Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][CH3:15])/[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[P:16](Cl)([O:21][CH2:22][CH3:23])([O:18][CH2:19][CH3:20])=[O:17]>N1C=CC=CC=1>[CH2:19]([O:18][P:16]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH3:15])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)([O:21][CH2:22][CH3:23])=[O:17])[CH3:20]
Reactant: CCOP(=O)(Cl)OCC
Reactant: CCOC(=O)/C(=N\OC)c1csc(N)n1
Solvent: c1ccncc1
Product: CCOC(=O)C(=NOC)c1csc(NP(=O)(OCC)OCC)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.3 %

Procedure:
To a stirred solution of 4.6 g (0.02 mol) of ethyl 2-(aminothiazol-4-yl)-Z-2-methoxyiminoacetate in 40 ml pyridine at 10°-20° was added 9.0 ml (0.6 mol) diethyl chlorophosphate. The solution was stirred at room temperature for 2 hours. Pyridine was evaporated and the residue was codistilled with benzene and partitioned between water and methylene chloride. The methylene chloride layer was washed with excess 10% aqueous HCl, water, aqueous bicarbonate, saturated sodium chloride, and dried over sodium sulfate. Upon evaporation, 5.5 g brown oil was obtained which was purified on Biosil A using hexane/ethyl acetate (1:4) to afford 2.8 g of yellow crystals, m.p. 96.5-98.0; NMR (300MH2, DCCl3) δ 1.35 (3t, 9, CH2CH3), 3.97 (S, 3, OCH3), 4.17 (q, 4, OCH2), 4.39 (q, 2, OCH2), 6.93 (s, 1, thiazole H).
Reaction SMILES: C(OC(C1C(=O)OC2C(C=1)=CC(Cl)=C(O)C=2[N+:18]([O-:20])=[O:19])=O)C.[CH2:22]([O:24][C:25]([C:27]1[C:28](=[O:41])[O:29][C:30]2[C:35]([CH:36]=1)=[CH:34][CH:33]=[C:32]([O:37][CH3:38])[C:31]=2[O:39][CH3:40])=[O:26])[CH3:23]>>[CH2:22]([O:24][C:25]([C:27]1[C:28](=[O:41])[O:29][C:30]2[C:35]([CH:36]=1)=[CH:34][C:33]([N+:18]([O-:20])=[O:19])=[C:32]([O:37][CH3:38])[C:31]=2[O:39][CH3:40])=[O:26])[CH3:23]
Reactant: CCOC(=O)c1cc2cc(Cl)c(O)c([N+](=O)[O-])c2oc1=O
Reactant: CCOC(=O)c1cc2ccc(OC)c(OC)c2oc1=O
Product: CCOC(=O)c1cc2cc([N+](=O)[O-])c(OC)c(OC)c2oc1=O

Procedure:
Compound 227 was prepared following the preparation of compound 241, except that 3-ethoxycarbonyl-7,8-dimethoxycoumarin was nitrated to give the title compound 227.
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([CH:9]=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.COCCOC>[C:16]1([C:2]2[C:3]3[C:8]([CH:9]=[C:10]4[C:15]=2[CH:14]=[CH:13][CH:12]=[CH:11]4)=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Brc1c2ccccc2cc2ccccc12
Reactant: OB(O)c1ccccc1
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: c1ccc(-c2c3ccccc3cc3ccccc23)cc1
Temperature: 90 °C
Reaction time: 5 h
Yield: 98.3 %

Procedure:
25.7 g (100 mmol) of 9-bromoanthracene, 12.8 g (105 mmol) of phenylboronic acid, 233 mg (1.0 mmol) of palladium acetate(II), and 913 mg (3.0 mmol) of tri(o-tolyl)phospine were put into a 500-mL three-neck flask and nitrogen substitution was carried out. Then, 100 mL of ethylene glycol dimethyl ether and 75 mL (190 mmol) of a sodium carbonate aqueous solution (2.0 mol/L) were added thereto, and the reaction mixture was stirred at 90° C. for 5 hours. After the reaction, the reaction mixture was subjected to suction filtration to collect a precipitated solid. The obtained solid was dissolved into toluene, and the resulting solution was subjected to suction filtration through Florisil, celite, and then alumina. The filtrate was washed with water and saturated saline, and then an organic layer was dried with magnesium sulfate. This mixture is naturally filtrated, and the filtrate was condensed to obtain 25.0 g of a light-brown solid that was a target matter with the yield of 98%.
Reaction SMILES: [CH3:1][C:2]1[C:14]([OH:15])=[C:13]([CH3:16])[C:12]([CH3:17])=[C:11]2[C:3]=1[CH:4](O)[CH2:5][C:6]1([O:10]2)[CH2:9][CH2:8][CH2:7]1.[CH3:19][CH:20]([SH:22])[CH3:21].O.C(=O)(O)[O-].[Na+]>O.Cl.C(OCC)(=O)C>[CH:20]([S:22][CH:4]1[C:3]2[C:11](=[C:12]([CH3:17])[C:13]([CH3:16])=[C:14]([OH:15])[C:2]=2[CH3:1])[O:10][C:6]2([CH2:9][CH2:8][CH2:7]2)[CH2:5]1)([CH3:21])[CH3:19]
Reactant: CC(C)S
Reactant: Cc1c(C)c2c(c(C)c1O)C(O)CC1(CCC1)O2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1c(C)c2c(c(C)c1O)C(SC(C)C)CC1(CCC1)O2
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a solution of 5,7,8-trimethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutane]-4,6-diol (290 mg) in acetonitrle (2 mL) was added 2-propanethiol (0.5 mL) and concentrated HCl water solution (5 drops). The solution was stirred at room temperature for 7 hours. The solution was neutralized using sodium bicarbonate water solution to pH about 7. Ethyl acetate was added, washed with water and brine. Evaporation and chromatography (silica gel, hexane-ethyl acetate 0 to 4%) gave 140 mg of 4-(isopropylthio)-5,7,8-trimethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-6-ol
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]([C:12]([Cl:15])([Cl:14])[Cl:13])[O:9][CH:8]([C:16]([Cl:19])([Cl:18])Cl)[C:7]=2[CH:20]=1)#[N:2].[Cl-].[NH4+].[N-:23]=[N+:24]=[N-:25].[Na+]>CN(C)C=O>[Cl:18][C:16]([Cl:19])=[C:8]1[C:7]2[CH:20]=[C:3]([C:1]3[NH:25][N:24]=[N:23][N:2]=3)[CH:4]=[CH:5][C:6]=2[O:11][CH:10]([C:12]([Cl:13])([Cl:14])[Cl:15])[O:9]1
Reactant: N#Cc1ccc2c(c1)C(C(Cl)(Cl)Cl)OC(C(Cl)(Cl)Cl)O2
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: ClC(Cl)=C1OC(C(Cl)(Cl)Cl)Oc2ccc(-c3nnn[nH]3)cc21
Reaction time: 16 h

Procedure:
A mixture of 6-cyano-2,4-bis(trichloromethyl)benzo[1,3]dioxin (1.98 g.), ammonium chloride (0.33 g.) and sodium azide in anhydrous dimethylformamide was warmed on the steam bath for 16 hours. The reaction mixture was cooled, poured onto ice and kept for 16 hours. The amorphous white product was filtered off, triturated with acetic acid, and crystallised from chloroform to give 4-dichloromethylene-6-(tetrazol-5-yl)-2-trichloromethylbenzo[1,3]dioxin, m.p. 222° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[H-].[Na+].[Cl:15][C:16]1[CH:21]=[C:20]([O:22][C:23]2[CH:30]=[CH:29][C:28]([CH2:31][OH:32])=[CH:27][C:24]=2[C:25]#[N:26])[CH:19]=[CH:18][N:17]=1>CN(C=O)C>[Cl:15][C:16]1[CH:21]=[C:20]([O:22][C:23]2[CH:30]=[CH:29][C:28]([CH2:31][O:32][C:2]3[CH:3]=[C:4]4[N:11]([CH3:12])[CH2:10][CH2:9][N:5]4[C:6](=[O:8])[N:7]=3)=[CH:27][C:24]=2[C:25]#[N:26])[CH:19]=[CH:18][N:17]=1
Reactant: CN1CCn2c1cc(Cl)nc2=O
Reactant: N#Cc1cc(CO)ccc1Oc1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCn2c1cc(OCc1ccc(Oc3ccnc(Cl)c3)c(C#N)c1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (65 mg, 0.350 mmol), sodium hydride (22 mg, 0.550 mmol) and 2-((2-chloropyridin-4-yl)oxy)-5-(hydroxymethyl)benzonitrile (91 mg, 0.350 mmol) in DMF (2 mL).
Reaction SMILES: [O:1]=[C:2]1[C@H:8]2[CH2:9][C@H:4]([CH2:5][CH2:6][C@@H:7]2[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[O:3]1.[Li+].[OH-:18]>C1COCC1.O>[C:13]([O:12][C:10]([C@H:7]1[CH2:6][CH2:5][C@H:4]([OH:3])[CH2:9][C@@H:8]1[C:2]([OH:18])=[O:1])=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)[C@H]1CC[C@H]2C[C@@H]1C(=O)O2
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@H]1CC[C@H](O)C[C@@H]1C(=O)O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
tert-Butyl(1S,2S,5S)-7-oxo-6-oxabicyclo(3,2,1)octane-2-carboxylate was dissolved in THF—H2O. At 0° C., LiOH (3 eq.) was added and the resulting mixture was stirred at 0° C. for 2 hours. TLC showed starting material was consumed. The mixture was then acidified to pH of about 2. The product was extracted with EtOAc (×3). The combined extracts were washed with brine (×1); dried over MgSO4. After filtration, the filtrate was concentrated to give (1S,2S,5S)-2-(tert-butoxycarbonyl)-5-hydroxycyclohexanecarboxylic acid (quantitative).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:20][C:21]4[NH:26][C:25](=S)[CH2:24][O:23][C:22]=4[N:28]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[NH:36]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[NH2:37]>C1COCC1>[C:1]([O:5][C:6]([NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:20][C:21]4[NH:26][C:25](=[N:37][NH:36][C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:24][O:23][C:22]=4[N:28]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)=[O:35])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)NN
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=S)CO4)cc2)CCC1
Solvent: C1CCOC1
Product: CCOC(=O)NN=C1COc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc2N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl(1-(4-(7-phenyl-2-thioxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (20 mg, 0.04 mmol) in dry THF (1 mL) was added ethyl hydrazinecarboxylate (21 mg, 0.20 mmol) and mercuric acetate (21 mg, 0.06 mmol) under nitrogen. The reaction mixture was stirred for 2 h at room temperature, filtered on celite and concentrated to dryness under reduced pressure to give the title compound which was used without purification in the next step.
Reaction SMILES: [CH:1]([CH:4]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:5]([OH:7])=[O:6])([CH3:3])[CH3:2].[N+:15]([O-])([OH:17])=[O:16]>C(O)(=O)C>[CH:1]([CH:4]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([N+:15]([O-:17])=[O:16])[CH:9]=1)[C:5]([OH:7])=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)C(C(=O)O)c1ccc(O)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CC(C)C(C(=O)O)c1ccc(O)c([N+](=O)[O-])c1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
A mixture of α-isopropyl-4-hydroxyphenylacetic acid (18.2 g, 0.094 mol) in acetic acid (130 ml) is heated to 40° C. and nitric acid (70%, 9.56 g, 0.095 mol) is added at such a rate that the reaction temperature is maintained at 38°-40° and never exceeded 45° C. The reaction mixture is stirred at 40°-42° C. overnight and poured into ice-water. The yellow solid is collected by filtration, washed and dried (19.1 g); m.p. 103°-105°.
Reaction SMILES: O[CH2:2][C:3]1[O:7][C:6]([C:8]#[N:9])=[CH:5][CH:4]=1.[Cl:10][C:11]1[CH:12]=[CH:13][C:14](=[O:48])[N:15]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][C:24]3[N:25]=[CH:26][N:27](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:28]=3)=[CH:19][N:18]=2)[CH:16]=1.C(N(C(C)C)CC)(C)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>ClCCl>[Cl:10][C:11]1[CH:12]=[CH:13][C:14](=[O:48])[N:15]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][C:24]3[N:25]([CH2:2][C:3]4[O:7][C:6]([C:8]#[N:9])=[CH:5][CH:4]=4)[CH:26]=[N:27][CH:28]=3)=[CH:19][N:18]=2)[CH:16]=1
Reactant: O=c1ccc(Cl)cn1-c1ccc(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cn1
Reactant: N#Cc1ccc(CO)o1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(Cn2cncc2Cc2ccc(-n3cc(Cl)ccc3=O)nc2)o1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of the alcohol from step 2 (0.017 g, 0.137 mmol), 5-chloro-5'-(1-triphenylmethyl-1H-imidazol-4-ylmethyl)-[1,2']bipyridinyl-2-one from Example 23, Step 5 (0.0758 g, 0.143 mmol) and diisopropylethylamine (0.047 mL, 1.49 mmol) in dichloromethane (1.3 mL) at -78° C. was added trifluoromethanesulfonic anhydride (0.023 mL, 0.136 mmol) and the mixture stirred at -78° C. for 1 hour. The mixture was allowed to warm to 0° C. and stirred for 2 hours. The solvent was evaporated in vacuo. The residue was dissolved in methanol (1 mL), heated at reflux for 2 hour, and the solvent evaporated in vacuo. The residue was partitioned between CH2Cl2 and sat. aq. NaHCO3 solution. The organic layer was dried, (Na2SO4) and the solvent evaporated in vacuo. The residue was chromatographed (Silica gel, 1:99 to 3:97 MeOH:CH2Cl2) to afford the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]([CH2:4][C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])=[O:3].[S:11](Cl)([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12]>N1C=CC=CC=1>[CH3:1][C:2]([CH2:4][C@@H:5]([C@@H:7]([CH2:9][O:10][S:11]([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[OH:8])[OH:6])=[O:3]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(=O)C[C@H](O)[C@H](O)CO
Solvent: c1ccncc1
Product: CC(=O)C[C@H](O)[C@H](O)COS(=O)(=O)c1ccc(C)cc1
Reaction time: 14 h
Yield: 83.3 %

Procedure:
Methyl-2-deoxy-D-ribose (8 g, 54 mmol) was dissolved in pyridine (60 mL). To this solution was added tosylchloride (10.86 g, 57 mmol) over 1 hour at 0° C. After 14 hours at room temperature, the solution was concentrated, quenched with ice water (250 mL), and extracted with ethyl acetate. The extract was washed with saturated NaHCO3, water, dried, filtered, and concentrated. The residue (13.6 g, 83.5% yield) was used directly. NMR
Reaction SMILES: S(Cl)(Cl)=O.O[C@@H:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[NH:11][C:12]1[N:13]([CH3:29])[C:14](=[O:28])[C:15]2[C:16](=[N:18][NH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:17]=1>C(Cl)Cl>[CH3:29][N:13]1[C:14](=[O:28])[C:15]2=[C:20]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[NH:19][N:18]=[C:16]2[N:17]2[C@H:6]3[CH2:10][CH2:9][CH2:8][C@H:7]3[N:11]=[C:12]12
Reactant: Cn1c(N[C@@H]2CCC[C@H]2O)nc2n[nH]c(Nc3ccccc3)c2c1=O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CN1C(=O)c2c(n[nH]c2Nc2ccccc2)N2C1=N[C@@H]1CCC[C@@H]12
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
2.0 M solution of thionyl chloride in CH2Cl2 (7.5 mL, 15.4 mmol) is added dropwise to a solution of 6-((1R,2R)-2-hydroxycyclopentylamino)-5-methyl-3-(phenylamino)-2H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (3.5 g, 10.3 mmol) in CH2Cl2 (30 mL) at room temperature. After the completion of the addition, the reaction mixture is stirred at r.t. for 2 h. Solvent and excess SOCl2 are removed under reduced pressure. The residue is suspended in water (100 mL), and then carefully neutralized with 7% ammonium hydroxide (5 mL) to pH=6.5-7. The mixture is extracted with CH2Cl2 and MeOH (10:1, v/v) five times. The combined organic phase is washed with water, dried over Na2SO4, and then evaporated under reduced vacuum to give 2.9 g of crude product. MS (ESI) m/z 323.2 [M+H]+.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH:16]2[O:28][CH2:29][C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)=[CH:11][CH:10]=1)(=O)=O.[N-:40]=[N+:41]=[N-:42].[Na+]>CS(C)=O>[N:40]([CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH:16]2[O:28][CH2:29][C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)=[CH:13][CH:14]=1)=[N+:41]=[N-:42]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCOS(C)(=O)=O)cc2)C(OCc2ccc3ccccc3c2)C1
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCN=[N+]=[N-])cc2)C(OCc2ccc3ccccc3c2)C1
Temperature: 80 °C
Reaction time: 3.5 h

Procedure:
A mixture of 569 mg of crude tert-butyl (3RS,4RS)-4-[4-(2-methylsulphonyloxy-ethoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate and 650 mg of sodium azide in 20 ml of dimethyl sulphoxide was stirred at 80° C. for 3.5 hours. Subsequently, this reaction solution was poured into 50 ml of an ice/water mixture and extracted three times with ethyl acetate. The organic phases were washed with water, dried over magnesium sulphate, evaporated under reduced pressure and dried in a high vacuum. The yellow oil (670 mg) was separated on silica gel using a 9:1 mixture of hexane and ethyl acetate as the eluent. There were obtained 271 mg (54% of theory over both steps) of tert-butyl (3RS,4RS)-4-[4-(2-azido-ethoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless solid; MS: 503 (M+H)+.
Reaction SMILES: [C:1]([O:7][C@H:8]([CH2:20][C@H:21]1[C@H:24]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:23](=[O:31])[O:22]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])(=[O:6])[CH2:2][C:3]([OH:5])=O.CN(C(O[N:40]1N=N[C:42]2C=CC=[CH:46][C:41]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N)(C)C>C(#N)C>[CH2:25]([C@@H:24]1[C:23](=[O:31])[O:22][C@H:21]1[CH2:20][C@@H:8]([O:7][C:1](=[O:6])[CH2:2][C:3]([NH:40][CH:41]([CH3:46])[CH3:42])=[O:5])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCCCC[C@@H](C[C@@H]1OC(=O)[C@H]1CCCCCC)OC(=O)CC(=O)O
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CC(C)N
Product: CCCCCCCCCCC[C@@H](C[C@@H]1OC(=O)[C@H]1CCCCCC)OC(=O)CC(=O)NC(C)C
Yield: 84.9 %

Procedure:
A solution of 33.5 mg of (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl hydrogen malonate (Example N) in 2 ml of acetonitrile was treated with 60 mg of HBTU and 75 mg of iso-propylamine. After stirring the reaction mixture was filtered, the filtrate was concentrated and the residue was chromatographed on silica gel with hexane/methylene chloride/ethyl acetate (2:2:1). There were obtained 31.1 mg of (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl-N-isopropylmalonamate, m.p. 59°.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][C:7]=1[O:15][CH3:16].O.C(C(O)=[O:23])(F)(F)F>CC#N>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH2:13][OH:23])=[CH:8][C:7]=1[O:15][CH3:16]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Solvent: CC#N
Solvent: O
Product: COc1cc(C(=O)CO)ccc1OCCCCl

Procedure:
A solution of 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (4.3 g, 17.7 mmol), [bis(trifluoroacetoxy)iodolbenzene (15.6 g, 36.2 mmol), H2O (18 ml), CF3CO2H (2.8 ml) and CH3CN (90 ml) was refluxed for 3 hours. The CH3CN was removed under reduced pressure and the resulting yellow liquid was partitioned between H2O and CH2Cl2. The biphasic mixture was filtered, the organic phase collected, washed with saturated NaHCO3 solution and concentrated to afford 1.5 g of an amorphous brown solid. The solid was flash chromatographed on silica gel, eluting the column with 5% EtOAc/CH2Cl2. Concentration of similar fractions afforded 0.7 g of the compound as a pale yellow solid, m.p. 99°-101° C.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][N:15](C(OCC)=O)[CH2:14][C@@H:13]1[O:23][CH2:24][CH3:25])=[O:10].[OH-].[K+].O.NN.O>C(O)CO>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][NH:15][CH2:14][C@@H:13]1[O:23][CH2:24][CH3:25])=[O:10]
Reactant: CCOC(=O)N1CC[C@@H](NC(=O)c2[nH]c(C)c(Cl)c2Cl)[C@@H](OCC)C1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: CCO[C@H]1CNCC[C@H]1NC(=O)c1[nH]c(C)c(Cl)c1Cl
Yield: 64.4 %

Procedure:
A solution of ethyl (3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-ethoxypiperidine-1-carboxylate (Intermediate 25, 1.9 g, 4.85 mmol), potassium hydroxide (1.9 g, 34.01 mmol), and hydrazine hydrate (1.71 mL, 34.01 mmol) in ethylene glycol (150 mL) was stirred for 40 h at 120° C. The reaction mixture was poured in to water (120 mL) and extracted with ethyl acetate (2×150 mL). The combined organic extracts were dried over anhydrous sodium sulphate, filtered, concentrated in vacuo to yield the crude product, which was triturated with water (30 mL) to afford 3,4-dichloro-N-[(3S,4R)-3-ethoxypiperidin-4-yl]-5-methyl-1H-pyrrole-2-carboxamide 1.0 g (65%) as solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:32])=[C:5]([C:23]([O:30][CH3:31])=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH2:6][C:7]1[C:8]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([O:12]C)=[O:11]>[OH-].[Na+].O1CCOCC1.O>[CH3:1][O:2][C:3]1[C:4]([CH3:32])=[C:5]([C:23]([O:30][CH3:31])=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH2:6][C:7]1[C:8]([C:17]2[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=2)=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([OH:12])=[O:11]
Reactant: COC(=O)c1cccc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)c1-c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1c(C)c(Cc2cccc(C(=O)O)c2-c2ccncc2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
Methyl 3-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-(4-pyridyl)benzoate (301 mg, 0.5508 mmol) was dissolved in a mixed solution of a 1N aqueous solution of sodium hydroxide (10 ml) and 1,4-dioxane (10 ml) followed by stirring at room temperature for 16 hours. The reaction solution was diluted with water (100 ml), washed with ether, acidified with concentrated hydrochloric acid and extracted with ether. The extract was washed with water and dried and the solvent was evaporated therefrom to give the title compound (233 mg, 0.5508 mmol, 80%).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[C:26]2[C:25]3[C:20](=[CH:21][C:22]([OH:27])=[CH:23][CH:24]=3)[NH:19][C:18]=2[C:17]([C:28]([NH2:30])=[O:29])=[CH:16][CH:15]=1>N1C=CC=CC=1.CCOC(C)=O>[C:2](=[O:3])([O:4][CH2:5][CH3:6])[O:27][C:22]1[CH:23]=[CH:24][C:25]2[C:26]3[C:18](=[C:17]([C:28](=[O:29])[NH2:30])[CH:16]=[CH:15][C:14]=3[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[F:7])[NH:19][C:20]=2[CH:21]=1
Reactant: CCOC(=O)Cl
Reactant: NC(=O)c1ccc(-c2ccccc2F)c2c1[nH]c1cc(O)ccc12
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)Oc1ccc2c(c1)[nH]c1c(C(N)=O)ccc(-c3ccccc3F)c12
Reaction time: 17 h
Yield: 30.8 %

Procedure:
Ethyl chloroformate (8.19 mg, 0.075 mmol) was added to a solution of 4-(2-fluorophenyl)-7-hydroxy-9H-carbazole-1-carboxamide (Example 40-1, 18.6 mg, 0.058 mmol) in pyridine (1 mL). After 17 h, additional ethyl chloroformate (8.19 mg, 0.075 mmol) was added. After 5 h more, additional ethyl chloroformate (0.05 mL) was added. After 15 h more, the mixture was diluted with EtOAc (30 mL), washed with water (10 mL) and brine (5 mL), dried and concentrated. The residue was purified by preparative HPLC to provide 8-carbamoyl-5-(2-fluorophenyl)-9H-carbazol-2-yl ethyl carbonate as a white solid (7.0 mg, 28%). 1H NMR (400 MHz, chloroform-d) δ 10.44 (1H, br. s.), 7.62 (1H, dd, J=7.92, 1.98 Hz), 7.41-7.57 (2H, m), 7.20-7.40 (4H, m), 7.16 (1H, dd, J=7.81, 1.65 Hz), 6.79-6.92 (1H, m), 6.60 (2H, br. s.), 4.34 (2H, q, J=7.26 Hz), 1.41 (3H, t, J=7.15 Hz). Mass spectrum m/z 393.0 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[O:8][C:7]([C:9](Cl)=[O:10])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:12][NH:13][CH3:14]>O1CCCC1>[CH3:12][N:13]([CH3:14])[C:9]([C:7]1[O:8][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=1)=[O:10]
Reactant: CNC
Reactant: CC(=O)c1ccc(C(=O)Cl)o1
Solvent: C1CCOC1
Product: CC(=O)c1ccc(C(=O)N(C)C)o1
Temperature: 25 °C

Procedure:
To a stirred solution of 9.1 g. (0.053 mole) of 5-acetylfuran-2-carbonyl chloride in 150 ml. of tetrahydrofuran at ca -30° C. was added, dropwise, 7.0 ml. (0.106 mole) of dimethylamine. Stirring was continued, and the reaction mixture was allowed to warm to room temperature and then stirred overnight. The tetrahydrofuran was removed by evaporation in vacuo, and the residue was diluted with water and extracted with ethyl acetate. The extracts were washed with water, dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with 1:20 methanol-chloroform, to give 7.33 g. of the title compound as a solid, mp 101°-104° C. A small sample was recrystallized from cyclohexane to give a pale yellow solid, mp. 104°-106° C.