Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH2:13]([O:15][C:16]([CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1)=[O:17])C.[CH2:31]([O:35][C:36]1[CH:41]=[CH:40][C:39]([S:42](F)(=[O:44])=[O:43])=[CH:38][CH:37]=1)[C:32]#[C:33][CH3:34]>C1COCC1>[CH3:13][O:15][C:16]([C:18]1([S:42]([C:39]2[CH:38]=[CH:37][C:36]([O:35][CH2:31][C:32]#[C:33][CH3:34])=[CH:41][CH:40]=2)(=[O:44])=[O:43])[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1)=[O:17]
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC#CCOc1ccc(S(=O)(=O)F)cc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OC)CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 52.3 %

Procedure:
To a solution of diisopropylamine (1.58 mL, 11.3 mmol) in THF (25 mL) at 0° C. was added 2.5M n-BuLi(4.68 mL, 11.7 mmol) and the resulting mixture was stirred for 15 min at that temperature. The reaction mixture was cooled to −78° C. and a solution of 1-(tert-butyl)-4-methyl 1,4-piperidinecarboxylate (prepared from example 30, step 1) (2.67 g, 11.0 mmol) in THF (40 mL) was added. The resulting mixture was stirred for 1 h and a solution of 4-but-2-ynyloxy benzenesulfonyl fluoride (2.5 g, 11.0 mmol) in THF (25 mL) was added into it. After stirring for 4 h at rt, the reaction was quenched with satd. aqueous NH4Cl solution and extracted with EtOAc, dried over anhydrous Na2SO4. The crude product was purified by silica gel chromatography to obtain 2.6 g(53%) of the product as a solid; 1H NMR(300 MHz, CDCl3) δ1.44(s, 9H), 1.87(m, 3H), 1.98(m, 2H), 2.32(m, 2H), 2.62(m, 2H), 3.74(s, 3H), 4.17(m, 2H), 4.74(m, 2H), 7.09(d, 2H, J=7.2 Hz), 7.71(d, 2H, J=7.2 Hz).
Reaction SMILES: [CH:1]1([O:6][N:7]=[C:8]([C:42]2[N:43]=[C:44]([NH:47]C=O)[S:45][CH:46]=2)[C:9]([NH:11][CH:12]2[C:40](=[O:41])[N:14]3[C:15]([C:37]([OH:39])=[O:38])=[C:16]([CH2:19][S:20][C:21]4[N:25]([CH2:26][CH2:27][CH2:28][NH:29]C(OC(C)(C)C)=O)[N:24]=[N:23][N:22]=4)[CH2:17][S:18][C@H:13]23)=[O:10])[CH2:5][CH2:4][CH:3]=[CH:2]1.Cl.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>CO.O>[CH:1]1([O:6][N:7]=[C:8]([C:42]2[N:43]=[C:44]([NH2:47])[S:45][CH:46]=2)[C:9]([NH:11][CH:12]2[C:40](=[O:41])[N:14]3[C:15]([C:37]([OH:39])=[O:38])=[C:16]([CH2:19][S:20][C:21]4[N:25]([CH2:26][CH2:27][CH2:28][NH2:29])[N:24]=[N:23][N:22]=4)[CH2:17][S:18][C@H:13]23)=[O:10])[CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)NCCCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC3C=CCC3)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: NCCCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC3C=CCC3)c3csc(N)n3)[C@H]2SC1
Yield: 21.5 %

Procedure:
To a solution of 7-[2-(2-cyclopenten-1-yl)oxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-[1-[3-(N-tertbutoxycarbonylamino)propyl]-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer)(1.75 g) in methanol (13 ml) was added conc. hydrochloric acid (1.0 g) with stirring and the mixture was stirred for 3 hours at room temperature. After the evaporation of the resulting mixture, to the residue was added methanol (20 ml) to give a homogeneous solution and then the solution was evaporated. Solution and evaporation were repeated three times and to the resulting reaction mixture were added ethyl acetate and water. After the mixture was adjusted to pH 7.5 with sodium bicarbonate, the aqueous layer was separated, washed with ethyl acetate and the remaining ethyl acetate was distilled off. The resulting aqueous layer was adjusted to pH 3.8 with 1N hydrochloric acid and then filtered. The precipitates thus collected were washed with water and dried over phosphorus pentoxide under reduced pressure to give 7-[2-(2-cyclopenten-1 -yl)oxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[1-(3-aminopropyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer)(0.31 g).
Reaction SMILES: C(O[C:5]1[O:6][CH2:7][C:8](=[O:16])[C:9]=1[C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])(C)C.C(OC(C)C)(=O)CC(OC(C)C)=O.ClCC(Cl)=O.[CH:35]1([NH2:38])[CH2:37][CH2:36]1.[NH:39]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][N:46]=2)[C:41]([CH:48]=O)=[CH:40]1.N1CCCCC1>CC(O)C>[NH:39]1[C:47]2=[N:46][CH:45]=[CH:44][CH:43]=[C:42]2[C:41]([CH:48]=[C:7]2[O:6][C:5]([NH:38][CH:35]3[CH2:37][CH2:36]3)=[C:9]([C:10]([O:12][CH:13]([CH3:14])[CH3:15])=[O:11])[C:8]2=[O:16])=[CH:40]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CC(C)OC(=O)C1=C(OC(C)C)OCC1=O
Reactant: NC1CC1
Agent: CC(C)OC(=O)CC(=O)OC(C)C
Agent: O=C(Cl)CCl
Solvent: CC(C)O
Solvent: C1CCNCC1
Product: CC(C)OC(=O)C1=C(NC2CC2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 1.3 %

Procedure:
A solution of isopropyl 2-isopropoxy-4-oxo-4,5-dihydrofuran-3-carboxylate (0.10 g, 0.44 mmol) which similarly prepared according to the procedure described in the Example 74, Third step using diisopropyl malonate and chloroacetyl chloride, and cyclopropylamine (0.034 mL, 0.48 mmol) in 2-propanol (2.0 mL) was stirred at ambient temperature for 14 h. To this reaction mixture, 7-azaindole-3-carboxaldehyde (0.065 g, 0.44 mmol) and piperidine (0.0044 mL, 0.044 mmol) were added then the mixture was refluxed for further 12 days. Cooled to ambient temperature, the reaction mixture was purified by preparative HPLC to afford the titled compound as solid (0.0020 g, y. 1%).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][NH:6][N:5]=1)[CH3:3].[CH3:13][O:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1.N1C=CC=CC=1>CN(C)C(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:13][O:14][C:15]1[CH:20]=[C:19]([N:6]2[CH:7]=[C:8]([C:9]([O:11][CH3:12])=[O:10])[C:4]([CH:2]([CH3:1])[CH3:3])=[N:5]2)[CH:18]=[CH:17][CH:16]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: COC(=O)c1c[nH]nc1C(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)N(C)C
Solvent: c1ccncc1
Product: COC(=O)c1cn(-c2cccc(OC)c2)nc1C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.5 %

Procedure:
Methyl 3-(1-methylethyl)-1H-pyrazole-4-carboxylate (2.8 g) synthesized in Example 7(1) was dissolved in N,N-dimethylacetamide (50 mL), 3-methoxyphenylboronic acid (5.0 g), copper acetate (6.0 g) and pyridine (5.3 mL) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through celite, 1N hydrochloric acid (50 mL) was added to the filtrate, and the mixture was extracted with diethyl ether. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2, volume ratio) to give the title object compound (3.4 g, 75%) as a pale-yellow oil.
Reaction SMILES: C([N:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)=O.[C:9]([Cl:12])([Cl:11])=O>>[Cl-:11].[Cl:12][CH:9]=[N+:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: O=C(Cl)Cl
Reactant: O=CN1CCOCC1
Product: ClC=[N+]1CCOCC1
Product: [Cl-]
Yield: 65.1 %

Procedure:
Utilizing a procedure similar that used in Preparation 1, but beginning with N-formylmorpholine (346 gm, 3.01 mol) and phosgene (301 gm, 3.05 mol), a 65% yield (333 gm, 1.96 mol) of N-(chloromethylene)-morpholinium chloride is obtained.
Reaction SMILES: [C:1]([O:4][CH3:5])(=[S:3])[CH3:2].C(N(C(C)C)CC)(C)C.Cl[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][N:17]=1.CN(C)C=O>O>[N+:22]([C:19]1[CH:20]=[CH:21][C:16]([CH2:2][C:1]([O:4][CH3:5])=[S:3])=[N:17][CH:18]=1)([O-:24])=[O:23]
Reactant: COC(C)=S
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=S)Cc1ccc([N+](=O)[O-])cn1
Temperature: 80 °C
Reaction time: 1 h
Yield: 30.3 %

Procedure:
A mixture of methyl thioacetate (3 g), diisopropylethylamine (8.14 g), 2-chloro-5-nitropyridine (5 g) and dimethylformamide (50 ml) was heated at 80° C. for 18 hours. The reaction mixture was cooled and then poured into water (500 ml). After stirring for 1 hour at ambient temperature the mixture was filtered to give the title compound (2.03 g) as a brown solid.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[NH:20][C:19](=[O:21])[C:18]2[C:13](=[C:14](I)[CH:15]=[CH:16][CH:17]=2)[N:12]=1)[CH2:2][CH3:3].C(N(CCCC)CCCC)CCC.[CH2:36]=[CH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[NH:20][C:19](=[O:21])[C:18]2[C:13](=[C:14]([CH:36]=[CH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH:15]=[CH:16][CH:17]=2)[N:12]=1)[CH2:2][CH3:3]
Reactant: C=CCCCCC
Reactant: CCCOc1ccccc1-c1nc2c(I)cccc2c(=O)[nH]1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCCCN(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCC=Cc1cccc2c(=O)[nH]c(-c3ccccc3OCCC)nc12
Temperature: 25 °C

Procedure:
5 g (12.31 mmoles) of the compound from Example III, 3.7 ml (15.4 mmoles) of tributylamine, 6.6 ml (46.2 mmoles) of 1-heptene, 375 mg of tri-o-tolylphosphine (1.23 mmoles), and 138 mg of palladium(II) acetate (0.6 mmole) are stirred in 50 ml of dry DMF for 2.5 h at 100° C. The mixture is cooled to room temperature, 50 ml of ethyl acetate is added, and the mixture is washed 3 times with 50-ml portions of H2O. After drying over MgSO4, the organic phase is evaporated under vacuum, and the residue is chromatographed on silica gel with toluene/ethyl acetate 95:5 as eluant. The fractions containing the product are combined and the solvent is evaporated under vacuum. The initially oily residue is crystallized by stirring with 35 ml petroleum ether.
Reaction SMILES: [C:1]1([NH:7][C:8]2[N:9]=[N:10][N:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)[N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N1N=NC(NC2C=CC=CC=2)=N1)CCCCCCCCCCC.Cl[C:53](Cl)([O:55]C(=O)OC(Cl)(Cl)Cl)Cl.Cl.[CH3:65][O:66][C:67]1[CH:73]=[C:72]([O:74][CH3:75])[CH:71]=[C:70]([O:76][CH3:77])[C:68]=1[NH2:69].C(N(C(C)C)CC)(C)C>>[C:1]1([N:7]([C:8]2[N:9]=[N:10][N:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)[N:12]=2)[C:53]([NH:69][C:68]2[C:70]([O:76][CH3:77])=[CH:71][C:72]([O:74][CH3:75])=[CH:73][C:67]=2[O:66][CH3:65])=[O:55])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(Nc2nnn(CCCCCCCCOC3CCCCO3)n2)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc(OC)c(N)c(OC)c1
Agent: CCCCCCCCCCCCn1nnc(Nc2ccccc2)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(OC)c(NC(=O)N(c2ccccc2)c2nnn(CCCCCCCCOC3CCCCO3)n2)c(OC)c1

Procedure:
When in the procedure of Example 1(f) an appropriate amount of (±)N-phenyl-2-[8-[(tetrahydro-2H-pyran-2-yl)oxy]octyl]-2H-tetrazol-5-amine was substituted for 2-dodecyl-N-phenyl-2H-tetrazol-5-amine, and reacted with triphosgene and 2,4,6-trimethoxyaniline hydrochloride in the presence of two equivalents of diisopropylethylamine, the title compound was obtained. 1H NMR (CDCl3): 8.7 (br s, 0.6H), 8.6 (br s, 0.4H), 7.4 (m, 5H), 6.2 (s, 2H), 4.6 (m, 1H), 4.5 (m, 2H), 3.8 (two s, 9H), 3.7 (m, 1H), 3.6 (t, 1H), 3.5 (m, 1H), 3.4 (m, 1H), 1.9 (m, 2H), 1.7-1.9 (m, 6H), 1.6 (m, 4H), 1.3 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:17][C:18]([OH:20])=O)[C:5]2[C:6]([CH:16]=1)=[C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[O:8][N:9]=2.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:17][C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])[C:5]2[C:6]([CH:16]=1)=[C:7]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[O:8][N:9]=2
Reactant: O=C(O)Cc1cc(Cl)cc2c(-c3ccccc3)onc12
Reactant: C1COCCN1
Product: O=C(Cc1cc(Cl)cc2c(-c3ccccc3)onc12)N1CCOCC1

Procedure:
The title compound is prepared by reacting the acid chloride of 5-chloro-3-phenyl-2,1-benzisoxazole-7-acetic acid with morpholine in an aprotic solvent and washing the reaction mixture with sodium bicarbonate solution.
Reaction SMILES: [C:1]([C:5]1[NH:14][C:8]2=[CH:9][N:10]=[C:11]([NH2:13])[CH:12]=[C:7]2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([C:24]3([C:27](O)=[O:28])[CH2:26][CH2:25]3)=[CH:23][C:18]=2[O:17][CH2:16]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(#N)C>[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([C:24]3([C:27]([NH:13][C:11]4[CH:12]=[C:7]5[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[NH:14][C:8]5=[CH:9][N:10]=4)=[O:28])[CH2:25][CH2:26]3)=[CH:23][C:18]=2[O:17][CH2:16]1
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Reactant: CC(C)(C)c1cc2cc(N)ncc2[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ncc2[nH]1
Reaction time: 16 h
Yield: 665.7 %

Procedure:
2-tert-Butyl-1H-pyrrolo[2,3-c]pyridin-5-amine (325 mg, 0.158 mmol) and 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (300 mg, 1.58 mmol) were dissolved in acetonitrile (10 mL) containing triethylamine (659 μL, 0.470 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (608 mg, 1.60 mmol) was added to the mixture and the resulting solution was allowed to stir for 16 hours during which time a large amount of precipitate formed. The reaction mixture was filtered and the filtercake was washed with acetonitrile and then dried to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1H-pyrrolo[2,3-c]pyridin-5-yl)cyclopropanecarboxamide (397 mg, 67%). ESI-MS m/z calc. 377.2. found; 378.5 (M+1)+; Retention time 1.44 minutes. 1H NMR (400 MHz, DMSO) 11.26 (s, 1H), 8.21 (s, 1H), 8.06 (s, 1H), 7.83 (s, 1H), 7.13 (d, J=1.5 Hz, 1H), 7.04-6.98 (m, 2H), 6.20 (d, J=1.0 Hz, 1H), 6.09 (s, 2H), 1.49-1.45 (m, 2H), 1.38 (s, 9H), 1.12-1.08 (m, 2H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([OH:12])[CH:8]=[CH:7]2.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCOC(C)=O>CN(C=O)C.O>[CH2:19]([O:12][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[C:2]([I:1])[CH:3]=[CH:4][CH:5]=2)[CH:10]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Oc1ccc2cccc(I)c2c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Ic1cccc2ccc(OCc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product from Step A (1.18 g, 4.37 mmol) in 20 mL of DMF was added cesium carbonate (2.48 g, 8.74 mmol) and benzyl bromide (0.52 mL, 4.37 mmol). After stirring overnight at room temperature, the reaction was poured into EtOAc and water, washed with 5% NaOH solution, water, 10% NaHSO3 solution and brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (5% EtOAc/hexane) to yield the desired product as a pink solid.
Reaction SMILES: [CH:1]1([CH2:7][S:8][C:9]2[CH:22]=[CH:21][C:12]3[NH:13][C:14]([NH:16][C:17](=[O:20])[O:18][CH3:19])=[N:15][C:11]=3[CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:31])C=1>C(Cl)(Cl)Cl.CC(O)=O>[CH:1]1([CH2:7][S:8]([C:9]2[CH:22]=[CH:21][C:12]3[NH:13][C:14]([NH:16][C:17](=[O:20])[O:18][CH3:19])=[N:15][C:11]=3[CH:10]=2)=[O:31])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)Nc1nc2cc(SCC3CCCCC3)ccc2[nH]1
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)Nc1nc2cc(S(=O)CC3CCCCC3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of 3.2 g of [5-[(cyclohexylmethyl)thio]-1H-benzimidazol-2-yl]carbamic acid, methyl ester in 120 ml CHCl3 and 120 ml HOAc at -20° C there is added a solution of 2.1 g of m-chloroperbenzoic acid. The resulting mixture is stirred and allowed to warm to room temperature. Stirring is continued for 5 hours and then CHCl3 is removed in vacuo. Water is added and the solution is neutralized with NaHCO3. The resulting solid is filtered off and crystallized from acetonitrile (1.5 g) to give the title compound, m.p. 272°-274° C.
Reaction SMILES: C([NH:3][CH2:4][CH2:5][NH:6][CH2:7][CH3:8])C.[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]3[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=3)[N:16]=2)[CH:10]=1.[CH2:31](N(CC)CC)[CH3:32]>COCCOC>[CH2:31]([N:6]([CH2:7][CH3:8])[CH2:5][CH2:4][NH:3][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][C:22]([NH:21][C:17]2[N:16]=[C:15]([C:11]3[CH:10]=[N:9][CH:14]=[CH:13][CH:12]=3)[CH:20]=[CH:19][N:18]=2)=[CH:23][CH:24]=1)[CH3:32]
Reactant: CCNCCNCC
Reactant: O=C(Cl)c1ccc(Nc2nccc(-c3cccnc3)n2)cc1
Reactant: CCN(CC)CC
Solvent: COCCOC
Product: CCN(CC)CCNC(=O)c1ccc(Nc2nccc(-c3cccnc3)n2)cc1
Reaction time: 2 h

Procedure:
A 1.55 ml portion of diethylethylenediamine was added to a solution of 0.01 mole of 4-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoic acid chloride in 50 ml of 1,2-dimethoxyethane. A 10 ml portion of triethylamine was added and the mixture was stirred for 2 hours. The solid was collected, washed with water and recrystallized from absolute ethanol, giving 1.22 g of the desired product, mp 148°-150° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([OH:12])=O)=[CH:7][C:6]=2[CH:13]=1.CN(C(ON1N=[N:29][C:24]2[CH:25]=[CH:26][CH:27]=[N:28][C:23]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:38](N(CC)C(C)C)(C)[CH3:39]>CN(C=O)C>[ClH:1].[N:28]12[CH2:27][CH2:26][CH:25]([CH2:38][CH2:39]1)[C@@H:24]([NH:29][C:10]([C:8]1[O:9][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:13][C:6]=3[CH:7]=1)=[O:12])[CH2:23]2
Reactant: O=C(O)c1cc2cc(Cl)ccc2o1
Reactant: CCN(C(C)C)C(C)C
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cl
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cc(Cl)ccc2o1

Procedure:
190 mg (0.98 mmol) of 5-chlorobenzofuran-2-carboxylic acid, 200 mg (0.98 mmol) of R-3-aminoquinuclidine dihydrochloride, 450 mg (1.18 mmol) of HATU, 460 mg (3.54 mmol) of N,N-diisopropylethylamine and 2.0 ml of DMF are reacted according to the general procedure (variant B). The reaction mixture is purified by preparative HPLC. An excess of 1N hydrochloric acid is then added to the product. The solvent is removed under reduced pressure. 145 mg (43% of theory) of the title compound are isolated.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[C@H:16]2[C@H:20]([OH:21])[C@H:19]([OH:22])[C@@H:18]([C:23]([NH:25][CH2:26][CH3:27])=[O:24])[O:17]2)=[C:9]([NH:28][CH2:29][CH:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:8]=1)=[O:6].[N:43]1([CH2:49][CH2:50][NH:51][C:52](N2C=CN=C2)=[O:53])[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1.C1(C)C=CC=CC=1.C(O)(C)C>ClCCl>[C:31]1([CH:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:29][NH:28][C:9]2[N:8]=[C:7]([C:5]([NH:4][CH2:3][CH2:2][NH:1][C:52]([NH:51][CH2:50][CH2:49][N:43]3[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]3)=[O:53])=[O:6])[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[C@H:16]2[C@H:20]([OH:21])[C@H:19]([OH:22])[C@@H:18]([C:23]([NH:25][CH2:26][CH3:27])=[O:24])[O:17]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(NCCN1CCCCC1)n1ccnc1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCN)nc32)[C@H](O)[C@@H]1O
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCNC(=O)NCCN4CCCCC4)nc32)[C@H](O)[C@@H]1O
Reaction time: 4 h
Yield: 54.9 %

Procedure:
N-(2-Aminoethyl)-6-[(2,2-diphenylethyl)amino]-9-{(2R,3R,4S, 5S)-5-[(ethylamino)carbonyl]-3,4-dihydroxytetrahydro-2-furanyl}-9H-purine-2-carboxamide (Preparation 10) (90 mg, 0.15 mmol) and N-[2-(1-piperidinyl)ethyl]-1H-imidazole-1-carboxamide (Preparation 18) (36 mg, 0.16 mmol) were dissolved in dichloromethane (3 ml). Toluene (4 ml) and isopropanol (1 ml) were added and the dichloromethane removed by evaporation at atmospheric pressure. The residual solution was heated under reflux for four hours. TLC analysis showed the reaction to be incomplete so further N-[2-(1-piperidinyl)ethyl]-1H-imidazole-1-carboxamide (25 mg, 0.11 mmol) was added and heating continued for four hours. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel eluting with dichloromethane:methanol concentrated aqueous ammonia (90:10:1, by volume). Product containing fractions were evaporated and the resulting solid triturated with diethyl ether, filtered and dried to afford the title compound as a white powder (60 mg).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:12]2[C:13]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20][C:14]=3[NH:15][C:16]=2[CH:17]=[CH:18][CH:19]=1)[CH2:2][CH3:3].C([BH3-])#N.[Na+]>FC(F)(F)C(O)=O.CO.O>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:12]2[C@@H:13]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20][C@@H:14]3[NH:15][C:16]=2[CH:17]=[CH:18][CH:19]=1)[CH2:2][CH3:3]
Reactant: CCCOc1ccccc1-c1cccc2[nH]c3c(c12)CCNCC3
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CO
Product: CCCOc1ccccc1-c1cccc2c1[C@@H]1CCNCC[C@@H]1N2
Temperature: 25 °C
Yield: 40.3 %

Procedure:
A 0° C. solution of 10-(2-propoxyphenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (257 mg, 0.80 mmol) in trifluoroacetic acid (4 mL) was treated with a solution of sodium cyanoborohydride (269 mg 4.28 mmol) in methanol (2 mL). The reaction was allowed to slowly warm to room temperature over 1.6 hours then diluted with water and concentrated in vacuo to remove the majority of acid. The residue was made basic with 15% NaOH, extracted twice with CH2Cl2 dried over MgSO4 and concentrated in vacuo and passed through a column of silica gel with 1:19 methanol/chloroform with 1% NH4OH to give 104 mg (40%) of a brown oil as the title compound: 1H NMR (400 MHz, CDCl3) δ 7.32-7.30 (m, 1H), 7.25 (dd, J=7.4 Hz, 1.7 Hz, 1H), 7.11-7.07 (m, 1H), 7.02-6.96 (m, 2H), 6.65-6.59 (m, 1H), 4.24-4.21 (m, 1H), 3.97-3.84 (m, 2H), 3.73 (dt, J=9.7 Hz, 3.3 Hz, 1H), 3.13-3.08 (m, 1H), 2.80-2.76 (m, 1H), 2.73-2.67 (m, 1H), 2.47-2.41 (m, 1H), 2.06-2.04 (m, 1H), 1.95-1.92 (m, 1H), 1.75-1.70 (m, 2H), 1.59-1.55 (m, 1H), 1.37-1.34 (m, 1H) 0.95 (t, J=7.4 Hz, 3 H); HRMS (FAB) calcd for C21H26N2O+H1: 323.2123 found 323.2116.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].S([O-])(=O)(=O)C.O[CH2:22][CH2:23][O:24][C:25]1[CH:38]=[CH:37][C:36]2[C:27](=[CH:28][C:29]3[C:34]([CH:35]=2)=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:26]=1>CN(C)C=O.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:22][CH2:23][O:24][C:25]2[CH:38]=[CH:37][C:36]3[C:27](=[CH:28][C:29]4[C:34]([CH:35]=3)=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH:26]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Reactant: OCCOc1ccc2cc3ccccc3cc2c1
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COC(=O)C(=O)c1ccc(OCCOc2ccc3cc4ccccc4cc3c2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 46.6 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.724 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.175 g), stirred for 15 minutes and treated with the mesylate of 2-(2-hydroxyethoxy)anthracene (1.26 g). The mixture was heated under argon at 60° C. overnight. The cooled mixture was treated with glacial acetic acid (2 drops) and the volatiles were removed under vacuum. The residue was mixed with water and the solids were filtered off, dissolved in dichloromethane, dried (Na2SO4), filtered, and evaporated to give crude product. Crystallization from dichloro-methane-diethyl ether provided 0.75 g of 4-[[2-(2anthracenyloxy)ethyl]oxy]-alpha-oxobenzeneacetic acid methyl ester as a yellow solid, mp 188°-189° C.