Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH:17]([C:18]([OH:20])=O)[CH2:16][C:13]2([CH2:15][CH2:14]2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-].Cl.CC[N:26](CC)CC.Br[CH2:32][C:33]([C:35]1[CH:44]=[CH:43][C:42]2[C:37](=[CH:38][CH:39]=[C:40]([Br:45])[CH:41]=2)[CH:36]=1)=[O:34]>CO.CC#N>[CH2:1]([O:8][C:9]([N:11]1[CH:17]([C:18](=[O:20])[NH:26][CH2:32][C:33]([C:35]2[CH:44]=[CH:43][C:42]3[C:37](=[CH:38][CH:39]=[C:40]([Br:45])[CH:41]=3)[CH:36]=2)=[O:34])[CH2:16][C:13]2([CH2:14][CH2:15]2)[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1CC2(CC2)CN1C(=O)OCc1ccccc1
Reactant: CCN(CC)CC
Reactant: O=C(CBr)c1ccc2cc(Br)ccc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CC#N
Product: O=C(CNC(=O)C1CC2(CC2)CN1C(=O)OCc1ccccc1)c1ccc2cc(Br)ccc2c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
5-Aza-spiro[2.4]heptane-5,6-dicarboxylic acid 5-benzyl ester (2.217 g, 7.66 mmol) was dissolved in MeOH (30 mL) and LiOH (1 M in H2O, 15 mL, 15 mmol) was added. After stirring for 15 hours at room temperature, the reaction mixture was poured into 10% HCl and the aqueous phase was extracted 3× with DCM. The combined organics were dried over MgSO4, filtered and concentrated. The residue was treated with MeCN (40 mL), Et3N (1.2 mL, 8.4 mmol) and 2-Bromo-1-(6-bromo-naphthalen-2-yl)-ethanone and the mixture was stirred at room temperature for 20 hours before being filtered over CELITE and concentrated. The resulting oil was dissolved in the minimum amount of DCM and EtOAc (30 mL) was added causing the product to precipitate. The mixture was cooled to 0° C. then the solid was filtered off and rinsed with EtOAc giving clean product (4.00 g, 100%).
Reaction SMILES: C(O[CH:5]([C:21]1[N:25]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])[C:24]([CH2:34][CH2:35][CH2:36][CH3:37])=[N:23][CH:22]=1)[CH:6]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]2[O:18][CH2:19][O:20][C:14]=2[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])(=O)C.C1(C)C=CC=CC=1>CCOCC>[CH2:34]([C:24]1[N:25]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])[C:21](/[CH:5]=[C:6](\[CH2:11][C:12]2[CH:17]=[CH:16][C:15]3[O:18][CH2:19][O:20][C:14]=3[CH:13]=2)/[C:7]([O:9][CH3:10])=[O:8])=[CH:22][N:23]=1)[CH2:35][CH2:36][CH3:37]
Reactant: CCCCc1ncc(C(OC(C)=O)C(Cc2ccc3c(c2)OCO3)C(=O)OC)n1Cc1ccccc1Cl
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCCCc1ncc(/C=C(\Cc2ccc3c(c2)OCO3)C(=O)OC)n1Cc1ccccc1Cl
Yield: 91.3 %

Procedure:
A solution of methyl 3-acetoxy-3-[2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5-yl]-2-(3,4-methylenedioxyphenyl)methylpropanoate (1.36 g, 2.58 mmol), 1,8-diazobicyclo[5,4,0]undec-7-ene (1 mL, 6.48 mmol) and toluene (10 mL) was heated at 90 ° C. for 18 hours under argon. The cooled reaction mixture was diluted with ether, the solution was filtered and the filtrate was concentrated. Chromatography of the product over silica gel with a gradient of ethyl acetate in hexane provided 1.1 g (87%) of methyl (E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5yl]-2-(3,4-methylenedioxyphenyl)methyl-2-propenoate as a low melting solid whose NMR showed the E or trans relationship of the ester group to the imidazole ring.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[OH-:6].[Al+3:7].[OH-].[OH-].[I-].[Al+3].[I-].[I-].[I-].[NH2:15][CH2:16][C:17]([O-:19])=[O:18]>O>[NH2:1][CH2:2][C:3]([O-:5])=[O:4].[OH:6][Al+2:7].[NH2:15][CH2:16][C:17]([O-:19])=[O:18]
Reactant: NCC(=O)O
Reactant: [Al+3]
Reactant: [OH-]
Agent: NCC(=O)[O-]
Agent: [I-]
Solvent: O
Product: O[Al+2]
Temperature: 75 °C
Reaction time: 0.5 h

Procedure:
Monohydroxyaluminum glycinate was prepared by reacting 2 grams of glycine with 1.25 grams of aluminum hydroxide (28.8% Al) powder in 10 grams of water. The mixture was agitated at 75° C. for 1/2 hour. To 15 grams of a 331/2 solution of 5/6 basic aluminum iodide solution, Al2 (OH)5I (5.49% Al), was added 31.2 grams of a zirconyl iodide solution (6.3% Zr). The glycinate mixture was then added to the above solution while agitating at 80° C. for 30 minutes. The resultant clear solution was evaporated at 55° C. under a vacuum of 150 mm of Hg. The product contained 6.63% Al, 11.1% Zr, 48.3% I, and 11.1% glycine.
Reaction SMILES: [CH3:1][N:2]([CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:3]1[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([C:13]([O:15]C)=[O:14])=[CH:8][CH:7]=2.[OH-].[Na+]>CO.O>[CH3:1][N:2]([CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:3]1[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([C:13]([OH:15])=[O:14])=[CH:8][CH:7]=2
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N(C)CCc3ccccc3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(CCc1ccccc1)c1nc2cc(C(=O)O)ccc2nc1-c1ccccc1

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 3-(methyl(phenethyl)amino)-2-phenylquinoxaline-6-carboxylate (144.7 mg, 0.35 mmol, 1.00 equiv, 96%) in methanol (20 mL). This was followed by the dropwise addition of a solution of sodium hydroxide (72.9 mg, 1.82 mmol, 5.00 equiv) in water (2 mL) with stirring. The resulting solution was stirred overnight at 50° C. in an oil bath. Then it was concentrated under vacuum and diluted with 10 ml of water. The pH value of the aqueous solution was adjusted to 3-4 with 1N aq. hydrogen chloride. The resulting solid was collected by filtration and washed with methanol. This resulted in 52.6 mg (38%) of 3-(methyl(phenethyl)amino)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[C:7]([O:11][C:12]([N:14]1[CH2:21][CH:20]2[CH:16]([CH2:17][NH:18][CH2:19]2)[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].[F:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]2[N:36]=[CH:35][CH:34]=[N:33]2)[C:24]=1[C:25](Cl)=[O:26]>C1(C)C=CC=CC=1>[C:7]([O:11][C:12]([N:14]1[CH2:15][CH:16]2[CH:20]([CH2:19][N:18]([C:25](=[O:26])[C:24]3[C:28]([N:32]4[N:33]=[CH:34][CH:35]=[N:36]4)=[CH:29][CH:30]=[CH:31][C:23]=3[F:22])[CH2:17]2)[CH2:21]1)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: O=C(Cl)c1c(F)cccc1-n1nccn1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC2CN(C(=O)c3c(F)cccc3-n3nccn3)CC2C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.8 %

Procedure:
In a 3-neck round bottom 100 mL flask was added toluene (8.5 mL), aqueous sodium carbonate (1.42 g in 10.7 mL water), and Intermediate 15 (0.905 mg, 4.26 mmol). The biphasic mixture was cooled to 0° C. After cooling to 0° C., 2-fluoro-6-[1,2,3]triazol-2-yl-benzoyl chloride was poured over the stirring biphasic mixture of amine and aqueous sodium carbonate. An exotherm was observed. The mixture was allowed to warm to room temperature. After 1 h, a sample of the organic layer was quenched into methanol and a small amount of acid chloride was determined to remain (observed as its methyl ester). Additional amine (˜50 mg) was added and the mixture was stirred overnight at room temperature. At the end of this period, the layers were separated and 100 mL of methanol were added to the organic layer. The organic was concentrated and purified using flash column chromatography (FCC), gradient of 5-50% of a solution of 10% MeOH, 0.1% NH4OH in DCM/DCM. The desired fractions were combined and concentrated to provide a white foamy solid (1.327 g, 76.8%). MS (ESI): mass calculated for C20H24FN5O3, 401.44, m/z found 346.2 [M+H-56]+. 1H NMR (400 MHz, CDCl3): 7.91-7.73 (m, 3H), 7.53-7.39 (m, 1H), 7.18-7.06 (m, 1H), 4.00-2.76 (m, 10H), 1.52-1.33 (m, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:4]=1[CH:5]=O.[N+:13]([CH3:16])([O-:15])=[O:14]>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:4]=1[CH2:5][CH2:16][NH2:13].[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:4]=1[CH:5]=[CH:16][N+:13]([O-:15])=[O:14]
Reactant: COc1cccc(OC)c1C=O
Reactant: C[N+](=O)[O-]
Product: COc1cccc(OC)c1C=C[N+](=O)[O-]
Product: COc1cccc(OC)c1CCN

Procedure:
The starting material 2,6-dimethoxy-phenethylamine was prepared from 2,6-dimethoxy-benzaldehyde. Reaction with nitromethane according to the procedure described in Vogel, Textbook of Practical Organic Chemistry, p. 176 (Longman 1978, 4th Ed.) yielded 2,6-dimethoxy-β-nitrostyrene. This compound (1.1 g, 5.3 mmole) was dissolved in diethyl ether/tetrahydrofuran (2:1, 200 ml) and lithium aluminium hydride (0.5 g, 13 mmol) was added in small portions. The mixture was refluxed for 120 minutes and then treated with 0.6 ml H2O, 0.6 ml 15% NaOH (aq) and 1.8 ml H2O. The mixture was filtered and purified by acid-base partitioning (NH4OH (aq) HCl dil. (aq)) and evaporated. The crude product 2,6-dimethoxyphenethylamine was pure enough to be used directly in the following reaction where it was condensed with the product of Example 103, in a manner analogous to Example 105, to give the titled product.
Reaction SMILES: [CH3:1][Si:2]([CH3:29])([CH3:28])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2=[N:12][CH:13]=[CH:14][C:15]([C:16]3[CH:17]=[N:18][N:19]([C:21]4([CH2:25][C:26]#[N:27])[CH2:24][NH:23][CH2:22]4)[CH:20]=3)=[C:10]2[CH:9]=[CH:8]1.O=[C:31]1[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]1.C(N(CC)C(C)C)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[ClH:67].O1CCOCC1>C1COCC1>[ClH:67].[ClH:67].[ClH:67].[NH:34]1[CH2:35][CH2:36][CH:31]([N:23]2[CH2:22][C:21]([CH2:25][C:26]#[N:27])([N:19]3[CH:20]=[C:16]([C:15]4[CH:14]=[CH:13][N:12]=[C:11]5[N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:28])([CH3:1])[CH3:29])[CH:8]=[CH:9][C:10]=45)[CH:17]=[N:18]3)[CH2:24]2)[CH2:32][CH2:33]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)ccnc21
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(C5CCNCC5)C4)c3)ccnc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of {3-[4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile.2[HCl] (347 mg, 0.70 mmol), tert-butyl 4-oxo-1-piperidinecarboxylate (134 mg, 0.70 mmol) and N,N-diisopropylethylamine (0.467 mL, 2.68 mmol) in THF (10.0 mL) was added sodium triacetoxyborohydride (284 mg, 1.34 mmol). The mixture was stirred at room temperature for 2 hours and quenched with brine. The resulting solution was extracted with EtOAc (2 times). The combined extracts were washed with water, brine and dried over Na2SO4. After filtration and evaporation, the residue was purified by flash chromatography on silica gel eluting with 50-100% EtOAc/hexanes. The purified intermediate (MS: [M+H]+=592.3) was dissolved in THF (6 mL). To the solution was added a 4.0 M solution of HCl in 1,4-dioxane (6 mL, 24 mmol). The mixture was stirred at room temperature for 2 hours and concentrated to give 260 mg of {1-piperidin-4-yl-3-[4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile trihydrochloride as a yellowish solid. LC/MS found: 492.0 (M+H)+. 1H NMR (400 MHz, DMSO-d6), δ 9.45 (s, 1H), 8.96 (s, 1H), 8.73 (s, 1H), 8.35 (d, 1H), 8.46 (s, 1H), 8.33 (d, 1H), 7.81 (d, 1H), 7.50 (d, 1H), 7.10 (m, 1H), 5.69 (s, 2H), 4.93 (d, 2H), 4.54 (d, 2H), 3.75-3.60 (m, 1H), 3.55 (s, 2H), 3.55 (s, 2H), 3.52 (t, 2H), 3.49-3.37 (m, 2H), 2.81 (m, 2H), 2.12 (d, 2H), 1.80 (m, 2H), 0.82 (t, 2H), −0.11 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:17])[C:15]3[N:14]=[CH:13][N:12]([CH3:18])[C:11]=3[N:10]=[C:9]2Cl)=[CH:4][CH:3]=1.[F:20][C:21]1[C:26]([F:27])=[C:25]([F:28])[CH:24]=[CH:23][C:22]=1[OH:29].CO>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:17])[C:15]3[N:14]=[CH:13][N:12]([CH3:18])[C:11]=3[N:10]=[C:9]2[O:29][C:22]2[CH:23]=[CH:24][C:25]([F:28])=[C:26]([F:27])[C:21]=2[F:20])=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)c(F)c1F
Reactant: Cn1cnc2c(=O)n(-c3ccc(Br)cc3)c(Cl)nc21
Solvent: ClCCl
Solvent: CO
Product: Cn1cnc2c(=O)n(-c3ccc(Br)cc3)c(Oc3ccc(F)c(F)c3F)nc21
Temperature: 140 °C
Reaction time: 23 h

Procedure:
1-(4-Bromophenyl)-2-chloro-9-methyl-1,9-dihydro-6H-purin-6-one (150 mg, 0.4417 mmol) and 2,3,4-trifluorophenol (130.8 mg, 0.8834 mmol) are added to a vial, and the sealed mixture is heated with stirring at 140° C. for 23 h. Silica gel column chromatography (MeOH:CH2Cl2=0.5:99.5) gives the title compound as a white solid. 1H NMR (400 MHz, CDCl3) 7.66 (3H, m), 7.24 (2H, m), 7.00 (2H, m), 3.58 (3H, s). MS (M+1): 451.08; RT=1.31 min. The IC50 determined as described in Example 6 is 100 nanomolar or less.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1([NH2:9])[CH2:8][CH2:7]1)=[O:5].[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17](Cl)(=[O:19])=[O:18].C(N(CC)CC)C.O>C(Cl)Cl>[CH3:2][O:3][C:4]([C:6]1([NH:9][S:17]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[Br:10])(=[O:19])=[O:18])[CH2:8][CH2:7]1)=[O:5]
Reactant: O=S(=O)(Cl)c1ccccc1Br
Reactant: COC(=O)C1(N)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COC(=O)C1(NS(=O)(=O)c2ccccc2Br)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 84.9 %

Procedure:
methyl-1-aminocyclopropanecarboxylate hydrochloride (300 mg, 1.979 mmol) was dissolved in CH2Cl2 (7 ml), added with 2-bromobenzene-1-sulfonyl chloride (550 mg, 2.17 mmol) and triethylamine (1.1 ml, 7.92 mmol), and stirred at room temperature for 12 hours. The resultant solution was added with H2O, extracted with CH2Cl2 (×2), dried with MgSO4, and filtered. Through vacuum distillation, the solvent was removed. The resultant mixture was purified with column chromatography so as to obtain methyl-1-(2-bromophenylsulfonamido)cyclopropanecarboxylate (560 mg, 1.68 mmol, 85%).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=2)[CH:3]=1.[CH:18]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)=[O:19].C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:15][C:14]([F:17])([F:16])[O:13][C:10]1[CH:11]=[CH:12][C:7]([N:4]2[CH:5]=[CH:6][C:2]([C:23]3[CH:24]=[CH:25][C:20]([CH:18]=[O:19])=[CH:21][CH:22]=3)=[CH:3]2)=[CH:8][CH:9]=1
Reactant: FC(F)(F)Oc1ccc(-n2ccc(Br)c2)cc1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=Cc1ccc(-c2ccn(-c3ccc(OC(F)(F)F)cc3)c2)cc1
Temperature: 150 °C
Yield: 18.9 %

Procedure:
A suspension of crude 3-bromo-1-(4-trifluoromethoxyphenyl)-1H-pyrrole (356 mg, 1.26 mmol, 1.00 eq), 4-formylphenylboronic acid (283 mg, 1.89 mmol, 1.50 eq), bis(triphenylphosphine)palladium(II) dichloride (27 mg, 0.04 mmol, 0.03 eq), 2M Na2CO3 (aq) (1.26 mL, 2.52 mmol, 2.0 eq), and 1,4-dioxane (5 mL) were heated at 150° C. in a microwave reaction vessel for 45 min. The cooled solution was then diluted with EtOAc (20 mL), filtered over Celite®, concentrated to dryness, and purified via chromatography (2:2:1, hexane:EtOAc:acetone) to afford the desired intermediate (79 mg, 21%).
Reaction SMILES: [CH3:1][CH:2]([CH3:10])[CH2:3][C:4](=[CH:8][CH3:9])[C:5]([OH:7])=O.[CH3:11]N1CCOCC1.C(Cl)(=O)C(Cl)=O.[CH3:24][NH:25][C:26](=[O:38])[C@H:27]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][C:31]=1C)[NH2:28]>ClCCl>[CH3:24][NH:25][C:26](=[O:38])[C@H:27]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:11])=[CH:32][CH:31]=1)[NH:28][C:5](=[O:7])[C:4]([CH2:3][CH:2]([CH3:1])[CH3:10])=[CH:8][CH3:9]
Reactant: CNC(=O)[C@@H](N)Cc1ccc(O)cc1C
Reactant: CN1CCOCC1
Reactant: CC=C(CC(C)C)C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CC=C(CC(C)C)C(=O)N[C@@H](Cc1ccc(OC)cc1)C(=O)NC
Temperature: 25 °C

Procedure:
2-(2-Methylpropyl)-but-2-enoic acid (37 g, 0.261 M) prepared as described in Example 1 in dry dichloromethane (200 ml) and N-methyl morpholine (65 ml) was treated at -5° C. with oxalyl chloride (33.2 g, 0.261 M) over 30 minutes. The mixture was heated under reflux for 10 minutes, then re-cooled to ca -60° C. and 0-methyl-L-tyrosine N-methylamide (51 g, 0.245 M) in dry dichloromethane (100 ml) added over 30 minutes. The mixture was left to warm up to room temperature over ca 1 hour, diluted with more dichloromethane then washed with aqueous sodium hydroxide (0.1 N), aqueous saturated sodium hydrogen carbonate solution and saturated brine. The organic extract was dried, then evaporated in vacuo to afford N-[2-(2-methylpropyl)-but-2-enoyl]-O-methyl-L-tyrosine-N-methylamide as a yellow gum (81 g).
Reaction SMILES: [CH3:1][CH:2]([NH:4][CH2:5][C@H:6]([OH:19])[CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([NH2:18])=[O:17])=[CH:13][CH:14]=1)[CH3:3].[CH3:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]([OH:29])=[O:28])=[CH:25][CH:26]=1>CC(C)=O>[CH3:3][CH:2]([NH:4][CH2:5][C@H:6]([OH:19])[CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([NH2:18])=[O:17])=[CH:13][CH:14]=1)[CH3:1].[C:21]1([CH3:20])[CH:26]=[CH:25][C:24]([C:27]([O-:29])=[O:28])=[CH:23][CH:22]=1
Reactant: Cc1ccc(C(=O)O)cc1
Agent: CC(C)NC[C@H](O)COc1ccc(CC(N)=O)cc1
Solvent: CC(C)=O
Product: Cc1ccc(C(=O)[O-])cc1
Reaction time: 10 h

Procedure:
The S-atenolol having an optical purity of 96.5% ee (10.77 g) thus obtained and p-toluic acid (5.54 g) are dissolved in acetone (1 liter) by heating with stirring and the mixture is sitrred at room temperature for 10 hours. The precipitated crystals are separated by filtration and the filtrate is concentrated under reduced pressure to give S-atenolol p-toluate having an optical purity of 98.5% ee (14.47 g).
Reaction SMILES: Br[C:2]1[C:10]2[C:6](=[N:7][N:8]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)[N:9]=2)[C:5]([Br:17])=[CH:4][CH:3]=1.[CH2:18]([C:24]1([CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[C:36]2[CH:35]=[C:34](B(O)O)[CH:33]=[CH:32][C:31]=2[C:30]2[C:25]1=[CH:26][C:27](B(O)O)=[CH:28][CH:29]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C(=O)([O-])[O-].[Na+].[Na+].[Br:55][C:56]1[CH:61]=[CH:60][C:59](CCCC)=[CH:58][CH:57]=1>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1.C(O)CCC>[Br:17][C:5]1[C:6]2=[N:7][N:8]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)[N:9]=[C:10]2[C:2]([C:27]2[CH:28]=[CH:29][C:30]3[C:31]4[C:36](=[CH:35][C:34]([C:59]5[C:58]6[C:57](=[N:7][N:8]([C:11]7[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=7)[N:9]=6)[C:56]([Br:55])=[CH:61][CH:60]=5)=[CH:33][CH:32]=4)[C:24]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])([CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[C:25]=3[CH:26]=2)=[CH:3][CH:4]=1
Reactant: Brc1ccc(Br)c2nn(-c3ccncc3)nc12
Reactant: CCCCCCC1(CCCCCC)c2cc(B(O)O)ccc2-c2ccc(B(O)O)cc21
Reactant: CCCCc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCC1(CCCCCC)c2cc(-c3ccc(Br)c4nn(-c5ccncc5)nc34)ccc2-c2ccc(-c3ccc(Br)c4nn(-c5ccncc5)nc34)cc21
Temperature: 110 °C
Reaction time: 48 h
Yield: 10.4 %

Procedure:
A mixture of Intermediate A (3.52 g, 10 mmol), 9,9-dihexylfluorene-2,7-diboronic acid (1.90 g, 4.5 mmol), sodium carbonate (2.12 g, 20 mmol) in water (10 mL), tetrakis(triphenylphosphine)palladium (0) (1.00 g, 0.86 mmol), n-butanol (80 mL), and toluene (20 mL) was stirred and heated under argon at 110° C. After 48 hours, 1-bromo-4-butylbenzene (3.0 mL, 17 mmol) was added followed by sodium carbonate (2.12 g, 20 mmol) in water (10 mL) and tetrakis(triphenylphosphine)palladium (0) (1.00 g, 0.86 mmol), and heating was continued for an additional 20 hours. The reaction mixture was poured into water (200 mL and extracted with ethyl acetate). The extract was dried over anhydrous sodium sulfate, the volatiles were removed under reduced pressure, and the residue was chromatographed (silica gel, dichloromethane/ethyl acetate 3:1). The first fraction gave Intermediate E (414 mg, 10%).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:8]=2[CH3:22])=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:32][C:33]([F:44])([F:43])[C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1>ClCCl>[CH3:22][C:8]1[N:9]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:10]2[C:15]([C:7]=1[CH2:6][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:38](=[O:39])[C:37]3[CH:41]=[CH:42][C:34]([C:33]([F:32])([F:43])[F:44])=[CH:35][CH:36]=3)=[CH:24][CH:23]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2
Reactant: CCOC(=O)Cn1c(C)c(Cc2ccc(N)cc2)c2ccccc21
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cn1c(C)c(Cc2ccc(NC(=O)c3ccc(C(F)(F)F)cc3)cc2)c2ccccc21
Yield: 74.8 %

Procedure:
In a dry reaction vessel, ethyl 2-[3-(4-aminobenzyl)-2-methyl-1H-indol-1-yl]acetate (1.0 g, 3.11 mmol) was added, and dissolved in 15 mL dichloromethane. Triethylamine (1.3 mL, 9.34 mmol) was added, and in an ice bath a dichloromethane solution dissolving 4-trifluoromethylbenzoyl chloride (0.649 g, 3.11 mmol) was added slowly. After completion of dropwise addition, it was reacted in an ice bath for 4 h, and filtered. An aqueous solution of sodium bicarbonate was added, extracted with dichloromethane, rotate evaporated to dryness, chromatographed on a column to obtain a white solid 1.15 g, at a yield of 74.9%.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([F:11])[C:3]=1[CH3:12].[CH2:13]([OH:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:13]([O:20][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([F:11])[C:3]=1[CH3:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1c(F)ccc([N+](=O)[O-])c1F
Reactant: OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(OCc2ccccc2)ccc([N+](=O)[O-])c1F
Temperature: 100 °C
Yield: 33.3 %

Procedure:
1,3-difluoro-2-methyl-4-nitrobenzene (16 g, 0.092 mol), benzyl alcohol (10 g, 0.092 mol) and K2CO3 (25.3 g, 0.18 mol) were combined in DMF (250 mL) and heated to 100° C. overnight. The mixture was poured into water and extracted with EtOAc (3×200 mL). The combined organics were washed with brine, dried (Na2SO4), concentrated in vacuo and purified by column chromatography on silica gel to give 1-benzyloxy-3-fluoro-2-methyl-4-nitrobenzene (8 g, 33% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.04 (t, J=8.8 Hz, 1H), 7.30-7.46 (m, 5H), 7.08 (d, J=9.2 Hz, 1H), 5.28 (s, 2H), 2.13 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:15]([O:17][C:18](=[O:24])[C@H:19]([C@@H:21]([CH3:23])[OH:22])[NH2:20])C>>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([NH:20][C@H:19]([C:18]([O:17][CH3:15])=[O:24])[C@@H:21]([CH3:23])[OH:22])=[O:13])[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@@H](N)[C@@H](C)O
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Product: COC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)[C@@H](C)O

Procedure:
The preparation was performed in a similar manner as Example 1.001 (d) Method B from N-(tert-butoxycarbonyl)-L-alanine (5.62 g, 29.7 mmol) and L-threonine ethyl ester hydrochloride (4.58 g, 27.0 mmol) to give methyl N-(tert-butoxycarbonyl)-L-alanyl-L-threoninate. MS (APCI): m/z 305 (M+H).