Azzindani/Open_Reaction_Data huggingface dataset:
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][C:17]1[CH:18]=[C:19]([C:22](C)=[CH:23][C:24]=1O)[CH:20]=[O:21].N1C=CC=C[CH:28]=1>O>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:24]1[C:23]([CH3:28])=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][C:17]=1[CH3:16])(=[O:5])=[O:4]
Reactant: c1ccncc1
Reactant: Cc1cc(C=O)c(C)cc1O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Product: Cc1cc(C=O)cc(C)c1OS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4.3 ml of trifluoromethanesulfonic anhydride were added under an inert gas atmosphere at 0° C., to a mixture of 3.0 g of 3,6-dimethyl-4-hydroxy-benzaldehyde and 20 ml of pyridine and the mixture was stirred for 3 hours at ambient temperature. Then the reaction medium was poured into ice-cooled water and after extraction with dichloromethane, and drying of the organic phase over magnesium sulfate and concentrated to dryness under reduced pressure, the residue was chromatographed on silica, eluting with a cyclohexane/ethyl acetate mixture (9/1) to obtain 4.11 g of the expected product.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=2)[CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH2:18][CH2:17]2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:37][I:38]>C(#N)C>[I-:38].[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([C:10]([N:12]([CH2:13][CH2:14][CH2:15][N+:16]2([CH3:37])[CH2:17][CH2:18][CH:19]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH2:20][CH2:21]2)[C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=2)=[O:11])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CI
Reactant: CC(=O)N1CCC(C(=O)N(CCCN2CCC(Cc3ccc(F)cc3)CC2)c2cccc(Cl)c2)CC1
Solvent: CC#N
Product: CC(=O)N1CCC(C(=O)N(CCC[N+]2(C)CCC(Cc3ccc(F)cc3)CC2)c2cccc(Cl)c2)CC1
Product: [I-]
Temperature: 25 °C
Reaction time: 14 h
Yield: 87 %

Procedure:
A mixture of the compound obtained in Example 18 (310 mg, 0.60 mmol), methyl iodide (0.75 ml) and acetonitrile (10 ml) was stirred at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure. To the concentrate was added diethyl ether, and the resulting precipitates were collected by filtration. The precipitates were washed with diethyl ether, and dried under reduced pressure to give the titled compound (344 mg, 0.52 mmol, Yield 87%) as white amorphous substance.
Reaction SMILES: [C:1]([C:9]1[CH:25]=[CH:24][C:12]([C:13]([N:15]2[CH2:20][CH2:19][C:18]3[CH:21]=[CH:22][O:23][C:17]=3[CH2:16]2)=[O:14])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1.[CH2:31]=O>C(O)(=O)C>[C:1]([C:9]1[CH:10]=[CH:11][C:12]([C:13]([N:15]2[CH2:20][CH2:19][C:18]3[CH:21]=[C:22]([CH2:31][N:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)[O:23][C:17]=3[CH2:16]2)=[O:14])=[CH:24][CH:25]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCNC1
Reactant: C=O
Reactant: O=C(c1ccccc1)c1ccc(C(=O)N2CCc3ccoc3C2)cc1
Solvent: CC(=O)O
Product: O=C(c1ccccc1)c1ccc(C(=O)N2CCc3cc(CN4CCCC4)oc3C2)cc1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.229 g (0.691 mmol) of 6-(4-benzoylbenzoyl)-4,5,6,7-tetrahydrofuro[2,3-c]pyridine in 10 ml of acetic acid, 0.09 ml (1.0 mmol) of pyrrolidine and 84 mg (1.0 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 0.5 hours. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with aqueous sodium hydroxide and extracted with ethyl acetate 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate to ethyl acetate/methanol=4/1) to yield the desired product.
Reaction SMILES: CC1(C)CC1C(N[CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=O.C1(C)C=CC(S(O[CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30](NC(OC(C)(C)C)=O)=[CH:29][CH:28]=2)(=O)=O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>[I-].[Na+].C(#N)C>[CH2:25]([N:11]1[CH2:10][CH2:9][CH2:8][CH2:13][CH2:12]1)[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(NC(=O)OC(C)(C)C)cc2)cc1
Reactant: CC1(C)CC1C(=O)NC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: c1ccc(CCN2CCCCC2)cc1
Temperature: 100 °C
Yield: 65.5 %

Procedure:
An acetonitrile (5 ml) solution of the piperidine compound (23:R=2,2-dimethylcyclopropane) (50 mg, 0.25 mmol) obtained in the process 1 of example 15 was added with 2-(4-t-butoxycarbonylaminophenyl)ethanol paratoluensulfonate (57 mg, 0.31 mmol), sodium carbonate (32 mg, 0.31 mmol) and sodium iodide (2 mg), which was in turn heated and refluxed at 100° C. for 2 hours. The resultant was extracted with ethyl acetate, and further washed with water and saturated saline solution, dried and vacuum concentrated, and then separately purified with a silica gel TLC plate (chloroform, methanol), thus obtained a phenethylpiperidine compound (31 mg, 29%).
Reaction SMILES: [N+:1]([C:4]1[CH:35]=[CH:34][C:7]([CH2:8][O:9][C:10]([C@@H:12]2[N:16]3[C:17](=[O:30])[C@@H:18]([NH:19][C:20](=[O:29])[CH2:21][O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C@H:15]3[S@@:14](=O)[C:13]2([CH3:33])[CH3:32])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:36]([N:39]=[C:40]=[O:41])(=[O:38])[CH3:37].S1[C@@H]2CC(=[O:49])N2CC1.S1[C@@H]2CC(=O)N2CCC1>O1CCOCC1>[N+:1]([C:4]1[CH:35]=[CH:34][C:7]([CH2:8][O:9][C:10]([C@@H:12]2[N:16]3[C:17](=[O:30])[C@@H:18]([NH:19][C:20](=[O:29])[CH2:21][O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C@H:15]3[S:14][C@:13]2([CH2:33][O:41][C:40](=[O:49])[NH:39][C:36](=[O:38])[CH3:37])[CH3:32])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC1(C)[C@H](C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@@H](NC(=O)COc3ccccc3)[C@H]2[S@]1=O
Reactant: CC(=O)N=C=O
Reactant: O=C1C[C@H]2SCCN12
Agent: O=C1C[C@H]2SCCCN12
Solvent: C1COCCO1
Product: CC(=O)NC(=O)OC[C@]1(C)S[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2[C@H]1C(=O)OCc1ccc([N+](=O)[O-])cc1
Yield: 40.2 %

Procedure:
A solution of (1S,3S,5R,6R) 2,2-dimethyl-6-phenoxyacetamidopenam-3-carboxylic acid-1-oxide p-nitrobenzyl ester (25.18 g, 50.0 mmol), acetyl isocyanate (8.50 ml, 9.53 g, 112 mmol), and dioxane (250 ml) was refluxed under nitrogen for 5 hours, cooled and concentrated in vacuo to a yellow foam. The foam was chromatographed on silica gel (1.7 Kg) with methylene chloride:acetone; 9:1; v:v to give four products; the 3-methyl-Δ3 -cephem; starting sulfoxide, the title penam, and the cepham (in order of elution). The penam fractions were concentrated to a colorless foam in 40.2% yield (11.80 g). Re-chromatography of a portion gave an analytical sample: m.p. 83°-85°; nmr 100 MHz (CDCl3) ppm 8.40 ##STR60## 8.20 (2, d, J=8.5, 1/2 aromatic AB pNB), 7.56 (3, d, J=8.5 over m, 1/2 AB, pNB and C6 -NH), 7.5 (2, m) and 6.9 (3, m, O-Ph-H's), 5.7 (2, m's, C5 -C6 -H's), 5.32 (2, br s, pNB methylene), 4.88 (1, s, C3 --H), 4.56 ##STR61## 4.26 and 4.06 (2, d's,J=11.5, AB of C2 --CH2O), 2.22 ##STR62## and 1.47 (3, s, C2 --CH3); nmr 13C 4 carbonyls ca 170 ppm, carbamate carbonyl C 157.0, C2 singlet at 67.4, while C2 --CH2O is t at 72.3, and C2 --CH3 is q at 21.7.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=O)[C:15]([F:18])([F:17])[F:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([F:17])([F:18])[F:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)C(F)(F)F)CC1
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(CC(F)(F)F)CC1
Temperature: 0 °C
Yield: 77.4 %

Procedure:
To 4-(2,2,2-trifluoro-acetyl)-piperazine-1-carboxylic acid tert-butyl ester (6.06 g) in dry THF (60 mL) was added borane dimethyl sulfide complex (4.5 ml) and the reaction mixture was heated to reflux. After 2 h the reaction mixture was cooled to 0° C. and MeOH was carefully added, followed by water. The organics were extracted into ethyl acetate, dried (MgSO4) and the solvent removed in vacuo to yield 4-(2,2,2-trifluoro-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (4.46 g). Treatment with HCl in DCM/MeOH yielded the desired compound, which was isolated as the hydrochloride salt.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[CH2:11]([NH2:14])[CH2:12][CH3:13].[Cl:15][CH2:16][CH2:17][N:18]=[C:19]=[O:20]>>[Cl:15][CH2:16][CH2:17][NH:18][C:19]([N:14]([CH2:11][CH2:12][CH3:13])[CH:9]1[O:10][CH2:2][C@@H:3]([OH:4])[C@H:5]([OH:6])[C@H:7]1[OH:8])=[O:20]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)CO
Reactant: CCCN
Reactant: O=C=NCCCl
Product: CCCN(C(=O)NCCCl)C1OC[C@@H](O)[C@H](O)[C@H]1O
Yield: 67.5 %

Procedure:
3.0 g of D-xylose, 1.5 g of n-propylamine and 2.5 g of 2-chloroethyl isocyanate are treated in the same manner as described in Example 5-(1). 4.0 g of 1-(2-chloroethyl)-3-n-propyl-3-D-xylopyranosylurea are thereby obtained as colorless caramel.
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2C(=NN(CC)N=2)N=1)(C)(C)C.[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][C:39]([F:42])([F:41])[C:38]([F:44])([F:43])[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1)([CH3:26])([CH3:25])[CH3:24].Cl.Cl[CH2:47][C:48]1[N:52]([CH3:53])[N:51]=[N:50][CH:49]=1>>[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][C:39]([F:41])([F:42])[C:38]([F:43])([F:44])[CH2:37]2)[C:30]2[C:31](=[N:33][N:34]([CH2:47][C:48]3[N:52]([CH3:53])[N:51]=[N:50][CH:49]=3)[N:35]=2)[N:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1nc(N2CC(F)(F)C(F)(F)C2)c2nn[nH]c2n1
Reactant: Cn1nncc1CCl
Agent: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Agent: Cl
Product: Cn1nncc1Cn1nc2nc(C(C)(C)C)nc(N3CC(F)(F)C(F)(F)C3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-Butyl-7-(3,3,4,4-tetrafluoro-pyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 5-(chloromethyl)-1-methyl-1H-1,2,3-triazole hydrochloride and isolated as yellow gum. MS (m/e): 414.3 (MH+).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:16][CH3:17])[C:4]1[C:13]([CH:14]=O)=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[N:5]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:29][CH2:30][CH2:31][N:32]([C:39]([O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])=[O:40])[CH2:33][C:34](OCC)=[O:35].C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][O:2][CH:3]([O:16][CH3:17])[C:4]1[C:13]([CH2:14][N:29]2[CH2:30][CH2:31][N:32]([C:39]([O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])=[O:40])[CH2:33][C:34]2=[O:35])=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[N:5]=1
Reactant: CCOC(=O)CN(CCN)C(=O)OCC[Si](C)(C)C
Reactant: COC(OC)c1nc2c(cc1C=O)CCCN2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COC(OC)c1nc2c(cc1CN1CCN(C(=O)OCC[Si](C)(C)C)CC1=O)CCCN2
Reaction time: 12 h

Procedure:
A mixture of 2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridine-3-carbaldehyde (intermediate 41, 2.50 g, 10.58 mmol), ethyl 2-((2-aminoethyl)((2-(trimethylsilyl)ethoxy)carbonyl)amino)acetate para-toluene sulphonate (intermediate 124, 8.37 g, 18.09 mmol) and triethylamine (3.23 ml, 23.28 mmol) in 1,2-dichloroethane (10 ml) at room temperature was stirred for 12 h and sodium triacetoxyborohydride (4.72 g, 21.16 mmol) added. The reaction mixture was stirred for 18 h at room temperature, partitioned between saturated aqueous NaHCO3 solution and EtOAc, the EtOAc phase washed with brine, dried over MgSO4 and evaporated. The residue was applied to a RediSep® silica column and purified by normal phase chromatography, eluting with a gradient from heptane to EtOAc. Product containing fractions were combined and evaporated to give the title compound as a yellow oil. (UPLC-MS 6) tR 0.42; ESI-MS 322.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:28]([O:30][CH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1)=[O:29])[CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([B:19]2[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]2)=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].BrC1C=CC(O)=CC=1[Cl:44]>>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:28]([O:30][CH:31]1[CH2:32][CH2:33][CH2:34][CH2:35]1)=[O:29])[CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([B:19]2[O:20][C:21]([CH3:26])([CH3:27])[C:22]([CH3:25])([CH3:24])[O:23]2)=[C:15]([Cl:44])[CH:14]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCOc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)C(=O)OC1CCCC1
Reactant: Oc1ccc(Br)c(Cl)c1
Product: CC(C)(C)OC(=O)N[C@@H](CCOc1ccc(B2OC(C)(C)C(C)(C)O2)c(Cl)c1)C(=O)OC1CCCC1

Procedure:
Synthesised by analogous methods to Intermediate 2b, using 4-bromo-3-chloro-phenol at Stage 6 of Scheme 2. m/z 524 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]([NH2:8])=[O:7])=[O:4].[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH:19]([C:21]2[CH:26]=[C:25]([OH:27])[C:24]3[C:28]4[CH2:29][NH:30][CH2:31][CH2:32][C:33]=4[C:34]([CH3:37])([CH3:36])[O:35][C:23]=3[CH:22]=2)[CH3:20])=[CH:12][CH:11]=1.C(N(CC)CC)C>CN(C)C=O>[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH:19]([C:21]2[CH:26]=[C:25]([OH:27])[C:24]3[C:28]4[CH2:29][N:30]([CH2:2][C:3]([NH:5][C:6]([NH2:8])=[O:7])=[O:4])[CH2:31][CH2:32][C:33]=4[C:34]([CH3:36])([CH3:37])[O:35][C:23]=3[CH:22]=2)[CH3:20])=[CH:12][CH:11]=1
Reactant: CC(CCCc1ccc(F)cc1)c1cc(O)c2c(c1)OC(C)(C)C1=C2CNCC1
Reactant: NC(=O)NC(=O)CCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(CCCc1ccc(F)cc1)c1cc(O)c2c(c1)OC(C)(C)C1=C2CN(CC(=O)NC(N)=O)CC1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A solution of 1.50 g. (0.011 mole) of chloroacetyl urea in 20 ml. of dimethylformamide was added dropwise to a stirred solution of 3.95 g. (0.01 mole) of 8-[5-(4-fluorophenyl)-2-pentyl]-10-hydroxy-5,5-dimethyl-1,2,3,4-tetrahydro-5H-[1]benzopyrano[4,3-c]pyridine in 25 ml. of dimethylformamide and 1.11 g. (0.011 mole) of triethylamine. After stirring at room temperature for 22 hours, the mixture was diluted with 45 ml. of water and extracted with ether. The combined ether extracts were washed with water, dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue was recrystallized from acetonitrile, m.p. 133°-134°.
Reaction SMILES: C[Sn](C)(C)[C:3]1[S:7][C:6]([S:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:5][CH:4]=1.Br[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[N:22]=1>CN1CCCC1=O.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:27][C:23]1[N:22]=[C:21]([C:3]2[S:7][C:6]([S:8]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)(=[O:10])=[O:9])=[CH:5][CH:4]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: Cc1cccc(Br)n1
Reactant: C[Sn](C)(C)c1ccc(S(=O)(=O)Oc2ccccc2)s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cccc(-c2ccc(S(=O)(=O)Oc3ccccc3)s2)n1
Temperature: 90 °C

Procedure:
A mixture of phenyl 5-(trimethylstannanyl)-2-thiophenesulfonate (1.3 g, 3.2 mmol) (WO 9827069), 2-bromo-6-methylpyridine (550 mg, 3.2 mmol) and dichlorobis(triphenylphosphine)palladium (II) (100 mg) in 1-methyl-2-pyrrolidinone (10 ml) was heated at 90° C. under argon for 4 hours. After cooling to room temperature the mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water, brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography (1:10 ethyl acetate:pentane) to afford the title product (D11). MS (ES+) m/e 332 [M+H]+.
Reaction SMILES: [F:1][CH:2]([F:26])[O:3][C:4]1[C:5]([OH:25])=[C:6](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]3[N:18]([C:19]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:17]=[CH:16][S:15]3)[CH:7]=[CH:8][CH:9]=1.Br[CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31].C(=O)([O-])[O-].[K+].[K+].FC(F)OC1C(OCC(C)(C)C)=C(/C=C/C2N=C3N(C=2C(O)=O)C=CS3)C=CC=1>CN(C)C=O>[F:26][CH:2]([F:1])[O:3][C:4]1[C:5]([O:25][CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31])=[C:6](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]3[N:18]([C:19]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:17]=[CH:16][S:15]3)[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)CCBr
Reactant: CCOC(=O)c1c(/C=C/c2cccc(OC(F)F)c2O)nc2sccn12
Agent: CC(C)(C)COc1c(/C=C/c2nc3sccn3c2C(=O)O)cccc1OC(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(/C=C/c2cccc(OC(F)F)c2OCCC(C)C)nc2sccn12
Yield: 100.2 %

Procedure:
Alkylation of Intermediate 6 (400 mg, 1.052 mmol) with 1-bromo-3-methylbutane (159 mg, 1.262 mmol) in presence of potassium carbonate (159 mg, 1.157 mmol) in anhydrous N,N-dimethylformamide (4 mL) as described in Intermediate 7A gave 475 mg of the compound as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.93 (t, J=6.6 Hz, 6H), 1.40 (t, J=7.2 Hz, 3H), 1.66 (q, J=6.3 Hz, 2H), 1.82-1.90 (m, 1H), 3.96 (t, J=6.3 Hz, 2H), 4.40 (q, J=6.9 Hz, 2H), 7.19 (t, J=71.4 Hz, 1H), 7.20-7.28 (m, 2H), 7.42-7.50 (m, 1H), 7.53-7.60 (m, 1H), 7.80 (s, 2H), 8.13 (d, J=4.2 Hz, 1H); APCI-MS (m/z) 451.23 (M+H)+.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:11][O:10][C:9](=[O:12])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:24][C:25]1[CH:40]=[CH:39][C:28]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])=[CH:27][CH:26]=1>C1COCC1>[CH2:32]([O:31][C:29]([C:28]1[CH:27]=[CH:26][C:25]([CH2:24][N:8]2[C@H:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:11][O:10][C:9]2=[O:12])=[CH:40][CH:39]=1)=[O:30])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: O=C1N[C@H](c2ccccc2)CO1
Reactant: O=C(OCc1ccccc1)c1ccc(CBr)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)c1ccc(CN2C(=O)OC[C@H]2c2ccccc2)cc1

Procedure:
490 mg (3 mmol) of (4R)-(-)-4-phenyl-2-oxazolidinone are dissolved in 9 ml of absolute THF, first 3.3 ml of sodium bistrimethylsilylamide (1M in THF) and then 1050 mg (3.45 mmol) of benzyl 4-bromomethylbenzoate, dissolved in 2 ml of absolute THF, are added. The crude product is purified by chromatography (eluent: CH2Cl2)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6](C(OC(C)(C)C)=O)[CH2:5]2.[CH2:18]([O:20][C:21]([C@@H:23]1[CH2:25][C@H:24]1[C:26]([OH:28])=O)=[O:22])[CH3:19].CC[N:31]=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.ClCCl>[NH2:31][CH:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:26]([C@@H:24]3[CH2:25][C@H:23]3[C:21]([O:20][CH2:18][CH3:19])=[O:22])=[O:28])[CH:3]=2)[CH2:7]1
Reactant: CC(C)(C)OC(=O)C1Cc2ccc(N)cc2C1
Reactant: CCN=C=NCCCN(C)C
Reactant: CCOC(=O)[C@@H]1C[C@H]1C(=O)O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1C[C@H]1C(=O)Nc1ccc2c(c1)CC(N)C2
Yield: 81 %

Procedure:
The same operation as in Example (93a) was performed using tert-butyl 5-amino-1,3-dihydro-2H-inden-2-carboxylate (described in Andronati, S. A.; Krys'ko, A. A.; Chugunov, B. M.; Kabanova, T. A.; Artemenko, A. G.; Russ. J. Org. Chem.; 42; 8; 2006; 1174-1182, 0.19 g, 0.77 mmol), trans-2-(ethoxycarbonyl)cyclopropanecarboxylic acid (described in Wessjohann, Ludger A.; Fulhorst, Michael; Zakharova, Svetlana; Pol. J. Chem.; 80; 4; 2006; 673-678, 182 mg, 1.15 mmol), WSC hydrochloride (0.29 g, 1.5 mmol), DMAP (10 mg) and dichloromethane (20 mL). Purification by silica gel column chromatography (elution solvent: hexane/ethyl acetate=4/1, 2/1, 1/1, 1/2) gave 0.24 g of the title compound as a colorless solid (81%).
Reaction SMILES: CN(C(ON1N=[N:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH3:32][CH:33]([O:35][C:36]([N:38]1[CH2:43][CH2:42][CH:41]([C:44]([OH:46])=O)[CH2:40][CH2:39]1)=[O:37])[CH3:34].[Br:47]C1N=CC(N)=CC=1>CN(C=O)C>[Br:47][C:14]1[CH:15]=[CH:10][C:11]([NH:16][C:44]([CH:41]2[CH2:42][CH2:43][N:38]([C:36]([O:35][CH:33]([CH3:34])[CH3:32])=[O:37])[CH2:39][CH2:40]2)=[O:46])=[CH:12][CH:13]=1
Reactant: CC(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Nc1ccc(Br)nc1
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)OC(=O)N1CCC(C(=O)Nc2ccc(Br)cc2)CC1
Yield: 54.2 %

Procedure:
1-Methylethyl 4-{[(4-bromophenyl)amino]carbonyl}-1-piperidinecarboxylate (1.86 g, 54%) was prepared as a white solid from TBTU (4.48 g, 13.95 mmol), diisopropylethylamine (2.43 mL, 13.95 mmol), 1-{[(1-methylethyl)oxy]carbonyl}-4-piperidinecarboxylic acid (2 g, 9.3 mmol), DMF (25 mL) and 6-bromo-3-pyridinamine (1.77 g, 10.23 mmol) in a manner similar to Example 172, Step 1. 1H NMR (400 MHz, CDCl3): δ 8.32 (d, 1H, J=2.7 Hz), 8.07 (dd, 1H, Ja=8.7 Hz, Jb=2.7 Hz), 7.42 (d, 1H, J=8.7 Hz), 7.37 (bs, 1H), 4.90 (septet, 1H, J=6.3 Hz), 4.21 (dd, 2H, Ja=2.4 Hz, Jb=1.4 Hz), 2.87-2.73 (m, 2H), 2.47-2.35 (m, 1H), 1.89 (d, 2H, J=11.9 Hz), 1.80-1.66 (m, 2H), 1.22 (d, 6H, J=6.2 Hz); LRMS (ESI), m/z 370/372 (M+H).
Reaction SMILES: [O:1]1[C:5]([CH2:6][OH:7])=[CH:4][C:3]2[CH:8]=[CH:9][C:10]3[C:15]([C:2]1=2)=[CH:14][CH:13]=[CH:12][CH:11]=3.[Mn]([O-])([O-])(=O)=O.[Ba+2]>C(Cl)Cl>[CH:4]1[C:3]2[CH:8]=[CH:9][C:10]3[C:11]4[CH:4]=[CH:3][CH:2]=[CH:15][C:12]=4[CH:13]=[CH:14][C:15]=3[C:2]=2[O:1][C:5]=1[CH:6]=[O:7]
Reactant: OCc1cc2ccc3ccccc3c2o1
Agent: O=[Mn](=O)([O-])[O-]
Agent: [Ba+2]
Solvent: ClCCl
Product: O=Cc1cc2ccc3c4ccccc4ccc3c2o1
Yield: 134.9 %

Procedure:
To a RB flask equipped with magnetic stirring bar, reflux condenser, N2 inlet line with bubbler was added naphtho[1,2-b]furan-2-methanol (11A, 4.8 g, 24.2 mmol), barium manganate (Aldrich, 12.4 g, 48 mmol) and dry CH2Cl2 (500 mL). The mixture was refluxed for 6 h, filtered and the resulting dark yellow solution filtered through a small plug of SiO2 to remove inorganic salts and polar materials. The solvent was then removed by rotary evaporation and the crude material recrystallized using CH2Cl2 /pentane to give after drying 4.02 g (84.7% yield) of phenanthro[1,2-b]furan-2-carbaldehyde, mp 123°, (C,H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:15]=[C:16]1[N:20]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[C:19]2[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=2[NH:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C.ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:24]2[CH2:23][CH2:22][CH:21]([N:20]3[C:19]4[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=4[NH:17][C:16]3=[O:15])[CH2:26][CH2:25]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(N2CCC(n3c(=O)[nH]c4ccccc43)CC2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 103.8 %

Procedure:
A mixture of 20.6 g N-t-butyloxycarbonyl-4-piperidone, 15 g of 4-(2-oxo-1-benzimidazolinyl)piperidine, 300 mL of 1,2-dichloroethane, 4.2 mL of glacial acetic acid and 24 g of sodium triacetoxyborohydride was stirred at room temperature for 48 h. The reaction mixture was poured into 500 mL chloroform and 500 mL saturated aqueous Na2CO3 and the layers separated. The aqueous layer was extracted with 2×250 mL of chloroform and the combined organic layers dried over MgSO4 and concentrated under reduced pressure. Recrystallization of the crude product from 200 mL of ethyl acetate gave in two crops 28.7 g of pure 1,3-dihydro-1-{1-[1-(t-butyloxycarbonyl)piperidin-4-yl]piperidin-4-yl}-2H-benzimidazol-2-one as a white solid.