Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[NH:12][C:13]([C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[CH2:23][NH:22][CH2:21][CH2:20]2)=[O:14].[N:25]1([C:30](N2C=CN=C2)=[S:31])C=CN=C1.N.CO.Br[CH:41]([CH2:49][CH2:50][CH2:51][Cl:52])[C:42](=O)[C:43]([O:45][CH2:46][CH3:47])=[O:44]>CN(C=O)C.CCO>[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[NH:12][C:13]([C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[CH2:23][N:22]([C:30]1[S:31][C:41]([CH2:49][CH2:50][CH2:51][Cl:52])=[C:42]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[N:25]=1)[CH2:21][CH2:20]2)=[O:14]
Reactant: CCOC(=O)C(=O)C(Br)CCCCl
Reactant: O=C(Nc1nc2ccccc2s1)c1cccc2c1CNCC2
Reactant: S=C(n1ccnc1)n1ccnc1
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Solvent: CCO
Solvent: CO
Product: CCOC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)sc1CCCCl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To N-(benzo[d]thiazol-2-yl)-1,2,3,4-tetrahydroisoquinoline-8-carboxamide dihydrochloride (1B) (11.5 g, 30 mmol) in DMF (125 mL) was added TEA (16.7 mL, 120 mmol) and stirred at rt for 15 minutes. Di(1H-imidazol-1-yl)methanethione (6.53 g, 33 mmol) was added and the reaction mixture was stirred at rt for 1 hour. 7N Ammonia in MeOH (171 mL, 1.2 mol) was added and the mixture was stirred at rt overnight. The reaction mixture was concentrated to remove ammonia, TEA, and MeOH. To the concentrate was added a solution of ethyl 3-bromo-6-chloro-2-oxohexanoate (2A) (11.4 g, 42 mmol) in EtOH (40 mL). The reaction mixture was heated at 50° C. under nitrogen for 4.5 hours. Additional ethyl 3-bromo-6-chloro-2-oxohexanoate (2A) (0.815 g, 3 mmol) in EtOH (3 mL) was added and heating was continued for 1.5 hours. The reaction mixture was concentrated under reduced pressure to remove EtOH and then extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography on silica gel eluting with a gradient of 30 to 50% EtOAc in hexanes to provide the desired product ethyl 2-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-chloropropyl)thiazole-4-carboxylate (2B) in 69% yield. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.89 (1H, s), 8.04 (1H, d), 7.79 (1H, d), 7.67 (1H, d), 7.42 (4H, m), 4.83 (2H, s), 4.19 (2H, q), 3.72 (2H, t), 3.64 (2H, t), 3.13 (2H, m), 3.04 (2H, t), 2.00 (2H, m), 1.21 (3H, t).
Reaction SMILES: Cl.[CH3:2]N(C)CCCN=C=NCC.[N:13]1([C:19]2[N:24]=[C:23]([CH2:25][C:26](=[O:42])[N:27]3[C:35]4[C:30](=[C:31](C5C=NC=CC=5)[CH:32]=[CH:33][CH:34]=4)[CH2:29][CH2:28]3)[NH:22][C:21](=[O:43])[CH:20]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.N1(C2N=C(CC([O-])=O)NC(=O)C=2)CCOCC1.[Na+].[OH2:62]>CN(C=O)C.N1C=CC=CC=1.ClCCl>[OH:62][CH2:2][CH:28]1[CH2:29][C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:27]1[C:26](=[O:42])[CH2:25][C:23]1[NH:22][C:21](=[O:43])[CH:20]=[C:19]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[N:24]=1
Reactant: O
Reactant: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1CCc2c(-c3cccnc3)cccc21
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1c2ccccc2CC1CO
Temperature: 25 °C
Reaction time: 18 h

Procedure:
890 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride and 500 mg of (+)-(2,3-dihydro-1H-indol-2-yl)methanol (reference example 13d) are added to a solution of 876 mg of sodium (4-morpholin-4-yl-6-oxo-1,6-dihydropyrimidin-2-yl)acetate in 26 ml of DMF and 26 ml of pyridine. The reaction medium is stirred at ambient temperature for 18 hours then a mixture of water and dichloromethane is added. After settling out, the organic phase is dried over magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue obtained is purified on a silica column, eluent: gradient: dichloromethane/methanol from 100/0 to 95/05, so as to give 708 mg of 2-[2-((−)-2-hydroxymethyl-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one, the characteristics of which are the following:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][C:17]1[CH:18]=[C:19]([NH:27][C:28]2[N:37]=[CH:36][C:35]3[N:34]([CH3:38])[C:33](=[O:39])[CH2:32][N:31]([CH:40]([CH3:42])[CH3:41])[C:30]=3[N:29]=2)[CH:20]=[C:21]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:22]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13](=[O:15])[NH:16][C:17]1[CH:22]=[C:21]([S:23]([CH3:26])(=[O:24])=[O:25])[CH:20]=[C:19]([NH:27][C:28]2[N:37]=[CH:36][C:35]3[N:34]([CH3:38])[C:33](=[O:39])[CH2:32][N:31]([CH:40]([CH3:42])[CH3:41])[C:30]=3[N:29]=2)[CH:18]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)N1CC(=O)N(C)c2cnc(Nc3cc(N)cc(S(C)(=O)=O)c3)nc21
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Product: CC(C)N1CC(=O)N(C)c2cnc(Nc3cc(NC(=O)[C@H]4CCCN4C(=O)OC(C)(C)C)cc(S(C)(=O)=O)c3)nc21
Yield: 29.5 %

Procedure:
Starting from (R)pyrrolidine-1,2-dicarboxylic acid tert butyl ester (74 mg; 0.346 mmol) and 2-(3-amino-5-(methylsulfonyl)-phenylamino)-8-isopropyl-5-methyl-7,8-dihydro-5H-pteridin-6-one (90 mg; 0.230), 40 mg (0.068 mmol; 29.5% yield) of the desired compound were obtained.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([OH:3])=[O:2].[F:12][C:13]([F:22])([F:21])[C:14]([CH3:20])(O)[C:15]([F:18])([F:17])[F:16].CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH:8]([C:7]1[CH:10]=[CH:11][C:4]([C:1]([O:3][C:14]([CH3:20])([C:15]([F:18])([F:17])[F:16])[C:13]([F:22])([F:21])[F:12])=[O:2])=[CH:5][CH:6]=1)=[O:9]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CC(O)(C(F)(F)F)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(OC(=O)c1ccc(C=O)cc1)(C(F)(F)F)C(F)(F)F

Procedure:
A mixture of 41.1 g (274 mmol) 4-carboxybenzaldehyde, 50 g (274 mmol) 1,1,1,3,3,3-hexafluoro-2-methyl-2-propanol, and 33.4 g (274 mmol) DMAP in 700 mL DCM was stirred until homogeneous (approximately 0.5 in). The solution was cooled over an ice bath, under Ar, and 52.3 g (274 mmol) EDCI was added portion-wise. The reaction was stirred at RT for 48 hr. and concentrated to an oil on the rotovap. The oil was taken up with EA and washed with water, 2× with dip. Citric acid, 2× with dip Sodium bicarbonate, and brine. The organic layer was dried over sodium sulfate and concentrated to 25.5 g pale yellow solid.
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:9]([OH:11])=O)=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].[NH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[C:22]([O:21][C:19]([N:16]1[CH2:17][CH2:18][CH:13]([NH:12][C:9]([C:5]2[C:4]([N+:1]([O-:3])=[O:2])=[CH:8][NH:7][N:6]=2)=[O:11])[CH2:14][CH2:15]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=C(O)c1n[nH]cc1[N+](=O)[O-]
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2n[nH]cc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 241.9 %

Procedure:
4-Nitropyrazole-3-carboxylic acid (7.3 g; 15.9 mmol) was added to a stirred solution of 4-amino-1-Boc-piperidine (10.2 mg; 51 mmol), EDC (10.7 g; 55.8 mmol), and HOAt (55.8 g; 19.1 mmol) in DMF (100 ml), and then stirred at room temperature overnight. The solvent was removed by evaporation under reduced pressure and the residue triturated with water (250 ml). The resultant cream solid was collected by filtration, washed with water then dried under vacuum to give 13.05 g of 4-[(4-nitro-1H-pyrazole-3-carbonyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (LC/MS: Rt 2.50, [M+H]+ 340).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([N+:7]([O-:9])=[O:8])=[C:4]([CH:10]=[N:11]O)[CH:3]=1.O.C1(C)C=CC(S(O)(=O)=[O:21])=CC=1.CCN(CCOC1C=CC(CC2C=CC=CC=2)=CC=1)CC.Cl>C1(C)C=CC=CC=1>[Br:1][C:2]1[S:6][C:5]([N+:7]([O-:9])=[O:8])=[C:4]([C:10]([NH2:11])=[O:21])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=[N+]([O-])c1sc(Br)cc1C=NO
Agent: CCN(CC)CCOc1ccc(Cc2ccccc2)cc1
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: NC(=O)c1cc(Br)sc1[N+](=O)[O-]
Temperature: 111 °C
Reaction time: 24 h

Procedure:
5-Bromo-2-nitrothiophene-3-carbaldehyde oxime (45 g, 179 mmol), p-toluenesulfonic acid monohydrate (2.73 g, 14.34 mmol), dppe (1.428 g, 3.58 mmol) and Ru(PPh3)3(CO)H2 (3.29 g, 3.58 mmol) were taken up in toluene (750 mL). The flask was evacuated and back-filled with N2 (3×) before stirring at 111° C. under N2 for 24 hours. After cooling to room temperature, the reaction mixture was purified directly by flash silica gel column chromatography (0-100% EtOAc/toluene) to give the title compound as brown needles after recrystallising from EtOH-hexanes.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH3:16][O:17][C:18]1[CH:19]=[C:20](O)[CH:21]=[C:22]([CH3:24])[CH:23]=1.O>N1C=CC=CC=1>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:20]1[CH:21]=[C:22]([CH3:24])[CH:23]=[C:18]([O:17][CH3:16])[CH:19]=1)(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COc1cc(C)cc(O)c1
Solvent: O
Solvent: c1ccncc1
Product: COc1cc(C)cc(OS(=O)(=O)C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 97.1 %

Procedure:
Trifluoromethanesulphonic anhydride (2.02 ml, 12.0 mmol) was added dropwise to a stirred solution of 3-methoxy-5-methylphenol (1.50 g, 10.9 mmol) in pyridine (20 ml) at −20° C. under nitrogen. The reaction was warmed to 0° C., stirred for 90 minutes and re-cooled to −20° C. More trifluoromethanesulphonic anhydride (1.01 ml, 6.00 mmol) was added dropwise. The reaction was allowed to warm to room temperature, stirred for 14 hours and cautiously poured into water (100 ml). The aqueous phase was extracted with ether (150 ml) and the organic phases were washed with water (3×75 ml), 0.2M hydrochloric acid (3×75 ml), 1.0M aqueous sodium carbonate solution (2×75 ml), water (75 ml) and brine (75 ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure to provide the title compound (2.86 g) as a pale brown oil.
Reaction SMILES: [C@@H:1]1(N2C=CC(=O)NC2=O)[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[N:18]1[C:26]([NH2:27])=[C:25]2[C:21]([N:22]=[CH:23][NH:24]2)=[N:20][CH:19]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[C@@H:36]1([N:45]2[CH:53]=[N:52][C:51]3[C:46]2=[N:47][CH:48]=[N:49][C:50]=3[NH2:54])[O:42][C@H:41]([CH2:43][OH:44])[C@@H:39]([OH:40])[C@H:37]1[OH:38]>>[CH:48]1[N:47]=[C:46]2[N:45]([C@@H:36]3[O:42][C@H:41]([CH2:43][OH:44])[C@@H:39]([OH:40])[C@@H:37]3[OH:38])[CH:53]=[N:52][C:51]2=[C:50]([NH2:54])[N:49]=1.[CH:1]1([C:19]2[N:20]=[C:21]3[C:25]([NH:24][CH:23]=[N:22]3)=[C:26]([NH2:27])[N:18]=2)[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@H:2]1[OH:3]
Reactant: Nc1ncnc2nc[nH]c12
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: Nc1nc(C2O[C@H](CO)[C@@H](O)[C@H]2O)nc2nc[nH]c12
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O
Reaction time: 1.5 h

Procedure:
For the determination of transglycosylation catalytic activity the mixture of cell lysates containing both UPase and PNPase were prepared by mixing the lysates so as to have UPase:PNPase enzymatic-activity ratio of about 1:1, determined as in Examples 6 and 7. Transglycosylation reaction was carried out at analytical scale in the following conditions: 250 μl of cell lysates (equivalent to 14 units of each UPase and PNPase enzymatic activities) was added to 10 ml of a solution having the following composition: 4 mM 1-β-D-ribofuranosyluracil (uridine nucleoside), 4 mM adenine base, 30 mM potassium phosphate buffer pH7, thermostatically controlled at 60° C. After 1.5 hours at 60° C., the reaction was stopped by diluting the mixture 1:5 and cooling in ice. The percentage of bioconversion of adenine base to 9-β-D-ribofuranosyladenine (adenosine nucleoside) was determined by analyzing an aliquot of the reaction mixture by high performance liquid chromatography (HPLC) with the use of Kromasil 100-5C18 (Akzo Nobel) column of a size of 250×4.6 mm and eluted with a 4% methanol-water solution. The transglycosylation catalytic activity was expressed as units·ml−1 (μmoles of Ara-A formed in 1.5 hours·ml−1 of mixture of cell lysates) or in units·g−1 of moist resin (μmoles of D-ribofuranosyladenine formed in 1.5 hours·ml−1 of cell lysate) and was calculated relative to a standard D-ribofuranosyladenine solution eluted by HPLC in the same conditions. Under these conditions, about 55 percent of adenosine nucleoside was formed (approximately 9 units per ml of cell lysate).
Reaction SMILES: Br.Br.[CH3:3][C:4]1([NH2:9])[CH2:6][C:5]1([CH3:8])[NH2:7].[F:10][C:11]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:12]=1[CH2:13][O:14][C:15]1[N:20]2[N:21]=[C:22]([CH3:27])[C:23]([C:24](O)=[O:25])=[C:19]2[CH:18]=[C:17]([CH3:28])[CH:16]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C.ClCCl>[NH2:7][C:5]1([CH3:8])[CH2:6][C:4]1([NH:9][C:24]([C:23]1[C:22]([CH3:27])=[N:21][N:20]2[C:15]([O:14][CH2:13][C:12]3[C:29]([F:33])=[CH:30][CH:31]=[CH:32][C:11]=3[F:10])=[CH:16][C:17]([CH3:28])=[CH:18][C:19]=12)=[O:25])[CH3:3]
Reactant: CC1(N)CC1(C)N
Reactant: Cc1cc(OCc2c(F)cccc2F)n2nc(C)c(C(=O)O)c2c1
Agent: Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Cc1cc(OCc2c(F)cccc2F)n2nc(C)c(C(=O)NC3(C)CC3(C)N)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
29 mg (0.11 mmol) of rac-1,2-dimethylcyclopropane-1,2-diamine dihydrobromide (described in: W. v. d. Saal et al. Liebigs Annalen der Chemie 1994, 569-580) were initially charged in a 96-well deep-well multititre plate. A solution of 33.2 mg (0.1 mmol) of 7-[(2,6-difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carboxylic acid from Example 4A in 0.4 ml of DMF/dichloromethane (1:1, v/v) and a solution of 49.4 mg (0.13 mmol) of HATU in 0.4 ml of DMF/dichloromethane (1:1, v/v) were added successively. After adding 20.2 mg (0.20 mmol) of 4-methylmorpholine, the mixture was shaken at RT overnight. Subsequently, the mixture was heated to 60° C. and shaken at this temperature for 7 h. Then the solvent was evaporated off completely. The residue was dissolved in 0.8 ml of DMF and filtered, and the target compound was isolated by preparative LC-MS (Method 9). The product-containing fractions were concentrated under reduced pressure using a centrifugal dryer. The residue of each product fraction was dissolved in 0.6 ml of DMSO. These were combined and finally freed of the solvent in a centrifugal dryer. 2.3 mg (5% of theory) of the title compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[C:5]([F:14])=[C:4](Cl)[N:3]=1.Cl.[F:17][C:18]1[CH:19]=[CH:20][C:21]([C@@H:24]([NH2:26])[CH3:25])=[N:22][CH:23]=1.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:1][C:2]1[N:3]=[C:4]([NH:26][C@H:24]([C:21]2[CH:20]=[CH:19][C:18]([F:17])=[CH:23][N:22]=2)[CH3:25])[C:5]([F:14])=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:7]=1
Reactant: C[C@H](N)c1ccc(F)cn1
Reactant: Fc1c(Cl)nc(Cl)nc1N1CCOCC1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1nc(Cl)nc(N2CCOCC2)c1F)c1ccc(F)cn1
Temperature: 130 °C
Yield: 42 %

Procedure:
A mixture of 4-(2,6-dichloro-5-fluoropyrimidin-4-yl)morpholine (Preparation 11a, 1.18 g, 4.68 mmol), (S)-1-(5-fluoropyridin-2-yl)ethanamine hydrochloride (prepared as described in WO2006/123113, 1.00 g, 4.69 mmol) and N,N′-diisopropylethylamine (3.27 mL, 18.77 mmol) in n-butanol (20 mL) was heated at 130° C. for two days. The solvent was evaporated under reduced pressure and the residue was purified by flash chromatography (0-5% ethyl acetate in hexanes to 5:94:1 ethyl acetate/hexanes/triethylamine) to give the title compound (0.700 g, 42%) as one major regioisomer. The chemical structures of both regioisomers were confirmed by NMR experiments (gHSQCAD and gHMBCAD).
Reaction SMILES: O[C:2]1[C:3]([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:30]=[N:31][C:32]([C:35](=[O:38])[NH:36][CH3:37])=[CH:33][CH:34]=3)=[CH:25][CH:24]=2)=[N:4][N:5]([CH3:22])[C:6]=1[C:7]1[NH:21][C:10]2=[CH:11][C:12]3[CH2:13][N:14](C([O-])=O)[CH2:15][C:16]=3[CH:17]=[C:9]2[N:8]=1.CC(C)([O-:42])C.[K+].[CH2:45]([N:47]([CH2:51][CH3:52])[C:48](Cl)=[O:49])[CH3:46]>CN(C)C=O.C(OCC)(=O)C>[CH2:45]([N:47]([CH2:51][CH3:52])[C:48](=[O:42])[O:49][C:2]1[C:3]([C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:30]=[N:31][C:32]([C:35](=[O:38])[NH:36][CH3:37])=[CH:33][CH:34]=3)=[CH:27][CH:28]=2)=[N:4][N:5]([CH3:22])[C:6]=1[C:7]1[NH:8][C:9]2=[CH:17][C:16]3[CH2:15][NH:14][CH2:13][C:12]=3[CH:11]=[C:10]2[N:21]=1)[CH3:46]
Reactant: CNC(=O)c1ccc(-c2ccc(-c3nn(C)c(-c4nc5cc6c(cc5[nH]4)CN(C(=O)[O-])C6)c3O)cc2)cn1
Reactant: CC(C)(C)[O-]
Reactant: CCN(CC)C(=O)Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN(CC)C(=O)Oc1c(-c2ccc(-c3ccc(C(=O)NC)nc3)cc2)nn(C)c1-c1nc2cc3c(cc2[nH]1)CNC3
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2-(4-hydroxy-1-methyl-3-(4-(6-(methylcarbamoyl)pyridin-3-yl)phenyl)-1H-pyrazol-5-yl)-5,7-dihydroimidazo[4,5-f]isoindole-6(1H)-carboxylate 1-16 (63 mg, 0.11 mmol) in anhydrous N,N-dimethylformamide (2 mL) was added potassium tert-butoxide (25 mg, 0.22 mmol) and diethylcarbamoyl chloride (21 mg, 0.15 mmol). The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with ethyl acetate. The organic layer was washed with water and saturated brine. The organic layer was dried over sodium sulfate. Solvent was evaporated under reduced pressure. To the residue was added a 30% solution of trifluoroacetic acid in dichloromethane (4 mL). The reaction mixture was stirred at room temperature for 2 hours. Solvent was evaporated under reduced pressure. The crude product was purified by RP-HPLC to afford the desired 1-methyl-3-(4-(6-(methylcarbamoyl)pyridin-3-yl)phenyl)-5-(1,5,6,7-tetrahydroimidazo[4,5-f]isoindol-2-yl)-1H-pyrazol-4-yl diethylcarbamate T-17 (48 mg, 0.085 mmol).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:14]2[O:15][C:16]([CH3:19])([CH3:18])[O:17][C@:13]32[C@H:8]([C@H:9]([C:21]([OH:25])(C)[CH2:22]O)[CH2:10][CH2:11][C@@H:12]3[CH3:20])[CH:7]=[C:6]1[CH3:26])(=[O:3])[CH3:2].I([O-])(=O)(=O)=O.[Na+]>CO.O>[C:1]([O:4][C@H:5]1[C@@H:14]2[O:15][C:16]([CH3:18])([CH3:19])[O:17][C@:13]32[C@H:8]([C@H:9]([C:21](=[O:25])[CH3:22])[CH2:10][CH2:11][C@@H:12]3[CH3:20])[CH:7]=[C:6]1[CH3:26])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1C(C)=C[C@H]2[C@H](C(C)(O)CO)CC[C@H](C)[C@]23OC(C)(C)O[C@@H]13
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CO
Product: CC(=O)O[C@@H]1C(C)=C[C@H]2[C@H](C(C)=O)CC[C@H](C)[C@]23OC(C)(C)O[C@@H]13
Reaction time: 0.25 h
Yield: 80.1 %

Procedure:
A solution of the product of (3aS,4R,6aS,7R,10S,10aS)-7-(1,2-dihydroxy-1-methylethyl)-2,2,5,10-tetramethyl-4,6a,7,8,9,10-hexahydro-3aH-naphtho[1,8a-d][1,3]dioxol-4-yl acetate (Preparation 147, 930 mg) in methanol (50 ml) was treated with sodium periodate (540 mg) and sonicated in an ultrasonic bath for 15 minutes. As the sodium periodate dissolved, a cloudy suspension formed. A further amount of sodium periodate (540 mg) was added and sonication was resumed for 15 min. After standing for 1 hour, the reaction mixture was diluted with water and solvent was evaporated. The residue was partitioned between water and dichloromethane and the organic phase was separated, washed with water and brine, dried (Na2SO4) and, concentrated in vacuo. The residual oil was purified by flash column chromatography on silica gel eluting with ethyl acetate:hexane (1:4) to give the product as a colourless oil (680 mg).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:16]=[O:17])[C:7]2[C:12]([C:13]=1[OH:14])=[C:11]([CH3:15])[CH:10]=[CH:9][CH:8]=2)([CH3:3])[CH3:2].[C:18](OC(=O)C)(=[O:20])[CH3:19].O>N1C=CC=CC=1>[C:18]([O:14][C:13]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[CH3:15])[C:6]([CH:16]=[O:17])=[CH:5][C:4]=1[CH:1]([CH3:3])[CH3:2])(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cccc2c(C=O)cc(C(C)C)c(O)c12
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Oc1c(C(C)C)cc(C=O)c2cccc(C)c12

Procedure:
0.7 g of 3-isopropyl-4-hydroxy-5-methyl-1-naphthalenecarbaldehyde and 10 ml of acetic anhydride were dissolved in 10 ml of pyridine and reacted at room temperature for 1 hour. The reaction solution was poured into water and extracted with ethyl acetate. The organic phase was washed with dilute hydrochloric acid, a saturated sodium hydrogencarbonate aqueous solution and a saturated saline solution in this order, dried with anhydrous magnesium sulfate and concentrated under reduced pressure, thereby obtaining 0.5 g of the captioned compound as a black oily substances.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH2:12])=[O:11])=[CH:8][CH:7]=1.[NH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1>CN(C=O)C>[C:25]([O:24][C:22]([N:19]1[CH2:20][CH2:21][CH:16]([NH:15][CH2:3][CH:2]([OH:1])[CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]([C:10](=[O:11])[NH2:12])=[CH:8][CH:7]=2)[CH2:17][CH2:18]1)=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: NC(=O)c1ccc(OCC2CO2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(NCC(O)COc2ccc(C(N)=O)cc2)CC1
Temperature: 80 °C
Reaction time: 48 h
Yield: 40.1 %

Procedure:
4-Oxiranylmethoxy-benzamide (76 mg, 0.393 mmol) was dissolved in 8 mL of dry DMF, followed by the addition of 4-amino-1-N-boc-piperidine (178 mg, 0.889 mmol). The reaction mixture was stirred at 80° C. for 48 h. The reaction mixture was concentrated and the residue was purified by flash chromatography eluting with 0-5% 2M NH3 in MeOH/CH2Cl2. The product fractions were collected and concentrated to afford 62 mg of 4-[3-(4-carbamoyl-phenoxy)-2-hydroxy-propylamino]-piperidine-1-carboxylic acid tert-butyl ester as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][C:3]=1[O:10][CH2:11][CH2:12][CH3:13].[CH:14]([Si:17](Cl)([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])([CH3:16])[CH3:15].N1C=CN=C1>ClCCl>[Cl:1][C:2]1[C:3]([O:10][CH2:11][CH2:12][CH3:13])=[CH:4][CH:5]=[C:6]([CH2:8][O:9][Si:17]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:14]([CH3:16])[CH3:15])[N:7]=1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: CCCOc1ccc(CO)nc1Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CCCOc1ccc(CO[Si](C(C)C)(C(C)C)C(C)C)nc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (6-chloro-5-propoxy-pyridin-2-yl)-methanol (0.93 g, 4.61 mmole), 20 mL of dichloromethane, tri(isopropyl)silyl chloride (1.0 g, 5.19 mmole) and imidazole (0.47 g, 6.9 mmole) is stirred overnight at ambient temperature. The reaction mixture is washed with water, dried over sodium sulfate, filtered and evaporated in-vacuo to give an oil which is chromatographed on silica gel with 10:1 hexane/ethyl acetate to give 2-chloro-3-propoxy-6-triisopropylsilanyloxymethyl-pyridine as a clear liquid, 1.06 g, (64%); MS (ES+): m/z 358.2, 360.2 (M+H). A portion of this (716 mg, 2.0 mmole) and 5 mL of 1M sodium benzyloxide in benzyl alcohol is heated in a microwave reactor 5 minutes at 120° C. The reaction mixture is cooled, transferred to a separatory funnel with ethyl acetate, washed with water, the organic layer is dried, filtered, evaporated and chromatographed on silica gel with hexane/ethyl acetate to give a clear liquid, 524 mg, (61%); MS (ES+): m/z 430.3 (M+H).