Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][Si](C)(C)C)=[CH:4][C:3]=1[CH2:14][CH2:15][CH2:16][C:17]#[N:18].CO.C(=O)([O-])[O-].[Cs+].[Cs+]>C(Cl)Cl.C(OCC)C>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH2:14][CH2:15][CH2:16][C:17]#[N:18])[CH:4]=1)#[CH:9]
Reactant: C[Si](C)(C)C#Cc1ccc(F)c(CCCC#N)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CO
Solvent: ClCCl
Product: C#Cc1ccc(F)c(CCCC#N)c1
Reaction time: 2 h

Procedure:
To a stirred solution of 4-(2-Fluoro-5-trimethylsilanylethynyl-phenyl)-butyronitrile (0.27 g, 1.04 mmol), in dry methylene chloride (2.5 mL) and methanol (2.5 mL) was added cesium carbonate (0.41 g, 1.2 mmol) and stirred for 2 h under a nitrogen atmosphere. The mixture was diluted with diethyl ether (15 mL), and partitioned between diethyl ether and H2O (10 mL), and the aqueous layer was extracted with diethyl ether (10 mL), washed with brine and dried over MgSO4, filtered and concentrated in vacuo. Purification by flash chromatography (5-10% ethyl acetate/petroleum ether) gave the title compound as a brown semi solid (0.154 g, 79%), identified by NMR and mass spectral analyses. MS (EI+): 187 (M+).
Reaction SMILES: Br[C:2]([CH3:9])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:10]([O-:13])(=[S:12])[CH3:11].[K+]>CN(C)C=O>[CH2:6]([O:5][C:3](=[O:4])[C:2]([S:12][C:10](=[O:13])[CH3:11])([CH3:9])[CH3:8])[CH3:7]
Reactant: CC([O-])=S
Reactant: CCOC(=O)C(C)(C)Br
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)SC(C)=O
Reaction time: 16 h

Procedure:
To a solution of ethyl α-bromoisobutyrate (62 g, 0.32 mol) in N,N-dimethylformamide (500 mL) at room temperature is added potassium thioacetate (72 g, 0.63 mol). The reaction is stirred for 16 h and then concentrated under reduced pressure. The residue is diluted with a 2M aqueous hydrochloric acid solution (500 mL) and extracted with ethyl acetate (3×500 mL). The organic fractions are combined, washed with brine (300 mL), dried (MgSO4), filtered and concentrated under reduced pressure. Purification by chromatography on silica eluting with heptanes/dichloromethane provides the title compound, m/z 191 [M+H+].
Reaction SMILES: [CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6]([C:15]4[CH:20]=[CH:19][C:18]5[O:21][CH2:22]C[O:24][C:17]=5[CH:16]=4)=[N:7][C:8](=[O:14])[NH:9]3)=[CH:4][C:3]=2[O:2]1.CC([O-])(C)C.[K+].Cl.[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35]Cl.[OH-].[Na+]>CN(C=O)C.C1C=CC=CC=1>[CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6]([C:15]4[CH:20]=[CH:19][C:18]5[O:21][CH2:22][O:24][C:17]=5[CH:16]=4)=[N:7][C:8]([O:14][CH2:35][CH2:34][N:33]([CH3:37])[CH3:32])=[N:9]3)=[CH:4][C:3]=2[O:2]1
Reactant: O=c1nc(-c2ccc3c(c2)OCCO3)c2cc3c(cc2[nH]1)OCO3
Reactant: CN(C)CCCl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CN(C)CCOc1nc(-c2ccc3c(c2)OCO3)c2cc3c(cc2n1)OCO3
Temperature: 110 °C
Reaction time: 0.75 h

Procedure:
To a suspension of 6,7-methylenedioxy-4-(3,4-ethylenedioxyphenyl)quinazolin-2-one (400 mg, 1.29 mmol) in DMF (15 mL) was added KOtBu (95%, 232 mg, 2.06 mmol) at room temp. and stirred for 45 minutes. Separately, a solution of 2-dimethylaminoethyl chloride hydrochloride (371 mg, 2.58 mmol) in benzene (12 mL) was treated with a solution of 2 N NaOH 10 mL). The benzene layer, which contained the free base, was dried over anhydrous MgSO4, and added to the above reaction mixture at room temp. The resulting mixture was then heated at 110° C. under argon gas for 15 h. The reaction mixture was then poured into ice-water (50 mL). It was stirred for 30 minutes. The resulting precipitate was collected by filtration. It was dissolved in ethyl acetate. The organic layer was washed with water and brine. After being dried over anhydrous MgSO4 the solvent was removed in vacuo. This crude product was then dissolved in a small amount of CHCl3 and poured on a column of silica gel. Elution with acetone:CH2Cl2:MeOH (90:5:5) gave 6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)-2-(2-(dimethylamino) ethoxy)-quinazoline as a first fraction as yellow solid (110 mg); C21H21N3O5; mp120-123° C. 1H NMR (CDCl3) δ 7.33 (s, 1H), 7.20-7.27 (m, 2H), 7.14 (s, 1H), 6.95 (d, J=7.80 Hz, 1H), 6.08 (s, 2H), 4.59 (m, 2H), 4.32 (s, 4H), 2.83 (m, 2H), 2.38 (s, 6H). Further elution with the same solvent mixture gave 1-(2-(dimethylamino)ethyl)-6,7-methylenedioxy-4-(3,4-ethylenedioxyphenyl)quinazolin-2(1H)-one as pale yellow solid (90 mg); C21H21N3O5; mp 220-225° C. 1H NMR (CDCl3) δ 7.24 (s, 1H), 7.23 (s, 1H), 7.16-7.19 (m, 2H), 6.95 (d, J=8.4 Hz, 1H), 6.09 (s, 2H), 4.40 (m, 2H), 4.31 (s, 4H), 2.76 (m, 2), 2.43 (s, 6H).
Reaction SMILES: C[O:2][C:3](=[O:34])[C:4]1[C:5](=[CH:10][C:11]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:12]([NH:14][C:15]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=2)[CH:13]=1)[C:6]([O:8]C)=[O:7].O.[OH-].[Li+].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+].Cl>CO.O>[NH:27]([C:11]1[CH:10]=[C:5]([C:6]([OH:8])=[O:7])[C:4](=[CH:13][C:12]=1[NH:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=1)[C:3]([OH:34])=[O:2])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COC(=O)c1cc(Nc2ccccc2)c(Nc2cc(OC)c(OC)c(OC)c2)cc1C(=O)OC
Agent: Cl
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Li+]
Solvent: O
Solvent: CO
Product: COc1cc(Nc2cc(C(=O)O)c(C(=O)O)cc2Nc2ccccc2)cc(OC)c1OC
Temperature: 25 °C

Procedure:
A steady stream of argon is passed through a suspension of 245 mg (0.5 mmol) of 4-anilino-5-(3,4,5-trimethoxy-anilino)phthalic acid dimethylester in 1.6 ml of methanol, and a solution of 94.4 mg (2.25 mmol, 4.5 eq) of lithium hydroxide monohydrate and 10 mg sodium ascorbate in 0.8 ml of water is added. The reaction mixture is heated to reflux for 17 hours and then cooled to RT. The resulting mixture is treated dropwise with 0.5 ml of 4N hydrochloric acid, the green suspension is filtered, and the crystals are washed with water to yield the title compound in the form of green crystals, m.p. 145°-6° C., FAB-MS: 439 [M+ +H].
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Cl.[OH:22][CH2:23][C@H:24]1[C@H:28]([C:29]([F:32])([F:31])[F:30])[CH2:27][NH:26][CH2:25]1.C(N(CC)CC)C>CS(C)=O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:26]4[CH2:27][C@@H:28]([C:29]([F:31])([F:32])[F:30])[C@H:24]([CH2:23][OH:22])[CH2:25]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: OC[C@@H]1CNC[C@H]1C(F)(F)F
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3C[C@@H](CO)[C@H](C(F)(F)F)C3)c(F)cc2c1=O
Temperature: 50 °C
Reaction time: 18 h
Yield: 95.4 %

Procedure:
In 6 ml of dimethylsulfoxide, is dissolved 283 mg (1 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. To the above solution, are added 411 mg (2 mmol) of trans-3-hydroxymethyl-4-trifluoromethylpyrrolidine hydrochloride and 0.42 ml (3 mmol) of triethylamine. The mixture is stirred at 50° C. for 18 hours. The reaction mixture was concentrated under reduced pressure. Water was added to the residue. The resulting precipitate was obtained by filtration and washed successively with water, isopropanol and diethyl ether to give 412 mg of the objective substance as a slightly yellow powder (yield 95.4%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9]2[CH:17]=[CH:16][C:12]3[S:13][CH:14]=[CH:15][C:11]=3[CH:10]=2)[N:5]=[C:4]([C:18]([O:20]C)=[O:19])[C:3]=1[Cl:22].O1CCCC1.O.O.[OH-].[Li+]>CO>[NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9]2[CH:17]=[CH:16][C:12]3[S:13][CH:14]=[CH:15][C:11]=3[CH:10]=2)[N:5]=[C:4]([C:18]([OH:20])=[O:19])[C:3]=1[Cl:22]
Reactant: COC(=O)c1nc(-c2ccc3sccc3c2)c(Cl)c(N)c1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Nc1c(Cl)c(C(=O)O)nc(-c2ccc3sccc3c2)c1Cl
Temperature: 25 °C

Procedure:
In a 100 mL round bottom flask, methyl 4-amino-6-(benzo[b]thiophen-5-yl)-3,5-dichloropicolinate (210 mg, 0.595 mmol) was dissolved in methanol (2.3 mL), tetrahydrofuran (2.3 mL), and H2O (1.2 mL). Lithium hydroxide hydrate (74.8 mg, 1.784 mmol) was added as a solid. The reaction was stirred at room temperature until complete. The reaction mixture was concentrated to dryness. The resulting residue was dissolved in H2O (2.0 mL) and 1 N HCl was used to adjust the pH to 3.0, causing a precipitate to form. This suspension was extracted with ethyl acetate (3×15 mL). The organic extracts were combined, washed with Saturated NaCl solution, dried (MgSO4), filtered and concentrated. Additional purification of the resulting solid was performed, as needed, using a Teledyne ISCO reverse phase system with a gradient eluent system of acetonitrile and H2O to yield the title compound as a white solid (110 mg, 55.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.Cl[CH2:12][CH2:13][N:14]([CH2:25][CH2:26]Cl)[S:15]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)(=[O:17])=[O:16].[NH2-].[Na+]>C1C=CC=CC=1>[C:21]1([CH3:24])[CH:20]=[CH:19][C:18]([S:15]([N:14]2[CH2:25][CH2:26][C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)([C:9]#[N:10])[CH2:12][CH2:13]2)(=[O:17])=[O:16])=[CH:23][CH:22]=1
Reactant: N#CCc1ccc(Cl)cc1
Reactant: Cc1ccc(S(=O)(=O)N(CCCl)CCCl)cc1
Agent: [NH2-]
Agent: [Na+]
Solvent: c1ccccc1
Product: Cc1ccc(S(=O)(=O)N2CCC(C#N)(c3ccc(Cl)cc3)CC2)cc1
Reaction time: 1 h

Procedure:
To a solution of 60.3 parts of 4-chlorophenylacetonitrile and 118 parts of N,N-bis(2-chloroethyl)-4-toluenesulfonamide in 720 parts of dried benzene under N2 there is added portionwise with stirring at 10°-13° C 32.6 parts of sodamide. The cooling bath is then removed and the mixture is stirred for one hour during which time the temperature rises to 70° C and then falls back to 43° C. Ice cold water is added to the mixture and a fine solid forms. This is separated by filtration and washed successively with water and benzene and dried and then triturated in boiling methanol. The undissolved solid is separated by filtration, washed with water and dried to give 1-(4-toluenesulfonyl)-4-(4-chlorophenyl)-4-piperidinecarbonitrile melting at about 202°-206° C.
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])[C:7]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[CH:6][C:3]=1[C:4]#[N:5].[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>C1(C)C=CC=CC=1>[Cl:17][C:11]1[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=1[C:8]1[C:7]([C:18]2[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=2)=[CH:6][C:3]([C:4]#[N:5])=[C:2]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[N:9]=1
Reactant: C1CCNCC1
Reactant: Cc1ccc(-c2cc(C#N)c(Cl)nc2-c2ccc(Cl)cc2Cl)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2cc(C#N)c(N3CCCCC3)nc2-c2ccc(Cl)cc2Cl)cc1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
To an oven-dried round bottom flask fitted with a rubber septa was added toluene (1 mL), the product of Step D of Example 114 (0.050 g; 0.134 mmol) and piperidine (0.070 mL; 0.670 mmol). The sealed reaction mixture was heated at 100° C. and stirred for 16 hours. The reaction mixture was allowed to cool to room temperature, then it was partitioned between ethyl acetate and saturated NaHCO3 solution. The organic portion was separated and washed with more saturated NaHCO3 solution (2×), brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification was done by MPLC (silica gel; 0-10% ethyl acetate:hexane) to afford the desired product: m/e=422 (M+1) Rt=5.10 min on LCMS.
Reaction SMILES: [CH2:1]([Mg]Br)[CH:2]([CH3:4])[CH3:3].[Si:7]([O:14][CH2:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[C:18]([O:24][CH3:25])[CH:17]=1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].CCCCCC.C(OCC)(=O)C>O1CCCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Si:7]([O:14][CH2:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]([OH:21])[CH2:1][CH:2]([CH3:4])[CH3:3])=[C:18]([O:24][CH3:25])[CH:17]=1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:8])[CH3:9]
Reactant: CC(C)C[Mg]Br
Reactant: COc1cc(CO[Si](C)(C)C(C)(C)C)ccc1C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cc(CO[Si](C)(C)C(C)(C)C)ccc1C(O)CC(C)C
Yield: 57 %

Procedure:
55 ml (55 mmol) of a 1.0 M solution of isobutyl magnesium bromide in tetrahydrofuran were added to a solution of 23.6 g (73.1 mmol) of tetrabutyl ammonium bromide in 50 ml of tetrahydrofuran, and the resulting mixture was immediately cooled in a dry ice-acetone bath, after which a solution of 10.25 g (36.5 mmol) of 4-t-butyldimethylsilyloxymethyl-2-methoxybenzaldehyde (prepared as described in Preparation 40) in 60 ml of tetrahydrofuran were added dropwise over 30 minutes. After the dropwise addition, the reaction temperature was gradually allowed to return to room temperature, and then the reaction was terminated by adding a saturated aqueous solution of ammonium chloride. The reaction mixture was then extracted with diethyl ether, and the extract was washed with water and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through 250 g of silica gel using a gradient elution method, with mixtures of hexane and ethyl acetate ranging from 3:1 to 2:1 by volume as the eluent, to give 6.81 g (yield 57%) of the title compound as an oily substance.
Reaction SMILES: [NH2:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([S:10](=[O:13])(=[O:12])[NH2:11])=[CH:5][C:3]=1[NH2:4].[C:14](O)(=O)[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>Cl>[Cl:9][C:7]1[C:6]([S:10](=[O:12])(=[O:13])[NH2:11])=[CH:5][C:3]2[NH:4][C:14]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:1][C:2]=2[CH:8]=1
Reactant: O=C(O)CCc1ccccc1
Reactant: Nc1cc(Cl)c(S(N)(=O)=O)cc1N
Agent: Cl
Product: NS(=O)(=O)c1cc2[nH]c(CCc3ccccc3)nc2cc1Cl
Reaction time: 0.08 h

Procedure:
To 40 ml of 4 N hydrochloric acid containing 9.4 g of 2-amino-4-chloro-5-sulfamylaniline was added 9.5 g of hydrocinnamic acid and the mixture refluxed for 6 hours. The dark reaction mixture was concentrated in vacuo to a semi-solid which was then added with stirring to 200 ml of 38% ammonium hydroxide. After stirring for thirty minutes, the solid was collected by filtration and then suspended in 200 ml of water at 50° C. Upon stirring for thirty minutes, the product was collected by filtration, dissolved in methanol, and the solution treated with charcoal and boiled for five minutes. The suspension was cooled, filtered through Celite, and concentrated in vacuo to yield pink crystals. Recrystallization from acetonitrile provided 2.6 g of off-white crystals, mp 226°-228°.
Reaction SMILES: [OH:1][CH:2]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][CH2:10][C:11]1[C:12]([C:16]([O:18]CC)=[O:17])=[N:13][NH:14][CH:15]=1.[Li+].[OH-].C(OCC)(=O)C>C1COCC1.O>[OH:1][CH:2]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][CH2:10][C:11]1[C:12]([C:16]([OH:18])=[O:17])=[N:13][NH:14][CH:15]=1
Reactant: CCOC(=O)c1n[nH]cc1CNc1ccccc1C(O)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)c1n[nH]cc1CNc1ccccc1C(O)c1ccccc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 113.9 %

Procedure:
To a solution of product (1-A) (1.34 g, 3.8 mmol) in THF (30 mL) was added drop-wise a solution of LiOH (0.24 g, 10 mmol) in H2O (30 mL) at 0° C. The reaction mixture was stirred at 50° C. for about 2 h. After cooling, ethyl acetate (20 mL) and H2O (20 mL) were added to the solution. The aqueous layer was separated and acidified with citric acid (to pH=5) and extracted with ethyl acetate (50 mL×3). The combined organic phases were dried over Na2SO4 and concentrated to give crude product (2-A) (1.4 g, 100%) as a light yellow solid. LC-MS (M+H)+=324.
Reaction SMILES: O.[NH2:2][NH2:3].[CH:4](=[C:11]([CH2:14][CH3:15])[CH:12]=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O>CCOCC>[CH2:14]([CH:11]1[CH:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[NH:3][N:2]=[CH:12]1)[CH3:15]
Reactant: CCC(C=O)=Cc1ccccc1
Reactant: NN
Solvent: CCOCC
Solvent: O
Product: CCC1C=NNC1c1ccccc1
Temperature: -10 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
62 ml (10 equiv.) hydrazine hydrate was added to 150 mL diethylether. The emulsion was cooled with an ice/NaCl bath to −10° C. A solution of 20.4 g 2-benzylidene-butyraldehyde in 100 mL ether was added dropwise at −10° C. and stirred at −10° C. for 3 hours. The mixture was stirred overnight (with ice bath) and allowed to slowly reach room temperature. H2O was added, the organic layer was separated and the aqueous layer was extracted 2 times with diethylether. The combined organic layers were dried over Na2SO4, filtrated and concentrated in vacuo. Vacuum destillation yielded 6.1 g of a clear fluid (102-106° C., 0.6 mbar) containing 94% of the desired product (mixture of diastereomeric pairs). Characteristic signals of the first diastereomeric pair: 1H NMR (400 MHz, CDCl3) δ 0.83 (t, J=6.5 Hz, 3H), 3.03-3.13 (m, 1H), 4.74-4.81 (m, 1H), 6.83 (br s, 1H). Characteristic signals of the second diastereomeric pair: 1H NMR (400 MHz, CDCl3) δ 1.00 (t, J=7.5 Hz, 3H), 2.84-2.93 (m, 1H), 4.28-4.34 (m, 1H), 6.76 (br s, 1H).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:16][C:11]=3[N:10]=[C:9]2[C:21]([F:24])([F:23])[F:22])=[N:6][CH:7]=1.[F:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:27]=1[C:28]([NH2:30])=[O:29].[O-]P([O-])([O-])=O.[K+].[K+].[K+].O.C(N)CN>O1CCOCC1.O.[Cu]I>[F:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:27]=1[C:28]([NH:30][C:2]1[N:3]=[CH:4][C:5]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:16][C:11]=3[N:10]=[C:9]2[C:21]([F:22])([F:24])[F:23])=[N:6][CH:7]=1)=[O:29]
Reactant: NC(=O)c1c(F)cccc1F
Reactant: COC(=O)c1ccc2c(c1)nc(C(F)(F)F)n2-c1cnc(Br)cn1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: NCCN
Solvent: O
Product: COC(=O)c1ccc2c(c1)nc(C(F)(F)F)n2-c1cnc(NC(=O)c2c(F)cccc2F)cn1
Reaction time: 0.75 h
Yield: 4.2 %

Procedure:
Into a 50 mL 3-necked roundbottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of methyl 1-(5-bromopyrazin-2-yl)-2-(trifluoromethyl)-1H-benzo[d]imidazole-5-carboxylate (xii) (200 mg, 0.50 mmol) in 1,4-dioxane (10 mL). To this was added 2,6-difluorobenzamide (235.5 mg, 1.50 mmol), followed by addition of K3PO4.H2O (500 mg, 1.48 mmol). CuI (11.7 mg, 0.06 mmol) was then added to the mixture, followed by ethane-1,2-diamine (EDA) (3.2 mg, 0.05 mmol). The resulting solution was allowed to stir for 45 minutes under reflux then diluted with 50 mL of H2O and extracted three times with 300 mL of EtOAc. The organic layers were combined then dried over Na2SO4 and concentrated by evaporation under vacuum using a rotary evaporator. The residue was purified by eluting through a silica gel column with a 1:10 EtOAc/PE solvent system to provide the final product methyl 1-(5-(2,6-difluorobenzamido)pyrazin-2-yl)-2-(trifluoromethyl)-1H-benzo[d]imidazole-5-carboxylate (10 mg, 4% yield) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]([CH3:15])[CH3:14])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.Br[C:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[S:21][CH:20]=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(P(C(C)(C)C)[C]1[CH][CH][CH][CH]1)(C)C.C1C=CC([C]2[C](C3C=CC=CC=3)[C](C3C=CC=CC=3)[C](C3C=CC=CC=3)[C]2C2C=CC=CC=2)=CC=1.[Fe]>[S:21]1[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:19]([NH:1][C:2]2[CH:17]=[CH:16][C:5]([C:6]([N:8]3[CH2:12][CH2:11][CH:10]([N:13]([CH3:14])[CH3:15])[CH2:9]3)=[O:7])=[CH:4][CH:3]=2)=[CH:20]1
Reactant: Brc1csc2ccccc12
Reactant: CN(C)C1CCN(C(=O)c2ccc(N)cc2)C1
Agent: [Fe]
Agent: [Pd]
Agent: CC(C)(C)P([C]1[CH][CH][CH][CH]1)C(C)(C)C
Product: CN(C)C1CCN(C(=O)c2ccc(Nc3csc4ccccc34)cc2)C1
Temperature: 80 °C
Yield: 14.3 %

Procedure:
A mixture of 1-(4-aminobenzoyl)-3-dimethylamino-pyrrolidine (50 mg, 0.21 mmol), 3-bromobenzothiophene (50 mg, 0.23 mmol), sodium tert-butoxide (44 mg, 34 mmol), tris(dibenzylideneacetone)dipalladium(0) (3 mg, 0.002 mmol), CTC-Q-Phos (6 mg, 0.004 mmol) is heated to 80° C. for 16 h and concentrated in vacuo. The resultant residue is dissolved in a mixture of DMSO, methanol and water and purified by reverse-phase semi-preparative HPLC1 to give the title compound as a white powder (11 mg), identified by HPLC and mass spectral analyses. Retention Time, 2.62 min.; MS [366.2 m/e (M+H)]. 1Semi-preparative HPLC Conditions: A=0.02% TFA in water, B=0.02% TFA in acetonitrile, 10-95% B in 8 min., 34 mL/min, 50° C., 215 nm detection, Waters Xterra™ 20×50 mm column.
Reaction SMILES: [CH:1]([C:3]1[CH:26]=[CH:25][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:24])[C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)=[CH:10][N:9]=2)=[CH:5][CH:4]=1)=O.Cl.[CH2:28]([O:30][C:31](=[O:34])[CH2:32][NH2:33])[CH3:29].C([O-])(=O)C.[Na+].C([BH3-])#N.[Na+].Cl>CO>[CH2:28]([O:30][C:31](=[O:34])[CH2:32][NH:33][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:24])[C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)=[CH:10][N:9]=2)=[CH:25][CH:26]=1)[CH3:29]
Reactant: O=Cc1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cn2)cc1
Reactant: CCOC(=O)CN
Agent: CC(=O)[O-]
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Product: CCOC(=O)CNCc1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cn2)cc1
Reaction time: 1 h

Procedure:
A solution of N-[2-(4-formylphenoxy)-5-pyridyl]-3,4-dichlorobenzamide (1.00 g, 2.58 mmol), glycine ethyl ester hydrochloride (0.400 g, 2.84 mmol) and sodium acetate (0.230 g, 2.84 mmol) in methanol (20 mL) was stirred for 30 minutes at 60° C. The reaction solution was cooled with ice, and then sodium cyanoborohydride (0.180 g, 2.84 mmol) was added. The resulting solution was stirred at the same temperature for 1 hour. To the reaction solution was added 5 M hydrochloric acid (2 mL) and concentrated under reduced pressure. To the residue was added a saturated sodium bicarbonate solution, and extracted with dichloromethane. The dichloromethane layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:2), to thereby yield 0.752 g of the title compound.
Reaction SMILES: [Cl-].[CH2:2]([O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][NH2+:8]1)=[O:6])[CH3:3].Cl[C:14]1[O:15][C:16]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:17]=2[N:18]=1>>[F:23][C:20]1[CH:21]=[CH:22][C:16]2[O:15][C:14]([N:8]3[CH2:9][CH2:10][CH2:11][CH2:12][C@H:7]3[C:5]([O:4][CH2:2][CH3:3])=[O:6])=[N:18][C:17]=2[CH:19]=1
Reactant: CCOC(=O)[C@@H]1CCCC[NH2+]1
Reactant: Fc1ccc2oc(Cl)nc2c1
Agent: [Cl-]
Product: CCOC(=O)[C@@H]1CCCCN1c1nc2cc(F)ccc2o1

Procedure:
The title compound was prepared by a similar method to Preparation 2 from (2S)-2-(ethoxycarbonyl)piperidinium chloride [see J. Am. Chem. Soc. (1993), 115, 9925-9938] and 2-chloro-5-fluoro-1,3-benzoxazole [see J. Med. Chem. (1988), 31, 1719-1728]. The crude product was purified by column chromatography on silica gel eluting with a solvent system of 3:1, by volume, hexane:ethyl acetate, to afford ethyl(2S)-1-(5-fluoro-1,3-benzoxazol-2-yl)-2-piperidinecarboxylate as an oil.