Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[NH:8][N:7]=1)=[O:5])[CH3:2].[OH-].[K+].[CH3:21]I>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:21])[N:8]=[C:9]([C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2].[CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[C:9]([C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[N:8]([CH3:21])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1n[nH]c(-c2ccc(Cl)cc2)c1C
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)c1c(C)c(-c2ccc(Cl)cc2)nn1C
Product: CCOC(=O)c1nn(C)c(-c2ccc(Cl)cc2)c1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 47 %
Yield: 36 %

Procedure:
5-(4-Chloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (58 mg, 0.22 mmol; PCT Int. Appl. (1997), WO 9721682 A1) was added to a solution of KOH (15 mg, 0.27 mmol) in absolute ethanol (1.6 ml). The solution was stirred at ambient temperature for 15 min. Methyl iodide (30 μl, 0.44 mmol) was added and the reaction solution was heated under reflux for 2 h. The solvent was removed under reduced pressure and the residue dissolved in brine/ice water 1/1 and ethyl acetate. The layers were separated and the aqueous layer was extracted two times with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography (silica gel, heptane/AcOEt) to give 29 mg (0.1 mmol, 47%) 5-(4-chloro-phenyl)-2,4-dimethyl-2H-pyrazole-3-carboxylic acid ethyl ester as colorless crystals and 22 mg (0.08 mmol, 36%) 5-(4-chloro-phenyl)-1,4-dimethyl-1H-pyrazole-3-carboxylic acid ethyl ester as colorless crystals.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([Li])CCC.[B:21](OC(C)C)([O:26]C(C)C)[O:22]C(C)C.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([B:21]([OH:26])[OH:22])=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)Oc1ccc(B(O)O)cc1
Temperature: -60 °C
Reaction time: 1 h

Procedure:
To a solution of 4-tert-butyldimethylsilyloxybromobenzene (11.49 g) in tetrahydrofuran (100 ml) was added a solution of n-butyllithium in n-hexane (1.59M, 32.7 ml) dropwise at −55° C. under a nitrogen atmosphere, and the mixture was stirred for 1 hour at −60° C. To the reaction mixture was added triisopropyl borate (12.84 ml), and the mixture was stirred at −60° C. for 1 hour. The reaction mixture was warmed to ambient temperature, poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The solid was triturated with n-hexane, filtered and washed with n-hexane to give 4-tert-butyldimethylsilyloxyphenylboronic acid (7.45 g).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[C:19]([O:20][CH3:21])=[CH:18][C:17]([O:22][CH3:23])=[C:16]([F:24])[C:15]=1[CH2:25][CH2:26][C:27]1[N:28]=[C:29]2[CH:35]=[CH:34][N:33]([S:36]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)(=[O:38])=[O:37])[C:30]2=[N:31][CH:32]=1.[Br:45]C(Cl)(Cl)C(Br)(Cl)Cl>O1CCCC1>[Br:45][C:34]1[N:33]([S:36]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)(=[O:38])=[O:37])[C:30]2=[N:31][CH:32]=[C:27]([CH2:26][CH2:25][C:15]3[C:16]([F:24])=[C:17]([O:22][CH3:23])[CH:18]=[C:19]([O:20][CH3:21])[C:14]=3[F:13])[N:28]=[C:29]2[CH:35]=1
Reactant: COc1cc(OC)c(F)c(CCc2cnc3c(ccn3S(=O)(=O)c3ccccc3)n2)c1F
Reactant: ClC(Cl)(Br)C(Cl)(Cl)Br
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1cc(OC)c(F)c(CCc2cnc3c(cc(Br)n3S(=O)(=O)c3ccccc3)n2)c1F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 70456.4 %

Procedure:
To a stirred solution of N,N-diisopropylamine (0.150 mL, 1.07 mmol) in tetrahydrofuran (0.48 mL) at 78° C., n-butyllithium (2.5 M in hexanes, 0.428 mL, 1.07 mmol) was added dropwise. After a white precipitate formed, the mixture was warmed up to 0° C. for 10 minutes. The resulting solution was added to a stirred solution of 2-[2-(2,6-difluoro-3,5-dimethoxyphenyl)ethyl]-5-(phenylsulfonyl)-5H-pyrrolo[2,3-b]pyrazine (400 mg, 0.871 mmol) in tetrahydrofuran (3 mL) at 78° C. After 10 minutes, a solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (0.283 g, 0.870 mmol) in tetrahydrofuran (2 mL) was added dropwise. After another 1 hour, the reaction mixture was quenched with saturated aq. NH4Cl, then extracted with methylene chloride. The combined organic layers were dried over MgSO4, then concentrated. The residue was purified on silica gel (eluting with 0 to 50% EtOAc in hexanes) to give the desired product (330 g, 70%). LCMS calculated for C22H19BrF2N3O4S (M+H)+: m/z=538.0. Found: 538.0.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH:7]([NH2:16])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([I:15])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:27][C:28]1[CH:36]=[C:35]([CH3:37])[CH:34]=[C:33]([CH3:38])[C:29]=1[C:30](Cl)=[O:31].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:17])[CH:7]([NH:16][C:30](=[O:31])[C:29]1[C:33]([CH3:38])=[CH:34][C:35]([CH3:37])=[CH:36][C:28]=1[CH3:27])[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([I:15])=[CH:13][CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C(N)Cc1ccc(I)cc1
Reactant: Cc1cc(C)c(C(=O)Cl)c(C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)c(C(=O)NC(Cc2ccc(I)cc2)C(=O)OC(C)(C)C)c(C)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 85.9 %

Procedure:
1.5 g (4.32 mmol) of (1) and 2.9 ml (17.3 mmol) of DIPEA were dissolved in 15 ml of DCM and cooled to 0° C. 1.73 g (9.51 mmol) of 2,4,6-trimethylbenzoyl chloride were added and the solution was stirred at room temperature for 3 h. The solution was poured into saturated NaHCO3 and the aqueous layer was extracted with ethyl acetate. The organic layer was extracted with saturated NaHCO3, brine and dried over Na2SO4. The solvent was removed at the evaporator. The product was purified by column chromatography on silica gel using ethyl acetate/hexane to give 1.83 g of (2).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=O)[CH2:7][CH2:8][C:2]1=2.[N:10]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=[C:11]=S.C[Si](C)(C)[Si](C)(C)C.[Li].O.[NH2:31][NH2:32]>C1COCC1.O.C(O)(=O)C>[S:1]1[CH:5]=[CH:4][C:3]2[C:6]3[NH:31][N:32]=[C:11]([NH:10][C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=4)[C:7]=3[CH2:8][C:2]1=2
Reactant: COc1ccc(N=C=S)cc1
Reactant: NN
Reactant: O=C1CCc2sccc21
Agent: C[Si](C)(C)[Si](C)(C)C
Agent: [Li]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc(Nc2n[nH]c3c2Cc2sccc2-3)cc1
Reaction time: 8 h
Yield: 34 %

Procedure:
A mixture of 5,6-Dihydro-cyclopenta[b]thiophen-4-one (1.0 g, 7.4 mmol) and 1-Isothiocyanato-4-methoxy-benzene (1.5 g, 7.2 mmol) in THF (2.0 mL) was added to lithium hexamethyl disilane (7.0 mL, 7.2 mmol) dropwise at room temperature. The reaction mixture was stirred for 8 hr. Hydrazine monohydrate (0.4 mL, 7.9 mmol) and glacial acetic acid (0.5 mL) were added to the reaction mixture, which was then heated at the reflux temperature for 24 hr. The resulting mixture was added to water (30 mL) and then extracted with ethyl acetate. The target product was purified by gravity column chromatography (50% EtOAc in hexane) to give (4,7-Dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-(4-methoxy-phenyl)-amine as brown solid in 34% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([C:11]3[CH:12]=[C:13]([NH2:25])[CH:14]=[C:15]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=4[F:24])[CH:16]=3)[C:5]2=[N:6][CH:7]=1.N1C=CC=CC=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([C:11]3[CH:12]=[C:13]([NH:25][S:33]([CH3:32])(=[O:35])=[O:34])[CH:14]=[C:15]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=4[F:24])[CH:16]=3)[C:5]2=[N:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(Br)cnc32)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(Br)cnc32)c1
Reaction time: 1 h
Yield: 75 %

Procedure:
To a solution of 5-(6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-amine (133 mg, 0.33 mmol) in DCM was added pyridine (52 mg, 0.66 mmol, 2.0 eq.) followed by methanesulfonyl chloride (76 mg, 0.66 mmol, 2 eq.). The reaction was stirred for 1 h, and quenched and extracted as in Example 2(b). The solvent was distilled off to afford the crude residue which was taken next step without further purification. Yield 75.0% (120 mg). 1H NMR (300 MHz, DMSO-d6): δ 10.30 (s, 1H), 9.30 (s, 1H), 8.56 (s, 1H), 7.83 (s, 1H), 7.45 (s, 1H), 7.44 (s, 2H), 3.16 (s, 3H); LC-MS (ESI): Calculated mass: 479.5; Observed mass: 480.2 [M+H]+ (rt: 1.59 min).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([C:28]([O:30][CH3:31])=[O:29])[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].[C:32](OC(=O)C)(=[O:34])[CH3:33]>N1C=CC=CC=1>[C:1]([O:4][C:5]1[CH:6]=[C:7]([C:28]([O:30][CH3:31])=[O:29])[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]2[C:32](=[O:34])[CH3:33])(=[O:3])[CH3:2]
Reactant: COC(=O)c1cc(OC(C)=O)c2c(c1)N1CC3NC3C(OC(C)=O)(O1)C2COC(N)=O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COC(=O)c1cc(OC(C)=O)c2c(c1)N1CC3C(N3C(C)=O)C(OC(C)=O)(O1)C2COC(N)=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of methyl 6,9-diacetoxy-8-carbamoyloxymethyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-triene-4-carboxylate (5 mg) in pyridine (1.0 ml) was added acetic anhydride (0.5 ml), and the solution was stirred for 5 hours at room temperature. The reaction mixture was evaporated to dryness in vacuo and the residue was subjected to preparative thin layer chromatography, which was developed with a mixture of chloroform and methanol (30:1, v/v) to afford methyl 6,9-diacetoxy-11-acetyl-8-carbamoyloxymethyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-triene-4-carboxylate (5 mg).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:15](=[O:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].O>C(Cl)Cl>[O:4]1[CH2:5][CH2:6][N:1]([C:15](=[O:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:2][CH2:3]1
Reactant: CCOC(=O)CC(=O)Cl
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)CC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of morpholine (479 mg, 5.5 mmol, 1.1 eq) and triethylamine (1.01 g, 10 mmol, 10 eq) in DCM (20 mL) at 0° C., ethyl 3-chloro-3-oxopropanoate (750 mg, 5 mmol, 1.0 eq) was added and the resulting mixture was stirred at RT for 1 h. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (1-50% ethyl acetate-hexanes) to afford the product ethyl 3-morpholino-3-oxopropanoate 33.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:19][CH2:18][CH:17]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([S:35][CH2:36][CH3:37])[CH:30]=3)(=[O:28])=[O:27])=[CH:22][C:21]=2[O:38][CH3:39])[CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[CH2:36]([S:35][C:31]1[CH:30]=[C:29]([S:26]([C:23]2[CH:24]=[CH:25][C:20]([CH:17]3[CH2:18][CH2:19][NH:15][CH2:16]3)=[C:21]([O:38][CH3:39])[CH:22]=2)(=[O:28])=[O:27])[CH:34]=[CH:33][CH:32]=1)[CH3:37]
Reactant: CCSc1cccc(S(=O)(=O)c2ccc(C3CCN(C(=O)OC(C)(C)C)C3)c(OC)c2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCSc1cccc(S(=O)(=O)c2ccc(C3CCNC3)c(OC)c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (1 mL) was added to a solution of 3-[4-(3-ethylsulfanyl-benzenesulfonyl)-2-methoxy-phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (60 mg, 0.1256 mmol) in DCM (3 mL), and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure and the residue was partitioned between NaOH (2 M) and DCM. The organic layer was separated and washed with water, dried over Na2SO4, and evaporated under reduced pressure, affording 3-[4-(3-ethylsulfanyl-benzenesulfonyl)-2-methoxy-phenyl]-pyrrolidine, which was transformed in the corresponding hydrochloride (white foam, 53 mg) by addition of a small excess of HCl in 1,4-dioxane. MS (M+H)=378.
Reaction SMILES: BrCC1C=CSC=1.[CH2:8](Br)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[O:16]=[C:17]1[CH:26]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:25][C:24]2[C:19](=[C:20]([N:35]3[CH2:39][CH2:38][CH2:37][C:36]3=[O:40])[CH:21]=[CH:22][CH:23]=2)[NH:18]1>>[CH2:8]([N:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][C:20]=2[N:35]2[CH2:39][CH2:38][CH2:37][C:36]2=[O:40])[CH2:25][CH:26]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:33])[CH3:32])[C:17]1=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)NC1Cc2cccc(N3CCCC3=O)c2NC1=O
Reactant: BrCc1ccccc1
Agent: BrCc1ccsc1
Product: CC(C)(C)OC(=O)NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccccc2)C1=O

Procedure:
Instead of 3-bromomethylthiophene, benzylbromide (1.48 mL) was used with respect to tert-butyl 2-oxo-8-(2-oxopyrrolidin-1-yl)-1,2,3,4-tetrahydroquinolin-3-ylcarbamate (Compound B) (4.3 g), which had been produced through the same method as employed in Example 7(a), whereby the title compound (5.87 g) was yielded.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[O:3][C:4]1[CH:32]=[CH:31][C:7]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][NH:16][CH2:15][CH2:14][N:13]2[S:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[O:11])=[CH:6][CH:5]=1.Cl[C:36]1[S:37][C:38]2[C:43]([Cl:44])=[N:42][C:41]([CH:45]3[CH2:47][CH2:46]3)=[N:40][C:39]=2[N:48]=1.C(N(CC)C(C)C)(C)C>C(Cl)(Cl)Cl>[F:34][C:2]([F:1])([F:33])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][N:16]([C:36]3[S:37][C:38]4[C:43]([Cl:44])=[N:42][C:41]([CH:45]5[CH2:46][CH2:47]5)=[N:40][C:39]=4[N:48]=3)[CH2:15][CH2:14][N:13]2[S:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[O:11])=[CH:31][CH:32]=1
Reactant: Clc1nc2nc(C3CC3)nc(Cl)c2s1
Reactant: O=C(NCc1ccc(OC(F)(F)F)cc1)[C@H]1CNCCN1S(=O)(=O)c1ccc(C(F)(F)F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: O=C(NCc1ccc(OC(F)(F)F)cc1)[C@H]1CN(c2nc3nc(C4CC4)nc(Cl)c3s2)CCN1S(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
To a mixed solution of the compound (0.75 g) obtained in Step 2 and 2,7-dichloro-5-cyclopropyl-thiazolo[4,5-d]pyrimidine (0.36 g) in chloroform (7.5 ml) was added at room temperature N,N-diisopropylethylamine (0.31 ml). After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=2:3-3:2) to give the title compound (0.99 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:16][CH3:17])[C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].[Cl:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[C:23]([F:28])[CH:22]=1.C(OC(O)C)C.C(=O)([O-])[O-].[Na+].[Na+]>O>[Cl:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][C:2]2[C:11]3[C:6](=[C:7]([O:16][CH3:17])[C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:18]#[N:19])=[C:23]([F:28])[CH:22]=1
Reactant: COc1cc2c(Cl)c(C#N)cnc2c(OC)c1OC
Reactant: Nc1ccc(Cl)cc1F
Agent: CCOC(C)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)c(C#N)cnc2c(OC)c1OC
Yield: 67.2 %

Procedure:
A mixture of 0.279 g of 4-chloro-6,7,8trimethoxy-quinoline-3-carbonitrile, 0.177 g of 4-chloro-2-fluoroaniline, and 10 ml of ethoxyethanol was stirred under nitrogen, at reflux temperature for 30 minutes. The mixture was cooled and added to 100 ml of water. To this mixture was added sodium carbonate to pH 9. The product was extracted with ethyl acetate, washed with water, dried and concentrated in vacuo. The solid thus obtained was chromatographed on silica gel eluting with hexanes-ethyl acetate 9:1 to 2:1. Solvent was removed from product fractions giving 0.261 g of 4-(4-chloro-2-fluoro-phenylamino)-6,7,8-trimethoxy-quinoline-3-carbonitrile as a yellow solid: mp 166-168° C.; mass spectrum (EI, m/e): M 387.0777.
Reaction SMILES: [Li].[Na].N.[C:4]1([O:10][CH:11]=O)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O=[CH:14]C(Cl)(Cl)Cl>CCOC(C)=O.CC(O)(C)C.C1COCC1>[CH3:14][CH2:11][O:10][CH2:4][CH3:9].[C:4]1([OH:10])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=COc1ccccc1
Reactant: O=CC(Cl)(Cl)Cl
Agent: N
Agent: [Li]
Agent: [Na]
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOCC
Product: Oc1ccccc1

Procedure:
Neutralization to pH 4-5 with concentrated aqueous NH3 and reduction with an equimolar quantity of NaCNBH3 or sodium borohydride in refluxing 45% MeOH (final concentration) for 1.5 h afforded pure (TLC) 7 (86%), mp 199.5°-201.5° C. Birch reduction with lithium or sodium in liquid ammonia of 85 mmol of unpurified 7 with 1.92 g atom of lithium in 450 ml of liquid NH3, 225 mL each of dry THF and t-BuOH at -55° to -65° C. for 4 h, then at -75° C. until no 7 remained by TLC 9 (~1.5 h) afforded (90%) essentially pure (TLC) 8, mp 179.5°-181.5° C. Refluxing unpurified 8 with 1.5 equivalents of pure PhOCHO or chloral in 10 volumes of EtOAc until homogeneous then ~0.75 h until TLC showed absence of 8 gave (94%) pure 10, mp 141°-143° C. (Et2O-PhOH) which, as the N-formyl derivatives described below and others, existed as two distinct rotomers, as shown by NMR. This N-formyl derivative introduces a protective group for the nitrogen in the subsequent steps of the reaction. Compound 7 or 8 may be N-methylated with methyl halide or sulfonate to give compound 9. Stirring a solution of 10 (25° C., 1 h) in 20 volumes of dry THF containing 1% (v/v) CH3SO3H and 3 molar equivalents of ethylene glycol generated a solution of ketal 11 (quantitatively by TLC) which was treated at 0°-5° C. during 0.5 h with 1.05 equivalents of recrystallized N-bromoacetamide (NBA) to afford essentially pure bromoketal 12 after neutralization with NH3 gas, solvent evaporation and workup with CHCl3 -H2O. Bromoketal 12, mp 182.5°-184° C., (EtOAc) could be readily isolated in 88% yield but was most efficiently deketalized in 6 volumes of 5:1 88% HCO2H-H2O (25° C., 1 h) followed by CHCl3 -aqueous NaHCO3 workup to afford 13, mp 203.5°-206.5° C. (DMF-EtOAc), IR (CHCl3) 1717 (C=O) and 1665 (NCHO) cm,-1 in 90% yield from 10.
Reaction SMILES: [C:1]([C:5]1[C:6]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:11]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[O:31][N:30]=[C:29]([C:32]([O:34]CC)=[O:33])[CH:28]=4)=[CH:23][CH:22]=3)[C:10](=[O:37])[C:7]=2[NH:8][N:9]=1)([CH3:4])([CH3:3])[CH3:2].CO.[OH-].[Na+].Cl>O.C1COCC1>[C:1]([C:5]1[C:6]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:11]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[O:31][N:30]=[C:29]([C:32]([OH:34])=[O:33])[CH:28]=4)=[CH:23][CH:22]=3)[C:10](=[O:37])[C:7]=2[NH:8][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cc(-c2ccc(N3C(=O)c4[nH]nc(C(C)(C)C)c4C3c3ccccc3OC)cc2)on1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1ccccc1C1c2c(C(C)(C)C)n[nH]c2C(=O)N1c1ccc(-c2cc(C(=O)O)no2)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
To a mixture of 3-t-butyl-5-[4-(3-ethoxycarbonyl-5-isoxazolyl)phenyl]-4-(2-methoxyphenyl)-4,5-dihydro-1H-pyrrolo[3,4-c]pyrazol-6-one (1.26 g, 2.5 mmol), methanol (4 mL), THF (4 mL) and water (3 mL), 2N aqueous sodium hydroxide (1.5 mL, 3 mmol) was added and the mixture was stirred at 50° C. for 1 hr. Water (40 mL) and 1N hydrochloric acid (2 mL) were added to the mixture, which was then extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was suspended in ether, and the precipitate was collected to give 3-t-butyl-5-[4-(3-carboxy-5-isoxazolyl)phenyl]-4-(2-methoxyphenyl)-4,5-dihydro-1H-pyrrolo[3,4-c]pyrazol-6-one (0.84 g, 71%) as pale yellow crystals.
Reaction SMILES: O1[CH2:5][CH2:4][N:3]=C1.[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2C=[CH:20][CH:19]=[CH:18][C:14]=2C(O)=O)=[CH:9][CH:8]=1.C(O)(=O)C1C=CC=CC=1.C1(C)C=CC([Mg]Br)=CC=1>C(#N)C1C=CC=CC=1>[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:18][CH:19]=[CH:20][C:5]=2[C:4]#[N:3])=[CH:9][CH:8]=1
Reactant: C1=NCCO1
Reactant: Cc1ccc(-c2ccccc2C(=O)O)cc1
Agent: Cc1ccc([Mg]Br)cc1
Agent: O=C(O)c1ccccc1
Solvent: N#Cc1ccccc1
Product: Cc1ccc(-c2ccccc2C#N)cc1

Procedure:
Carini et al., J. Med. Chem., vol. 34 (1991), 2525-2547 disclose the application of the Meyers oxazoline method to the preparation of 2-(4'-methylphenyl) benzonitrile by the following steps: 1) 2-methoxybenzoic acid is reacted with thionyl chloride; 2) the acyl chloride formed is treated with 2-amino-2-methyl-1-propanol, which provides an amide in the crude form; 3) this amide is subjected to the action of thionyl chloride, forming 4,4-dimethyl-2-(2-methoxyphenyl)-oxazoline (yield 88% from the acid chloride); 4) this oxazoline derivative is reacted with p-tolyl-magnesium bromide and the complex formed is hydrolyzed, which gives 4,4-dimethyl-2-(4'-methylbiphenyl-2'-yl)-oxazoline (yield 91%); and 5) the oxazoline derivative formed is then treated with phosphorus oxychloride, which finally provides 2-(4'-methylphenyl)benzonitrile (yield 96%). The overall yield is 77% but this process has the disadvantage of requiring the use of 5 steps, starting from commercially available products, due to the prior formation of the dimethyloxazolinyl group and its subsequent conversion to the cyano group. U.S. Pat. No. 5,128,355 (to Carini et al.) similarly exemplifies the application of the multistep Meyers oxazoline method to the preparation of 2-(4'-methylphenyl)benzoic acid (Example 85), and the conversion of this benzoic acid to the benzonitrile (Example 89). Implicitly, these references illustrate that when an aryl magnesium reagent (in this case, p-tolyl magnesium bromide) is used directly to provide the aryl group in an arylbenzonitrile (in this case, 2-(4'-methylphenyl)benzonitrile) the nitrile group cannot be present in the substrate that is treated with the aryl magnesium reagent. It must be in a protected precursor form during the coupling process (in this case, as the dimethyloxazolinyl group).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][OH:8])[CH2:2]1.[OH-].[Na+].[CH3:11][CH:12]([CH3:17])[CH2:13][C:14](Cl)=[O:15]>O.C1COCC1.CCOCC>[OH:8][CH2:7][CH:3]1[CH2:4][CH2:5][CH2:6][N:1]([C:14](=[O:15])[CH2:13][CH:12]([CH3:17])[CH3:11])[CH2:2]1
Reactant: OCC1CCCNC1
Reactant: CC(C)CC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)CC(=O)N1CCCC(CO)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94 %

Procedure:
To a solution of piperidin-3-ylmethanol (10 g, 86.83 mmol) in water (25 mL), was added a solution of NaOH (13.89 g, 347.31 mmol) in water (25 mL) dropwise at 0° C. The mixture was stirred for 15 minutes, after which time, a solution of 3-methylbutanoyl chloride (20.94 g, 173.66 mmol) in THF (25 mL) was added dropwise with vigorous stirring. The reaction was slowly warmed to room temperature and, upon completion was diluted with Et2O (500 mL) was added with vigouous stirring. After 15 minutes, the phases were separated, and the aqueous phase was extracted with Et2O (2×). The combined organic extracts were washed with brine, dried over Na2SO4, concentrated under reduced pressure and flash chromatographed on silica gel (0-100% EtOAc in hexanes) to give the title compound as a colorless oil (16.27 g, 94%). MS 200 (MH+).