Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC[O:3][P:4](=[O:15])([O:10][C:11](C)(C)C)[O:5]C(C)(C)C.C([O-])([O-])=O.[Cs+].[Cs+].[NH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([C:31]2[C:32](=[O:54])[NH:33][C:34](=[O:53])[C:35]=2[C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[N:39]=[C:38]([N:46]3[CH2:51][CH2:50][N:49]([CH3:52])[CH2:48][CH2:47]3)[N:37]=2)=[CH:23]1.C(O)(C(F)(F)F)=O>CC(C)=O.ClCCCl.C(#N)C.CO>[NH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([C:31]2[C:32](=[O:54])[N:33]([CH2:11][O:10][P:4](=[O:15])([OH:3])[OH:5])[C:34](=[O:53])[C:35]=2[C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[N:39]=[C:38]([N:46]3[CH2:51][CH2:50][N:49]([CH3:52])[CH2:48][CH2:47]3)[N:37]=2)=[CH:23]1
Reactant: CC(C)(C)OP(=O)(OCCl)OC(C)(C)C
Reactant: CN1CCN(c2nc(C3=C(c4c[nH]c5ccccc45)C(=O)NC3=O)c3ccccc3n2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCCl
Solvent: CC#N
Solvent: CO
Product: CN1CCN(c2nc(C3=C(c4c[nH]c5ccccc45)C(=O)N(COP(=O)(O)O)C3=O)c3ccccc3n2)CC1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
Under argon, phosphoric acid di-tert-butyl ester chloromethyl ester (1.24 g, 4.81 mmol) and Cs2CO3 (3.14 g, 9.63 mmol) were added to a solution of 3-(1H-indol-3-yl)-4-[2-(4-methyl-piperazin-1-yl)-quinazolin-4-yl]-pyrrole-2,5-dione (2.0 g, 4.01 mmol) in acetone (40 mL). The reaction mixture was stirred under argon for 16 h at 50° C. followed by concentration at reduced pressure. The residue was partitioned between EtOAc and a saturated aqueous NH4Cl solution, the layers were separated and the organic layer was dried over anhydrous Na2SO4. Concentration at reduced pressure afforded the crude product as a red foam. The crude product was purified by reverse phase Gilson HPLC as described above. After concentration of the desired fractions in vacuo, a red solid was obtained. UPLC-MS indicated that partial cleavage of the t-butyl ester groups had occurred. The thus obtained mixture (280 mg) was dissolved in a mixture of 1,2-dichloroethane (4 mL) and acetonitrile (2.0 mL). TFA (145 mg, 98 μL, 1.27 mmol) was added and the resulting solution was stirred for 3 h under argon at 0° C. when UPLC-MS indicated that full conversion of the starting material had occurred. The reaction mixture was diluted with 1,2-dichloroethane (4.0 mL) and concentrated at reduced pressure to afford the crude product as a red solid. The crude reaction product was dissolved in MeOH (3 mL) and slowly concentrated at reduced pressure until crystallization started to occur. The crystals were filtered off and washed with Et2O and pentane to afford the title compound as an orange solid. 1H-NMR (400 MHz, DMSO-d6): 12.27 (s, 1H), 8.21 (s, 1H), 7.72-7.66 (m, 2H), 7.58 (d, 1H), 7.40 (d, 1H), 7.14 (t, 1H), 7.02 (t, 1H), 6.65 (t, 1H), 6.24 (d, 1H), 5.34 (d, 2H), 4.14-3.72 (bs, 4H), 3.00-2.73 (bs, 4H), 2.60 (s, 3H). 31P-NMR (162 MHz, DMSO-d6): −2.7. LCMS: [M]+=548.6, Rt(1)=1.72 min., Rt(2)=0.73 min.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[CH:21]=[C:20]([Cl:22])[C:17]([C:18]#[N:19])=[C:16](Br)[C:15]=3[O:24][CH2:25][CH3:26])[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12.[CH3:27][S:28]([C:31]1[CH:32]=[N:33][CH:34]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:36]=1)(=[O:30])=[O:29].C(#N)C.C(=O)([O-])[O-].[Na+].[Na+].O.ClCCl>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[CH:21]=[C:20]([Cl:22])[C:17]([C:18]#[N:19])=[C:16]([C:35]4[CH:34]=[N:33][CH:32]=[C:31]([S:28]([CH3:27])(=[O:30])=[O:29])[CH:36]=4)[C:15]=3[O:24][CH2:25][CH3:26])[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12
Reactant: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1Br
Reactant: CC1(C)OB(c2cncc(S(C)(=O)=O)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1-c1cncc(S(C)(=O)=O)c1
Temperature: 100 °C
Yield: 19.5 %

Procedure:
To a mixture of 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-bromo-6-chloro-3-ethoxybenzonitrile (20 mg, 0.04 mmol) and 3-(methylsulfonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (19 mg, 0.069 mmol) in acetonitrile (2 mL, 40 mmol) was added sodium carbonate (10 mg, 0.09 mmol) in water (0.5 mL, 30 mmol). The reaction was degassed with bubbling nitrogen. [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (2 mg, 0.002 mmol) was added and degassed more with N2. Reaction was heated at 100° C. for 2 hours. The crude product was purified on preparative LC-MS (acetonitrile, water, TFA) to give the desired product (0.004 g, 20%) as white amorphous solid. The product was isolated as a racemic mixture. LCMS calculated for C23H22ClN7O3S (M+H)+: m/z=512.1; found: 512.2. 1H NMR (500 MHz, DMSO) δ 9.20 (d, J=2.1 Hz, 1H), 9.12 (d, J=1.9 Hz, 1H), 8.61 (t, J=2.0 Hz, 1H), 8.12 (s, 1H), 7.80 (s, 1H), 6.36 (q, J=7.0 Hz, 1H), 3.54 (dt, J=14.0, 7.0 Hz, 1H), 3.37 (s, 3H), 3.36-3.30 (m, 1H), 2.58 (s, 3H), 1.81 (d, J=7.0 Hz, 3H), 0.92 (t, J=6.9 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:51]=[C:52]2[C:56](=[CH:57][CH:58]=1)[NH:55][C:54]([CH2:59][NH2:60])=[CH:53]2.C(OCC)(=O)C.C(O)C.N.ClCl>CN(C)C=O>[Cl:49][C:50]1[CH:51]=[C:52]2[C:56](=[CH:57][CH:58]=1)[NH:55][C:54]([CH2:59][NH:60][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([C:11]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])=[C:2]([CH3:1])[CH:3]=1)=[CH:53]2
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Reactant: NCc1cc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)NCc2cc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Yield: 31 %

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and C-(5-chloro-1H-indol-2-yl)methylamine in dimethylformamide. Yield: 31%; Rf value: 0.61 (silica gel; ethyl acetate/ethanol/ammonia=9:1:0.1); C22H22ClN3O2 (395.89); mass spectrum: (M+H)+=396/398 (chlorine isotope) and (M−H)−=394/396 (chlorine isotope).
Reaction SMILES: COC1C=C(C(Cl)=O)C=CC=1OC.[Cl:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1[O:22][C:23]1[C:32]2[C:27](=[CH:28][C:29]([O:35][CH3:36])=[C:30]([O:33][CH3:34])[CH:31]=2)[N:26]=[CH:25][CH:24]=1)[NH2:18].[CH3:37][O:38][C:39]1[CH:40]=[C:41]([C:47]([N:49]=[C:50]=[S:51])=[O:48])[CH:42]=[CH:43][C:44]=1[O:45][CH3:46]>C1(C)C=CC=CC=1.C(O)C>[CH3:37][O:38][C:39]1[CH:40]=[C:41]([C:47]([N:49]=[C:50]=[S:51])=[O:48])[CH:42]=[CH:43][C:44]=1[O:45][CH3:46].[Cl:14][C:15]1[CH:16]=[C:17]([NH:18][C:50]([NH:49][C:47](=[O:48])[C:41]2[CH:42]=[CH:43][C:44]([O:45][CH3:46])=[C:39]([O:38][CH3:37])[CH:40]=2)=[S:51])[CH:19]=[CH:20][C:21]=1[O:22][C:23]1[C:32]2[C:27](=[CH:28][C:29]([O:35][CH3:36])=[C:30]([O:33][CH3:34])[CH:31]=2)[N:26]=[CH:25][CH:24]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Agent: COc1ccc(C(=O)Cl)cc1OC
Agent: COc1ccc(C(=O)N=C=S)cc1OC
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)NC(=S)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)c(Cl)c2)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
3,4-Dimethoxy-1-benzenecarbonyl isothiocyanate was prepared using commercially available 3,4-dimethoxy-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 3,4-dimethoxy-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (49 mg, yield 58%).
Reaction SMILES: O=C1CC([O:8][C@@H:9]2[CH2:13][NH:12][C:11](=[O:14])[CH2:10]2)CCO1.[CH2:15]([NH:22][C:23]([C:25]1[S:29][C:28](Br)=[N:27][C:26]=1[CH3:31])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+].ClCCl>C1(C)C=CC=CC=1.C(OCC)(=O)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH2:15]([NH:22][C:23]([C:25]1[S:29][C:28]([N:12]2[CH2:13][C@@H:9]([OH:8])[CH2:10][C:11]2=[O:14])=[N:27][C:26]=1[CH3:31])=[O:24])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C1C[C@H](OC2CCOC(=O)C2)CN1
Reactant: Cc1nc(Br)sc1C(=O)NCc1ccccc1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1nc(N2C[C@@H](O)CC2=O)sc1C(=O)NCc1ccccc1
Temperature: 50 °C
Yield: 52.8 %

Procedure:
A mixture of (4S)-4-(2-oxotetrahydro-2H-pyran-4-yloxy)pyrrolidin-2-one (0.036 g, 0.19 mmol), N-benzyl-2-bromo-4-methylthiazole-5-carboxamide (0.050 g, 0.16 mmol), cesium carbonate (0.079 g, 0.24 mmol), [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (0.003 g, 0.003 mmol) and xantphos (0.004 g, 0.006 mmol) in anhydrous toluene (3 mL) was subjected to microwave irradiation at 80° C. for 20 min. The reaction mixture was diluted with ethyl acetate (10 mL) and washed with water (4 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in ethanol and a catalytic amount of pyridinium p-toluenesulfonate was added to the solution. The reaction mixture was heated at 50° C. for 6 hours and concentrated in vacuo. The residue was dissolved in dichloromethane (15 mL) and washed with water (5 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The obtained white solid was washed with diethyl ether (25 mL) and dried in air to afford the title compound (0.028 g, 53%): mp 203-204° C. (diethyl ether); 1H NMR (300 MHz, DMSO-d6) δ 8.60 (t, J=6.0 Hz, 1H), 7.33-7.17 (m, 5H), 5.46 (d, J=3.8 Hz, 1H), 4.47-4.41 (m, 1H), 4.35 (d, J=6.0 Hz, 2H), 4.12-4.04 (m, 1H), 3.93-3.85 (m, 1H), 3.00-2.90 (m, 1H), 2.48 (s, 3H), 2.42-2.33 (m, 1H); 13C NMR (75 MHz, DMSO-d6) δ 173.3, 162.1, 155.9, 140.0, 128.7, 127.7, 127.2, 119.4, 63.6, 57.0, 43.1, 41.7, 17.5; MS (ES+) m/z 332.2 (M+1).
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]([C:8]1[N:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[C:11]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:10]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:9]=1[O:34][CH2:35]C1C=CC=CC=1)=[O:7])(=O)[CH3:2].CC[N+](S(N=C(OC)[O-])(=O)=O)([CH2:47][CH3:48])CC>C1COCC1>[CH2:27]([O:26][C:10]1[C:9]([O:34][CH2:35][C:48]2[CH:47]=[CH:10][CH:9]=[CH:8][CH:6]=2)=[C:8]([C:6]2[O:7][C:1]([CH3:2])=[N:4][N:5]=2)[N:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[C:11]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)c1c(OCc2ccccc2)c(OCc2ccccc2)c(C(=O)NNC(C)=O)n1-c1ccc(OC)cc1
Reactant: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Product: CCOC(=O)c1c(OCc2ccccc2)c(OCc2ccccc2)c(-c2nnc(C)o2)n1-c1ccc(OC)cc1
Temperature: 100 °C
Yield: 76.1 %

Procedure:
A solution of ethyl 3,4-bis(benzyloxy)-1-(4-methoxyphenyl)-5-(2-acetylhydrazinecarbonyl)-1H-pyrrole-2-carboxylate (31) (155 mg, 0.56 mmol) and Burgess reagent (132 mg, 0.56 mmol) were dissolved in THF (2 mL). The mixture was heated in a microwave at 100° C. for 30 min and the volatiles removed in vacuo. The crude product was purified by silica gel chromatography (12 g, 0-30% EtOAc in isohexane) to afford ethyl 3,4-bis(benzyloxy)-1-(4-methoxyphenyl)-5-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-pyrrole-2-carboxylate (UL1-087) (115 mg, 77%) as a colourless oil: m/z 540 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 7.51-7.46 (m, 2H), 7.43-7.31 (m, 8H), 7.18-7.12 (m, 2H), 6.93-6.87 (m, 2H), 5.17 (s, 2H), 5.07 (s, 2H), 4.02 (q, J=7.1 Hz, 2H), 3.78 (s, 3H), 2.35 (s, 3H), 1.01 (t, J=7.1 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([N:15]2[CH2:19][CH2:18][C@@H:17]([OH:20])[CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:27].[Na+]>CO.C(#N)C>[NH2:27][CH:12]([C:10]1[C:9]([N:15]2[CH2:19][CH2:18][C@@H:17]([OH:20])[CH2:16]2)=[C:8]2[C:3]([CH:4]=[CH:5][CH:6]=[N:7]2)=[C:2]([F:1])[CH:11]=1)[CH3:13]
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cc(F)c2cccnc2c1N1CC[C@@H](O)C1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: CC(N)c1cc(F)c2cccnc2c1N1CC[C@@H](O)C1
Temperature: 65 °C

Procedure:
A mixture of 1-{5-fluoro-8-[(3R)-3-hydroxypyrrolidin-1-yl]quinolin-7-yl}ethanone (10 mg, 0.04 mmol) and ammonium acetate (28.1 mg, 0.364 mmol) in methanol (0.20 mL) and acetonitrile (0.21 mL) was heated at 65° C. in a sealed tube for 30 minutes. After cooling to room temperature, sodium cyanoborohydride (4.6 mg, 0.073 mmol) was added. The reaction was heated at 65° C. for another 4 hours, then cooled to room temperature and quenched with sat. sodium bicarbonate, extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The residue was used directly in the next step. LCMS calculated for C15H19FN3O (M+H)+: m/z=276.1; Found: 276.1.
Reaction SMILES: [OH:1][CH:2]([CH2:48][OH:49])[CH2:3][N:4]([CH3:47])[S:5]([C:8]1[CH:9]=[C:10]([CH:44]=[CH:45][CH:46]=1)[C:11]([NH:13][C:14]1[S:15][C:16]2[CH2:43][CH2:42][CH2:41][CH2:40][C:17]=2[C:18]=1[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]2[CH:39]=[CH:38][C:33]([C:34]([O:36]C)=[O:35])=[CH:32][CH:31]=2)=[CH:24][CH:23]=1)=[O:20])=[O:12])(=[O:7])=[O:6].[OH-].[Na+]>C(O)C>[OH:1][CH:2]([CH2:48][OH:49])[CH2:3][N:4]([CH3:47])[S:5]([C:8]1[CH:9]=[C:10]([CH:44]=[CH:45][CH:46]=1)[C:11]([NH:13][C:14]1[S:15][C:16]2[CH2:43][CH2:42][CH2:41][CH2:40][C:17]=2[C:18]=1[C:19]([NH:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:28][CH2:29][C:30]2[CH:31]=[CH:32][C:33]([C:34]([OH:36])=[O:35])=[CH:38][CH:39]=2)=[CH:26][CH:27]=1)=[O:20])=[O:12])(=[O:7])=[O:6]
Reactant: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(NC(=O)c4cccc(S(=O)(=O)N(C)CC(O)CO)c4)sc4c3CCCC4)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN(CC(O)CO)S(=O)(=O)c1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)O)cc4)cc2)CCCC3)c1
Yield: 79.8 %

Procedure:
A mixture of 230 mg of methyl 4-{2-[4-({[2-({3-[(2,3-dihydroxypropyl)(methyl)sulfamoyl]benzoyl}amino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl}amino)phenyl]ethyl}benzoate, 1.5 mL of a 1.0 M aqueous sodium hydroxide solution, and 2.3 mL of ethanol was heated and refluxed overnight. The reaction mixture was concentrated under reduced pressure, and to the residue were added water, citric acid, and dichloromethane in this order. The organic layer was separated and concentrated under reduced pressure. The obtained residue was solidified with THF-hexane to obtain 180 mg of 4-{2-[4-({[2-({3-[(2,3-dihydroxypropyl)(methyl)sulfamoyl]benzoyl}amino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl}amino)phenyl]ethyl}benzoic acid as a colorless solid.
Reaction SMILES: [Cl-:1].[C:2]([NH+:6]1[CH2:10][C@@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])[C@@H:8]([C:19]([N:21]2[CH:26]3[CH2:27][CH2:28][CH:22]2[CH2:23][C:24]([CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)([CH2:29][S:30][CH3:31])[CH2:25]3)=[O:20])[CH2:7]1)([CH3:5])([CH3:4])[CH3:3].Cl.C([OH:41])C>O.CCOCC>[Cl-:1].[C:2]([NH+:6]1[CH2:10][C@@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])[C@@H:8]([C:19]([N:21]2[CH:26]3[CH2:27][CH2:28][CH:22]2[CH2:23][C:24]([CH:32]2[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]2)([CH2:29][S:30]([CH3:31])=[O:41])[CH2:25]3)=[O:20])[CH2:7]1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CSCC1(C2CCCCC2)CC2CCC(C1)N2C(=O)[C@H]1C[NH+](C(C)(C)C)C[C@H]1c1ccc(F)cc1F
Reactant: CCO
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CCOCC
Product: CS(=O)CC1(C2CCCCC2)CC2CCC(C1)N2C(=O)[C@H]1C[NH+](C(C)(C)C)C[C@H]1c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
To a solution of (3R,4R)-1-tert-butyl-3-({3-cyclohexyl-3-[(methylthio)methyl]-8-azabicyclo[3.2.1]oct-8-yl}carbonyl)-4-(2,4-difluorophenyl)pyrrolidinium chloride (3-7) (0.150 g, 0.0270 mmol) in ethanol (6.0 mL) was added a solution of NaIO4 (0.174 g, 0.813 mmol) in 6.0 mL of water. The mixture was stirred at room temperature for 50 min. The solid was filtered and filtrate was concentrated, diluted with methylene chloride, washed with a saturated aqueous solution of Na2SO3. The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated, followed by the addition of one equivalent HCl in ether to afford (3-8) as white solid (m,z (ES) 534 (MH+)).
Reaction SMILES: [CH2:1]([C:3]1[C:11]([C:12]([O:14]CC)=[O:13])=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2].[OH-].[Na+].Cl>CO.O>[CH2:1]([C:3]1[C:11]([C:12]([OH:14])=[O:13])=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2]
Reactant: CCOC(=O)c1c(CC)nn2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCc1nn2ccccc2c1C(=O)O
Temperature: 60 °C
Yield: 93.7 %

Procedure:
Ethyl 2-ethylpyrazolo[1,5-a]pyridine-3-carboxylate (5.0 g, 23 mmol) was stirred in methanol (200 mL) and a solution of sodium hydroxide in water (100 mL, 3 N) was added. The mixture was heated at 60° C. for 16 h. Evaporation gave a thick suspension which was treated with aqueous hydrogen chloride (100 mL, 3 N). The solids briefly dissolved and a new precipitate formed. The solid was filtered and washed with water to give the desired compound (4.1 g, 96%). LCMS for C10H11N2O2 (M+H)+: m/z=191.1. 1H NMR (300 MHz, DMSO-d6): δ 8.52 (m, 1 H), 8.15 (m, 1 H), 7.23 (m, 1 H), 6.81 (m, 1 H), 3.05 (m, 2 H), 1.22 (m, 3 H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([O:22]S(C)(=O)=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31](O)=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([O:22][C:31]2[CH:32]=[CH:33][C:28]([Cl:27])=[CH:29][CH:30]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1)OS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1)Oc1ccc(Cl)cc1
Yield: 62.6 %

Procedure:
In a similar manner to that described in Reference example 35(b), a reaction was carried out using ethyl 3-(4-benzyloxyphenyl)-2-methanesulfonyloxypropionate (8.82 g), which is the product of Reference example 35(a), 4-chlorophenol (3.00 g) and potassium carbonate (6.44 g) and the reaction mixture was treated to afford the desired compound (5.99 g) as colorless crystals.
Reaction SMILES: CCN(C(C)C)C(C)C.[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:15]([NH:17][CH2:18][C:19]([OH:21])=O)=[O:16].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[N:45]1([C:51]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=2[C:59]([F:62])([F:61])[F:60])=[O:52])[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1>CN(C=O)C.O>[O:21]=[C:19]([N:48]1[CH2:49][CH2:50][N:45]([C:51](=[O:52])[C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=2[C:59]([F:62])([F:60])[F:61])[CH2:46][CH2:47]1)[CH2:18][NH:17][C:15]([C:11]1[O:10][CH:14]=[CH:13][CH:12]=1)=[O:16]
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Reactant: O=C(O)CNC(=O)c1ccco1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccco1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33 %

Procedure:
DIPEA (0.143 mL, 0.83 mmol) was added to a stirred solution of [(furan-2-carbonyl)-amino]-acetic acid (40 mg, 0.24 mmol) in DMF (1 mL). HOBT (38 mg, 0.28 mmol), EDCI.HCl (54 mg, 0.28 mmol) were added, followed by the addition of piperazine-1-yl-(2-trifluoromethyl-phenyl)-methanone hydrochloride (0.2602 mmol) at room temperature. The resulting mixture was stirred at room temperature overnight. Water was then added, and the product was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the crude product. Purification using column chromatography (using silica gel, 60-120 A° and 10% methanol in chloroform as the eluent) afforded furan-2-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazine-1-yl]-ethyl}-amide in 33% yield. LC-MS purity: 83%, 1H NMR (CDCl3): δ 7.74 (d, 1H), 7.60 (m, 2H), 7.56 (d, 2H), 7.48 (s, 1H), 7.12 (t, 1H), 6.50 (q, 1H), 4.30 (m, 2H), 4.08-3.82 (m, 2H), 3.78-3.64 (m, 2H), 3.62-3.48 (m, 2H), 3.22 (m, 2H).
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CN1CCOCC1.C(OC(Cl)=O)C(C)C.C(O)(C(F)(F)F)=O.[NH:42]1[CH2:49][CH2:48][CH2:47][C@H:43]1[C:44]([NH2:46])=[O:45].C(N(C(C)C)CC)(C)C>CN(C)C=O.COCCOC>[NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10]([N:42]1[CH2:49][CH2:48][CH2:47][C@H:43]1[C:44]([NH2:46])=[O:45])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: NC(=O)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: COCCOC
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(N)=O
Temperature: -15 °C
Reaction time: 0.08 h
Yield: 77.8 %

Procedure:
87.6 g Boc-L-Phe-OH was dissolved in a mixture of 50 ml dimethylformamide (DMF) and 300 ml 1,2-dimethoxyethane (DME) and cooled to −15° C. Subsequently, 37 ml N-methylmorpholine (NMM) (1 equivalent) was added at once and subsequently 45 ml isobutylchloroformate (IBCF) (1 equivalent) was added dropwise over 10 min. The mixture was then stirred for further 5 min at −15° C. 40 g TFA.H-L-Pro-NH2 (1.06 equivalents) was subsequently added in portions over 5 min, and then 315 ml N,N-diisopropyl-N-ethylamine (DIEA) (1 equivalent) was added at once. The reaction mixture was reacted over night at room temperature and atmospheric pressure. Subsequently, the reaction mixture was concentrated in a rotatory evaporator equipped with a water aspirator and a dry ice/acetone trap, and the residue was taken in 1 l of ethylacetate followed by twelve washes with 80 ml 1N aqueous KHSO4 solution, one wash with 80 ml brine, ten washes with 80 ml saturated aqueous NaHCO3 solution, one wash with 80 ml brine in a 2 l separatory funnel. The subsequent drying was carried out over 50 g Na2SO4. After filtration through a sinter glass funnel (coarse porosity) was concentrated as described above. The residue of evaporation (dry foam) was then triturated in 1 l hexane, and a solid was collected on a sinter glass funnel (120 mm i.d.×120 mm, medium porosity). This was followed by drying in a desiccator over 12 hours at room temperature and a pressure of 0.1 to 1 mm Hg (vacuum oil pump, with dry ice/acetone trap). Thus, 92.8 g Boc-L-Phe-L-Pro-NH2 was obtained (yield: 77.8%).
Reaction SMILES: C[C:2](C)([O-:4])C.[K+].[Cl:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].C(OCC)=O.Cl>C1COCC1.C(OCC)C>[Cl:7][CH:8]([CH:2]=[O:4])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)CCl
Reactant: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCOC=O
Product: CCOC(=O)C(Cl)C=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a three neck 2 L round bottom flask charged with potassium t-butoxide (0.5 mol, 500 mL of a 1M solution in THF) and 500 mL of dry THF cooled to 0° C. was added dropwise from an addition funnel a solution of ethyl chloroacetate (0.5 mol, 53.5 mL) and ethyl formate (0.5 mol, 40.4 mL), in 200 mL of THF over 3 hours. After completion of addition, the reaction mixture was stirred for 1 hour and allowed to stand overnight. The resulting solid was diluted with diethyl ether and cooled in an ice bath. Then, the pH was lowered to approximately 3 using 6N HCl. The organic phase was separated, and the aqueous layer was washed 3 times with diethyl ether. The combined ethereal portions were dried over NaSO4, and concentrated in vacuo. The crude desired compound was stored at -30° C. and used without further purification.