C:49](=[O:61])[C:50]([CH2:56][CH:57]([CH3:59])[CH3:58])([O:20][C:21]1[CH:43]=[CH:42][C:24]2[C:25]3[N:29]([CH2:30][CH2:31][O:32][C:23]=2[CH:22]=1)[CH:28]=[C:27]([C:33]1[N:34]([CH:39]([CH3:41])[CH3:40])[N:35]=[C:36]([CH3:38])[N:37]=1)[N:26]=3)[C:51]([O:53][CH2:54][CH3:55])=[O:52])[CH3:47]
Reactant: CCC(Oc1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CCOC(=O)C(Br)(CC(C)C)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC(C)C)(Oc1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 50.6 %

Procedure:
To a suspension of 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-ol from Example 4 (465 mg, 1.429 mmol) in DMF (8 mL) was added sodium hydride (57.2 mg, 60% in oil, 1.429 mmol). The mixture was stirred at RT for 15 min, then a solution of 2-bromo-2-isobutylmalonic acid diethyl ester (633 mg, 2.14 mmol) in DMF (1 mL) was added. The reaction mixture was stirred at 70° C. for 4 h. The cooled reaction mixture was partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc. The combined organic phases were washed with water, followed by brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 2-10% MeOH in DCM) affording the title compound (0.39 g, 51%). LCMS (Method B): RT 3.96 min [M+H]+ 540.
Reaction SMILES: [C:1]([O:6][CH2:7][CH:8]=[CH2:9])(=[O:5])[C:2]([CH3:4])=[CH2:3].[Cl:10][SiH:11]([Cl:13])[Cl:12].C1C2NC3C(=CC=CC=3)SC=2C=CC=1.CCCCCCCCCCCCCCCCCCOC(CCSCCC(OCCCCCCCCCCCCCCCCCC)=O)=O>>[C:1]([O:6][CH2:7][CH2:8][CH2:9][Si:11]([Cl:13])([Cl:12])[Cl:10])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=CCOC(=O)C(=C)C
Reactant: Cl[SiH](Cl)Cl
Agent: CCCCCCCCCCCCCCCCCCOC(=O)CCSCCC(=O)OCCCCCCCCCCCCCCCCCC
Agent: c1ccc2c(c1)Nc1ccccc1S2
Product: C=C(C)C(=O)OCCC[Si](Cl)(Cl)Cl
Temperature: 150 °C

Procedure:
A methacryloxypropyl trichlorosilane was synthesized by a known method where allyl methacrylate and trichlorosilane were used as starting materials. 20 g of the obtained product and 5 mg of a styrenated phenothiazine (ANTAGE STDP-N, molecular weight was 407.6; the product of Kawaguchi Chemical Company, Ltd.) was sealed in a bottle with a threaded cap and heated in a 150° C. oil bath. The obtained product was not gelled and maintained flowability even 20 hours after the above-described treatment.
Reaction SMILES: N1CCCNC[CH2:2]1.N1CCNCC1.[N:14]1([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][C:22]=2[O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:20][CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.Cl>C=O.CO.C(O)=O>[CH3:2][N:17]1[CH2:18][CH2:19][CH2:20][N:14]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][C:22]=2[O:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:15][CH2:16]1
Reactant: c1ccc(Oc2cnccc2N2CCCNCC2)cc1
Reactant: C1CNCCNC1
Agent: C1CNCCN1
Agent: C=O
Agent: Cl
Solvent: CO
Solvent: O=CO
Product: CN1CCCN(c2ccncc2Oc2ccccc2)CC1
Temperature: 100 °C

Procedure:
By substituting 30 g of hexahydro-1H-1,4-diazepine for the piperazine in Example 1, the product is 4-(hexahydro-1H-1,4-diazepin-1-yl)-3-phenoxy pyridine, bp 143°-145° C./0.13 mm). Three and four tenths g of this material is dissolved in a mixture of 4.5 g 37% formalin and 2 ml of methanol and is treated with 6 g of 97-100% formic acid. The mixture is heated at 100° C. for 18 hours. The mixture is cooled, treated with an excess of dilute hydrochloric acid and concentrated in vacuo. The residue is shaken with 100 ml of toluene and excess dilute aqueous sodium hydroxide. The organic phase is dried, concentrated and distilled to give 4-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)-3-phenoxypyridine; bp 130°-131° C./0.1 mm.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.[CH:9](I)([CH3:11])[CH3:10]>>[I:1][C:2]1[CH:7]=[CH:6][N:5]([CH:9]([CH3:11])[CH3:10])[C:4](=[O:8])[CH:3]=1
Reactant: O=c1cc(I)cc[nH]1
Reactant: CC(C)I
Product: CC(C)n1ccc(I)cc1=O

Procedure:
4-iodo-1-isopropylpyridin-2(1H)-one was prepared from 4-iodopyridin-2(1H)-one and isopropyl iodide following a procedure analogous to that described in Example 59 Step 1.
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([OH:11])=[O:10])([C:5]([OH:7])=[O:6])[OH:4].[P:14]([O-:18])([O-:17])([O-:16])=[O:15].[Na+].[Na+].[Na+].[OH-].[Na+]>O>[C:1]([O-:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([O-:11])=[O:10])([C:5]([O-:7])=[O:6])[OH:4].[P:14]([O-:18])([O-:17])([O-:16])=[O:15]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Temperature: 25 °C

Procedure:
A citrate-phosphate buffer (pH 3.0) was prepared from 39.8 ml of 0.1 M citric acid and 10.2 ml of 0.2 M dibasic sodium phosphate diluted to 100 ml with distilled water. The lyophilized Fraction A from Preparation 1 was dissolved in this buffer solution in a proportion of 20 mg of Fraction A per ml of buffer. To this was added an aliquot of 5 mg of pepsin in 1 ml of distilled water to give a ratio of Fraction A to pepsin of 100 to 1. The solution was maintained for 24 hours at room temperature and then brought to pH 7.4 by the addition of 0.1 M sodium hydroxide. The resulting product was the crude ragweed polypeptide active immunosuppressant fraction.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([Br:15])[CH:12]=[CH:11][C:10]=1[N+:16]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+].O>C(O)C.[Fe]>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([Br:15])[CH:12]=[CH:11][C:10]=1[NH2:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1OCc1ccccc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccc(Br)cc1OCc1ccccc1
Temperature: 25 °C
Yield: 98.9 %

Procedure:
A mixture of 2-(benzyloxy)-4-bromo-1-nitrobenzene (14.1 g, 45.8 mmol), iron powder (12.8 g, 229.12 mmol) and ammonium chloride (2.9 g, 55.0 mmol) was taken up in ethanol (60 mL) and water (30 mL) and heated at 90° C. for 3 h. After cooling to ambient temperature, the reaction mixture was filtered through a celite bed and the filtrate concentrated in vacuo. The aqueous residue was extracted with dichloromethane and the organic layer washed with brine, dried over sodium sulfate and concentrated in vacuo to give 2-(benzyloxy)-4-bromoaniline (12.6 g, 99%) as a purple oil: 1H NMR (CDCl3, 300 MHz) δ 7.31-7.46 (m, 5H), 6.98 (d, J=2.1 Hz, 1H), 6.92 (dd, J=8.4, 2.1 Hz, 1H), 6.60 (d, J=8.4 Hz, 1H), 5.05 (s, 2H), 3.81 (br s, 2H).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:23])[C:15]([CH2:17][CH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)=[CH2:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]1[O:30][NH2:31]>>[CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:23])[CH:15]([CH2:17][CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22]1)[CH2:16][NH:31][O:30][CH:25]1[CH2:26][CH2:27][CH2:28][CH2:29][O:24]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C(CC1CCCC1)C(=O)N1C(=O)OCC1Cc1ccccc1
Reactant: NOC1CCCCO1
Product: O=C1OCC(Cc2ccccc2)N1C(=O)C(CNOC1CCCCO1)CC1CCCC1
Temperature: 45 °C
Reaction time: 48 h
Yield: 68.8 %

Procedure:
4-Benzyl-3-(2-cyclopentylmethyl-acryloyl)-oxazolidin-2-one (22.90 g, 73.1 mmol) and O-(tetrahydro-2H-pyran-2-yl)-hydroxylamine (34.24 g, 292.3 mmol) is combined at stirred at 45° C. for 48 hours under nitrogen. The crude product is purified by flash chromatography (SiO2, 0→30% EtOAc in hexane), which gives 4-benzyl-3-[2-cyclopentylmethyl-3-(tetrahydro-pyran-2-yloxyamino)-propionyl]-oxazolidin-2-one (21.65 g, 69% yield) as an oil.
Reaction SMILES: [CH3:1][C:2]1([OH:12])[CH2:11][CH2:10][C:5]2(OCC[O:6]2)[CH2:4][CH2:3]1.Cl>C1COCC1>[OH:12][C:2]1([CH3:1])[CH2:11][CH2:10][C:5](=[O:6])[CH2:4][CH2:3]1
Reactant: CC1(O)CCC2(CC1)OCCO2
Agent: Cl
Solvent: C1CCOC1
Product: CC1(O)CCC(=O)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 91.7 %

Procedure:
8-Methyl-1,4-dioxaspiro[4.5]decane-8-ol (650 mg, 3.77 mmol) was dissolved in THF (10 ml), followed by addition of 1N aqueous HCl solution (5 ml), and then the resulting mixture was stirred at room temperature for 6 hours. The resulting reaction liquid was concentrated under reduced pressure, and then extracted with 10% MeOH/MC (20 ml×5). The organic layer was dried over anhydrous sodium sulfate, followed by filtration and concentration, and then the residue thus obtained was subjected to MPLC (50% EtOAc/Hexanes), to obtain 443 mg of yellow oil (92%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[C:13](F)[CH:12]=2)[CH:7]=[N:6][CH:5]=1.NC1C=CC(O)=CC=1F>>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)[CH:7]=[N:6][CH:5]=1
Reactant: COC(=O)c1cncc(Oc2ccc(N)c(F)c2)c1
Agent: Nc1ccc(O)cc1F
Product: COC(=O)c1cncc(Oc2ccc(N)cc2)c1

Procedure:
The title compound was prepared in the same manner described 5-(4-Amino-3-fluorophenoxy)nicotinic acid methyl ester, substituting 4-aminophenol for 4-amino-3-fluorophenol. 1H NMR (DMSO-d6) δ 8.71 (s, 1H), 8.54 (d, J=2.9 Hz, 1H), 7.47 (t, J=1.9 Hz, 1H), 6.85 (d, J=8.7 Hz, 2H), 6.61 (d, J=8.7 Hz, 2H), 5.12 (br, 2H), 3.81 (s, 3H); MS LC-MS [M+H]+=245.2, RT=1.08 min.
Reaction SMILES: [NH2:1][CH:2]1[C:8]2=[N:9][C:10]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[CH:11][C:12](=[O:13])[N:7]2[CH2:6][CH2:5][O:4][CH2:3]1.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26](O)=[O:27].C(OC(N1CCC2C(=CC(C(O)=O)=CC=2)C1)=O)(C)(C)C>>[O:13]=[C:12]1[N:7]2[C:8]([CH:2]([NH:1][C:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=3)=[O:27])[CH2:3][O:4][CH2:5][CH2:6]2)=[N:9][C:10]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:11]1
Reactant: NC1COCCn2c1nc(-c1ccncc1)cc2=O
Reactant: O=C(O)c1ccccn1
Agent: CC(C)(C)OC(=O)N1CCc2ccc(C(=O)O)cc2C1
Product: O=C(NC1COCCn2c1nc(-c1ccncc1)cc2=O)c1ccccn1

Procedure:
By analogy with the method described in example 1 (step 1.4), using (+/−) 9-amino-2-pyridin-4-yl-5,6,8,9-tetrahydro-7-oxa-1,4-a-diaza-benzocyclohepten-4-one and 2-pyridine carboxylic acid in place of (+/−)-9-amino-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-7-oxa-1,4-a-diaza-benzocyclohepten-4-one and 3,4-dihydro-1H-isoquinoline-2,7-dicarboxylic acid 2-tert-butyl ester, the compound, 0.035 g (57%), was obtained as a white powder.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]2[CH2:21][CH:20]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]=3[CH2:17][C:16]=2[CH:32]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCO>[OH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]2[CH2:21][CH:20]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]=3[CH2:17][C:16]=2[CH:32]=1
Reactant: CCOC(=O)CC1Cc2ccc(CCCCOC3CCCCO3)cc2Cc2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: CCOC(=O)CC1Cc2ccc(CCCCO)cc2Cc2ccccc21
Reaction time: 2 h
Yield: 93.4 %

Procedure:
A solution of ethyl (±)-10,11-dihydro-3-[4-(2-tetrahydropyranyloxy)-1-butyl]-5H-dibenzo[a,d]cycloheptene-10-acetate (456.0 mg, 1.04 mmole) and p-toluenesulfonic acid monohydrate (60 mg, 0.31 mmole) in absolute EtOH (10 mL) was stirred at RT. After 2 hr, the reaction was quenched with 5% NaHCO3 (1 mL) and concentrated to remove the EtOH. The residue was diluted with H2O (2 mL) and extracted with CH2Cl2. Drying (MgSO4), concentration, and silica gel chromatography (1:1 EtOAc/hexanes) gave the title compound (342.4 mg, 93%) as a colorless oil: TLC (1:1 EtOAc/hexanes) Rf0.49; 1H NMR (250 MHz, CDCl3) δ6.85-7.25 (m, 7 H), 4.34 (d, J=15.1 Hz, 1 H), 4.08-4.30 (m, 2 H), 3.75-3.95 (m, 2 H), 3.53-3.72 (m, 2 H), 3.33 (dd, J=15.1, 4.1 Hz, 1 H), 2.95 (dd, J=15.1, 9.4 Hz, 1 H), 2.40-2.75 (m, 4 H), 1.45-1.80 (m, 4 H), 1.27 (t, J=7.1 Hz, 3 H); MS (ES) m/e 353 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH:8]([CH3:19])[C:9]([O:11][CH2:12][CH2:13][O:14][N:15]=[C:16]([CH3:18])[CH3:17])=[O:10].[Cl:20][C:21]1[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][C:22]=1[O:23][C:24]1[CH:25]=[C:26]([OH:30])[CH:27]=[CH:28][CH:29]=1>CC(C)=O>[Cl:20][C:21]1[CH:34]=[C:33]([C:35]([F:36])([F:38])[F:37])[CH:32]=[CH:31][C:22]=1[O:23][C:24]1[CH:25]=[C:26]([CH:27]=[CH:28][CH:29]=1)[O:30][CH:8]([CH3:19])[C:9]([O:11][CH2:12][CH2:13][O:14][N:15]=[C:16]([CH3:18])[CH3:17])=[O:10]
Reactant: Oc1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1
Reactant: CC(C)=NOCCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)=NOCCOC(=O)C(C)Oc1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1

Procedure:
2.76 g of anhydrous potassium carbonate and 3.78 g of 2-isopropylideneaminooxy-ethyl 2-bromopropionate are added to a solution of 2.89 g of 3-(o-chloro-p-trifluoromethyl-phenoxy)-phenol in 40 ml of acetone and the mixture is heated at reflux temperature for 6 hours. The resulting solution is then concentrated to 30 ml and the concentrate is poured into 100 ml of water. The mixture is extracted three times with 80 ml of ethyl acetate each time, the combined organic phases are back-washed twice with 50 ml of water each time, the solvent is evaporated from the organic phase and there is obtained by distillation in a bulb-tube at 100°-170° C./0.05 mm Hg 2-isopropylideneaminooxy-ethyl 2-[3-(o-chloro-p-trifluoromethyl-phenoxy)-phenoxy]-propionate.
Reaction SMILES: [CH:1]1[N:6]=[C:5](Cl)[C:4]2[N:8]=[CH:9][N:10]([C@@H:11]3[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]3[OH:19])[C:3]=2[N:2]=1.[NH2:20][CH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22]1.C(N(CC)CC)C>C(O)C>[CH:21]1([NH:20][C:5]2[C:4]3[N:8]=[CH:9][N:10]([C:3]=3[N:2]=[CH:1][N:6]=2)[C@@H:11]2[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]2[OH:19])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22]1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Reactant: NC1CCc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCO
Product: OC[C@H]1O[C@@H](n2cnc3c(NC4CCc5ccccc54)ncnc32)[C@H](O)[C@@H]1O
Yield: 56.1 %

Procedure:
Four grams 6-Chloropurine riboside, 2.32 g 1-aminoindane and 2.11 g of triethylamine are refluxed in 100 ml of absolute ethanol under nitrogen for 20 hours. Volatiles are evaporated to dryness. Residue is dissolved in 20 ml 2-propanol and diluted with 200 ml H2O. Clear aqueous solution is decanted and residual oily material is washed with cold water. Coevaporation with ethanol several times gives solid material. Crystallization from CHCl3 /2-propanol (10:1) and hexane affords 3.0 g (56.2%) N(6)-(1-indanyl)adenosine having a melting point of 120°-122° C. (foam).
Reaction SMILES: [CH:1]([O:4][P:5]([CH:11]1[CH:16]=[CH:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:13]=[CH:12]1)(=[O:10])[O:6][CH:7]([CH3:9])[CH3:8])([CH3:3])[CH3:2].C(=O)=O.CC(C)=O.C([Li])CCC.[Br:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39]Br)=[CH:37][CH:36]=1.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH:7]([O:6][P:5]([C:11]1([CH2:39][C:38]2[CH:41]=[CH:42][C:35]([Br:34])=[CH:36][CH:37]=2)[CH:12]=[CH:13][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:15]=[CH:16]1)(=[O:10])[O:4][CH:1]([CH3:2])[CH3:3])([CH3:9])[CH3:8]
Reactant: BrCc1ccc(Br)cc1
Reactant: CCOC(=O)N1C=CC(P(=O)(OC(C)C)OC(C)C)C=C1
Agent: O=C=O
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)N1C=CC(Cc2ccc(Br)cc2)(P(=O)(OC(C)C)OC(C)C)C=C1
Reaction time: 20 h
Yield: 60 %

Procedure:
3.0 g of diisopropyl-1-ethoxycarbonyl-1,4-dihydropyridine-4-phosphonate was dissolved in 50 ml of tetrahydrofuran. The solution was cooled to -78° C. with a dry ice-acetone freezing mixture. In a stream of nitrogen, 6.8 ml of a hexane solution of n-butyllithium was slowly added dropwise. A solution of 2.50 g of p-bromobenzyl bromide in 10 ml of tetrahydrofuran was added dropwise. The temperature of the solution was returned to room temperature, and the solution was stirred for 20 hours. The excess of n-butyllithium was decomposed with ammonium chloride, and the solvent was evaporated. The residue was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogen carbonate, a saturated aqueous solution of sodium thiosulfate and a saturated aqueous solution of sodium chloride in this order, and the solvent was evaporated. The residue was subjected to silica gel column chromatography. The column was eluted with a 1:9 mixture of acetone and benzene to give 2.76 g (yield 56.6%) of diisopropyl-4-(4-bromobenzyl)-1-ethoxycarbonyl-1,4-dihydropyridine-4-phosphonate as a brown oil.
Reaction SMILES: C(OC(=O)[C@@H]([N:10]1[C@H:15]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=2)[C@@H:14]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)[CH2:13][C@@:12]([CH2:31][C:32](O)=O)([CH3:30])[C:11]1=[O:35])CC)(C)(C)C.[C:37](O)(C(F)(F)F)=O>>[CH2:31]([C@@:12]1([CH3:30])[CH2:13][C@H:14]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)[C@@H:15]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=2)[NH:10][C:11]1=[O:35])[CH:32]=[CH2:37]
Reactant: CC[C@@H](C(=O)OC(C)(C)C)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cn1
Reactant: O=C(O)C(F)(F)F
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cn2)NC1=O
Temperature: 25 °C

Procedure:
(5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-1-(2,4-dimethoxybenzyl)-3-methylpiperidin-2-one (3.6 g, 6.85 mmol, mixture of C-3 epimers, Example 124, Step B) was dissolved in TFA (26.4 mL, 343 mmol) and the reaction was heated to 70° for 1.5 h. It was then cooled to ambient temperature and the TFA was removed by concentration under reduced pressure. The product was azeotroped with heptanes, dissolved in DCM and the organic layer was washed with sat. aq. NaHCO3 solution and sat. NaCl solution. Purification by flash chromatography on silica gel (eluent: 35 to 45% EtOAc/hexanes which had been NH3 sparged, gradient elution) provided the title compound as the more polar isomer as a white solid: (Rf in 75% EtOAc/Hexanes=0.44).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:18]=[CH:17][O:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B.[O:20]1CCCC1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:18]=[CH:17][O:16][CH:15]=2)[CH:12]([OH:20])[CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccoc2)CC1
Reactant: C1CCOC1
Agent: B
Product: CC(C)(C)OC(=O)N1CCC(c2ccoc2)C(O)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
To a solution of 4 (2.33 g, 9.358 mmol) in THF (10 mL) at 0° C. borane-tetrahydrofuran, BH3-THF (28.07 mL, 28.07 mmol, 3 eq., 1M sol. in THF) was added dropwise. After stirring the reaction mixture under inert atmosphere at room temperature for 3 h, the unreacted borane was quenched by the addition of methyl alcohol (30 mL). After quenching, 3N NaOH (30 mL) was added slowly to the reaction mixture. This was followed by the addition of 30% H2O2 (15 mL). The reaction mixture was stirred under inert atmosphere at room temperature for 16 h. Solvents were removed under reduced pressure and the crude mixture was dissolved in ethyl acetate (60 mL). The ethyl acetate solution was washed with water (40 mL), bicarbonate solution (40 mL), water (40 mL), and brine (40 mL), dried over anhydrous magnesium sulfate and filtered. Removal of solvent at reduced pressure yielded the pure, white, crystalline solid 5 (2.18 g, 87%). TLC Rf=0.48 (95% CH2Cl2—MeOH); 400 MHz 1H-NMR (CDCl3) δ 1.47 (s, 9H), 1.57-1.69 (m, 1H), 1.82-1.85 (m, 0.5H), 1.86-1.88 (m, 0.5H), 2.50 (ddd, J=12.4, 10.0, 4.0 Hz, 1H), 2.62 (t, J=10.8 Hz, 1H), 2.76 (m, 1H), 3.47 (m, 1H), 4.12 (m, 1H), 4.32 (m, 1H), 6.35 (s, 1H), 7.38 (d, J=18.8 Hz, 2H); 125 MHz 13C-NMR (CDCl3) δ 14.4, 20.2, 28.6, 40.2, 60.1, 70.1, 80.1, 109.5, 126.0, 139.7, 143.6, 154.9. HRMS Calcd. for C14H21NO4Na [M++Na]: 290.1368. Found: 290.1368.