Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([S:12]([Cl:15])(=[O:14])=[O:13])[CH:9]=[CH:8][C:4]=1[C:5](O)=O.[CH3:16][NH:17][CH3:18].[NH2:19][C:20]1[C:25]([NH2:26])=[CH:24][N:23]=[CH:22][N:21]=1>>[ClH:15].[CH3:1][O:2][C:3]1[CH:11]=[C:10]([S:12]([N:17]([CH3:18])[CH3:16])(=[O:14])=[O:13])[CH:9]=[CH:8][C:4]=1[C:5]1[NH:26][C:25]2[C:20](=[N:21][CH:22]=[N:23][CH:24]=2)[N:19]=1
Reactant: COc1cc(S(=O)(=O)Cl)ccc1C(=O)O
Reactant: Nc1cncnc1N
Reactant: CNC
Product: COc1cc(S(=O)(=O)N(C)C)ccc1-c1nc2ncncc2[nH]1
Product: Cl

Procedure:
Prepared analogously to Example 51 from 2-methoxy-4-chlorosulfonyl-benzoic acid, aqueous dimethylamine solution, and 4,5-diamino-pyrimidine. The hydrochloride was recrystallized from ethanol/water (4:1).
Reaction SMILES: C[N:2]([CH:4]=[O:5])C.C(Cl)(=O)[C:7](Cl)=[O:8].[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2(C(O)=O)[CH2:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1)([O-:14])=[O:13].[N-]=[N+]=[N-].[Na+]>C(Cl)Cl.O.C(Cl)(Cl)Cl>[N+:12]([C:15]1[CH:16]=[CH:17][C:18]([C:21]2([NH:2][C:4](=[O:5])[O:8][CH3:7])[CH2:22][CH2:23][CH2:24]2)=[CH:19][CH:20]=1)([O-:14])=[O:13]
Reactant: O=C(O)C1(c2ccc([N+](=O)[O-])cc2)CCC1
Reactant: CN(C)C=O
Reactant: O=C(Cl)C(=O)Cl
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: ClC(Cl)Cl
Product: COC(=O)NC1(c2ccc([N+](=O)[O-])cc2)CCC1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
A drop of DMF and oxalyl chloride (0.283 mL, 3.30 mmol) was added to a stirred solution of 1-(4-nitrophenyl)cyclobutanecarboxylic acid (503 mg, 2.27 mmol) in DCM (7 mL) under a nitrogen atmosphere and the resulting mixture was stirred for 25 minutes at room temperature. The volatiles were removed in vacuo and the residue was dissolved in acetone (4.50 mL). A solution of sodium azide (400 mg, 5.23 mmol) in water (4.50 mL) was added with the temperature maintained below 0° C. After stirring for 30 minutes, the mixture was diluted with chloroform and washed with cold water and saturated aqueous NaCl. The organics were dried with Na2SO4 and concentrated carefully. Toluene (10.0 mL) was added and the resulting solution was heated at 80° C. for 1 hour. MeOH (10 mL) was added and the resulting mixture heated at 60° C. for 1.5 hours under a nitrogen atmosphere. The volatiles were evaporated under reduced pressure then the residue adsorbed on silica gel and purified using silica gel column chromatography (CombiFlash Rf, SiO2 cartridge, 0-20% EtOAc in cyclohexane) to give the title compound A118 (404 mg, 71%); 1H NMR (300 MHz, CDCl3): δ 8.17 (d, J=9.0 Hz, 2H), 7.59 (d, J=8.9 Hz, 2H), 5.74 (br s, 1H), 3.57 (s, 3H), 2.52 (m, 4H), 2.15 (m, 1H), 1.92 (m, 1H); LCMS-B: rt 6.55 min; m/z 251.3 [M+H]+.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Li]CCCC.CCCCCC.[CH2:25]1[O:27][CH2:26]1.CCOCC>C1COCC1>[CH:1]1[C:13]2[CH:12]([CH2:25][CH2:26][OH:27])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: C1CO1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCCC1c2ccccc2-c2ccccc21
Reaction time: 5 h

Procedure:
2-(9-Fluorenyl)ethanol was prepared from a solution of fluorene (116.35 g, 0.7 mmol) in 800 ml of dry THF at -20° C. which was added n-BuLi in hexane (0.7 mol) keeping the temperature below -10° C. To the clear solution was rapidly added 357 ml of 1.4M ethylene oxide in ether (0.5 mol) keeping the temperature below 5° C. The reaction mixture was stirred for 5 hours, then quenched with 50 ml of saturated ammonium chloride solution. The THF was removed at a rotary evaporator. The residue was partitioned between water and ethyl acetate. The organic layer was separated, dried with MgSO4 and concentrated in vacuo until crystallization began. The solution was allowed to stand overnight and the crystals were collected and dried (mp 97° C.) (85.5 g, (81%)).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:12][CH:13]([CH2:21][CH3:22])[C:14]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:15]>>[CH2:17]([O:16][C:14](=[O:15])[CH:13]([NH:12][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH2:21][CH3:22])[CH:18]([CH3:19])[CH3:20]
Reactant: CCC(N)C(=O)OCC(C)C
Reactant: O=C(O)Cc1ccc(F)cc1
Product: CCC(NC(=O)Cc1ccc(F)cc1)C(=O)OCC(C)C

Procedure:
Following General Procedure I above and using 4-fluorophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure J above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6].[N:11]([O-])=O.[Na+].[OH-].[Na+]>Cl.O>[CH3:1][O:2][CH2:3][C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH:6][NH2:11]
Reactant: COCc1ccccc1N
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COCc1ccccc1NN
Temperature: -10 °C
Yield: 71 %

Procedure:
6.86 g (50 m moles) of 2-methoxymethylaniline was dissolved in 50 ml of concentrated hydrochloric acid. The solution was cooled to −10° C. Thereto was dropwise added a solution of sodium nitrite (4.14 g, 60 m moles) dissolved in water (50 ml) while a temperature of −10° C. to 0° C. was being kept. Then, a solution of 44.6 g (235 m moles) of stannous chloride dissolved in concentrated hydrochloric acid (50 ml) was dropwise added at the above temperature in 1 hour. After the completion of the dropwise addition, stirring was conducted with a gradual temperature increase to about 20° C. Then, a 10% aqueous sodium hydroxide solution was dropped to obtain a pH of 14, after which extraction with toluene was conducted. The toluene layer was washed with water and concentrated under reduced pressure using a rotary evaporator to obtain 5.40 g (35.5 m moles) of liquid 2-methoxymethylphenylhydrazine. Yield: 71%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1.Cl[CH2:18][C:19](Cl)=[O:20].CCCCCCCCCC.[Cl-].[Al+3].[Cl-].[Cl-]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:10]2[C:11](=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[CH2:18][C:19]1=[O:20]
Reactant: O=C(Cl)CCl
Reactant: Cc1ccc(Nc2c(F)cccc2Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCCCCCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1ccc2c(c1)CC(=O)N2c1c(F)cccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Alternatively, a mixture of 169.8 g of crude N-(2′-chloro-6′-fluorophenyl)-4-methylaniline, 172 ml (2.15 mol) of chloroacetyl chloride in 580 ml of toluene is heated under a nitrogen atmosphere for 2 hours at 70°. The reaction is cooled to room temperature, 450 ml of decane is added, and the volatiles are distilled off under 200 mbar pressure at 62–72°. To the mixture is added 150 ml of toluene and 385 g of aluminum chloride (2.87 mol) slowly at 20–40°. The mixture is heated at 120° for 5 hours, cooled to 20°, and added over 30 minutes to 800 ml of ethyl acetate. The mixture is quenched by addition to a pre-cooled solution of 67 ml of 37% hydrochloric acid in 800 ml of water at 20±10°, and the resultant mixture is filtered through a pad of Celite. The organic layer is separated and the volatiles are distilled off. To the residue is added 100 ml of heptane and the mixture is cooled to 0° over a 30 minute period and stirred for one hour. The mixture is filtered and the filter cake is washed three times with 45 ml of heptane. To the crude product is added 90 g of charcoal (DARCO G-60) and 4500 ml of methanol. The mixture is heated to reflux for two hours, cooled to room temperature, and filtered through a pad of Celite. After distilling off 4390 ml of methanol, the mixture is cooled to 15°. The product is collected by filtration, washed three times with 30 ml of methanol, and dried to give N-(2′-chloro-6′-fluorophenyl)-5-methyloxindole.
Reaction SMILES: [N:1]1([C:8]([NH:10][C@@H:11]([CH:15]([CH3:17])[CH3:16])[C:12]([OH:14])=O)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:51][C:52]1[CH:57]=[CH:56][C:55]([CH:58]([C:65]2[CH:70]=[CH:69][C:68]([F:71])=[CH:67][CH:66]=2)[N:59]2[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]2)=[CH:54][CH:53]=1>CN(C=O)C.C(OCC)C>[F:71][C:68]1[CH:67]=[CH:66][C:65]([CH:58]([C:55]2[CH:56]=[CH:57][C:52]([F:51])=[CH:53][CH:54]=2)[N:59]2[CH2:60][CH2:61][N:62]([C:12]([C@@H:11]([NH:10][C:8]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]3)=[O:9])[CH:15]([CH3:17])[CH3:16])=[O:14])[CH2:63][CH2:64]2)=[CH:70][CH:69]=1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Reactant: CC(C)[C@H](NC(=O)N1CCCCCC1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@H](NC(=O)N1CCCCCC1)C(=O)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.8 %

Procedure:
(S)-2-[(Azepane-1-carbonyl)-amino]-3-methyl-butyric acid (0.26 g, 1.1 mmol, Example 26, Step B) was dissolved in dry DMF (5 mL) under nitrogen atmosphere and cooled to 0° C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (0.37 mL, 2.1 mmol) and solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.40 g, 1.1 mmol). The resulting reaction mixture was stirred at that temperature for 30 minutes; solid 1-bis(4-fluorophenyl)methyl piperazine (0.31 g, 1.1 mmol) was then added. After additional 90 minutes stirring at 0° C., reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2×50 mL), brine (2×50 mL), and dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was further purified by flash chromatography (60% EtOAc in hexane) to provide 0.45 g (82%) of the pure titled compound as a white foam; mp 72-82° C. APCI-MS m/z 513.2 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]([NH:12][S:13]([C:16]2[CH:20]=[CH:19][S:18][C:17]=2[C:21]([O:23]C)=[O:22])(=[O:15])=[O:14])=[O:11])[N:3]=1.Cl>C(O)C.[OH-].[Na+].O>[CH3:8][C:6]1[CH:7]=[C:2]([CH3:1])[N:3]=[C:4]([NH:9][C:10]([NH:12][S:13]([C:16]2[CH:20]=[CH:19][S:18][C:17]=2[C:21]([OH:23])=[O:22])(=[O:15])=[O:14])=[O:11])[N:5]=1
Reactant: COC(=O)c1sccc1S(=O)(=O)NC(=O)Nc1nc(C)cc(C)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc(C)nc(NC(=O)NS(=O)(=O)c2ccsc2C(=O)O)n1
Temperature: 0 °C

Procedure:
A solution of 1.0 g of methyl 3-[[(4,6-dimethylpyrimidin-2-yl)aminocarbonyl]aminosulfonyl]-2-thiophenecarboxylate in 10 ml of ethanol and 1 ml of 50% sodium hydroxide in water was stirred overnight at room temperature. To this was added ice-water and aqueous hydrochloric acid until acidic, and the precipitate was filtered and washed first with acetone and then with methylene chloride. The product, 0.8 g, melted at 127°.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH2:23][CH2:24][CH3:25])[NH:13][C:14](=[O:15])[C:8]2=[CH:7][N:6]=1)(=O)=O.Cl.[CH2:27]([O:29][C:30](=[O:34])[CH2:31][CH2:32][NH2:33])[CH3:28].C(N(CC)CC)C>ClCCl>[CH2:27]([O:29][C:30]([CH2:31][CH2:32][NH:33][C:5]1[N:10]=[C:9]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH2:23][CH2:24][CH3:25])[NH:13][C:14](=[O:15])[C:8]2=[CH:7][N:6]=1)=[O:34])[CH3:28]
Reactant: CCCOc1ccccc1-c1nc2nc(S(C)(=O)=O)ncc2c(=O)[nH]1
Reactant: CCOC(=O)CCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCOc1ccccc1-c1nc2nc(NCCC(=O)OCC)ncc2c(=O)[nH]1

Procedure:
A solution of 7-methylsulphonyl-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine (1.0 g), β-alanine ethyl ester hydrochloride (1.10 g) and triethylamine (0.73 g) in dichloromethane (20 ml) was stirred at ambient temperature for 2.5 hours. The reaction mixture was extracted with dilute hydrochloric acid (20 ml) then water (10 ml), and the extracts back washed with dichloromethane (10 ml). The combined organic extracts were dried (magnesium sulphate) and evaporated under reduced pressure to yield a crude product which was recrystallized from ethanol:water to yield the title compound, 0.83 g, m.p. 142-3° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].Cl.[NH2:25]O>C(O)(=O)C.O>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:25])=[CH:11][C:10]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: COc1cc(C=O)ccc1OCc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(C#N)ccc1OCc1ccccc1
Yield: 100.3 %

Procedure:
4-benzyloxy-3-methoxybenzaldehyde (4.84 g, 20 mmol) in acetic acid (25 ml) and sodium acetate (3.3 g, 40 mmol) was reacted with hydroxylamine hydrochloride (2.8 g, 40 mmol) at reflux for 6 hours. The mixture was cooled, diluted with water, extracted with methylene chloride, dried over MgSO4, concentrated to give title compound (4.8 g, 100%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:25][CH:26]([CH3:28])[CH3:27])=[CH:4][C:5]2[NH:9][C:8](=[O:10])[N:7]([CH:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[C:6]=2[CH:24]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[C:3]([O:25][CH:26]([CH3:28])[CH3:27])=[CH:4][C:5]2[NH:9][C:8](=[O:10])[N:7]([CH:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]3)[C:6]=2[CH:24]=1
Reactant: Cc1cc2c(cc1OC(C)C)[nH]c(=O)n2C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc2c(cc1OC(C)C)[nH]c(=O)n2C1CCNCC1
Reaction time: 1 h
Yield: 291.3 %

Procedure:
A solution of 1,1-dimethylethyl 4-{6-methyl-5-[(1-methylethyl)oxy]-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl}-1-piperidinecarboxylate (D76) (0.14 mmol, 53 mg) in dichloromethane (1 mL) was treated with trifluoroacetic acid (1 mL) under argon at room temperature and was allowed to stir for 1 h. The mixture was then concentrated under reduced pressure, the residue was treated with 10% aqueous sodium carbonate solution and extracted 3 times with ethyl acetate. The organics were combined, dried and concentrated under reduced pressure to give the title compound (118 mg, >>100%). M+H 290.3.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][CH2:36]Cl)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:42][CH2:41][C@@H:40]([OH:43])[CH2:39]1.CCN(C(C)C)C(C)C.O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][CH2:36][N:38]5[CH2:42][CH2:41][C@@H:40]([OH:43])[CH2:39]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O[C@@H]1CCNC1
Reactant: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCN1CC[C@@H](O)C1
Temperature: 50 °C
Reaction time: 5 h
Yield: 16.4 %

Procedure:
(1-(5-Tert-butyl-isoxazol-3-yl)-3-{3-[7-(3-chloro-propoxy)-6-methoxy-quinazolin-4-yloxy]-phenyl}-urea (210 mg, 0.4 mmol) from Example 27B was treated with (R)-(+)-3-pyrrolidinol (65 μL, 0.8 mmol), tetrabutylammonium iodide (148 mg, 0.4 mmol) and N,N′-diisopropylethylamine (69 μL, 0.4 mmol) in N,N′-dimethylformamide (4 mL). The mixture was stirred at 50° C. for 5h. After cooling to room temperature water (4 mL) was added and the precipitating solid filtered off and dried. The solid residue was purified by preparative HPLC (phenylhexyl reverse phase column). The obtained solid was triturated with water to give (R)-1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-(3-(3-hydroxypyrrolidin-1-yl)propoxy)-6-methoxyquinazolin-4-yloxy)phenyl)urea (37.76 mg, 16%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.60 (s, 1H), 9.10 (s, 1H), 8.55 (s, 1H), 7.58-7.56 (m, 2H), 7.40-7.38 (m, 2H), 7.25 (d, 1H), 6.98 (d, 1H), 6.48 (s, 1H), 4.70 (s, 1H), 4.31-4.20 (m, 3H), 3.99 (s, 3H), 3.32 (s, 1H), 2.81-2.69 (m, 2H), 2.40-2.19 (m, 3H), 2.10-1.98 (m, 3H), 1.67-1.4 (m, 1H), 1.27 (s, 9H); LC-MS (ESI) m/z 577 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH2:15][CH3:16])[C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.Cl.[CH2:18]([O:20][CH2:21][CH2:22][N:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N:25]=[C:24]1[N:32]1[CH2:38][CH2:37][CH2:36][N:35]([CH2:39][CH2:40][C:41]2([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH2:45][CH2:44][NH:43][CH2:42]2)[CH2:34][CH2:33]1)[CH3:19]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH2:15][CH3:16])[C:11]=1[O:12][CH3:13])[C:6]([N:43]1[CH2:44][CH2:45][C:41]([CH2:40][CH2:39][N:35]2[CH2:36][CH2:37][CH2:38][N:32]([C:24]3[N:23]([CH2:22][CH2:21][O:20][CH2:18][CH3:19])[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[N:25]=3)[CH2:33][CH2:34]2)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:42]1)=[O:8]
Reactant: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Reactant: CCOc1cc(C(=O)O)cc(OC)c1OC
Agent: Cl
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(OC)c(OC)c(OCC)c4)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 56.1 using 3,4-dimethoxy-5-ethoxybenzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt) to give the title compound.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C=C[C@@H]1[C@@H]2C[C@H]([C@@H](O)C3C4C(=CC=CC=4)N=CC=3)N(CC2)C1.N1C=CC=CC=1.[CH3:36][NH:37][C:38]([C:40]1[CH:49]=[CH:48][C:47]2[C:42](=[CH:43][CH:44]=[C:45]([C:50]([C:52]3[N:53]=[CH:54][N:55]([C:57]([C:70]4[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=4)([C:64]4[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=4)[C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=4)[CH:56]=3)=[O:51])[CH:46]=2)[CH:41]=1)=[O:39]>C1COCC1.C(OCC)(=O)C.Cl>[OH:51][C@@:50]([C:45]1[CH:44]=[CH:43][C:42]2[C:47](=[CH:48][CH:49]=[C:40]([C:38]([NH:37][CH3:36])=[O:39])[CH:41]=2)[CH:46]=1)([C:52]1[N:53]=[CH:54][N:55]([C:57]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)([C:70]2[CH:71]=[CH:72][CH:73]=[CH:74][CH:75]=2)[C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)[CH:56]=1)[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CNC(=O)c1ccc2cc(C(=O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Reactant: CCOC(=O)CBr
Agent: C=C[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](O)c1ccnc2ccccc12
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C[C@](O)(c1ccc2cc(C(=O)NC)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 68 %

Procedure:
Under argon atmosphere, a solution of 8.44 mL (76.5 mmol) of ethyl bromoacetate in 35 mL of THF was added to a solution of 5 g of Rieke-Zn in 105 mL of THF at 19˜21° C. over 20 minutes. The mixture was stirred at 20˜25° C. for 20 minutes, and allowed to stand for 3 hours and 30 minutes. 1.26 g (4.3 mmol, 1.25 eq) of (+)-cinchonine was added to 30 mL of the above Reformatsky reagent at 8° C. 1.1 mL (13.8 mmol, 4 eq) of pyridine was added dropwise at 5˜7° C. The mixture was stirred at 4˜7° C. for 15 minutes, and a solution of 1.79 g (3.4 mmol) of N-methyl-6-[(1-trityl-1H-imidazol-4-yl)carbonyl]-2-naphthamide in 15 mL of THF was added dropwise at −8˜−6° C. The mixture was stirred at −10˜−8° C. for 2 hours and 30 minutes. 10 mL of 1N hydrochloric acid was added dropwise, and the mixture was warmed to 0° C. After diluted with 50 mL of ethyl acetate, 10 mL of 1N hydrochloric acid was added, and the layers were separated. The organic layer was washed successively with 20 mL of 1N hydrochloric acid two times, 20 mL of water, 20 mL of an aqueous saturated sodium bicarbonate solution, and 20 mL of an aqueous saturated sodium chloride solution. After concentrated under reduced pressure, 4 mL of ethyl acetate and 2 mL of IPE were added to the concentration residue. Crystals were filtered, and washed with 2 mL of ethyl acetate three times. Vacuum drying (40° C.) to a constant weight afforded 1.41 g of ethyl (3S)-3-hydroxy-3-{6-[(methylamino)carbonyl]-2-naphty}-3-(1-trityl-1H-imidazol-4-yl)propanoate (yield 68%, enantiomer excess 63.1% ee).
Reaction SMILES: [Cl:1][C:2]([Cl:13])=[CH:3][CH:4]([CH:10]([CH3:12])[CH3:11])[C:5]([O:7]CC)=[O:6].[OH-].[Na+]>C(O)C.O>[Cl:1][C:2]([Cl:13])=[CH:3][CH:4]([CH:10]([CH3:11])[CH3:12])[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)C(C=C(Cl)Cl)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)C(C=C(Cl)Cl)C(=O)O
Yield: 84.9 %

Procedure:
In 20 g of chloroform were dissolved 6.0 g of the ethyl α-bromo-α-(2,2,2-trichloroethyl)isovalerate and, after the addition of 3.5 g of 1,5-diazabicyclo[5,4,0]undecene-5(DBU), the solution was stirred at room temperature for 2 hours. The reaction mixture was then diluted with diethyl ether, washed with water and dilute aqueous hydrogen chloride and dried over anhydrous magnesium sulfate. The low-boiling fraction was removed by distillation, whereupon 4.6 g of oily product were obtained. Based on its NMR spectrum and GC-mass spectrum, this product was identified to be ethyl α-isopropyl-β-trichloromethylacrylate containing a certain amount of ethyl α-bromo-α-(2,2-dichlorovinyl) isovalerate. In 50 ml of ethanol were dissolved 4.6 g of the oily product obtained above and, following the addition of 0.4 g of 5% palladium-on-carbon, the solution was stirred in an atmosphere of hydrogen gas at 55° C. for 6 hours. Thereafter, the reaction mixture was filtered to remove the catalyst and the ethanol was distilled off. By the above procedure there were obtained 3.9 g of ethyl α-(2,2-dichlorovinyl)isovalerate as an oil. Then, 3.9 g of this ethyl α-(2,2-dichlorovinyl)isovalerate were dissolved in 20 ml of ethanol and a solution of 2.0 g of sodium hydroxide in 10 ml of water was added to the above ethanol solution. The mixture was stirred at room temperature for 10 hours, at the end of which time the ethanol was distilled off. The residue was neutralized with aqueous hydrogen chloride and extracted with diethyl ether. The ethereal solution yielded 2.9 g of α-(2,2-dichlorovinyl)isovaleric acid having the following NMR spectrum [yield: 84% based on ethyl α-bromo-α-(2,2,2-trichloroethyl)isovalerate].
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[C:3]=1[CH2:22][C:23]([O:25][CH3:26])=[O:24].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:37]1[CH2:41]OC[CH2:38]1.ICCC>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[C:3]=1[CH:22]([CH2:38][CH2:37][CH3:41])[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccccc1F)CCCC3
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCCI
Product: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccccc1F)CCCC3
Yield: 75.2 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-(2-fluorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate (0.320 g; 0.86 mmol), LHMDS 1N in THF (1.29 mL; 1.29 mmol), 1-iodopropane (0.168 mL; 1.72 mmol) in DMF (4.3 mL) for 18 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2-40%) in heptane furnished 0.266 g (75%) of the title compound as a yellow oil.