Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)C.C(O)(=O)C.[Cl:8][C:9]1[CH:17]=[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:30])[CH2:20][CH2:19]2)[C:15]([N+:31]([O-])=O)=[CH:14][C:10]=1[C:11]([OH:13])=[O:12]>[Fe]>[NH2:31][C:15]1[C:16]([N:18]2[CH2:19][CH2:20][N:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:30])[CH2:22][CH2:23]2)=[CH:17][C:9]([Cl:8])=[C:10]([CH:14]=1)[C:11]([OH:13])=[O:12]
Reactant: Cc1ccccc1N1CCN(c2cc(Cl)c(C(=O)O)cc2[N+](=O)[O-])CC1
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1ccccc1N1CCN(c2cc(Cl)c(C(=O)O)cc2N)CC1
Temperature: 75 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
In a 500 ml round bottom flask equipped with a magnetic stir bar, the iron powder (5.59 g, 100.15 mmol) was suspended in clean, dry, reagent-grade ethanol (300.00 ml, 5138.06 mmol) and the mixture was stirred vigorously under nitrogen at room temperature. To this was added the acetic acid (30.00 ml, 524.05 mmol) and the reaction was allowed to stir for 5 min before the 2-chloro-5-nitro-4-(4-o-tolyl-piperazin-1-yl)-benzoic acid 1d (1.51 g, 4.01 mmol) was added in one portion. The reaction was then warmed to 75° C. and allowed to stir overnight. The reaction was cooled to room temperature and was then filtered through Celite, washing heavily with methanol. The deep red product solution was then concentrated under reduced pressure and the resultant ruby red oil was taken up in 200 ml of ethyl acetate. To this solution was added 200 ml of saturated NaHCO3 (aq) solution and the layers were then separated and the product was extracted out of the aqueous using ethyl acetate (3×100 ml). The organic phases were then combined and washed with brine (1×200 ml) and dried over Na2SO4. The solution was then decanted and the solvent was removed under reduced pressure. The crude product, 5-amino-2-chloro-4-(4-o-tolyl-piperazin-1-yl)-benzoic acid 14a (1.22 g, 3.53 mmol), was isolated as a brown solid and was carried on without further purification. LCMS=346 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[CH3:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>>[CH3:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:24])=[CH:21][CH:20]=1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: Cc1ccc(C(=O)Cl)cc1
Product: Cc1ccc(C(=O)Nc2ccc3[nH]cc(C4CCN(C)CC4)c3n2)cc1
Yield: 65.2 %

Procedure:
Beginning with 0.010 gm (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.007 mL (0.058 mMol) 4-methylbenzoyl chloride, 0.010 gm (66%) of the title compound were prepared essentially by the procedure described in Example 7.
Reaction SMILES: C(O[CH2:5][C:6]([CH3:27])=[CH:7][CH:8]=[C:9]([CH3:26])[CH:10]=[CH:11][CH:12]=[C:13]([CH3:25])[CH:14]=[CH:15][C:16]1[C:21]([CH3:23])([CH3:22])[CH2:20][CH2:19][CH2:18][C:17]=1[CH3:24])(=O)C.[S-:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[Na+]>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C.C(OCC)C>[C:29]1([S:28][CH2:5][C:6]([CH3:27])=[CH:7][CH:8]=[C:9]([CH3:26])[CH:10]=[CH:11][CH:12]=[C:13]([CH3:25])[CH:14]=[CH:15][C:16]2[C:21]([CH3:22])([CH3:23])[CH2:20][CH2:19][CH2:18][C:17]=2[CH3:24])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: [S-]c1ccccc1
Reactant: CC(=O)OCC(C)=CC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CC(C=CC1=C(C)CCCC1(C)C)=CC=CC(C)=CC=C(C)CSc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1.85 g (5 mmol) of 2,5,9-trimethyl-11-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8,10-undecapentaenyl acetate in 25 ml of anhydrous THF and 8 ml of HMPA is added in portions 0.68 g (5.2 mmol) of sodium thiophenoxide. The resulting mixture is stirred at room temperature for 18 hours and then taken up in 250 ml of diethyl ether. The solution is washed with saturated aqueous NH4Cl and water, dried annd evaporated in vacuo to give an oil. Purification on a silica gel dry column gives the desired product.
Reaction SMILES: F[P-](F)(F)(F)(F)F.[N:8]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:12]2C=CC=CC=2N=N1.[F:28][CH:29]([F:45])[C:30]1[C:34]([C:35]([OH:37])=O)=[CH:33][N:32]([C:38]2[N:43]=[CH:42][C:41]([F:44])=[CH:40][N:39]=2)[N:31]=1.[C:46]12(NC)[CH2:55][CH:50]3[CH2:51][CH:52]([CH2:54][CH:48]([CH2:49]3)[CH2:47]1)[CH2:53]2.CC(N(C)C)=O>CN(C=O)C>[C:46]12([CH2:12][NH:8][C:35]([C:34]3[C:30]([CH:29]([F:28])[F:45])=[N:31][N:32]([C:38]4[N:43]=[CH:42][C:41]([F:44])=[CH:40][N:39]=4)[CH:33]=3)=[O:37])[CH2:47][CH:48]3[CH2:49][CH:50]([CH2:51][CH:52]([CH2:54]3)[CH2:53]1)[CH2:55]2
Reactant: CNC12CC3CC(CC(C3)C1)C2
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: O=C(O)c1cn(-c2ncc(F)cn2)nc1C(F)F
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cn(-c2ncc(F)cn2)nc1C(F)F
Temperature: 0 °C
Reaction time: 20 h

Procedure:
BOP (98 mg, 0.22 mmol) is added to a solution of 3-(difluoromethyl)-1-(5-fluoropyrimidin-2-yl)-1H-pyrazole-4-carboxylic acid (38 mg, 0.147 mmol), admantan-1-yl-methylamine (24 mg, 0.147 mmol) and DMA (0.052 mL) in DMF (1.0 mL) at rt. The mixture is stirred for 20 h. The mixture is poured into ice water (5 mL), extracted with EtOAc (3×20 mL) and dried over anhydrous MgSO4. The crude product is purified by silica gel column chromatography using 30% EtOAc/hexane to afford the title compound as a white solid. 1H NMR (DMSO-D6): 9.45 (s, 1H), 9.05 (s, 2H), 8.35 (m, 1H), 7.29-7.36 (t, 1H), 2.93 (d, 2H), 1.91 (m, 3H), 1.47-1.65 (m, 12H). MS (M+1)=406.28; RT=1.34 min *IC50.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([NH:12][CH:13]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:14][CH2:15][O:16][Si](C(C)(C)C)(C)C)[CH:5]=1.CI.[C:32](O)(=O)C>O1CCCC1.O>[Cl:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([N:12]([CH:13]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:14][CH2:15][OH:16])[CH3:32])[CH:5]=1
Reactant: CC(=O)O
Reactant: CC(C)(C)[Si](C)(C)OCCC(Nc1cc(Cl)ccc1C#N)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CI
Product: CN(c1cc(Cl)ccc1C#N)C(CCO)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of sodium hydride (60% dispersion, 270 mg, 6.75 mmol) in dry tetrahydrofuran (20 ml) under nitrogen and at 0° C. was added 4-chloro-2-[[3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-1-phenylpropyl]amino]benzonitrile (2.3 g, 5.74 mmol) in tetrahydrofuran (10 ml). The resulting yellow suspension was stirred at room temperature for 2 h, and then treated with methyl iodide (3.6 ml, 57.4 mmol). The resulting mixture was heated under reflux for 10 h, and then treated with acetic acid (10 ml) and water (2 ml). Heating and stirring were continued overnight. The mixture was concentrated under vacuum and the residue partitioned between water (50 ml) and ethyl acetate (100 ml). The organic extract was collected and dried over magnesium sulphate. After concentration of the extract the residue was purified on silica gel using 80% isohexane/diethyl ether as eluent. The title compound was isolated as a colourless oil (1 g, 58%).
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:5]=2[N:6]=1.N1C=CC=CC=1.Cl[C:19]([O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[O:20].O>O1CCCC1>[Cl:11][C:8]1[CH:9]=[CH:10][C:4]2[O:3][C:2]([NH:1][C:19](=[O:20])[O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[N:6][C:5]=2[CH:7]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Nc1nc2cc(Cl)ccc2o1
Solvent: O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(Nc1nc2cc(Cl)ccc2o1)OCC(Cl)(Cl)Cl

Procedure:
To a solution of 2-amino-5-chlorobenzoxazole (1.00 g, 5.39 mmol) and pyridine (0.564 ml, 7.12 mmol) in tetrahydrofuran (20 ml) was added, under ice-cooling, 2,2,2-trichloroethyl chloroformate (0.850 ml, 7.12 mmol), and the mixture was stirred at room temperature for 2 hours and half. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Hexane was poured to the residue, and 394 mg (19.3%) of the desired product as a solid was separated by filtration.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.[CH3:13][C:14]([Si:17](Cl)([CH3:19])[CH3:18])([CH3:16])[CH3:15]>C(Cl)Cl>[Si:17]([O:1][CH:2]1[CH2:3][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:5]1)([C:14]([CH3:16])([CH3:15])[CH3:13])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(O[Si](C)(C)C(C)(C)C)C1
Yield: 75.4 %

Procedure:
A solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (1 g, 5.77 mmol), TBSCl (6.35 mmol, 956 mg) in DCM (11.5 mL), was stirred for 72 hrs at room temperature. The solvent was removed under reduced pressure, EtOAc was added to the residue, and the solid material was removed by filtration. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography with gradient elution wit EtOAc/hexane (9:1) to EtOAc/hexane (1:1), to afford title compound 295 (1.25 g, 75% yield) as a syrup. MS (m/z): 310.1 (M+23).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]5[CH2:27][CH2:26][CH2:25][NH:24]5)[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][C:6]([CH3:28])=[N:5]1)([CH3:3])[CH3:2].C(O)(=O)C.[O-:33][C:34]#[N:35].[K+].CN(C)C=O>O>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[CH:20][C:21]([C@@H:23]5[CH2:27][CH2:26][CH2:25][N:24]5[C:34]([NH2:35])=[O:33])=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][C:6]([CH3:28])=[N:5]1)([CH3:3])[CH3:2]
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(C4CCCN4)cc2OCC3)n(C(C)C)n1
Reactant: N#C[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: O
Product: Cc1nc(-c2cn3c(n2)-c2ccc([C@@H]4CCCN4C(N)=O)cc2OCC3)n(C(C)C)n1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-pyrrolidin-2-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene (0.009 g, 0.00002 mol) in Acetic acid (4.06 uL, 0.0713 mmol) and water (0.13 mL) was added a solution of Potassium cyanate (0.00579 g, 0.0713 mmol) in water (0.13 mL) dropwise. N,N-Dimethylformamide (0.13 mL, 0.0017 mol) was added to solubilize the reagents. The reaction was stirred at 50° C. overnight, cooled down, filtered, and rinsed with cold water. The crude was purified by precipitation in MeOH/water to give 10 mg of each enantiomer 379 and 380. MS (ESI+) 422.2. 1H NMR (400 MHz, DMSO) δ 8.32 (d, J=8.3 Hz, 1H), 7.85 (s, 1H), 6.95 (dd, J=8.3, 1.6 Hz, 1H), 6.79 (d, J=1.3 Hz, 1H), 5.90-5.76 (m, 1H), 5.69 (br, 2H), 4.89 (dd, J=7.9, 1.3 Hz, 1H), 4.53-4.44 (m, 4H), 3.58-3.49 (m, 1H), 3.42-3.34 (m, 1H), 2.25 (s, 3H), 2.25-2.17 (m, 1H), 1.92-1.65 (m, 3H), 1.45 (dd, J=6.6, 3.9 Hz, 6H).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=1)[C:5](=[O:21])[O:6][CH2:7][C@@:8]([OH:20])([CH3:19])[CH2:9][N:10]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[N:12]=[C:11]1Cl.O.C(OCC)(=O)C>CN(C=O)C>[CH3:3][N:4]([C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=1)[C:5](=[O:21])[O:6][CH2:7][C@:8]1([CH3:19])[O:20][C:11]2=[N:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][N:10]2[CH2:9]1
Reactant: CN(C(=O)OC[C@](C)(O)Cn1cc([N+](=O)[O-])nc1Cl)c1ccc(OC(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(=O)OC[C@@]1(C)Cn2cc([N+](=O)[O-])nc2O1)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.3 %

Procedure:
Sodium hydride (0.48 g, 11.9 mmol) was added to a solution of (R)-3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl N-methyl-N-(4-trifluoromethoxyphenyl)carbamate prepared in Example 76 (4.50 g, 9.94 mmol) in DMF (13.5 ml) with cooling on ice-bath followed by stirring at room temperature for 1 hour. Water and ethyl acetate were added to the reaction mixture, and the precipitates were filtered off. The precipitates were recrystallized from isopropanol to afford (R)-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl N-methyl-N-(4-trifluoromethoxyphenyl)carbamate (2.95 g, yield 71%) as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([C:7]([O:9][CH2:10][CH2:11][O:12][CH3:13])=[O:8])=[CH:5][C:4]=1[O:16][CH2:17][CH2:18][O:19][CH3:20].[N+:21]([O-])([OH:23])=[O:22]>CC(O)=O>[CH3:1][O:2][C:3]1[C:4]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:5][C:6]([C:7]([O:9][CH2:10][CH2:11][O:12][CH3:13])=[O:8])=[C:14]([N+:21]([O-:23])=[O:22])[CH:15]=1
Reactant: O=[N+]([O-])O
Reactant: COCCOC(=O)c1ccc(OC)c(OCCOC)c1
Solvent: CC(=O)O
Product: COCCOC(=O)c1cc(OCCOC)c(OC)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 2-methoxyethyl 4-methoxy-3-(2-methoxyethoxyl)benzoate (15.05 g, 52.9 mmol) in AcOH (54 mL) under an atmosphere of N2 was added conc. HNO3 (13.5 mL) in one portion. The reaction was stirred at RT for 72 h. The mixture was poured into ice-water (ca. 800 mL) and extracted with EtOAc (2×400 mL). The combined organics were washed with water (2×200 mL) and brine (1×200 mL), dried (Na2SO4) and conc. in vacuo. The residue was azeotroped with heptane (2×300 mL) to remove residual AcOH giving 2-methoxyethyl 4-methoxy-5-(2-methoxyethoxy)-2-nitrobenzoate as a dark colored oil. (15.5 g, 47.1 mmol, 89%). HPLC retention time 6.24 mins.
Reaction SMILES: [C:1](=[O:6])([O:4]C)[O:2][CH3:3].[CH2:7]([N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[CH3:8]>>[CH3:3][O:2][C:1](=[O:4])[O-:6].[CH2:7]([N+:9]([CH2:12][CH3:13])([CH2:10][CH3:11])[CH3:1])[CH3:8]
Reactant: COC(=O)OC
Reactant: CCN(CC)CC
Product: CC[N+](C)(CC)CC
Product: COC(=O)[O-]
Yield: 89.9 %

Procedure:
From EP-A-291 074, it is known that dimethyl carbonate acts as a methylating agent during its reaction with an approximately stoichiometric amount of a tertiary amine. Thus, for example, the reaction of triethylamine with dimethyl carbonate gives the product triethylmethylammonium methyl carbonate in 89.9% yield (loc. cit., Example 1).
Reaction SMILES: [Br-:1].[Li+].[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH2:4]1>C(#N)C.O>[Br:1][C:10]1[CH:9]=[CH:8][C:7]2[O:3][CH2:4][O:5][C:6]=2[CH:11]=1
Reactant: c1ccc2c(c1)OCO2
Reactant: [Br-]
Agent: [Li+]
Solvent: O
Solvent: CC#N
Product: Brc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of ceric ammonium nitrate (9.88 g, 18.0 mmol) and lithium bromide (1.5 g, 18.0 mmol) in acetonitrile (20 mL) was stirred for 30 minutes at 25° C. under nitrogen atmosphere. A solution of benzo[1,3]dioxol (2 g, 16 mmol) in acetonitrile (20 mL) was added slowly to it and the mixture was stirred for 4 hours at 25° C. The mixture was then diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The organic layers were collected, combined, washed with water (50 mL), dried over anhydrous sodium sulphate, and concentrated under vacuum to give the desired product.
Reaction SMILES: [NH2:1][C:2]1([C:8]([OH:10])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.O.[C:12](=[O:15])([O-])[O-:13].[K+].[K+]>O1CCCC1.CN(C1C=CN=CC=1)C>[C:2]([O:13][C:12]([NH:1][C:2]1([C:8]([OH:10])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)=[O:15])([CH3:8])([CH3:7])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: NC1(C(=O)O)CCCCC1
Agent: CN(C)c1ccncc1
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(C(=O)O)CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
To a slurry of 1-amino-1-cyclohexane-carboxylic acid, 5.0 g (35.0 mmol) in 50 mL of tetrahydrofuran and 50 mL of water was added 14.5 g (105.0 mmol) of potassium carbonate, 7.7 g (35.0 mmol) of BOC-anhydride and 5 mg of DMAP. The mixture was stirred overnight at rt. and the organics were evaporated off in vacuo. The aqueous layer was acidified to pH=1 with 5 N HCl and extracted with 20% isopropanol/chloroform. The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated to dryness to yield 1.83 g (21%) of the desired product as a white oil that solidifies upon standing. MS (IS) 244.2 (M+).
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]=1.[F:21][C:22]1[CH:33]=[CH:32][C:25]([C:26](N(OC)C)=[O:27])=[CH:24][CH:23]=1.[Na+].[Cl-]>C(OCC)(=O)C.C1COCC1>[Cl:13][C:14]1[CH:19]=[C:18]([CH2:20][C:26]([C:25]2[CH:32]=[CH:33][C:22]([F:21])=[CH:23][CH:24]=2)=[O:27])[CH:17]=[CH:16][N:15]=1
Reactant: CON(C)C(=O)c1ccc(F)cc1
Reactant: Cc1ccnc(Cl)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(Cc1ccnc(Cl)c1)c1ccc(F)cc1
Temperature: -50 °C
Reaction time: 0.92 h

Procedure:
n-BuLi (15% strength solution in n-hexane, 45 ml, 104 mmol) was added dropwise to a solution, cooled to −85° C., of diisopropylamine (15 ml, 106 mmol) in abs. THF (150 ml) in a double-necked flask which had been dried by heating and flushed with argon: temperature increase to −50° C. After the addition had ended, the light-yellow solution was stirred at −85° C for 55 min. At −85° C., a solution of 2-chloro-4-methylpyridine (2-chloro-γ-picoline, 8.6 g; 68 mmol) in abs. THF (75 ml) was added dropwise to this initial charge: temperature increase to −50° C., initial change of color to purple. After the addition had ended, the reaction mixture was stirred at −85° C. for 1 h, and a solution of 20 (12.4 g; 68 mmol) in abs. THF (75 ml) was added at this temperature over a period of 3 min: temperature increase to −60° C. The purple slurry of the reaction mixture was stirred at −85° C. for 1 h and then, over a period of 1 h, warmed to 0° C. The mixture was poured into saturated NaCl solution (300 ml) which had been covered with ethyl acetate (300 ml). The organic phase was removed and the aqueous phase was extracted with ethyl acetate (2×250 ml) and a little brown foamy precipitate of 1,3-bis-(2-chloropyridin-4-yl)-2-(4-fluorophenyl)propan-2-ol separated off at the interface. The combined organic extract was washed with saturated NaCl solution, dried over NaSO4 and concentrated. The oily residue was taken up in a little tert-butyl methyl ether and stored at 4° C. overnight. The crystals were filtered off and dried.
Reaction SMILES: [ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.[O:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH:15]=[C:14]1[C:22](O)=[O:23].N>>[ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH:12][C:22]([C:14]3[O:13][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[CH:15]=3)=[O:23])[CH2:3]1)[CH2:9]2
Reactant: NC1C2CC3CC1CN(C3)C2
Reactant: O=C(O)c1cc2ccccc2o1
Agent: Cl
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1cc2ccccc2o1

Procedure:
Prepared from (4r)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and benzofuran-2-carboxylic acid according to methods A and C. 1H NMR (300 MHz, methanol-d4) δ ppm 2.08-2.34 (m, 5H), 2.51 (s, 2H), 3.42-3.64 (m, 4H), 3.88 (d, J=12.5 Hz, 2H), 4.33 (s, 1H), 7.29-7.38 (m, 1H), 7.44-7.52 (m, 1H), 7.57 (s, 1H), 7.61 (d, J=7.4 Hz, 1H), 7.74 (d, J=7.8 Hz, 1H). MS (DCI/NH3) m/z 297. Anal. Calculated for C18H20N2O2.HCl: C, 64.96; H, 6.36; N, 8.42. Found: C, 64.51; H, 6.23; N, 8.14.
Reaction SMILES: [CH2:1]([S:11]([NH:14][C:15]([C:17]1[CH:18]=[C:19]([O:26][CH3:27])[C:20]([C:23]([OH:25])=O)=[N:21][CH:22]=1)=[O:16])(=[O:13])=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH2:39]([O:43][C:44](=[O:47])[CH2:45][NH2:46])[CH2:40][CH2:41][CH3:42].NCC(O)=O.C(O)CCC>O.C1(C)C=CC=CC=1>[CH2:39]([O:43][C:44]([CH2:45][NH:46][C:23]([C:20]1[C:19]([O:26][CH3:27])=[CH:18][C:17]([C:15]([NH:14][S:11]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])(=[O:12])=[O:13])=[O:16])=[CH:22][N:21]=1)=[O:25])=[O:47])[CH2:40][CH2:41][CH3:42]
Reactant: CCCCCCCCCCS(=O)(=O)NC(=O)c1cnc(C(=O)O)c(OC)c1
Reactant: CCCCOC(=O)CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: NCC(=O)O
Solvent: CCCCO
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCS(=O)(=O)NC(=O)c1cnc(C(=O)NCC(=O)OCCCC)c(OC)c1

Procedure:
The title compound was prepared from 0.5 g (1.25 mmol) of 5-[((1-decylsulfonyl)amino)carbonyl]-3-methoxypyridine-2-carboxylic acid (cf. Example 25a)) and 0.46 g (1.5 mmol) of glycine 1-butyl ester tosylate (prepared from glycine, 1-butanol, p-tos.OH using toluene in a water separator). 0.31 g of product was obtained, m.p. 82°-85° C. (from diisopropyl ether/ethyl acetate (2:1)).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[C:18](=[O:29])[CH2:17]1)(=[O:15])=[O:14])[CH:7]=[CH:6]2.S(O)(O)(=O)=O.CS[C:37](=[NH:39])[NH2:38].CSC(=N)N.C(N(CC)CC)C.O>CN(C=O)C>[ClH:2].[C:37]([N:26]1[CH2:27][CH2:28][CH:23]([CH2:22][N:19]2[CH2:20][CH2:21][N:16]([S:13]([C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[CH:11][CH:12]=[C:3]([Cl:2])[CH:4]=4)[CH:9]=3)(=[O:15])=[O:14])[CH2:17][C:18]2=[O:29])[CH2:24][CH2:25]1)(=[NH:38])[NH2:39]
Reactant: CSC(=N)N
Reactant: O=C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1CC1CCNCC1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N=C(N)N1CCC(CN2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2=O)CC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 127.4 %

Procedure:
To a solution of 4-(6-chloronaphthalene-2-sulfonyl)-1-(4-piperidylmethyl)-2-piperazinone hydrochloride (230 mg) in DMF (10 ml) were added S-methylisothiourea hemisulfate (348 mg), triethylamine (0.418 ml) and water (2 ml), and the mixture was stirred at 50° C. overnight. To the mixture was added S-methylisothiourea hemisulfate (348 mg) and triethylamine (0.418 ml), and the mixture was additionally stirred at 50° C. overnight. The solvent was concentrated and purified with CHP20 column chromatography (water:acetonitrile:1 N hydrochloric acid=70:30:1) to give colorless amorphous of the title compound (160 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[CH2:9]([NH:11][CH2:12][CH3:13])[CH3:10].CC([O-])(C)C.[K+]>C1(C)C=CC=CC=1>[CH2:9]([N:11]([C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1)[CH2:12][CH3:13])[CH3:10]
Reactant: Cc1ccc(Cl)cc1
Reactant: CCNCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCN(CC)c1ccc(C)cc1
Temperature: 25 °C
Yield: 87 %

Procedure:
20 mmol of p-chlorotoluene (2.53 g), 24 mmol of diethylamine (1.75 g), 28 mmol of KOtBu (3.13 g) and 44 mg of trans-di-μ-acetatobis[2-[bis(1,1-dimethylethyl)-phosphino]-2-methylpropyl-C,P]dipalladium(II) (0.3 mol %) are suspended in 50 ml of toluene and refluxed for 24 hours. After cooling to room temperature, the salts are filtered off and washed with petroleum ether. The solvents are removed from the filtrate on a rotary evaporator. Distillation via a bulb tube (100° C./12 torr) gives 4-(N,N-diethylamino)toluene as a colorless liquid in a yield of 87%.