Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][C:6]=2[N:7]=1.[C:25]([Li])(C)(C)C.CI>O1CCCC1.CCCCC>[Cl:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:8]([CH3:25])[C:6]=2[N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(nc(Cl)nc2N2CCOCC2)C1
Reactant: [Li]C(C)(C)C
Solvent: CI
Solvent: CCCCC
Solvent: C1CCOC1
Product: CC1c2nc(Cl)nc(N3CCOCC3)c2CCN1C(=O)OC(C)(C)C
Reaction time: 0.67 h
Yield: 87 %

Procedure:
To a solution of tert-butyl 2-chloro-4-morpholino-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (dp) (501 mg, 1.41 mmol) in Tetrahydrofuran (14 mL) was added 1.7 M of tert-Butyllithium in Pentane (1.1 mL) at −78° C., which resulted orange color solution. The reaction was kept at −78° C. for 40 min before Methyl iodide (0.44 mL, 7.1 mmol) was injected. The solution was kept at −78° C. for another 40 min before quenching with water. The mixture was diluted by Dichloromethane, which was washed by water and brine till pH 7. After evaporation, the residue was purified on a silica gel column. Tert-butyl 2-chloro-8-methyl-4-morpholino-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (qe) (452 mg, 87% yield) was obtained as white solid: 1H NMR (500 MHz, CDCl3) δ 5.02 (bs, 1H), 4.26 (bs, 1H), 3.91-3.79 (m, 2H), 3.79-3.67 (m, 2H), 3.61 (m, 2H), 3.36 (m, 2H), 2.89 (bs, 1H), 2.75 (bs, 1H), 2.46 (d, J=15.0 Hz, 1H), 1.50 (d, J=7.0 Hz, 3H), 1.48 (s, 9H); LC-MS m/z=369 (M+H). Tert-butyl 2-chloro-8,8-dimethyl-4-morpholino-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (qf) (44 mg, 8% yield) was obtained as white solid: 1H NMR (400 MHz, CDCl3) δ 3.87-3.73 (m, 4H), 3.60-3.52 (m, 2H), 3.52-3.42 (m, 4H), 2.65-2.56 (m, 2H), 1.74 (s, 6H), 1.50 (s, 9H); LC-MS m/z=383 (M+H).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[N:6]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[F:18])[CH:7]=[CH:8][CH:9]=1)=[O:4].[C:19]1([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>CO>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:6]2[CH:7]=[CH:8][CH:9]=[C:5]2[C:3](=[O:4])[CH2:2][N:28]2[CH2:29][CH2:30][N:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:26][CH2:27]2)=[C:12]([F:18])[CH:13]=1
Reactant: O=C(CCl)c1cccn1Cc1ccc(Cl)cc1F
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(CN1CCN(c2ccccc2)CC1)c1cccn1Cc1ccc(Cl)cc1F

Procedure:
A mixture of 2-chloroacetyl-1-(4-chloro-2-fluorobenzyl)pyrrole, N-phenylpiperazine and triethylamine in methanol is treated by the procedure described in Example 1b to produce 1-(4-chloro-2-fluorobenzyl)-2-[α-(4-phenylpiperazino)acetyl]pyrrole.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:8]([CH2:9][CH3:10])=[N:7][C:6]2[N:11]([CH2:14][CH3:15])[N:12]=[CH:13][C:5]=2[C:4]=1[NH:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[CH3:23][O:24][C:25]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](O)=[O:31])=[O:26].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:14]([N:11]1[C:6]2=[N:7][C:8]([CH2:9][CH3:10])=[C:3]([CH2:2][NH:1][C:30]([C:29]3[CH:28]=[C:27]([CH:35]=[CH:34][CH:33]=3)[C:25]([O:24][CH3:23])=[O:26])=[O:31])[C:4]([NH:16][CH:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[C:5]2[CH:13]=[N:12]1)[CH3:15]
Reactant: COC(=O)c1cccc(C(=O)O)c1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine, previously described in WO2007036733A1, (250 mg, 0.83 mmol) in DMF (70 mL) was treated with 3-[(methyloxy)carbonyl]benzoic acid (149 mg, 0.83 mmol), PyBOP (473 mg, 0.91 mmol) and diisopropylethylamine (0.573 mL, 3.3 mmol) and the mixture was stirred at ambient temperature under a nitrogen atmosphere for 4 h. The mixture was then concentrated to dryness and the residue treated with water (150 mL) and extracted with dichloromethane (2×100 mL). The combined organics were dried (hydrophobic frit) and concentrated to dryness to afford 383 mg of the title compound. LC-MS m/z 466 (M+H)+, 0.90 min (ret time).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([OH:20])[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[CH2:7][CH2:6]1.[O:21]=[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([C:32](O)=[O:33])=[CH:24][NH:23]1>>[Cl:19][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[Cl:18])[O:11][CH:8]1[CH2:9][CH2:10][N:5]([CH2:4][C@H:3]([OH:20])[CH2:2][NH:1][C:32]([C:25]2[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:22](=[O:21])[NH:23][CH:24]=2)=[O:33])[CH2:6][CH2:7]1
Reactant: O=C(O)c1c[nH]c(=O)c2ccccc12
Reactant: NC[C@@H](O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Product: O=C(NC[C@@H](O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1)c1c[nH]c(=O)c2ccccc12

Procedure:
Prepared as described in Example 1 from (2R)-1-amino-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]propan-2-ol (0.1 g) and 1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid (0.059 g). Title compound obtained as white solid (0.047 g).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:22]=2)[C:17]([OH:32])=[C:16]([C:33](OCC)=[O:34])[C:15]1=[O:38].[CH2:39]([O:41][CH2:42][CH2:43][NH2:44])[CH3:40]>CCO>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[CH:22]=2)[C:17]([OH:32])=[C:16]([C:33]([NH:44][CH2:43][CH2:42][O:41][CH2:39][CH3:40])=[O:34])[C:15]1=[O:38]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2C(=O)c3ccccc3C2=O)c1=O
Reactant: CCOCCN
Solvent: CCO
Product: CCOCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2C(=O)c3ccccc3C2=O)c1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of ethyl 1-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (0.021 g, 0.041 mmol) in EtOH (2 mL) under nitrogen was treated with Ethoxyethylamine (0.021 mL, 0.2 mmol) for 10 min.@150° C. in a microwave vessel then@180° C. for an additional 10 min. After the reaction was cooled to ambient temperature the resulting suspension was filtered, and the filtered solid was washed with water and Et2O then thoroughly dried under high vacuum to provide the title compound as a beige solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.07 (t, J=6.95 Hz, 4 H), 1.56-1.91 (m, 1 H), 3.34-3.41 (m, 7 H), 3.88-3.92 (m, 2 H), 4.11 (s, 2 H), 4.53-4.56 (m, 1 H), 7.12-7.13 (m, 1 H), 7.32-7.37 (m, 2 H), 7.81-7.82 (m, 4 H), 8.14-8.15 (m, 1 H), 8.52 (dd, J=1.47, 0.35 Hz, 1 H), 9.76-10.16 (m, 1 H); ES+ MS: 559 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[CH2:5][CH:4]([C:6]([OH:8])=[O:7])[CH2:3]1.CO.Cl.[CH2:12](N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.ClCCl>[O:1]=[C:2]1[CH2:5][CH:4]([C:6]([O:8][CH3:12])=[O:7])[CH2:3]1
Reactant: O=C1CC(C(=O)O)C1
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C1CC(=O)C1

Procedure:
3-Oxocyclobutanecarboxylic acid 1 (350 g, 3.06 mol), methanol (190 mL, 4.69 mol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (885 g, 4.69 mol), 4-dimethylaminopyridine (37 g, 0.30 mol) and dichloromethane (6 L) were stirred at ambient temperature for 24 hours. After the completion of the reaction, it was taken in a separating funnel and washed with 1.5 N HCl solution (1 L), water (2 L×2) and brine (1 L×2). The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was taken to the next step without further purification. 1H NMR (300 MHz, CDCl3): δ 3.23-3.25 (m, 2H), 3.27-3.32 (m, 2H), 3.33-3.42 (m, 1H), 3.76 (s, 3H). GC-MS: [M]+ m/z=128.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=[C:12]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[C:13]1=O)[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.N1C(=O)NC(=O)NC1=O.COC(OC)(C)C>CC(C)=O>[CH3:1][O:2][CH2:3][C@H:4]1[C@H:12]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[C@H:13]2[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5]1
Reactant: COCC(Nc1ccccc1)=C1CCN(C(=O)OCc2ccccc2)C1=O
Agent: O=c1[nH]c(=O)[nH]c(=O)[nH]1
Solvent: CC(C)=O
Solvent: COC(C)(C)OC
Product: COC[C@@H]1Nc2ccccc2[C@H]2[C@@H]1CCN2C(=O)OCc1ccccc1
Temperature: 60 °C
Reaction time: 46 h

Procedure:
In a 120 mL stainless autoclave were charged benzyl 3-(2-methoxy-1-(phenylamino)ethylidene)-2-oxopyrrolidine-1-carboxylate (1.50 g) [mw. 366.41, 4.1 mmol], cyanuric acid (0.53 g) [mw. 129.07, 4.1 mmol] and RuBr2[(s,s)-ptbp-skewphos](pica) (42.4 mg) [mw. 1033.94, 0.041 mmol]synthesized in Reference Example 52, and the system was substituted with argon. To deaeration-treated dehydrated acetone (55 mL) was added 2,2-dimethoxypropane (1.5 mL) [mw. 104.15, d=0.85, 12.3 mmol, 3.0 eq.] and the mixture was added to the autoclave by argon pressure supply. Furthermore, 2,2-dimethoxypropane was rinsed with dehydrated acetone (5 mL), and added by argon pressure supply. Hydrogen was filled therein to 5 MPa, and the mixture was stirred at a reaction temperature of 60° C. for 46 hr. The reaction mixture was cooled to room temperature and depressurized. Quantification by high performance liquid chromatography confirmed that the starting material, benzyl 3-(2-methoxy-1-(phenylamino)ethylidene)-2-oxopyrrolidine-1-carboxylate, remained, the reaction intermediate, benzyl 3-(2-methoxy-1-(phenylamino)ethyl)-2-oxopyrrolidine-1-carboxylate, was not more than 1%, and the resultant product, (3aR,4R,9bR)-benzyl 4-(methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-carboxylate, was also not more than 1%.
Reaction SMILES: [Si:1]([N:8]1[CH:11]([CH2:12][CH:13]=[O:14])[CH2:10][C:9]1=[O:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:16][Mg+].[Br-].[O-]S([O-])(=O)=O.[Mg+2]>CCOCC>[Si:1]([N:8]1[CH:11]([CH2:12][CH:13]([OH:14])[CH3:16])[CH2:10][C:9]1=[O:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[Mg+]
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)CC1CC=O
Agent: O=S(=O)([O-])[O-]
Agent: [Br-]
Agent: [Mg+2]
Solvent: CCOCC
Product: CC(O)CC1CC(=O)N1[Si](C)(C)C(C)(C)C
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
1-(t-butyldimethylsilyl)-4-(2-oxoethyl)-2-azetidinone (2.27 g, 0.01 mole) is dissolved in 50 ml ether and cooled to -20° C. under N2. A solution of CH3MgBr in ether (0.011 mole CH3MgBr) is added dropwise over 1/2 hours at -20° C. and the reaction mixture is stirred for another 1/2 hr at -20°, allowing to rise to 25° C. The reaction mixture is treated with a saturated solution of MgSO4 (2 ml) and allowed to stir for 15 min. The mg salts are filtered off and washed with ether. The combined filtrate and washings are dried and evaporated. Chromatography of the residue on silica gel gives 1-(t-butyldimethylsilyl)-4-(2-hydroxypropyl)-2-azetidinone.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([NH:22][C:23]4[CH:27]=[CH:26][O:25][N:24]=4)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[N:12]=[CH:11][C:10]2=[O:28])=[C:4]([O:29][CH3:30])[CH:3]=1.[F:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(C1C(C(C)(C)C)=C([Pd]Cl)C=CC=1NC)(C)(C)C>[F:8][C:7]1[CH:6]=[C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([NH:22][C:23]4[CH:27]=[CH:26][O:25][N:24]=4)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[N:12]=[CH:11][C:10]2=[O:28])[C:4]([O:29][CH3:30])=[CH:3][C:2]=1[C:35]1[CH:36]=[CH:37][C:32]([F:31])=[CH:33][CH:34]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: COc1cc(Br)c(F)cc1-n1c(=O)cnc2cc(S(=O)(=O)Nc3ccon3)ccc21
Agent: CNc1ccc([Pd]Cl)c(C(C)(C)C)c1C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: COc1cc(-c2ccc(F)cc2)c(F)cc1-n1c(=O)cnc2cc(S(=O)(=O)Nc3ccon3)ccc21
Temperature: 80 °C
Yield: 51.5 %

Procedure:
A vial was charged with 1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoxaline-6-sulfonamide (201.5 mg, 0.407 mmol), (4-fluorophenyl)boronic acid (114 mg, 0.814 mmol), 1,1-bis[(di-t-butyl-p-methylaminophenyl]palladium(ii) chloride (28.8 mg, 0.041 mmol), and potassium phosphate (259 mg, 1.221 mmol). The vial was flushed with Ar (g), then 1,4-dioxane (1627 μl) and water (407 μl) were added. The vial was sealed and heated to 80° C. for 30 min. The mixture was cooled, the layers were separated, and the aq. layer was extracted with EtOAc. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was dissolved in MeOH and filtered through a 0.2 micron filter. The filtrate was purified by reverse-phase HPLC (25-70% CH3CN/H2O with 0.1% TFA). Fractions containing clean desired product were combined and lyophilized to give 1-(2,4′-difluoro-5-methoxy-4-biphenylyl)-N-3-isoxazolyl-2-oxo-1,2-dihydro-6-quinoxalinesulfonamide (107 mg, 82% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ=11.76 (s, 1H), 8.76 (d, J=1.9 Hz, 1H), 8.50 (s, 1H), 8.32 (d, J=2.2 Hz, 1H), 7.95 (dd, J=2.3, 8.9 Hz, 1H), 7.76 (ddd, J=1.5, 5.4, 8.8 Hz, 2H), 7.56 (d, J=10.3 Hz, 1H), 7.46-7.37 (m, 3H), 7.01 (d, J=8.9 Hz, 1H), 6.49 (d, J=2.0 Hz, 1H), 3.80 (s, 3H). m/z (ESI) 511.0 (M+H)+.
Reaction SMILES: [C:1]([NH:9][C:10]1[C:11]2[N:12]=[CH:13][N:14]([C:53]=2[N:54]=[CH:55][N:56]=1)[C@@H:15]1[O:52][C@H:42]([CH2:43][O:44][Si](C(C)(C)C)(C)C)[C@@H:17]([O:18][C:19]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:16]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:1]([NH:9][C:10]1[C:11]2[N:12]=[CH:13][N:14]([C:53]=2[N:54]=[CH:55][N:56]=1)[C@@H:15]1[O:52][C@H:42]([CH2:43][OH:44])[C@@H:17]([O:18][C:19]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:16]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C(O[C@H]2C[C@H](n3cnc4c(NC(=O)c5ccccc5)ncnc43)O[C@@H]2CO[Si](C)(C)C(C)(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc(C(O[C@H]2C[C@H](n3cnc4c(NC(=O)c5ccccc5)ncnc43)O[C@@H]2CO)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
N6-benzoyl-5′-O-(tert-butyldimethylsilyl)-3′-O-(4,4′-dimethoxytrityl)-2′-deoxyadenosine (16.2 g) was dissolved in 200 ml of dry THF. A THF solution (31 ml) of tetrabutylammonium fluoride was added to the resultant solution and 100 ml of dry THF was further added, followed by stirring at room temperature. After 8 hours, THF was distilled off and extract ion using chloroform was carried out. The extract was then washed by a saturated solution of sodium chloride and dried with anhydrous magnesium sulfate. The extract was then concentrated and purified by column chromatography (ethylacetate/hexane/methanol) to obtain 13.8 g of the titled compound as a white powder (yield: 98%).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH2:7][N:6]1C(OC(C)(C)C)=O)=[O:4].FC(F)(F)C(O)=O.[Cl:33]CCl>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:33])(=[O:12])=[O:11])[CH2:7][NH:6]1)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2)CN1C(=O)OC(C)(C)C
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1

Procedure:
In analogy to the procedure described in example 253a, (2S,4R)-4-benzenesulfonyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester was treated with trifluoroacetic acid in dichloromethane to give the title compound as yellow oil. MS (ESI): m/z=270.2 [M+H]+.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.[CH3:16][C:17]1[CH:21]=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[NH:19][N:18]=1.N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:16][C:17]1[CH:21]=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:19]([C:4]2[CH:5]=[CH:6][C:1]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:2][CH:3]=2)[N:18]=1
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)c1cc(C)n[nH]1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1cc(C)nn1-c1ccc(-c2ccccc2)cc1
Yield: 26 %

Procedure:
To a solution of 4-biphenylboronic acid (1.0 g, 5.1 mmol) and ethyl 3-methylpyrazole-5-carboxylate (0.78 g, 5.1 mmol) in 25 mL dry DCM were added pyridine (1.2 mL, 15 mmol) and anhydrous powder of copper(II) acetate (1.84 g, 10 mmol). Some activated molecular sieve powder was added afterwards. The resulting slurry was refluxed for 2 days under argon. The mixture was diluted with DCM, filtered through celite. The blue filtrate was washed with water (×2), dried, concentrated, purified with flush column to yield ethyl 3-methyl-1-(4-phenylphenyl)-1H-pyrazole-5-carboxylate (26%), Rf 0.67 (1:2 EtOAc: hexane), ES-MS: (M+H)+ 307; and its regioisomer, ethyl 5-methyl-1-(4-phenylphenyl)-1H-pyrazole-3-carboxylate (31%), Rf 0.50 (1:2 EtOAc: hexane), ES-MS: (M+H)+ 307.
Reaction SMILES: [CH:1]([C:3]1[C:24]([CH3:25])=[CH:23][C:6]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2/[C:15](=[CH:20]\[O:21][CH3:22])/[C:16]([O:18][CH3:19])=[O:17])=[C:5]([CH3:26])[CH:4]=1)=[O:2].[CH2:27]([Mg]Br)[CH3:28].Cl>O1CCCC1.O>[OH:2][CH:1]([C:3]1[C:24]([CH3:25])=[CH:23][C:6]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2/[C:15](=[CH:20]\[O:21][CH3:22])/[C:16]([O:18][CH3:19])=[O:17])=[C:5]([CH3:26])[CH:4]=1)[CH2:27][CH3:28]
Reactant: CC[Mg]Br
Reactant: CO/C=C(/C(=O)OC)c1ccccc1COc1cc(C)c(C=O)cc1C
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CCC(O)c1cc(C)c(OCc2ccccc2/C(=C\OC)C(=O)OC)cc1C
Yield: 79 %

Procedure:
A solution of 0.2 g (0.56 mmol) of (E)-methyl 2-(2-((4-formyl-2,5-dimethylphenoxy)methyl)phenyl)-3-methoxyacrylate obtained in Step 1 in 15 mL of tetrahydrofuran (THF) was refrigerated at −78° C. and reacted at that temperature for 2 hours with ethyl magnesium bromide (0.22 mL, 1.2 eq) while stirring. After completion of the reaction, the reaction mixture was adjusted to pH 7 at 0° C. with 1N-HCl and concentrated in a vacuum. The residue thus obtained was stirred in water (10 mL) and extracted twice with 10 mL of dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtrated and concentrated in a vacuum to remove the solvent. The concentrate was purified by silica gel chromatography to yield (E)-methyl 2-(2-((4-(1-hydroxypropyl)-2,5-dimethylphenoxy)methyl)phenyl)-3-methoxyacrylate as a white oil (0.17 g, yield 79%).
Reaction SMILES: [C:1]([N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH3:19])[C:11](=O)[C:10]2=[CH:21][S:22][CH:23]=[C:9]12)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].B.Cl>O1CCCC1>[CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH3:19])[CH2:11][C:10]2=[CH:21][S:22][CH:23]=[C:9]12)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC(=O)N1c2cscc2C(=O)N(C)c2ccccc21
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: CCCCCCN1c2cscc2CN(C)c2ccccc21

Procedure:
To a reaction mixture comprising 3.6 g. of 4,9-dihydro-4-hexanoyl-9-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one in 100 ml. of tetrahydrofuran is added, over a 15 minute period, with stirring, in an ice bath, under nitrogen, 90 ml. of 1M-borane. The reaction mixture is then refluxed with stirring for 19 hours. The mixture is cooled in an ice bath and 30 ml. of 6N hydrochloric acid is added dropwise with stirring. The tetrahydrofuran is removed by distillation and 23 g. of sodium hydroxide pellets are carefully added in the cold with stirring. A 15 ml. portion of water is added and the mixture is extracted with three 150 ml. portions of benzene. The benzene extracts are combined, washed with water, dried over sodium sulfate, filtered and concentrated to an oil. This crude product is dissolved in 10 ml. of 20% methylene chloride in hexane and chromatographed on an alumina column, eluting with the same solvent system. The first 150 ml. of eluent is discarded, then 100 ml. fractions are collected. Fractions 1-5 are combined and concentrated to an oil. The oil is extracted with ether repeatedly. The ether extracts are combined, washed with water, dried over sodium sulfate, filtered and concentrated to a residue. The residue is dissolved in 10 ml. of ether and shaken with 25 ml. of 1N sodium hydroxide. The ether is washed with water, dried over sodium sulfate, filtered and concentrated to residue. This residue is dissolved in 25 ml. of methylene chloride and purified by chromatography on a magnesol column, eluting with methylene chloride. The eluant is concentrated giving the desired product as a dark amber oil.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.N1C=CC=CC=1.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl>[CH3:18][S:19]([N:1]1[CH2:2][CH2:3][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:10][CH2:11]1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C1CCNCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C1CCN(S(C)(=O)=O)CC1
Reaction time: 1.5 h
Yield: 72 %

Procedure:
A solution of ethyl isonipecotate (4.9 mL, 31.8 mmol) and pyridine (2.8 mL, 34.6 mmol) was cooled to 0° C. Methanesulfonyl chloride (2.7 mL, 34.9 mmol) was added. After 1.5 hours, the reaction mixture was diluted with CH2Cl2 (300 mL) and extracted with saturated aqueous NaHCO3 (3×100 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The crude material was dissolved in EtOAc (400 mL), extracted with H2O (3×50 mL), dried over Na2SO4, filtered, and concentrated to give the pure product (5.42 g, 22.9 mmol, 72%) as a yellow solid. IR(CHCl3): 3027, 1726, 1331, 1158, 963.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]([F:33])([F:32])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1/[CH:27]=[CH:28]/[C:29](O)=[O:30]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:29](=[O:30])/[CH:28]=[CH:27]/[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[C:20]([F:32])([F:33])[F:19])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Reactant: O=C(O)/C=C/c1ccccc1C(F)(F)F
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)/C=C/c3ccccc3C(F)(F)F)n2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-(2-trifluoromethyl-phenyl)-acrylic acid.