Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)=O.[C:4]1([CH:10]2[CH:17]3[CH2:18][CH:13]4[CH2:14][CH:15]([CH2:19][C:11]2([CH2:20][CH:21]([CH3:24])[NH:22][CH3:23])[CH2:12]4)[CH2:16]3)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:25]=O.[ClH:27]>CCOCC.O>[ClH:27].[C:4]1([CH:10]2[CH:17]3[CH2:16][CH:15]4[CH2:14][CH:13]([CH2:12][C:11]2([CH2:20][CH:21]([CH3:24])[N:22]([CH3:25])[CH3:23])[CH2:19]4)[CH2:18]3)[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CNC(C)CC12CC3CC(CC(C3)C1c1ccccc1)C2
Reactant: C=O
Agent: Cl
Solvent: O=CO
Solvent: O
Solvent: CCOCC
Product: CC(CC12CC3CC(CC(C3)C1c1ccccc1)C2)N(C)C
Reaction time: 8 h

Procedure:
Formic acid (4.5 ml.) and water (0.5 ml.) were added to the 2-phenyl-N,α-dimethyl-1-adamantaneethylamine (1.0 g.) followed by a 40 percent formaldehyde solution (5 ml.). The mixture was heated on a boiling water bath for seven hours and then allowed to stand overnight. The aqueous solvents were removed in vacuo and the residue treated with dilute hydrochloric acid. Excess acid was removed in vacuo and the oily residue extracted between 3N sodium hydroxide and ether. The organic phase was washed twice with water and dried over magnesium sulfate. The ether was then removed in vacuo to leave 1.1 g. of the base as an oil. The base was dissolved in dry ether, and ethereal hydrochloric acid was added in excess. The resulting precipitate was filtered off and dried in vacuo, and then crystallized from an ethanol-ether mixture to yield 0.3 g. of crystals. Recrystallization from an ethanol-ether mixture yielded 2-phenyl-N,N,α-trimethyl-1-adamantaneethylamine hydrochloride, m.p., 186° -90° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([C:11]2([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=3)[CH2:16][CH2:15][N:14]([CH2:17][CH:18]([CH3:22])[CH2:19][CH2:20][CH3:21])[CH2:13][CH2:12]2)=[N:9][CH:10]=1)=O.[CH2:31]([Mg]Br)[CH3:32].[CH2:35]1COC[CH2:36]1>C(OC)(C)(C)C>[CH3:30][O:29][C:25]1[CH:24]=[C:23]([C:11]2([C:8]3[N:9]=[CH:10][C:5]([C:3]([OH:2])([CH2:31][CH3:32])[CH2:35][CH3:36])=[CH:6][N:7]=3)[CH2:12][CH2:13][N:14]([CH2:17][CH:18]([CH3:22])[CH2:19][CH2:20][CH3:21])[CH2:15][CH2:16]2)[CH:28]=[CH:27][CH:26]=1
Reactant: CC[Mg]Br
Reactant: CCCC(C)CN1CCC(c2cccc(OC)c2)(c2ncc(C(=O)OC)cn2)CC1
Reactant: C1CCOC1
Solvent: COC(C)(C)C
Product: CCCC(C)CN1CCC(c2cccc(OC)c2)(c2ncc(C(O)(CC)CC)cn2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-[4-(3-Methoxy-phenyl)-1-(2-methyl-pentyl)-piperidin-4-yl]-pyrimidine-5-carboxylic acid methyl ester (120 mg, 0.292 mmol) in THF (6 mL) at 0° C. was added ethyl magnesium bromide in t-butylmethyl ether (1 M, 3 mL). The reaction mixture was stirred at room temperature for 18 hours. The reaction was quenched by slow addition of water (5 mL). The aqueous layer was washed with CH2Cl2 (3×10 mL) and the organic extracts were dried (Na2SO4) and concentrated. Purification by flash chromatography with hexanes/EtOAc (3:1) yielded 28 mg of 3-{2-[4-(3-Methoxy-phenyl)-1-(2-methyl-pentyl)-piperidin-4-yl]-pyrimidin-5-yl}-pentan-3-ol. 1HNMR (400 MHz, CDCl3) δ 8.68 (s, 2H), 7.15 (t, 1H), 6.96-4.92 (comp, 2H), 6.67-6.64 (m, 1H), 3.73 (s, 3H), 2.94-2.90 (comp, 2H), 2.79-2.69 (comp, 2H), 2.35-2.28 (comp, 2H), 2.07-1.91 (comp, 3H), 1.81 (q, 2H), 1.62-1.59 (comp, 2H), 1.39-1.18 (comp, 4H), 0.89-0.82 (comp, 6H), 0.77 (t, 6H); MS (M+1) 440.3.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[C:29]([NH:35][C:36](=[O:40])[CH:37]([CH3:39])[CH3:38])[CH:30]=[CH:31][C:32]=2[O:33][CH3:34])[CH2:23][CH2:22]1>>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([NH:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:28]=[C:29]([NH:35][C:36](=[O:40])[CH:37]([CH3:38])[CH3:39])[CH:30]=[CH:31][C:32]=3[O:33][CH3:34])[CH2:23][CH2:22]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: COc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCN)CC1
Product: COc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCNC(=O)C(c2ccccc2)c2ccccc2)CC1

Procedure:
Example 20 was prepared from diphenylacetyl chloride and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methoxyphenyl}-2-methylpropanamide according to the procedures described in Scheme 8: ESMS m/e: 528.3 (M+H)+.
Reaction SMILES: [F:1][C@H:2]1[CH2:18][C@@H:17]2[C@:9]([F:25])([C@@H:10]([OH:24])[CH2:11][C@@:12]3([CH3:23])[C@H:16]2[CH2:15][CH:14]=[C:13]3[C:19](=[O:22])[CH2:20]O)[C@:8]2([CH3:26])[C:3]1=[CH:4][C:5](=[O:27])[CH:6]=[CH:7]2.CCN(C(C)C)C(C)C.[F-:37].[K+].CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>C(#N)C>[F:1][C@H:2]1[CH2:18][C@@H:17]2[C@:9]([F:25])([C@@H:10]([OH:24])[CH2:11][C@@:12]3([CH3:23])[C@H:16]2[CH2:15][CH:14]=[C:13]3[C:19](=[O:22])[CH2:20][F:37])[C@:8]2([CH3:26])[C:3]1=[CH:4][C:5](=[O:27])[CH:6]=[CH:7]2
Reactant: [F-]
Reactant: C[C@]12C=CC(=O)C=C1[C@@H](F)C[C@H]1[C@@H]3CC=C(C(=O)CO)[C@@]3(C)C[C@H](O)[C@@]12F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@]12C=CC(=O)C=C1[C@@H](F)C[C@H]1[C@@H]3CC=C(C(=O)CF)[C@@]3(C)C[C@H](O)[C@@]12F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.7 %

Procedure:
In a nitrogen atmosphere, intermediate 3 (100 mg, 0.264 mmol) was dissolved in acetonitrile (4 ml), and Mesyl-Cl (32 μl, 0.411 mmol) and DIPEA (78 μl, 0.447 mmol) were added. The mixture was stirred at RT for 30 minutes. Potassium fluoride (154 mg, 2.64 mmol) was added, and the mixture was stirred for 1 h at 60° C. TBAF 1M in THF (529 μl, 0.529 mmol) was added, and the mixture is stirred at 60° C. for 4 hours. The reaction mixture was partitioned between water and AcOEt, the organic layer was separated, dried over Na2SO4 and concentrated. The crude was purified by silica gel flash chromatography (eluent DCM/AcOEt=1:1) to yield intermediate 28 (62 mg, 61.7% yield).
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([CH3:26])[CH:20]=2)[CH2:10][C:11]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=O)=[CH:5][CH:4]=1.Cl.[NH2:29][OH:30].C([O-])(O)=O.[Na+]>>[CH3:1][N:2]([CH3:27])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([CH3:26])[CH:20]=2)[CH2:10][C:11]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:29][OH:30])=[CH:5][CH:4]=1
Reactant: NO
Reactant: Cc1ccc(C(CC(=O)c2ccncc2)c2ccc(N(C)C)cc2)cc1C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccc(C(CC(=NO)c2ccncc2)c2ccc(N(C)C)cc2)cc1C

Procedure:
In analogy to example 1, step 2, from 3-(4-dimethylamino-phenyl)-3-(3,4-dimethyl-phenyl)-1-pyridin-4-yl-propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a mixture of E and Z isomers (2.3:1) as a yellow foam, MS (ESI+): m/z=374.3 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[NH2:16][NH:17][C:18]([NH2:20])=[O:19]>>[NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4](=[N:16][NH:17][C:18]([NH2:20])=[O:19])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Nc1ccccc1C(=O)c1ccccc1
Reactant: NNC(N)=O
Product: NC(=O)NN=C(c1ccccc1)c1ccccc1N

Procedure:
A number of methods for preparing 1,3,4-benzotriazepine-2-ones have been described in the literature. In general, the compounds are prepared by either of two methods from a 2-aminobenzophenone. In the first method, the 2-aminobenzophenone is treated with semicarbazide to give an aminobenzophenone semicarbazone. This product is cyclized to give the benzotriazepine-2-one. See Bull. Chem. Soc. Jap., 43, 135-138 (1970); Japanese publications 70 11,148 (CA 73:25544a) and 70 11,147 (CA 73:25545b). Alternately, a 2-amino-benzophenone hydrazone is treated with phosgene to give the desired benzotriazepine-2-one. See U.S. Pat. No. 3,176,008; J. Pharm. Sci. 63 (b), 838-41 (1974) and J. Med. Chem. 7(3), 386 (1964).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH2:11])[N:10]=2)[N:7]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13].N1C=CC=CC=1>CN(C)C1C=CN=CC=1.ClCCl>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12](=[O:14])[CH3:13])[N:10]=2)[N:7]=1
Reactant: Nc1cn2nc(I)ccc2n1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1cn2nc(I)ccc2n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a 50-mL round bottom flask was added 6-iodo-imidazo[1,2-b]pyridazin-2-ylamine (130 mg, 0.5 mmol, 1 eq), anhydrous dichloromethane (10 mL), acetic anhydride (0.071 mL, 1.5 eq), pyridine (0.073 mL, 1.8 eq), and 4-(dimethylamino)pyridine (0.61 mg, 0.01 eq). After the mixture was stirred at room temperature for four hours, it was quenched with saturated aqueous sodium bicarbonate and extracted with i-PrOH—CHCl3 (1:4). The organic layer was isolated, washed with brine, and dried with anhydrous sodium sulfate. The upper clear solution was decanted, concentrated, and the residue was subject to a gradient column chromatography (from DCM to MeOH-DCM 1:30) to yield N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)acetamide as a white solid in amount of 67 mg.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[CH2:12]([NH:14][CH2:15][CH3:16])[CH3:13].[CH2:17]=O>C(O)C>[CH2:12]([N:14]([CH2:17][C:8]1[CH:9]=[CH:10][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][C:7]=1[OH:11])[CH2:15][CH3:16])[CH3:13]
Reactant: C=O
Reactant: CC(=O)Nc1cccc(O)c1
Reactant: CCNCC
Solvent: CCO
Product: CCN(CC)Cc1ccc(NC(C)=O)cc1O
Yield: 52.5 %

Procedure:
To a round bottomed flask containing 3-acetamidophenol (5 g) in ethanol (20 ml) was added diethylamine (2.6 g) and formaldehyde (1.1 g). The resulting mixture was stirred at reflux for 24 hours. After this time, the solvent was evaporated and the residue was purified by column chromatography (silica, dichloromethane/methanol 80:20) to give N-(4-Diethylaminomethyl-3-hydroxy-phenyl)-acetamide (4.1 g, 53%). 1H NMR (250 MHz, CDCl3) δH: 7.05 (1H, d, J=8.2), 6.89 (1H, d, J=8.2), 6.80 (1H, s), 3.70 (2H, s), 2.60 (2H, q, J=7.2), 2.12 (3H, s, NHCOCH3), 1.10 (3H, t, J=7.2). IR (NEAT) CM−1; 3500-2800 (broad-OH band), 1668, 1614, 1538, 1454, 1386, 1273, 1194, 1166, 1114, 1032, 863, 773 and 736.ACCURATE MASS: 237.16042 gmol−1 (C13H21O2N2 requires 237.16029); ELEMENTAL ANALYSIS; C, 64.07; H, 8.62; N, 10.88; (calc values; C, 65.67; H, 8.53; N, 11.86). MS; molecular ion peak at m/z=237
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.Cl.[CH3:54][NH:55][O:56][CH3:57]>C1COCC1.C(Cl)Cl>[F:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:55]([O:56][CH3:57])[CH3:54])=[O:6]
Reactant: COc1cccc(C(=O)O)c1F
Reactant: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cccc(C(=O)N(C)OC)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 36.7 %

Procedure:
To a solution of 2-fluoro-3-methoxy-benzoic acid (5.0 g, 29.4 mmol) and PyBOP (13.7 g, 29.4 mmol) in 7:1 CH2Cl2:THF was added triethylamine (4.10 mL, 29.4 mmol) over a 10 min period. N,O-Dimethylhydroxylamine hydrochloride (2.87 g, 29.4 mL) was then added and the reaction was allowed to stir at rt for 3 h. The reaction was then partitioned between dichloromethane and water. The organic phase was separated and the aqueous phase was extracted with 2×100 mL dichloromethane. The combined organic phases were dried (MgSO4) and concentrated in vacuo. The residue was taken up in ethyl acetate and was washed successively with 1N HCl, saturated aqueous NaHCO3, and brine. The organic phase was again dried (MgSO4) and concentrated in vacuo to yield the title compound (2.30 g, 37%).
Reaction SMILES: Br[C:2]1[C:3]([F:13])=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[CH:7][CH:6]=[CH:5]2.[CH2:14]([Sn](CCCC)(CCCC)C=C)[CH2:15]CC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[F:13][C:3]1[C:2]([CH:14]=[CH2:15])=[C:11]([F:12])[CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Fc1cc2ncccc2c(F)c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: C=Cc1c(F)cc2ncccc2c1F
Temperature: 150 °C
Reaction time: 0.42 h

Procedure:
6-Bromo-5,7-difluoro-quinoline ((viii), 1 g, 4.10 mmol), tetrakis(triphenylphosphine)palladium (0) (47 mg, 0.041 mmol) and tributyl(vinyl)tin (1.34 g, 4.10 mmol) were put together with dioxane (3.7 mL) in a microwave reactor and stirred for 25 min at 150° C. under microwave irradiations. The solvent was removed and the residue was purified by MPLC with hexane and EtOAc. The title compound was obtained as a colorless oil (tR 1.1 min (conditions 4), MH+=192).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:24](=[CH:25][CH:26]=1)[C:8]1=[N:9][O:10][C:11]([C:12]3[CH:13]=[CH:14][C:15]([O:20][CH:21]([CH3:23])[CH3:22])=[C:16]([CH:19]=3)[C:17]#[N:18])=[C:7]1[CH2:6][CH2:5]2.[Br-].[CH2:28]([O:30][C:31](=[O:35])[CH2:32][CH2:33][Zn+])[CH3:29]>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C.C1COCC1>[C:17]([C:16]1[CH:19]=[C:12]([C:11]2[O:10][N:9]=[C:8]3[C:24]4[C:4]([CH2:5][CH2:6][C:7]=23)=[CH:3][C:2]([CH2:33][CH2:32][C:31]([O:30][CH2:28][CH3:29])=[O:35])=[CH:26][CH:25]=4)[CH:13]=[CH:14][C:15]=1[O:20][CH:21]([CH3:23])[CH3:22])#[N:18]
Reactant: CC(C)Oc1ccc(-c2onc3c2CCc2cc(Br)ccc2-3)cc1C#N
Reactant: CCOC(=O)CC[Zn+]
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: [Br-]
Solvent: C1CCOC1
Product: CCOC(=O)CCc1ccc2c(c1)CCc1c-2noc1-c1ccc(OC(C)C)c(C#N)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 5-(7-bromo-4,5-dihydronaphtho[1,2-c]isoxazol-3-yl)-2-isopropoxybenzonitrile (Preparation 15B, 0.1 g, 0.244 mmol) in a 2-dram vial was added THF (1 mL). The vial was purged with nitrogen gas for 3 min and (3-ethoxy-3-oxopropyl)zinc(II) bromide (0.5 M in THF) (0.977 mL, 0.489 mmol) was added followed by dichlorobis(tri-o-tolylphosphine)palladium(II) (1.921 mg, 2.443 μmol) at room temperature. The vial was again purged with nitrogen gas for 30 seconds and the pale yellow heterogeneous reaction mixture was stirred at room temperature for 18 h. To the reaction mixture was added potassium fluoride (60 mg) dissolved in 0.2 mL of water at room temperature. The contents were stirred at room temperature for 5 min. and then filtered. The solid was washed with ethyl acetate (2×5 mL). The filtrate was concentrated under reduced pressure to yield a pale yellow solid. LC/MS M+1=401.1.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([O:14][CH3:15])[CH2:13][CH2:12][NH:11][CH2:10]1.[C:16](#N)[CH3:17].C(=O)([O-])[O-].[Na+].[Na+].ICC>O>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([O:14][CH3:15])[CH2:13][CH2:12][N:11]([CH2:16][CH3:17])[CH2:10]1
Reactant: COC1(c2cccc(F)c2F)CCNC1
Reactant: CC#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCI
Solvent: O
Product: CCN1CCC(OC)(c2cccc(F)c2F)C1
Temperature: 110 °C
Yield: 27 %

Procedure:
A mixture of 3-(2,3-difluorophenyl)-3-methoxypyrrolidine (0.4 g, 1.87 mmol), acetonitrile (5 ml), sodium carbonate (0.52 g, 3.74 mmol) and iodoethane (0.28 g, 1.87 mmol) was heated at 110° C. in a sealed tube under microwave irradiation for 10 minutes. Water (30 ml) was added and the aqueous phase was extracted with ethyl acetate (2×50 ml), the combined organic phases was dried (MgsO4) and evaporated to give the crude product (0.45 g). Purification by flash chromatography (ethyl acetate/methanol 1:1) and by HPLC on waters OBD C18, 5 μm (MeOH/33 mM NH3, 20:80 to 50:50) gave the title compound (0.12 g, 27%). The amine was converted to the fumaric acid salt and recrystallized from methanol/diethyl ether/diisopropyl ether: M.p. 94-98° C. MS m/z (rel. intensity, 70 eV) 241 (M+, 5), 226 (54), 211 (27), 141 (50), 71 (bp).
Reaction SMILES: [Br-].[CH3:2][N:3]([CH3:25])[CH2:4][CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[O:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH:33]1[O:38][CH2:39][CH2:40][O:41][C:42]1[C:43]([CH:48]=O)=[N:44][CH:45]=[CH:46][CH:47]=1>C1COCC1.CC(O)(C)C>[CH3:2][N:3]([CH3:25])[CH2:4]/[CH:5]=[CH:48]\[C:43]1[C:42]([O:41][CH2:40][CH2:39][O:38][CH:33]2[CH2:34][CH2:35][CH2:36][CH2:37][O:32]2)=[CH:47][CH:46]=[CH:45][N:44]=1
Reactant: CN(C)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ncccc1OCCOC1CCCCO1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: CN(C)C/C=C\c1ncccc1OCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 10.4 %

Procedure:
To a suspension of [2-(dimethylamino)ethyl](triphenyl)phosphonium bromide (32.1 g, 77.4 mmol) in dry THF (150 mL) was added a solution of potassium tert-butoxide (9.4 g, 83.7 mmol) in dry t-BuOH (100 mL). The suspension was sonicated for 15 minutes whereafter a solution of 3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]pyridine-2-carbaldehyde (from Step 1; 18.3 g, 72.8 mmol) in THF (30 mL) was added to the yellow suspension and stirred at room temperature for one hour and then for a further hour at 60° C. The solvent was removed under reduced pressure and the residue was mixed with water (0.8 L) and the pH was adjusted to 3–4 with HOAc (˜10 mL) and then extracted twice with CHCl3. The aqueous phase was made basic and extracted with CHCl3 (×3), the combined organic phases were dried (MgSO4) and the solvent was removed under reduced pressure. The crude product, consisting of the cis and trans* isomers were separated with preparative HPLC on an YMC ODS-AQ column (30×250 mm) with different gradients of 0.1% TFA in water/CH3CN. The cis isomer was isolated as a light yellow oil (2.33 g, 10%). HRMS m/z calcd for C17H26N2O3 (M)+ 306.1943. found 306.1942. *The corresponding trans isomer is described in Example 21, Step 1.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:31]=[O:32])[CH:8]=[C:9]2[C:17]=1[CH:16]([CH2:18][O:19][C:20](=[O:22])[NH2:21])[C:15]1([O:24][C:25](=[O:27])[CH3:26])[O:23][N:10]2[CH2:11][CH:12]2[CH:14]1[N:13]2C(=O)C)(=[O:3])[CH3:2].O.S(=O)(=O)(O)[OH:35].C(O)(C)C>CC(C)=O.[O-2].[O-2].[O-2].[Cr+6]>[C:1]([O:4][C:5]1[CH:6]=[C:7]([C:31]([OH:35])=[O:32])[CH:8]=[C:9]2[C:17]=1[CH:16]([CH2:18][O:19][C:20](=[O:22])[NH2:21])[C:15]1([O:24][C:25](=[O:27])[CH3:26])[O:23][N:10]2[CH2:11][CH:12]2[CH:14]1[NH:13]2)(=[O:3])[CH3:2]
Reactant: O=S(=O)(O)O
Reactant: CC(=O)Oc1cc(C=O)cc2c1C(COC(N)=O)C1(OC(C)=O)ON2CC2C1N2C(C)=O
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(C)=O
Solvent: CC(C)O
Solvent: O
Product: CC(=O)Oc1cc(C(=O)O)cc2c1C(COC(N)=O)C1(OC(C)=O)ON2CC2NC21
Reaction time: 0.5 h

Procedure:
To a solution of 11-acetyl-8-carbamoyloxymethyl-4-formyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-6,9-diyl diacetate (29 mg) in acetone (2 ml) was added a mixture of chromium trioxide (26 mg), water (76 μl) and sulfuric acid (22 μl) in an ice-water bath. After stirring for 30 minutes in an ice-water bath, isopropyl alcohol (2 ml) was added to the reaction mixture. The resultant mixture was then poured into water (10 ml) and extracted with a mixture of chloroform and methanol (2:1, v/v) (10 ml×5). The extracts were combined and dried over magnesium sulfate, and then evaporated in vacuo. The residue was subjected to preparative thin layer chromatography, which was developed with a mixture of chloroform, methanol and water (65:25:4, v/v) to afford 6,9-diacetoxy-8-carbamoyloxymethyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-triene-4-carboxylic acid (5 mg).
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([CH2:8][C:9]([O:11]CC)=O)[N:6]=[C:5]([N+:14]([O-:16])=[O:15])[CH:4]=1.[CH3:17][NH2:18]>ClCCl.O>[CH3:17][N:18]1[C:9](=[O:11])[CH2:8][N:7]2[N:6]=[C:5]([N+:14]([O-:16])=[O:15])[CH:4]=[C:3]2[CH2:2]1
Reactant: CN
Reactant: CCOC(=O)Cn1nc([N+](=O)[O-])cc1CCl
Solvent: O
Solvent: ClCCl
Product: CN1Cc2cc([N+](=O)[O-])nn2CC1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.4 %

Procedure:
To a solution of 146b (1.0 g, 4.0 mmol) in dichloromethane (30 mL) was added a solution of CH3NH2 (1.07 g, 12.0 mmol, 35% in methanol). This reaction mixture was stirred at room temperature for 3 h and diluted with water (30 mL). The organic layer was separated, dried over Na2SO4, and concentrated under reduced pressure. The residual was purified by silica-gel column chromatography eluting with 30:1 dichloromethane/methanol to afford 146c (450 mg, 57%) as a yellow solid. MS-ESI: [M+H]+ 196.9
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:26][CH2:27]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:25])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[C:34]1([C:40]2([C:46]([NH2:48])=[O:47])[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:26][CH2:27][N:43]3[CH2:42][CH2:41][C:40]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)([C:46]([NH2:48])=[O:47])[CH2:45][CH2:44]3)[CH2:13][CH2:12][N:11]([C:14](=[O:25])[C:15]3[CH:16]=[C:17]([O:23][CH3:24])[CH:18]=[C:19]([O:21][CH3:22])[CH:20]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Reactant: COc1cc(OC)cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)c1
Agent: Cl
Product: COc1cc(OC)cc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)c1

Procedure:
The method of example 3.3 was used with 2-[3-(3,4-dichloro-phenyl)-1-(3,5-dimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (0.96 mmol) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride (1.06 mmol) to prepare the title compound. Chromatography on silica gel eluting sequentially with ethyl acetate, 6% methanol in dichloromethane, and then 10% methanol in dichloromethane gave the title compound: Rf =0.55 (silica gel, 10% methanol in dichloromethane).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([Br:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2].[CH:16]([O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)([CH3:18])[CH3:17]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C:23]2[CH:24]=[CH:25][C:20]([O:19][CH:16]([CH3:18])[CH3:17])=[CH:21][CH:22]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([Br:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(Br)ccc2[nH]1
Reactant: CC(C)Oc1ccc(B(O)O)cc1
Product: CCOC(=O)c1cc2cc(Br)ccc2n1-c1ccc(OC(C)C)cc1

Procedure:
The sub-title compound was prepared in accordance with Example 8(c) from 5-bromoindole-2-carboxylic acid ethyl ester and 4-isopropoxyphenylboronic acid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CO.C([O:12][CH2:13][C:14]([N:16]1[CH2:20][CH2:19][CH2:18][CH:17]1[C:21]1[C:22]([O:36][C:37]2[CH:42]=[CH:41][C:40]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=3[F:49])=[CH:39][CH:38]=2)=[CH:23][C:24]2[N:28]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[NH:26][C:25]=2[CH:35]=1)=[O:15])(=O)C>C(Cl)(Cl)Cl>[F:49][C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=1[C:40]1[CH:39]=[CH:38][C:37]([O:36][C:22]2[C:21]([CH:17]3[CH2:18][CH2:19][CH2:20][N:16]3[CH:14]([OH:15])[CH:13]=[O:12])=[CH:35][C:25]3[NH:26][C:27]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)=[N:28][C:24]=3[CH:23]=2)=[CH:42][CH:41]=1
Reactant: CC(=O)OCC(=O)N1CCCC1c1cc2[nH]c(-c3ccccn3)nc2cc1Oc1ccc(-c2ccccc2F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=CC(O)N1CCCC1c1cc2[nH]c(-c3ccccn3)nc2cc1Oc1ccc(-c2ccccc2F)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
10 mg of potassium carbonate was added to a methanol (0.5 ml) solution of 11 mg of 2-(2-(5-((2′-fluorobiphenyl-4-yl)oxy)-2-pyridin-2-yl-1H-benzimidazol-6-yl)pyrrolidin-1-yl)-2-oxoethyl acetate obtained in Example 513, and the reaction liquid was stirred at room temperature for 1 day. The reaction liquid was diluted with chloroform, washed with water and saturated saline in order, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol=10/1) to obtain the entitled compound as a white solid.