Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][CH:11]3[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.CO>CO>[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH:24][CH:14]2[CH2:15][CH2:16][CH:11]([NH:10][C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[NH:1][N:2]=[CH:3]4)[CH2:12][CH2:13]2)=[CH:21][CH:20]=1
Reactant: NCc1ccc(F)cc1
Reactant: O=C1CCC(Nc2ccc3[nH]ncc3c2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Fc1ccc(CNC2CCC(Nc3ccc4[nH]ncc4c3)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 23.8 %

Procedure:
4-(1H-5-Indazolylamino)-1-cyclohexanone (intermediate 3) (57 mg) and 4-fluorobenzylamine (70 mg) were dissolved in methanol (1 ml), and sodium triacetoxyborohydride (105 mg) was added by portions to the solution at room temperature. The reaction mixture was stirred at room temperature for 18 hr. Hydrochloric acid-methanol was then added thereto, and the mixture was stirred and was then concentrated. The residue was purified by HPLC [0.5% aqueous trifluoroacetic acid solution/acetonitrile]. A saturated aqueous sodium hydrogencarbonate solution (2 ml) was then added to fractions containing respective compounds, followed by extraction with chloroform-propanol (3/1). The organic layers were dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure to give an anti-form compound (20 mg) and a syn-form compound (12 mg).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2C[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[O:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:5]=2[N:6]=1.CS(O[CH2:27][CH2:28][CH:29]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[C:30]1([CH:29]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:28][CH2:27][S:1][C:2]2[S:3][C:4]3[CH2:13][C:12]4[C:11]([O:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:10][CH:9]=[CH:8][C:7]=4[C:5]=3[N:6]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCOC(=O)COc1cccc2c1CCc1sc(S)nc1-2
Reactant: CS(=O)(=O)OCCC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1cccc2c1Cc1sc(SCCC(c3ccccc3)c3ccccc3)nc1-2
Temperature: 60 °C
Reaction time: 2 h
Yield: 61.2 %

Procedure:
To a solution of ethyl [(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acetate (4.00 g, 12.4 mmol) in N,N-dimethylformamide (30 mL) was added 3,3-diphenylpropyl methanesulfonate (3.96 g, 13.6 mmol) followed by addition of potassium carbonate (1.90 g, 13.6 mmol), and the mixture was stirred at 60° C. for 2 hours. This reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure to provide 3.81 g of ethyl [[2-(3,3-diphenypropyl)thio-8H-indeno[1,2-d]thiazol-7-yl]oxy]acetate. To a solution of this compound (1.10 g, 2.19 mmol) in ethanol (30 mL)-water (3 mL) was added sodium periodate (4.68 g, 21.9 mmol) and the mixture was refluxed for 14 hours. This reaction mixture was diluted with ethyl acetate and water and, after, phase separation, the aqueous layer was extracted with ethyl acetate. The organic layers were pooled, washed with water, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure and the residue was dissolved in acetic acid (10 mL). To this solution was added concentrated sulfuric acid (5 mL) and the mixture was refluxed for 1 hour. After cooling, the reaction mixture was diluted with water and extracted with 2 portions of ethyl acetate, and the combined extract was washed with water, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure and the residue was crystallized from hexane-ethyl acetate to provide 350 mg of the title compound. Yield 17%.
Reaction SMILES: Br[CH:2]1[C:6](=O)[CH2:5][CH2:4][CH:3]1[C:8]#[N:9].[NH2:10][C:11]([NH2:13])=[S:12]>O1CCOCC1>[NH2:13][C:11]1[S:12][C:2]2[CH:3]([C:8]#[N:9])[CH2:4][CH2:5][C:6]=2[N:10]=1
Reactant: N#CC1CCC(=O)C1Br
Reactant: NC(N)=S
Solvent: C1COCCO1
Product: N#CC1CCc2nc(N)sc21
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of 2-bromo-3-oxocyclopentanecarbonitrile (crude from A.1.2.1.; ca. 13 g) and thiourea (13.77 g, 181 mmol) in dioxane (600 mL) was stirred at 80° C. for 1 h. The mixture was allowed to cool to RT, quenched with aq. sat. NaHCO3 and extracted with EtOAc. The comb. org. layers were washed with brine, dried over MgSO4, and conc. in vacuo. Purification by means of CC (2-20% MeOH (0.5% Et3N)/DCM) provided a brown solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([CH2:11][CH2:12][OH:13])[N:6]2[N:5]=[CH:4][N:3]=1.CC(O)C.C(=O)=O.[Br:21]N1C(C)(C)C(=O)N(Br)C1=O>CN(C=O)C>[NH2:1][C:2]1[C:7]2=[C:8]([Br:21])[CH:9]=[C:10]([CH2:11][CH2:12][OH:13])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: Nc1ncnn2c(CCO)ccc12
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: O=C=O
Solvent: CC(C)O
Solvent: CN(C)C=O
Product: Nc1ncnn2c(CCO)cc(Br)c12
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 184.1 %

Procedure:
To a solution of 2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)ethanol (777 mg, 4.3 mmol) in DMF (22 mL) at −20° C. (IPA and dry ice) was added 1,3-dibromo-5,5-dimethyl-imidazolidine-2,4-dione (359 mg, 1.72 mmol) ) was added in 4 portions within 20 min. The reaction was stirred at −20° C. for 30 min. Analytical HPLC indicated 22% starting material remanded, additional B (90 mg, 0.30 mmol) was added and stirred for 20 min. The reaction was quenched with satd. Na2SO3 and warmed up to rt. The crude was extracted w/EtOAc 5×. The organic was washed with 5% aq K2CO3 and brine. Dried over Na2SO4 and concentrated. The crude was purified by MPLC with 0-7% MeOH/CH2Cl2 to give 814 mg of desired product (yield, 72.6%). MS [M+H]+=257.3; LCMS RT=1.14 min.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[Cl:15][C:16]1[N:21]=[C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:19]([F:28])=[C:18](Cl)[N:17]=1>C(O)C>[Cl:15][C:16]1[N:17]=[C:18]([NH:1][C@@H:2]2[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]2)[C:19]([F:28])=[C:20]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[N:21]=1
Reactant: Fc1c(Cl)nc(Cl)nc1N1CCOCC1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2nc(Cl)nc(N3CCOCC3)c2F)C1
Temperature: 25 °C
Yield: 48.7 %

Procedure:
(R)-tert-Butyl 3-aminopiperidine-1-carboxylate (1.60 g, 7.99 mmol) was added to a solution of 4-(2,6-dichloro-5-fluoropyrimidin-4-yl)morpholine (Preparation 11a, 1.01 g, 4.00 mmol) in ethanol (48 mL) and the resulting mixture was stirred and heated to reflux for 3 days. After cooling to ambient temperature, the solvent was evaporated under reduced pressure and the residue was partitioned between water and methylene chloride. The organic layer was separated, washed with water, dried (MgSO4) and the solvent evaporated under reduced pressure. The residue was purified by flash chromatography (0-100% ethyl acetate in hexanes) to give the title compound (0.810 g, 47%) as a white foam.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].Cl.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20]Cl.C(N(CC)CC)C>C(#N)C>[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][O:1][N:2]1[C:3](=[O:12])[C:4]2[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:7]
Reactant: ClCc1ccccn1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1OCc1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.5 %

Procedure:
Under anhydrous conditions (positive nitrogen pressure, presence of 3Å molecular sieves), a mixture of N-hydroxyphthalimide (10.0 g, 0.061 mole), 2-picolylchloride hydrochloride (10.0 g, 0.061 mole), and triethylamine (18.5 g, 0.183 mol) in 100 ml of anhydrous acetonitrile was refluxed for 6 hours. After overnight stirring at ambient temperature, TLC showed that the starting materials were practically consumed. The solvent was evaporated and the residue dissolved in 200 ml of EtOAc. The solution was washed with 1N NaOH (100 ml), water (2×200 ml), brine (1×200 m ml) and dried (MgSO4). After removal of the solvent, the crude product was recrystallized from EtOAc/hexane to afford 11.4 g (73.6%) of title product.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([OH:16])[CH:15]=1)[C:9]([O:11][CH3:12])=[O:10].Br[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:26]([O:25][C:23](=[O:24])[CH2:22][O:16][C:14]1[CH:13]=[C:8]([CH:7]=[C:6]([O:5][CH2:4][C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]=2[F:1])[CH:15]=1)[C:9]([O:11][CH3:12])=[O:10])([CH3:29])([CH3:28])[CH3:27]
Reactant: COC(=O)c1cc(O)cc(OCc2ccccc2F)c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCC(=O)OC(C)(C)C)cc(OCc2ccccc2F)c1
Yield: 89.1 %

Procedure:
Methyl 3-(2-fluorobenzyloxy)-5-hydroxybenzoate (1.9 g, 1.0 eq., 6.9 mmole) was reacted with tert-butyl bromoacetate (1.6 g, 1.2 eq., 8.3 mmole) in the presence of potassium carbonate (2.4 g., 2.5 eq., 17.3 mmole) in dimethylformamide (5 mL) over 18 h. The product was partitioned between ethyl acetate and aqueous media. The combined organic extracts were dried over magnesium sulfate, filtered and evaporated to give 2.4 g (89% yield) of a yellow oil. The LC/MS was as expected with an (M+H+) of 391 calculated and found.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[Br:9]Br>C(Cl)Cl>[NH2:1][C:2]1[C:7]([Br:9])=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1
Reactant: BrBr
Reactant: Nc1ccc(Cl)cn1
Solvent: ClCCl
Product: Nc1ncc(Cl)cc1Br

Procedure:
20 g (77.8 mmol) of 2-amino-5-chloropyridine dissolved in 160 ml of CH2Cl2 are reacted with 8 ml of bromine, which is added dropwise at 0° C. After the addition is complete, the mixture is left to react at 25° C. for 2 h. The suspension is washed with 10% strength sodium hydroxide solution, and the organic phase is washed with water and then dried over MgSO4, filtered and evaporated. The compound obtained is recrystallized in isopropanol. M.p. 82° C.
Reaction SMILES: [O:1]([CH:8]([OH:10])[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[Br:16]Br.S([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C.O.O>[Br:16][C:5]1[CH:6]=[CH:7][C:2]([O:1][CH:8]([OH:10])[CH3:9])=[CH:3][CH:4]=1
Reactant: BrBr
Reactant: CC(O)Oc1ccccc1
Agent: CC(=O)[O-]
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(O)Oc1ccc(Br)cc1
Temperature: 15 °C
Reaction time: 0.5 h
Yield: 91.2 %

Procedure:
Phenoxyethanol (440 g, 3.1874 mol) was dissolved in 880 ml of a mixed solution of acetic acid/water =7/3. Sodium acetate (340 g, 4.1436 mol) was added and cooled to 15° C. A solution resulting from dissolving bromine (514.5 g, 3.22 mol) in 1760 ml of a mixed solution of acetic acid/water=7/3 was dropped while keeping at 15-20° C. and then was stirred at 10-20° C. for 30 minutes. Yellow color remained a little. Six milliliter of a 10 W/W% aqueous sodium sulfite solutions was dropped. The mixture became colorless. Dropping 2200 ml of water caused clouding. Crystallization was conducted by addition of seed crystals and stirring at room temperature for 30 minutes. After adding 4400 ml of water, stirring was done at room temperature for 30 minutes and at 0-10° C. for 1.5 hours. The crystals were filtered and washed with 3 L of water. After overnight air-drying and vacuum drying (35-40° C.) for 16 hours, 631 g (Yield 91.3%) of p-bromophenoxyethanol was obtained as white crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]3[C:15]([C:16]=2[CH2:17][CH2:18][C:19]([N:21]2[CH2:26][CH2:25][N:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[O:33][CH3:34])[CH2:23][CH2:22]2)=[O:20])=[CH:14][C:13]([CH3:35])=[CH:12][CH:11]=3)=[CH:4][CH:3]=1.[C:36]1(B(O)O)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH3:34][O:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[N:24]1[CH2:25][CH2:26][N:21]([C:19](=[O:20])[CH2:18][CH2:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH3:35])[CH:14]=3)[NH:9][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:3][CH:4]=2)[CH2:22][CH2:23]1
Reactant: OB(O)c1ccccc1
Reactant: COc1ccccc1N1CCN(C(=O)CCc2c(-c3ccc(Br)cc3)[nH]c3ccc(C)cc23)CC1
Product: COc1ccccc1N1CCN(C(=O)CCc2c(-c3ccc(-c4ccccc4)cc3)[nH]c3ccc(C)cc23)CC1

Procedure:
Prepared from 1-{3-[2-(4-bromophenyl)-5-methyl-1H-indol-3-yl]-1-oxopropyl}-4-(2-methoxyphenyl)piperazine (Example 1) and phenylboronic acid according to the method of Example 117. 1H NMR (360 MHz, CDCl3) δ8.05 (1H, br s), 7.71-7.61 (6H, m), 7.48-7.44 (3H, m), 7.39-7.35 (1H, m), 7.29-7.25 (1H, m), 7.06-6.98 (2H, m), 6.90-6.77 (3H, m), 3.82 (3H, s), 3.78 (2H, t, J 5.0 Hz), 3.46 (2H, t, J 5.0 Hz), 3.33 (2H, m), 2.92 (2H, t, J 5.0 Hz), 2.74 (4H, m), and 2.48 (3H, s). m/z (ES+) 530 (M+1).
Reaction SMILES: Br[N:2]1C(=O)CC[C:3]1=O.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([CH3:20])([CH3:19])[C:17]#[N:18])=[CH:12][C:11]=1[CH3:21]>C(Cl)(Cl)(Cl)Cl>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([CH3:19])([CH3:20])[C:17]#[N:18])=[CH:12][C:11]=1[CH2:21][C:3]#[N:2]
Reactant: Cc1cc(C(C)(C)C#N)ccc1Br
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C#N)c1ccc(Br)c(CC#N)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-bromosuccinimide (1.04 g) and 2,2′-azobis(isobutylnitrile) (30 mg) were added to the carbon tetrachloride solution (7 ml) of 2-(4-bromo-3-methylphenyl)-2-methylpropionitrile (1.26 g) and then the solution was refluxed with heating for an hour. The solution was cooled on ice, then after removing the insoluble substances by filtration, the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in ethanol (10 ml) and water (1 ml) and a solution of potassium cyanide (0.41 g) was added to the solution. The reaction mixture was stirring overnight at room temperature. To the reaction mixture was added the ice-cold water and ethyl acetate, and the organic layer was separated. The obtained organic layer was sequentially washed with water (twice) and brine. After drying over anhydrous magnesium sulfate, the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier; Wakogel™ C-200; elution solvent; heptane:ethyl acetate, 19:1→5:1) to obtain the title compound. (917 mg) The property values of the obtained compound are as follows; 1H-NMR (CDCl3) δ (ppm): 1.74 (s, 6H), 3.87 (s, 2H), 7.38 (dd, J=8.4, 2.4 Hz, 1H), 7.57 (d, J=2.4 Hz, 1H), 7.64 (d, J=8.4 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH3:13])[C:4]2[C:9]([C:10]=1C=O)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:14][N:15]1C2C(=CC=CC=2)C(C=O)=[CH:16]1>>[Cl:1][C:2]1([CH2:14][NH:15][CH3:16])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH3:13]
Reactant: Cn1c(Cl)c(C=O)c2ccccc21
Reactant: Cn1cc(C=O)c2ccccc21
Product: CNCC1(Cl)Cc2ccccc2N1C
Yield: 90 %

Procedure:
According to the procedure of Preparation 12, except substituting 2-chloro-1-methyl-1H-indole-3-carboxaldehyde (3.0 g, 15.5 mmole) for the 1-methylindole-3-carboxaldehyde, the title compound (2.91 g, 90%) was prepared as an oil: 1H NMR (400 MHz, CDCl3) δ 7.60 (d, J=7.9 Hz, 1 H), 7.22 (m, 2 H), 7.13 (m, 1 H), 3.92 (s, 2 H), 3.71 (s, 3 H), 2.44 (s, 3 H).
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][C@H:8]([NH:12][CH:13]([CH3:15])[CH3:14])[CH2:7][C:6]=2[C:5]([O:16][CH3:17])=[CH:4][CH:3]=1.[C:18]1(=O)[CH2:21][CH2:20][CH2:19]1.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH:18]1([N:12]([C@@H:8]2[CH2:7][C:6]3[C:5]([O:16][CH3:17])=[CH:4][CH:3]=[C:2]([F:1])[C:11]=3[O:10][CH2:9]2)[CH:13]([CH3:15])[CH3:14])[CH2:21][CH2:20][CH2:19]1
Reactant: O=C1CCC1
Reactant: COc1ccc(F)c2c1C[C@@H](NC(C)C)CO2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(F)c2c1C[C@@H](N(C(C)C)C1CCC1)CO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.6 %

Procedure:
(R)-8-Fluoro-3-(N-isopropylamino)-5-methoxy-3,4-dihydro-2H-1-benzopyran (1.96 g, 8.19 mmol) was dissolved in anhydrous methanol (20 mL) and to this was cyclobutanone (6.1 mL, 81.9 mmol) added. The reaction was cooled (ice-bath) then sodium cyanoborohydride (2.0 g, 16.4 mmol) was added, the pH was adjusted to 4-5 with acetic acid, 3 Å molecular sieves were added and the reaction was allowed to stir at room temperature overnight. After 24 h the pH-was again adjusted to 4-5 and the reaction was allowed to stir for 3 more days. The reaction was filtered, solvent was removed in vacuo, the remains were taken into a 2M solution of NH3 and then extracted thrice with diethyl ether. The combined ether portions were dried (MgSO4) filtered, and the solvent removed in vacuo to give the crude residue. Chromatography on silica (eluent: 10% ethyl acetate/hexane) gave 1.60 g (77% yield) of the title compound as a clear oil. [α]21D =-95.1° (C=0.1; CHCl3). GC-MS (70 eV) M=293 (3%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[O:16][CH:15]([CH2:18]OS(C4C=CC(C)=CC=4)(=O)=O)[CH2:14][C:13]=3[CH:12]=[C:11]([O:30][CH3:31])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:32][NH2:33]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[O:16][CH:15]([CH2:18][NH:33][CH3:32])[CH2:14][C:13]=3[CH:12]=[C:11]([O:30][CH3:31])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CN
Reactant: COc1cc2c(c(-c3ccc(F)c(Cl)c3)c1)OC(COS(=O)(=O)c1ccc(C)cc1)C2
Product: CNCC1Cc2cc(OC)cc(-c3ccc(F)c(Cl)c3)c2O1

Procedure:
The title compound was prepared (0.052 g, 46%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(3-chloro-4-fluorophenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}4-methylbenzenesulfonate (0.14 g, 0.31 mmol) and methylamine (0.097 g, 3.1 mmol). mp 197-199° C.
Reaction SMILES: [CH3:1][Mg]Br.[O:4]=[C:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.[NH4+].[Cl-]>C(OCC)C>[OH:4][C:5]1([CH3:1])[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 3M methyl magnesium bromide in diethyl ether (2.0 mL) in diethyl ether (3 mL) at 0° C. was treated with a solution of tert-butyl 4-oxo-1-piperidinecarboxylate (1.0 g, 5.00 mmol) in diethyl ether (5 mL), warmed to room temperature, stirred for 18 hours, treated with saturated NH4Cl, and extracted with diethyl ether. The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated. The concentratet was purified by flash chromatography on silica gel with 20%-50% ethyl acetate/heptane to provide the desired product. MS (DCI(+)) m/e 216 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:13][C:14]([N:16]2[CH:20]=[CH:19]N=C2)=[O:15])[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1.NCC[C:24]([N:26]([CH3:28])[CH3:27])=[O:25]>O1CCOCC1>[CH3:27][N:26]([CH3:28])[C:24](=[O:25])[CH2:19][CH2:20][NH:16][C:14]([NH:13][C:4]1[S:5][C:6]([C:7]2[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=2)=[C:2]([CH3:1])[N:3]=1)=[O:15]
Reactant: CN(C)C(=O)CCN
Reactant: Cc1nc(NC(=O)n2ccnc2)sc1-c1ccncc1
Solvent: C1COCCO1
Product: Cc1nc(NC(=O)NCCC(=O)N(C)C)sc1-c1ccncc1
Temperature: 25 °C

Procedure:
To a stirred suspension of imidazole-1-carboxylic acid (4-methyl-5-pyridin-4-yl-thiazol-2-yl)-amide (example 18a) (0.15 g, 0.526 mmol) in dioxane (10 ml) is added 3-amino-N,N-dimethyl-propionamide (0.046 g, 0.526 mmol) in one portion. The reaction mixture is heated to reflux for 2 hours. The reaction mixture is allowed to cool to room temperature and the solvent is removed in vacuo. Trituration with ether/ethyl acetate yields the titled compound as a pale yellow solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=1.[C:19]1([C@H:29]([N:31]([CH2:39][C@@H:40]2[C@@H:44]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH2:43][NH:42][CH2:41]2)[C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH3:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1>CC(C)=O>[C:34]([O:33][C:32]([N:31]([CH2:39][C@@H:40]1[C@@H:44]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH2:43][N:42]([CH2:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)[CH2:41]1)[C@@H:29]([C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1)[CH3:30])=[O:38])([CH3:35])([CH3:36])[CH3:37]
Reactant: C[C@H](c1cccc2ccccc12)N(C[C@H]1CNC[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(CN2C[C@H](CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)[C@@H](c3ccccc3)C2)cc1
Temperature: 25 °C

Procedure:
Potassium carbonate and methyl 4-(bromomethyl)benzoate were added in that order to an acetone solution of tert-butyl [(1R)-1-(1-naphthyl)ethyl]{[(3R,4S)-4-phenylpyrrolidin-3-yl]methyl}carbamate and stirred at room temperature for 20Hours. Thereafter, work-up and purification were carried out in the standard method to obtain methyl 4-{[(3R,4S)-3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin 1-yl]methyl}benzoate. FP: 579.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:24](O)=[O:25])=[C:4]([C:18]([Cl:23])=[C:19]([Cl:22])[C:20]=1[Cl:21])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:9][CH:8]=1)=[O:6].[CH2:27]([N:29]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]3[CH:41]=[CH:40][CH:39]=[CH:38][C:36]3=2)[CH:31]=[C:30]1[CH3:42])[CH3:28].N>C(OC(=O)C)(=O)C>[CH2:14]([N:13]([CH2:16][CH3:17])[C:10]1[CH:9]=[CH:8][C:7]([C:5]2([C:31]3[C:32]4[C:37](=[C:36]5[CH:38]=[CH:39][CH:40]=[CH:41][C:35]5=[CH:34][CH:33]=4)[N:29]([CH2:27][CH3:28])[C:30]=3[CH3:42])[C:4]3[C:3](=[C:2]([Cl:1])[C:20]([Cl:21])=[C:19]([Cl:22])[C:18]=3[Cl:23])[C:24](=[O:25])[O:6]2)=[CH:12][CH:11]=1)[CH3:15]
Reactant: CCn1c(C)cc2ccc3ccccc3c21
Reactant: CCN(CC)c1ccc(C(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)O)cc1
Agent: N
Solvent: CC(=O)OC(C)=O
Product: CCN(CC)c1ccc(C2(c3c(C)n(CC)c4c3ccc3ccccc34)OC(=O)c3c(Cl)c(Cl)c(Cl)c(Cl)c32)cc1
Yield: 100.2 %

Procedure:
A solution of about 6.5 grams of 3,4,5,6-tetrachloro-2-carboxy-4'-diethylaminobenzophenone and about 3.1 grams of 1-ethyl-2-methyl-1H-benz[g]indole in 50 milliliters of acetic anhydride is refluxed for about one hour and then cooled. That reaction mixture is poured over ice and ammonia, extracted twice with a 1:1 toluene-chloroform mixture and dried using sodium sulfate. The solution is concentrated by evaporation of the solvent and the title compound is crystallized by washing with petroleum ether. 9.3 grams of the title compound is obtained having a melting point of 232°-235° C. A solution of product imparts a blue color to paper coated with a phenolic resin or silton clay or a combination of the two. The calculated analysis for C33H28N2O2Cl4, the title compound, is C, 63.28%; H, 4.51%; N, 4.57%; and Cl, 22.64%. Found, on analysis: C, 63.37%; H, 4.42%; N, 4.54%; an Cl, 22.49%.