Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]([O:16]C)=[O:15])=[CH:9][C:7]=2[CH:8]=1.[C:18]1([C:24]2[C:28]3[CH:29]=[CH:30][C:31](O)=[C:32]([CH2:33][CH2:34][CH3:35])[C:27]=3[O:26][N:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([C:24]2[C:28]3[CH:29]=[CH:30][C:31]([O:1][CH2:2][CH2:3][C:4]4[O:5][C:6]5[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[CH:9][C:7]=5[CH:8]=4)=[C:32]([CH2:33][CH2:34][CH3:35])[C:27]=3[O:26][N:25]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)Cc1ccc2oc(CCO)cc2c1
Reactant: CCCc1c(O)ccc2c(-c3ccccc3)noc12
Product: CCCc1c(OCCc2cc3cc(CC(=O)O)ccc3o2)ccc2c(-c3ccccc3)noc12

Procedure:
Using the procedure from Example 1, steps F and G, the title compound was prepared from methyl 2-(2-hydroxyethyl)benzofuran-5-acetate and 3-phenyl-7-propyl-6-hydroxybenz[4,5]isoxazole as a colorless oil.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:19]1[N:27]=[CH:26][N:25]=[C:24]2[C:20]=1[N:21]=[C:22]([C:34]1[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH:37]=[CH:36][CH:35]=1)[N:23]2[CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][O:29]1>CN(C=O)C>[Si:1]([O:8][CH2:9][C@H:10]1[CH2:14][CH2:13][C@H:12]([O:15][C:19]2[N:27]=[CH:26][N:25]=[C:24]3[C:20]=2[N:21]=[C:22]([C:34]2[C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[CH:37]=[CH:36][CH:35]=2)[N:23]3[CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Clc1ncnc2c1nc(-c1cccc3ccccc13)n2C1CCCCO1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CC[C@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CC[C@H](Oc2ncnc3c2nc(-c2cccc4ccccc24)n3C2CCCCO2)C1
Reaction time: 0.25 h
Yield: 70 %

Procedure:
To a solution of (1S,3S)-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-cyclopentanol (111.0 mg, 0.0004817 mol) (azeotroped with toluene) in DMF (3.6 mL) at 0° C. under an atmosphere of nitrogen was added sodium hydride (24.1 mg, 0.000602 mol). The mixture was stirred for 15 min. To this cold solution was added a solution of 6-chloro-8-(1-naphthyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (163 mg, 0.000401 mol) in DMF (1.8 mL). The flask was rinsed with DMF (1.0 mL)) and this was added to the reaction as well. The resulting mixture was stirred for 20 h. The reaction mixture was quenched with water and the mixture was extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered and collected in vacuo. The residue was purified by flash chromatography (10 to 40% EtOAc/hexanes) to obtain 156.9 mg (70%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][C:17]2[N:21](CCC#N)[C:20]3[CH:26]=[CH:27][CH:28]=[CH:29][C:19]=3[N:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].[C:31](OCC)(=O)[CH3:32].CO>C(O)(C)C.C(=O)(O)[O-].[Na+].C(N(CC)CC)C>[CH2:1]([CH:8]1[CH2:13][CH:12]2[N:11]([CH2:14][CH2:15][CH2:16][C:17]3[NH:21][C:20]4[CH:26]=[CH:27][CH:28]=[CH:29][C:19]=4[N:18]=3)[CH:10]([CH2:31][CH2:32]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CCCn1c(CCCN2CCC(Cc3ccccc3)CC2)nc2ccccc21
Reactant: CCOC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: c1ccc(CC2CC3CCC(C2)N3CCCc2nc3ccccc3[nH]2)cc1

Procedure:
A mixture of 0.4 g of 3-{2-[3-(4-benzyl-piperidin-1-yl)-propyl]-benzoimidazol-1-yl}-propionitrile, 20 mL of isopropanol and 2 mL of 0.4 M sodium in isopropanol was heated to reflux for 2 h. Conversion was complete by TLC (80:20:1 ethyl acetate:methanol:triethylamine). The mixture was cooled, diluted with 10 mL of saturated sodium bicarbonate and concentrated. The residue was partitioned between 3×100 mL of chloroform and 50 mL of water. After drying over magnesium sulfate and concentration under reduced pressure, the residue was purified by preparative TLC eluting with 400:100:25 ethyl acetate:methanol:triethylamine. The major band (UV visualization) was 2-[3-(4-benzyl-piperidin-1-yl)-propyl]-1H-benzimidazole (220 mg): MS (m+1)=334.2; 1H NMR (400 MHz, CDCl3) 7.4 (d, 2H), 7.32 (m, 2H), 7.25 (m, 1H), 7.2 (m, 4H), 3.1 (m, 4H), 2.65 (m, 2H), 2.6 (m, 2H), 2.1 (m, 2H), 2.0 (m, 2H), 1.8 (m, 2H), 1.7 (m, 1H), 1.5 (m, 2H).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[CH:9]=[C:10]([C:14]([CH2:22][CH3:23])([O:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH2:15][CH3:16])[CH:11]=[CH:12][CH:13]=1.[CH2:24]([C:26]([C:45]1[CH:58]=[CH:57][C:48]([O:49][CH2:50][C@@H:51]2[O:55][C:54](=[O:56])[CH2:53][CH2:52]2)=[C:47]([CH3:59])[CH:46]=1)([C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[C:31]([CH3:44])[CH:30]=1)[CH2:27][CH3:28])[CH3:25].C(OCC)(=O)C>CN(C)C=O>[CH2:24]([C:26]([C:45]1[CH:58]=[CH:57][C:48]([O:49][CH2:50][C@@H:51]2[O:55][C:54](=[O:56])[CH2:53][CH2:52]2)=[C:47]([CH3:59])[CH:46]=1)([C:29]1[CH:34]=[CH:33][C:32]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([CH2:22][CH3:23])([O:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH2:15][CH3:16])[CH:9]=2)=[C:31]([CH3:44])[CH:30]=1)[CH2:27][CH3:28])[CH3:25]
Reactant: CCC(CC)(c1ccc(OC[C@H]2CCC(=O)O2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: CCC(CC)(O[Si](C)(C)C)c1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC(CC)(O[Si](C)(C)C)c1cccc(-c2ccc(C(CC)(CC)c3ccc(OC[C@H]4CCC(=O)O4)c(C)c3)cc2C)c1
Temperature: 85 °C
Reaction time: 13.5 h
Yield: 49.1 %

Procedure:
A [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (1.49 mg, 0.002 mmol), a 2 M sodium carbonate solution (0.1 mL, 0.2 mmol) and [1-(3-bromo-phenyl)-1-ethyl-propoxy]-trimethyl-silane (Example 17-(1); 26.25 mg, 0.091 mmol) were added to a solution of (R)-5-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one (Example 15-(3); 30 mg, 0.061 mmol) in N,N-dimethylformamide (0.1 mL) at room temperature, and the mixture was stirred at 85° C. for 13.5 hours. Ethyl acetate was added to the reaction solution. The organic layer was washed with distilled water and brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (n-hexane/ethyl acetate=3/1, developed twice) to give the title compound (18 mg, 49.2%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:19])[CH2:13][CH2:12][NH:11][CH2:10][C:9]2([CH2:15][O:16][CH2:17][CH3:18])[CH3:14])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:27][CH2:28][CH:29]=[C:30]1[C:36]2[CH:37]=[CH:38][CH:39]=[N:40][C:35]=2[CH2:34][O:33][C:32]2[CH:41]=[CH:42][C:43]([C:45]([OH:48])([CH3:47])[CH3:46])=[CH:44][C:31]1=2>C(#N)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:19])[CH2:13][CH2:12][N:11]([CH2:27][CH2:28][CH:29]=[C:30]3[C:36]4[CH:37]=[CH:38][CH:39]=[N:40][C:35]=4[CH2:34][O:33][C:32]4[CH:41]=[CH:42][C:43]([C:45]([OH:48])([CH3:47])[CH3:46])=[CH:44][C:31]3=4)[CH2:10][C:9]2([CH2:15][O:16][CH2:17][CH3:18])[CH3:14])=[CH:4][CH:3]=1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Reactant: CCOCC1(C)CNCCC1(O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOCC1(C)CN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)CCC1(O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 65 %

Procedure:
To a solution of 4-(4-chloro-phenyl)-3-ethoxymethyl-3-methyl-piperidin-4-ol (0.038 g, 0.13 mmol) in acetonitrile/water (8:2) (1.3 mL) was added K2CO3 (0.075 g, 0.53 mmol) and 2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.050 g, 0.13 mmol). The solution was allowed to stir at room temperature for 48 h. The reaction was concentrated and partitioned between EtOAc/H2O, extracted with EtOAc (3×). The organics were collected, dried over MgSO4, filtered and evaporated in vacuo, then purified by Biotage flash chromatography (75% ethyl acetate/25% hexane) to yield the title compound in 65% yield. 1H-NMR (CDCl3): δ 0.81 (s, 3H), 0.98 (t, 3H), 1.58 (s, 6H), 1.84 (s, 1H), 2.31-2.49 (m, 5H), 2.58 (d, 1H), 2.67 (s, 1H), 2.77 (d, 2H), 3.26 (q, 2H), 3.65 (d, 2H), 5.33 (bs, 2H), 6.16 (t, 1H), 6.82 (d, 1H), 7.22-7.36 (m, 7H), 7.45 (d, 1H), 7.60 (d, 1H). ESI-MS m/z: 577 (M+1), retention time 1.58.
Reaction SMILES: C(N[C:6](=[O:38])[C:7]([NH:34]C(=O)C)([CH:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][N:28]=2)[CH2:23][CH2:22]1)[CH2:8][CH2:9][CH2:10][CH2:11][B:12]1[O:16]C(C)(C)C(C)(C)[O:13]1)(C)(C)C.[OH2:39]>Cl>[NH2:34][C:7]([CH:21]1[CH2:22][CH2:23][N:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][N:28]=2)[CH2:25][CH2:26]1)([CH2:8][CH2:9][CH2:10][CH2:11][B:12]([OH:13])[OH:16])[C:6]([OH:38])=[O:39]
Reactant: O
Reactant: CC(=O)NC(CCCCB1OC(C)(C)C(C)(C)O1)(C(=O)NC(C)(C)C)C1CCN(c2ccc(Cl)cn2)CC1
Agent: Cl
Product: NC(CCCCB(O)O)(C(=O)O)C1CCN(c2ccc(Cl)cn2)CC1
Temperature: 25 °C
Yield: 82 %

Procedure:
A solution of 2-acetylamino-2-(5′-chloro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-6-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)hexanoic acid, tert-butylamide (1.07 g) in 6 N HCl (20 mL) was stirred at 90° C. for 1 day. After cooling to room temperature, the reaction mixture was transferred to a separatory funnel, diluted with deionized water (10 mL) and washed with dichloromethane (3×). The aqueous layer was frozen in liquid nitrogen and lyophilized to give title compound as a white solid (590 mg, 82%); 1H NMR (D2O, 300 MHz) δ 8.00 (d, J=2.5 Hz, 1H), 7.47 (dd, J1=9.0 Hz, J2=2.5 Hz, 1H), 6.79 (d, J=9 Hz, 1H), 4.42 (d, J=13.5 Hz, 1H), 4.32 (d, J=13 Hz, 1H), 2.79 (t, J=12 Hz, 2H), 2.06 (m, 1H), 1.78-1.94 (m, 3H), 1.55-1.70 (m, 2H), 1.43 (m, 4H), 1.30 (m, 1H) and 0.82 (t, J=7 Hz, 2H); MS (+CI): m/z for C16H25BClN3O4: expected 369.2. found 370.2 (M+H)+, 352.23 (M+H−H2O)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][O:12][C:10](=[O:11])[C:9]2=[CH2:14])=[CH:4][CH:3]=1.[C:15]([OH:23])(=[S:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1.C(N(CC)CC)C.C(OCC)C>[C:15]([S:22][CH2:14][CH:9]1[CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:13][O:12][C:10]1=[O:11])(=[O:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C=C1C(=O)OCC1c1ccc(Cl)cc1
Reactant: OC(=S)c1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: O=C(SCC1C(=O)OCC1c1ccc(Cl)cc1)c1ccccc1
Reaction time: 18 h
Yield: 75 %

Procedure:
To a solution of 600 mg of β-(p-chlorophenyl)-α-methylene-γ-butyrolactone in 10 ml of toluene were added 0.44 ml of thiobenzoic acid and one drop of triethylamine and the reaction was effected at room temperature for 18 hours. The reaction mixture was diluted with 100 ml of ethyl ether, washed with water and saturated saline, dried over magnesium sulfate and the solvent was then distilled off. The crude product thus obtained was purified by a silica gel column chromatography to give 750 mg (yield 75%) of the title compound.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2C(C(=O)NC3C=CC=CC=3)=CN=C(SC)N=2)[CH:9]=1)(C)(C)C.C(OC(=O)NC1C=CC=C(OC2C(C(=O)NC3C=CC=CC=3)=CN=C(S(C)(=O)=O)N=2)C=1)(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH3:15][O:14][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=1)[NH2:7]
Reactant: CSc1ncc(C(=O)Nc2ccccc2)c(Oc2cccc(NC(=O)OC(C)(C)C)c2)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)OC(=O)Nc1cccc(Oc2nc(S(C)(=O)=O)ncc2C(=O)Nc2ccccc2)c1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1cccc(N)c1
Temperature: 100 °C
Reaction time: 16 h
Yield: 79.5 %

Procedure:
To a solution of 6 (1.69 g, 12.26 mmol), in toluene (50.0 mL) was added 7 (2.0 g, 12.26 mmol), BINAP (0.3 g, 0.49 mmol), cesium carbonate (7.9 g, 24.5 mmol). The solution was degassed (by purging N2 for 15 min) and to it was added Pd(OAc)2 (0.054 g, 0.25 mmol). The reaction mixture was stirred at 100° C. for 16 h under nitrogen atmosphere. It was cooled, diluted with ethyl acetate (100 mL) and filtered through Celite®. The filtrate was washed with water (2×25 mL), brine (25 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue obtained was further purified by column chromatography (SiO2, 60-120 mesh, Ethylacetete/hexane: 15/85). The solid obtained after evaporating the required fractions was washed with diethyl ether and dried under high vacuum to get 8 (1.2 g, 37%) as a light yellow solid.
Reaction SMILES: [BH4-].[Na+].[NH2:3][C:4]1[C:9]([Cl:10])=[CH:8][C:7]([C:11](=[O:29])[CH2:12][NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[CH:6][C:5]=1[Cl:30]>CO>[NH2:3][C:4]1[C:9]([Cl:10])=[CH:8][C:7]([CH:11]([CH2:12][NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[OH:29])=[CH:6][C:5]=1[Cl:30]
Reactant: Nc1c(Cl)cc(C(=O)CNCCCCCCOCCc2ccccn2)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Nc1c(Cl)cc(C(O)CNCCCCCCOCCc2ccccn2)cc1Cl
Reaction time: 1.5 h
Yield: 10.6 %

Procedure:
Sodium borohydride (0.16 g) was added portionwise over 5 min to a solution of 1-(4-amino-3,5-dichlorophenyl)-2-[[6-[2-(2-pyridinyl)ethoxy]hexyl]amino]ethanone (0.44 g) in methanol (7 ml) at 0°-5° with stirring. After 1.5 h, the solution was evaporated in vacuo and the residue partitioned between water (60 ml) and ethyl acetate (100 ml). The organic phase was dried and evaporated in vacuo to a gum which was purified by FCC eluting with System C (90:10:1) to afford a product, which was triturated with hexane (2 ml) to give the title compound as a colourless powder (47 mg), m.p. 94.5°-96.5°, t.l.c. (System A 39:10:1) Rf 0.44.
Reaction SMILES: [NH2:1][C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].Br[CH2:21][C:22]1[CH:34]=[CH:33][C:25]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:24][CH:23]=1.C(Cl)Cl>C(Cl)Cl.CCOC(C)=O>[NH2:1][C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]([CH2:21][C:22]2[CH:34]=[CH:33][C:25]([C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])=[CH:24][CH:23]=2)[C:3]1=[O:12]
Reactant: NC1(c2ccccc2Cl)C(=O)Nc2ccc(Cl)cc21
Reactant: CC(C)(C)OC(=O)c1ccc(CBr)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(CN2C(=O)C(N)(c3ccccc3Cl)c3cc(Cl)ccc32)cc1
Yield: 59.4 %

Procedure:
This compound is prepared according to the procedure described in EXAMPLE 89 from 1.0 g of 3-amino-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one and 1.01 g of tert-butyl 4-bromomethylbenzoate. Chromatography on silica using DCM and then a DCM/AcOEt mixture (95/5; v/v) as the eluent gives 0.98 g of the expected product, which is used as such in the next step.
Reaction SMILES: C(OC([N:6]1[CH2:21][CH2:20][C:10]2[C:11]3[C:12]([CH3:19])([CH3:18])[CH2:13][CH2:14][C:15]=3[CH:16]=[CH:17][C:9]=2[CH2:8][CH2:7]1)=O)C.[Si](I)(C)(C)C>C(Cl)(Cl)Cl>[CH3:18][C:12]1([CH3:19])[C:11]2[C:10]3[CH2:20][CH2:21][NH:6][CH2:7][CH2:8][C:9]=3[CH:17]=[CH:16][C:15]=2[CH2:14][CH2:13]1
Reactant: CCOC(=O)N1CCc2ccc3c(c2CC1)C(C)(C)CC3
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Product: CC1(C)CCc2ccc3c(c21)CCNCC3
Temperature: 60 °C
Yield: 49.7 %

Procedure:
Into a glass vial containing the product from step (a) (102 mg, 0.355 mmol) in CHCl3 (2 ml), TMSI (483 μL, 3.55 mmol) was added. The reaction mixture was heated to 60° C. for 2 hours. The volatiles were evaporated in vacuo and 2M HCl (5 ml) and water (25 ml) were added. The aqueous mixture was washed with diethyl ether (2×). The aqueous layer was then basified with 2M NaOH to pH 10 and extracted with DCM (3×). The combined DCM extracts were washed with brine, dried over Na2SO4, and solvent evaporated in vacuo to give the title product as a white semi-solid (38 mg). 1H NMR (300 MHz, CDCl3) δ 6.93-6.91 (m, 2H); 3.05-2.89 (m, 8H); 2.80 (t, J=7.5 Hz, 2H); 1.98 (br s, 1H); 1.90 (t, J=7.5 Hz, 2H); 1.35 (s, 6H); MS: ESI (positive): 216 (M+1).
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][CH:11]=[CH:12][C:13]=1[CH:14]([O:17][C:18](=[O:20])[CH3:19])[CH2:15][F:16])(=[O:8])=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[C:18]([O:17][CH:14]([C:13]1[CH:12]=[CH:11][S:10][C:9]=1[S:6]([NH2:5])(=[O:7])=[O:8])[CH2:15][F:16])(=[O:20])[CH3:19]
Reactant: CC(=O)OC(CF)c1ccsc1S(=O)(=O)NC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OC(CF)c1ccsc1S(N)(=O)=O
Reaction time: 12 h
Yield: 65.3 %

Procedure:
1.4 g (0.0043 mole) of N-t-butyl-3-(1-aceoxy-2-fluoroethyl) -2-thiophenesulfonamide synthesized in Example 2 dissolved in 5 ml of trifluoroacetic acid. The reaction solution was stirred at normal temperature for 12 hours and then concentrated under reduced pressure. The residue was dissolved in methylene chloride and washed with aqueous sodium bicarbonate solution. The organic layer was separated, dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated. The residue was recrystallized to obtain 750 mg (Yield: 74%) of the pure title compound as a white solid.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][N:9]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:31])[C@@H:16]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)[CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[N:10]1)(C)(C)C>Cl.C(O)C>[CH:18]1([CH2:17][C@H:16]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)[C:15]([NH:14][C:11]2[CH:12]=[CH:13][N:9]([CH2:8][CH2:7][OH:6])[N:10]=2)=[O:31])[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(Cl)c(Cl)c2)n1
Agent: Cl
Solvent: CCO
Product: O=C(Nc1ccn(CCO)n1)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 89.8 %

Procedure:
In a round bottom flask was placed (R)—N-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionamide (128 mg, 0.25 mmol), ethanol (10 mL) and concentrated hydrochloric acid (2 drops). This solution was then stirred at 25° C. until all starting material is consumed (˜1 hr). The reaction was then diluted with ethyl acetate (30 mL) and transferred to a separatory funnel where it was washed with a saturated aqueous solution of sodium bicarbonate (10 mL). The aqueous layer was then extracted with ethyl acetate (3×10 mL). The organic layers were then combined dried over magnesium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (4 g column, 20% ethyl acetate/hexanes to 60% ethyl acetate/hexanes) afforded (R)-3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-[1-(2-hydroxy-ethyl)-1H-pyrazol-3-yl]-propionamide (89 mg, 90%) as a white foam: [α]30589=−22.2° (c=0.18, methylene chloride); ES-HRMS m/e calcd for C19H23N3O2Cl2 (M+H)+ 418.1059, observed 418.1061; 1H NMR (300 MHz, DMSO-d6) δ 1.10 (m, 2H, CH2), 1.35-1.79 (m, 8H, 4×CH2), 2.05 (m, 1H, CH), 3.67 (q, J=5.6 Hz, 2H, OCH2), 3.79 (m, 1H, ArCHCO), 4.00 (t, J=5.6 Hz, 2H, NCH2), 4.83 (t, J=5.4 Hz, 1H, OH), 6.40 (d, J=2.2 Hz, 1H, Ar), 7.34 (dd, Jm=2.0 Hz, Jo=8.2 Hz, 1H, Ar), 7.53 (d, J=2.2 Hz, 1H, Ar), 7.58 (d, Jo=8.2 Hz, 1H, Ar), 7.59 (s, 1H, Ar), 10.71 (s, 1H, NH).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]([NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]1)=[O:6].[N+:20]([C:23]1[CH:53]=[CH:52][C:26]([CH2:27][O:28][C:29]([N:31]=[C:32]([NH:38][C:39](=[O:51])[O:40][CH2:41][C:42]2[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[CH:44][CH:43]=2)N2C=CC=N2)=[O:30])=[CH:25][CH:24]=1)([O-:22])=[O:21]>O1CCCC1>[N+:20]([C:23]1[CH:24]=[CH:25][C:26]([CH2:27][O:28][C:29]([N:31]=[C:32]([NH:38][C:39]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[CH:44][CH:43]=2)=[O:51])[NH:1][CH2:2][CH2:3][CH2:4][C:5]([NH:7][C@H:8]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]2)=[O:6])=[O:30])=[CH:52][CH:53]=1)([O-:22])=[O:21]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)CCCN)C1
Reactant: O=C(N=C(NC(=O)OCc1ccc([N+](=O)[O-])cc1)n1cccn1)OCc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)CCCNC(=NC(=O)OCc2ccc([N+](=O)[O-])cc2)NC(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Yield: 109 %

Procedure:
To a solution of tert-butyl (3S)-3-(4-aminobutanoylamino)-1-pyrrolidinecarboxylate (1.36 g) in anhydrous tetrahydrofuran (30 ml), 4-nitrobenzyl [(4-nitrobenzyloxy)carbonylimino-pyrazol-1-ylmethyl]carbamate (1.60 g) was added under ice cooling. The resulting (mixture was then treated in a similar manner to that described in Referential Example 16-(1), whereby the title compound (2.50 g) was obtained as an amorphous substance.
Reaction SMILES: [CH2:1]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[CH:7]=[CH:6][C:5]=2[S:4](=[O:15])[CH2:3][CH2:2]1.C(O[CH:19](OCC)[N:20]([CH3:22])[CH3:21])C>>[CH3:19][N:20]([CH:22]=[C:3]1[CH2:2][CH2:1][C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[CH:7]=[CH:6][C:5]=2[S:4]1=[O:15])[CH3:21]
Reactant: O=S1CCCc2c1ccc1ccccc21
Reactant: CCOC(OCC)N(C)C
Product: CN(C)C=C1CCc2c(ccc3ccccc23)S1=O

Procedure:
From 3-dimethylaminomethylenebenzo[f]thiochroman-4-one (400 mg, 1.26 mmol) and 4-(2-dimethylaminoethoxy)phenylguanidinium dinitrate (438 mg, 1.26 mmol) to afford the title compound (155 mg) as a canary yellow solid m.p. 165-167°. δH (CDCl3) 9.08 (1H, d, J 8.3 Hz), 8.38 (1H, s), 7.77 (2H, m), 7.55-7.46 (5H, m), 7.05 (1H, br s), 6.88 (2H, m), 4.05 (2H, t, J 5.8 Hz), 3.78 (2H, s), 2.73 (2H, t, J 5.8 Hz) and 2.34 (6H, s). MS (ES+) 429 (MH+). 3-Dimethylaminomethylenebenzo[f]thiochroman-4-one was prepared from benzo[f]thiochroman-4-one (1.50 g, 7.01 mmol) and N,N-dimethyl-formamide diethylacetal to give the compound as a yellow solid (1.67 g) m.p. 163-1650. MS(EI) 269 (M+, 49.8%), 82 (100%).
Reaction SMILES: C[O:2][C:3](=[O:40])[CH2:4][CH2:5][N:6]([C:11](=[O:39])[C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([O:19][CH2:20][CH2:21][N:22]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])C2C=CC=CN=2)[CH:13]=1)[C:7]([CH3:10])([CH3:9])[CH3:8].[OH-].[Na+].Cl.O1[CH2:49][CH2:48]OCC1>O>[CH2:32]([O:31][C:29]([N:22]([C:49]1[CH:48]=[CH:7][N:6]=[CH:5][CH:4]=1)[CH2:21][CH2:20][O:19][C:14]1[CH:13]=[C:12]([CH:17]=[C:16]([Cl:18])[CH:15]=1)[C:11]([N:6]([C:7]([CH3:9])([CH3:8])[CH3:10])[CH2:5][CH2:4][C:3]([OH:2])=[O:40])=[O:39])=[O:30])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: C1COCCO1
Reactant: COC(=O)CCN(C(=O)c1cc(Cl)cc(OCCN(C(=O)OCc2ccccc2)c2ccccn2)c1)C(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)N(CCC(=O)O)C(=O)c1cc(Cl)cc(OCCN(C(=O)OCc2ccccc2)c2ccncc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 3-({3-[2-(benzyloxycarbonyl-pyridin-yl-amino)-ethoxy]-5-chloro-benzoyl}-tert-butyl-amino)-propionic acid methyl ester (0.038 g) in a mixture of 1,4-dioxane (1 ml) and water (0.5 ml) was added 2M sodium hydroxide solution (0.066 ml). The reaction mixture was stirred at room temperature for 1 h, neutralised by the addition of 2M hydrochloric acid (0.066 ml) and then concentrated under reduced pressure. The residue was partitioned between ethyl acetate and brine, the aqueous layer was removed and the organic layer was dried over sodium sulphate and then concentrated under reduced pressure gave the title compound as a white solid (0.034 g).