Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])OCC.[NH:11]([C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[C@H:12](C=O)[CH2:13][CH:14]([CH3:16])[CH3:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH2:9]([O:8][CH:1]([O:5][CH2:6][CH3:7])[C@H:12]([CH2:13][CH:14]([CH3:16])[CH3:15])[NH:11][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[CH3:10]
Reactant: CC(C)C[C@@H](C=O)NC(=O)OCc1ccccc1
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(OCC)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Reaction time: 0.5 h

Procedure:
104 mL of triethyl orthoformate was added over a period of 30 min to a solution of CBZ-Leu-H (12 g) and p-toluenesulfonic acid (0.9 g) in 100 mL of anhydrous ethanol (EtOH). The mixture was stirred for 30 min, and then was evaporated and diluted with 500 mL of ether. The ether layer was washed consecutively with saturated solutions of NaHCO3 and sodium chloride. The yellowish brown semisolid was recrystallized from cold hexane to yield off-white needles of CBZ-Leucinal diethylacetal. 1H NMR (300 MHz, CDCl3) δ: 7.28(m, 5H), 5.03(s, 2H), 4.77(d, 1H), 4.27(d, 1H), 3.8(m, 1H), 3.63(m, 2H), 3.43(m, 2H), 1.6(dd, 2H), 1.30(m, 2H), 1.12(m, 6H), 0.83(d, 6H)
Reaction SMILES: N(CC)CC.S([O-])([O-])(=O)=O.C1C2C(COC([N:28]3[CH2:33][CH2:32][CH:31]([C:34]4[N:38]=[C:37]([C@@H:39]5[CH2:45][CH2:44][C@@H:43]6[CH2:46][N:40]5[C:41](=[O:52])[N:42]6[O:47][S:48]([OH:51])(=[O:50])=[O:49])[O:36][N:35]=4)[CH2:30][CH2:29]3)=O)C3C(=CC=CC=3)C=2C=CC=1.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl>[S:48]([OH:51])([O:47][N:42]1[C:41](=[O:52])[N:40]2[CH2:46][C@H:43]1[CH2:44][CH2:45][C@H:39]2[C:37]1[O:36][N:35]=[C:34]([CH:31]2[CH2:32][CH2:33][NH:28][CH2:29][CH2:30]2)[N:38]=1)(=[O:49])=[O:50]
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)N1CCC(c2noc([C@@H]3CC[C@@H]4CN3C(=O)N4OS(=O)(=O)O)n2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Solvent: CCNCC
Product: O=C1N2C[C@@H](CC[C@H]2c2nc(C3CCNCC3)no2)N1OS(=O)(=O)O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Et2NH (6.1 mL, 60.0 mmol) was added to a solution of tetrabutylammonium (9H-fluoren-9-yl)methyl 4-(5-((2S,5R)-7-oxo-6-(sulfooxy)-1,6-diaza-bicyclo[3.2.1]octan-2-yl)-1,2,4-oxadiazol-3-yl)piperidine-1-carboxylate sulfate (1.0 g, 1.2 mmol) in dried CH2Cl2 (30 mL). The mixture was stirred under N2 atmosphere at rt. for 12 hrs, then evaporated under vacuum. The residue was purified by prep-HPLC using the ammonium formate conditions. E SI-MS (EI+, m/z): 314.2. 1H NMR (300 MHz, D2O) δ 4.82 (d, J=8.0 Hz, 1H), 4.17 (br s, 1H), 3.47-3.45 (m, 2H), 3.25-3.12 (m, 3H), 2.96-2.92 (m, 1H), 2.39-1.94 (m, 8H).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SC)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][NH:44][C@@H:43]([C:47]([OH:49])=[O:48])[CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35]>>[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][N:44]([C:19]2[S:20][C:16](=[CH:15][C:11]3[CH:10]=[C:9]4[C:14](=[CH:13][CH:12]=3)[N:6]([CH2:5][C:4]3[CH:24]=[CH:25][C:26]([C:28]([F:31])([F:29])[F:30])=[CH:27][C:3]=3[C:2]([F:32])([F:33])[F:1])[N:7]=[CH:8]4)[C:17](=[O:23])[N:18]=2)[CH:43]([C:47]([OH:49])=[O:48])[CH2:42]1)=[O:40])([CH3:37])([CH3:35])[CH3:36].[F:32][C:2]([F:33])([F:1])[C:3]1[CH:27]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:44]4[CH2:45][CH2:46][NH:41][CH2:42][C@@H:43]4[C:47]([OH:49])=[O:48])=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CC(C)(C)OC(=O)N1CCN[C@@H](C(=O)O)C1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Product: CC(C)(C)OC(=O)N1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)C(C(=O)O)C1
Product: O=C1N=C(N2CCNC[C@@H]2C(=O)O)SC1=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1

Procedure:
4-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperazine-1,3-dicarboxylic acid 1-tert-butyl ester was prepared from 5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and piperazine-1,3-(R)-dicarboxylic acid 1-tert-butyl ester following General Procedure C. Compound was not isolated and 1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperazine-2-(R)-carboxylic acid acid was prepared following General Procedure H.
Reaction SMILES: CO[C:3]([CH:5]1[C:10](=O)[CH2:9][CH2:8][N:7]([C:12]2[CH:13]=[N:14][C:15]([O:19][CH3:20])=[C:16]([CH3:18])[CH:17]=2)[CH2:6]1)=[O:4].C(O)(=O)C.[CH:25]([NH2:27])=[NH:26].C[O-].[Na+].C(O)(=O)C>CO.C(Cl)Cl>[CH3:20][O:19][C:15]1[N:14]=[CH:13][C:12]([N:7]2[CH2:8][CH2:9][C:10]3[N:26]=[CH:25][N:27]=[C:3]([OH:4])[C:5]=3[CH2:6]2)=[CH:17][C:16]=1[CH3:18]
Reactant: COC(=O)C1CN(c2cnc(OC)c(C)c2)CCC1=O
Reactant: N=CN
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ncc(N2CCc3ncnc(O)c3C2)cc1C
Temperature: 90 °C
Yield: 76.1 %

Procedure:
A mixture of 6′-methoxy-5′-methyl-4-oxo-3,4,5,6-tetrahydro-2H-[1,3]bipyridinyl-3-carboxylic acid methyl ester (900 mg, 3.23 mmol), formamidine acetate (521 mg, 4.85 mmol), sodium methoxide (5.4 Molar) in methanol (2.395 mL, 12.94 mmol) and methanol (4 mL) was heated to 90° C. for 3 h. The mixture was allowed to cool down to rt, diluted in CH2Cl2, neutralized with acetic acid (0.741 mL, 12.94 mmol) and quenched with H2O. The layers were separated and aqueous was washed twice with CH2Cl2, organics were combined, washed with brine, dried over sodium sulfate, filtered and evaporated to give a yellow solid. The solid was triturated in ethylacetate to yield 6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ol (669 mg, yield 76%) as a white powder. 1H-NMR (400 MHz, DMSO-d6, 298K) δ ppm 2.14 (s, 3H) 2.72 (t, 2H) 3.39 (t, 2H) 3.81 (s, 3H) 3.90 (s, 2H) 7.42 (d, 1H) 7.67 (d, 1H) 8.07 (s, 1H) 12.46 (br.s., 1H). LCMS: [M+H]+=273.1, Rt(3)=1.30 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].N1C=CC=CC=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([NH:13][C:20](=[O:22])[CH3:21])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(N)ccc1OC
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(NC(C)=O)ccc1OC
Reaction time: 20 h

Procedure:
Combine methyl 2-methoxy-5-aminobenzoate (2.0 g, 11 mmol), pyridine, 2.8 mL, 35 mmol), and acetic anhydride (3.2 mL, 34 mmol) in tetrahydrofuran (50 mL). After 20 hours, concentrate the reaction mixture in vacuo to remove most of the tetrahydrofuran, partition between ethyl aqueous layer water. Separate the layers and extract the aqueous layer twice with ethyl acetate. Combine the organic layers, extract with brine, dry over MgSO4, filter, and evaporate in vacuo to give a residue. Crystallize the residue from ethyl acetate/cyclohexane to give methyl 2-methoxy-5-acetamidobenzoate.
Reaction SMILES: CS(OS(C)(=O)=O)(=O)=O.[C:10]([C:14]1[CH:15]=[C:16]([NH:20][C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[NH:31][C:32]2[CH:33]=[C:34]3[C:38](=[CH:39][CH:40]=2)[N:37]([CH2:41][CH2:42][CH2:43]O)[N:36]=[CH:35]3)=O)[N:17]([CH3:19])[N:18]=1)([CH3:13])([CH3:12])[CH3:11].[CH:45]([N:48](C(C)C)CC)([CH3:47])[CH3:46].C(N)(C)C.CC#N.[OH2:61]>>[C:10]([C:14]1[CH:15]=[C:16]([NH:20][C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[NH:31][C:32]2[CH:33]=[C:34]3[C:38](=[CH:39][CH:40]=2)[N:37]([CH2:41][CH2:42][CH2:43][NH:48][CH:45]([CH3:47])[CH3:46])[N:36]=[CH:35]3)=[O:61])[N:17]([CH3:19])[N:18]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: CCN(C(C)C)C(C)C
Reactant: Cn1nc(C(C)(C)C)cc1NC(=O)NCc1ccccc1Nc1ccc2c(cnn2CCCO)c1
Reactant: O
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: CC(C)N
Solvent: CC#N
Product: CC(C)NCCCn1ncc2cc(Nc3ccccc3CNC(=O)Nc3cc(C(C)(C)C)nn3C)ccc21
Reaction time: 1 h
Yield: 20 %

Procedure:
Methanesulfonic anhydride (18 mg, 0.11 mmol) was added to a solution of alcohol (7s) (36 mg, 0.076 mmol) and diisopropylethylamine (29 mg, 0.23 mmol) at room temperature. The solution was stirred for 1 hour. Isopropylamine (0.13 mL, 1.50 mmol) was added and the reaction was stirred at room temperature for 60 hours. The volatiles were removed in vacuo. The crude product was purified on silica gel with 5% MeOH/CH2Cl2 containing 1% Et3N and then on C18 silica with CH3CN/H2O to afford the desired compound (8s-2) (8 mg, 20% yield). 1H NMR (400 MHz, MeOD) δ 7.88 (s, 1H), 7.51 (d, J=8.6 Hz, 1H), 7.31-7.24 (m, 3H), 7.17-7.16 (m, 2H), 6.93-6.89 (m, 1H), 6.05 (s, 1H), 4.52 (t, J=10.2 Hz, 2H), 4.41 (s, 2H), 3.57 (s, 3H), 3.35-3.30 (m, 1H), 3.03 (t, J=11.7 Hz, 2H), 2.29-2.22 (m, 2H), 1.29 (d, J=6.3 Hz, 6H), 1.26 (s, 9H); MS (ESI+) m/z 517 (M+H)+; HPLC (5 to 95%) 2.61 min.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]=[C:18]=[S:19])=[CH:13][CH:12]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[SH:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24].O>CN(C)C=O>[C:23]([CH2:22][CH2:21][S:20][C:18](=[S:19])[NH:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[CH:12][CH:13]=1)([OH:25])=[O:24]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(N=C=S)cc2)cc1
Reactant: O=C(O)CCS
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)CCSC(=S)Nc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1

Procedure:
A solution of 27.2 g of 4-(4-nitrophenyloxy)-phenylisothiocyanate (m.p. 124°-125° C) and 10 ml of 3-mercaptopropionic acid in 250 ml of anhydrous dimethyl formamide is stirred at room temperature. When the reaction is complete, the solution is poured, with stirring, into 250 ml of water. The resultant fine precipitate is collected by filtration, washed with water and dried under reduced pressure to yield the N-[4-(4-nitro-phenyloxy)-phenyl]-dithiocarbamic acid-(2-carboxyethyl)-ester with a melting point of 146° C.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([OH:11])[C:9]#[CH:10].Cl[C:13]1[N:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]([CH3:23])[CH:18]=[C:17]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:16]2=[O:29].CN(C=O)C>CCOCC.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>[OH:11][CH2:8][C:9]#[C:10][C:13]1[N:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]([CH3:23])[CH:18]=[C:17]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:16]2=[O:29]
Reactant: CCOC(=O)c1cn(C)c2ccc(Cl)nc2c1=O
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C)c2ccc(C#CCO)nc2c1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 55 %

Procedure:
Triethylamine (10 mL) is added to dry cuprous iodide (52 mg) under nitrogen. The mixture is stirred for 5 minutes and propargyl alcohol (50 μL) is added. After stirring another 5 minutes, dichlorobis(triphenylphosphine)palladium(II) (48 mg) is added. The mixture is again stirred for 5 minutes before the addition of ethyl 6-chloro-1-methyl-4-oxo-1,4-dihydro[1,5]naphthyridine-3-carboxylate (Preparation 59, 367 mg) and DMF (10 mL). After stirring another 5 minutes, the remaining propargyl alcohol (660 μL) is added, and the reaction is tightly capped and stirred at 70° C. for 11 hours. After cooling, the dark mixture is diluted with ether (75 mL), sonicated to break up the solids, and filtered. The collected solid is washed with ether and dried under vacuum. The crude solid is recrystallized from 95% ethanol (100 mL, dissolved at reflux with the addition of a few drops of water, then cooled to 0° C. overnight), affording 219 mg (55%) of the title compound as a beige solid. Physical characteristics. 1H NMR (DMSO-d6) δ8.68, 8.21, 7.85, 5.5, 4.38, 4.23, 3.90, 1.29; HRMS (FAB) (C15H14N2O4+H) m/z 287.1035. Anal. Found (C15H14N2O4.0.12 H2O): C, 62.48; H, 5.00; N, 9.62.
Reaction SMILES: [CH:1]([Mg]Cl)=[CH2:2].[O:5]=[C:6]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7]/[CH:8]=[CH:9]/[I:10]>O1CCCC1>[OH:5][C:6]([CH:1]=[CH2:2])([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7]/[CH:8]=[CH:9]/[I:10]
Reactant: C=C[Mg]Cl
Reactant: CCCCC(=O)C/C=C/I
Solvent: C1CCOC1
Product: C=CC(O)(C/C=C/I)CCCC
Reaction time: 0.5 h

Procedure:
To a stirred solution of 7.8 ml of vinyl magnesium chloride (2.3M in tetrahydrofuran), at -25° C. is added a solution of 3.55 g of 4-oxo-1-iodo-trans-1-octene in 20 ml of tetrahydrofuran during 15 minutes. After the addition, the solution is stirred at -20° C. to -15° C. for 30 minutes. The reaction is quenched with a mixture of hexane and ice. The aqueous phase is separated and extracted with additional hexane. The combined hexane extracts are washed successively with water and brine. The solution is dried over magnesium sulfate and concentrated. The residue is subjected to dry column chromatography on silica gel with benzene as developing solvent to give a liquid, pmr spectrum (CDCl3): 5.2 (m, terminal CH2), 5.83 (q, CH=CH2), 6.13 (d, ICH=), and 6.52 (m, ICM=CH).
Reaction SMILES: [NH2:1][CH:2]([CH2:6][C:7]([F:10])([F:9])[F:8])[C:3]([OH:5])=[O:4].[ClH:11].[CH2:12](O)[CH3:13]>>[Cl-:11].[CH2:12]([O:4][C:3](=[O:5])[CH:2]([NH3+:1])[CH2:6][C:7]([F:10])([F:9])[F:8])[CH3:13]
Reactant: NC(CC(F)(F)F)C(=O)O
Reactant: Cl
Reactant: CCO
Product: CCOC(=O)C([NH3+])CC(F)(F)F
Product: [Cl-]
Temperature: 85 °C
Reaction time: 4 h

Procedure:
2-Amino-4,4,4-trifluorobutanoic acid (11.7 g, 52.8 mmol) was added to a saturated solution of HCl in ethanol (100 mL) and heated to 85° C. After 4 h, the mixture was allowed to cool to ambient temperature and concentrated. MS 186.0 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:13]2[CH2:17][CH2:16][O:15][C:14]2=[O:18])=[C:6]([CH:12]=1)[C:7]([N:9]([CH3:11])[CH3:10])=[O:8].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[C:35]2[C:30](=[N:31][CH:32]=[C:33](B3OC(C)(C)C(C)(C)O3)[CH:34]=2)[N:29]([CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50])[N:28]=1.O>O1CCCC1.C(#N)C>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[C:35]2[C:30](=[N:31][CH:32]=[C:33]([C:2]3[CH:3]=[CH:4][C:5]([N:13]4[CH2:17][CH2:16][O:15][C:14]4=[O:18])=[C:6]([CH:12]=3)[C:7]([N:9]([CH3:11])[CH3:10])=[O:8])[CH:34]=2)[N:29]([CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:50])([CH3:52])[CH3:51])[N:28]=1
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: CN(C)C(=O)c1cc(Br)ccc1N1CCOC1=O
Solvent: O
Solvent: C1CCOC1
Solvent: CC#N
Product: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3ccc(N4CCOC4=O)c(C(=O)N(C)C)c3)cc12

Procedure:
In a microwave vial 5-bromo-N,N-dimethyl-2-(2-oxo-oxazolidin-3-yl)-benzamide (150 mg, 0.45 mmol), 3-(2-methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridine (2.169 g, 0.45 mmol) in tetrahydrofuran/acetonitrile/1 N aqueous sodium bicarbonate (4 ml) was degassed with nitrogen and 1,1′-bis(diphenylphosphino) ferrocenepalladium(II)-dichloride dichloromethane adduct (36.8 mg, 0.05 mmol) was added and the vial sealed. This reaction mixture was irradiated to 100° C. for 30 minutes in a microwave reactor. 100 ml water was added and this mixture was extracted with ethyl acetate (3×). The combined organic layers were dried over magnesium sulfate and purified by silica gel chromatography to yield crude 5-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-N,N-dimethyl-2-(2-oxo-oxazolidin-3-yl)-benzamide which was dissolved in 2 ml trifluoroacetic acid and stirred for 16 hours. The volatiles were removed and the residue purified by preparative mass-triggered reverse-phase HPLC to give 5-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-N,N-dimethyl-2-(2-oxo-oxazolidin-3-yl)-benzamide as a white solid (62 mg, 49% yield). 1H NMR (500 MHz, DMSO-d6) δ 2.92 (s, 3H); 2.97 (s, 3H); 3.57 (s, 3H); 3.99 (m, 2H); 7.10 (t, J=8 Hz 1H) 7.23 (d, J=8 Hz 1H); 7.47 (t, J=8 Hz, 1H); 7.58 (d, J=8 Hz 1H); 7.66 (d, J=8 Hz 1H); 7.74 (s, 1H); 7.89 (d, J=8 Hz 1H); 8.39 (s, 1H); 8.89 (s, 1H); 13.83 (s, br, 1H) MS: m/z 458.5 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](O)=[O:7])#[N:2].S(Cl)([Cl:14])=O>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([Cl:14])=[O:7])#[N:2]
Reactant: N#Cc1cccc(C(=O)O)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: N#Cc1cccc(C(=O)Cl)c1

Procedure:
A mixture of 50 g. of 3-cyanobenzoic acid and 100 ml. of thionyl chloride were stirred overnight in 500 ml. of methylene chloride. The solvent and excess thionyl chloride were removed in vacuo providing 55.3 g. of crude subtitle intermediate which was used without further purification.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:59])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][Si:51]([C:54]([CH3:57])([CH3:56])[CH3:55])([CH3:53])[CH3:52])[CH:46]([OH:58])[CH2:45]2)[CH:7]([CH3:60])[CH2:6][CH2:5][C:4]1=[O:61])[CH3:2].ClC(Cl)(Cl)C(=N)O[CH2:66][CH:67]=[CH2:68].FC(F)(F)S(O)(=O)=O>C(Cl)Cl.C1CCCCC1.C(OCC)(=O)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:59])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][Si:51]([C:54]([CH3:57])([CH3:56])[CH3:55])([CH3:52])[CH3:53])[CH:46]([O:58][CH2:68][CH:67]=[CH2:66])[CH2:45]2)[CH:7]([CH3:60])[CH2:6][CH2:5][C:4]1=[O:61])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O[Si](C)(C)C(C)(C)C)C(O)C3)C(C)CCC1=O)C(C)CC2OC
Reactant: C=CCOC(=N)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Yield: 73.3 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(4"-(tert-butyldimethylsiloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (300 mg) in 9 ml 33% methylene chloride in cyclohexane was added allyl trichloroacetimidate (138 mg neat) and the reaction mixture was allowed to mix for 5 minutes. Trifluoromethanesulfonic acid (18 μl neat) was added slowly via syringe and the mixture stirred at room temperature. After 3 days the reaction was diluted with ethyl acetate and quenched with saturated sodium bicarbonate. The layers were separated, and the organic layer was washed with brine then dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate:hexane (1:4)+1% methanol) gave the title compound (230 mg; trichloroacatamide present). 1H NMR consistent with the desired structure.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3](=O)[CH2:4][C:5](=O)[C:6]([CH3:9])([CH3:8])[CH3:7].Cl.[N+:15]([C:18]1[CH:23]=[CH:22][C:21]([NH:24][NH2:25])=[CH:20][CH:19]=1)([O-:17])=[O:16]>>[C:6]([C:5]1[N:24]([C:21]2[CH:22]=[CH:23][C:18]([N+:15]([O-:17])=[O:16])=[CH:19][CH:20]=2)[N:25]=[C:3]([C:2]([F:13])([F:12])[F:1])[CH:4]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: NNc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)C(=O)CC(=O)C(F)(F)F
Agent: Cl
Product: CC(C)(C)c1cc(C(F)(F)F)nn1-c1ccc([N+](=O)[O-])cc1
Yield: 94.7 %

Procedure:
Using 1,1,1-trifluoro-5,5-dimethyl-2,4-hexanedione and 4-nitrophenylhydrazine hydrochloride as the raw materials, the same operation as the Example 538(1) gave the title compound.
Reaction SMILES: [CH2:1]1[C:11]2[C:10](=[O:12])[C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[CH2:7][S:6][C:5]=2[CH:4]=[CH:3][CH2:2]1.[BH4-].[Na+].O>CO>[CH:1]1[C:11]2[CH:10]([OH:12])[C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[CH2:7][S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1C2=C(C=CCC2)SCc2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OC1c2ccccc2CSc2ccccc21
Temperature: -10 °C
Reaction time: 3 h

Procedure:
48 g (212 mmol) 6.1-dihydro-dibenzo[b,e]thiepin-11-one are dissolved in 480 ml absolute methanol and cooled to ca. −10° C. 19.2 g (507 mmol) sodium borohydride is added portion wise to this solution. The mixture is stirred for three hours at RT without further cooling. After the careful addition of 30 ml water, the suspension is concentrated under vacuum. The residue is taken up in 500 ml dichloromethane and washed twice each with 150 ml water. The organic phase is dried over sodium sulfate and the solvent is removed under vacuum. The residue is crystallized from 180 ml toluene. Colorless crystals of MP. 108° C.: Yield 41.2 g (85%).
Reaction SMILES: O[C:2]1([C:15]2[CH:16]=[N:17][CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=2)[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.S(Cl)(Cl)=O>N1C=CC=CC=1>[F:24][C:21]([F:22])([F:23])[C:19]1[CH:20]=[C:15]([C:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])[CH2:4][CH:3]=2)[CH:16]=[N:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cncc(C(F)(F)F)c2)CC1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CC=C(c2cncc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.7 %

Procedure:
To a solution of tert-butyl 4-hydroxy-4-[5-(trifluoromethyl)pyridin-3-yl]piperidine-1-carboylate (300 mg, 0.433 mmol) in pyridine (3.00 mL) cooled in an ice bath was added thionyl chloride (0.158 mL, 2.16 mmol). After being stirred at room temperature overnight (16 h), the brown reaction mixture was quenched with ice water and extracted with methylene chloride three times. The combined extracts were dried (MgSO4), filtered, and concentrated. Purification by flash chromatography on silica gel (0 - 20% B over 35 min. Bottle A =hexanes, Bottle B =EtOAc) provided 65 mg (46%) of desired product as a light yellow oil. LC-MS calculated for C16H19F3N2O2:(M+H) 329; found 329.1.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4][CH:3]1[C:14]([O:16][CH3:17])=[O:15].[CH3:18][C:19]1[CH:28]=[C:27]([CH2:29][N:30]2[C:38]3[C:33](=[CH:34][C:35]([C:39](Cl)=[O:40])=[CH:36][CH:37]=3)[CH:32]=[CH:31]2)[C:26]2[CH2:25][CH:24]=[CH:23][CH2:22][C:21]=2[N:20]=1>C(Cl)Cl.O>[CH3:18][C:19]1[CH:28]=[C:27]([CH2:29][N:30]2[C:38]3[C:33](=[CH:34][C:35]([C:39]([NH:1][CH:2]4[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4][CH:3]4[C:14]([O:16][CH3:17])=[O:15])=[O:40])=[CH:36][CH:37]=3)[CH:32]=[CH:31]2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1
Reactant: Cc1cc(Cn2ccc3cc(C(=O)Cl)ccc32)c2c(n1)CC=CC2
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CC1N
Solvent: O
Solvent: ClCCl
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)CC1NC(=O)c1ccc2c(ccn2Cc2cc(C)nc3ccccc23)c1
Reaction time: 3.5 h
Yield: 69.1 %

Procedure:
The 1-tert-butyl 3-methyl 4-amino-1,3-pyrrolidinedicarboxylate (0.10 g, 0.41 mmol) was combined with the acid chloride from step (501b) (0.10 g, 0.32 mmol) in methylene chloride (15 mL) and water saturated sodium bicarbonate (15 mL). The reaction was stirred for 3.5 h, partitioned between methylene chloride and water. The organic layer was washed with brine, dried over magnesium sulfate and concentrated to give a solid. This was purified by flash chromatography on silica gel eluting hexane: ethyl acetate (30:60, v:v) to give the 1-tert-butyl 3-methyl 4-[({1-[(2-methyl-4-quinolinyl)methyl]-1H-indol-5-yl}carbonyl)amino]-1,3-pyrrolidinedicarboxylate (0.120 g, 70%) as a solid, MS (M+H)+=543.