Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([O:45][CH3:46])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]([NH:30][C@H:31]([C:35]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:36])[C@@H:32]([CH3:34])[OH:33])=O)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[N:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][N:14]=2)[CH:11]=1.COCCN(S(F)(F)F)CCOC.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:1][O:2][CH2:3][C@@H:4]([O:45][CH3:46])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]3[O:33][C@@H:32]([CH3:34])[C@@H:31]([C:35]([O:37][CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[O:36])[N:30]=3)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[N:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][N:14]=2)[CH:11]=1
Reactant: COC[C@@H](OC)Oc1cc(Oc2cnc(S(C)(=O)=O)cn2)cc(-c2ccc(C(=O)N[C@H](C(=O)OCc3ccccc3)[C@@H](C)O)[nH]2)c1
Agent: COCCN(CCOC)S(F)(F)F
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: COC[C@@H](OC)Oc1cc(Oc2cnc(S(C)(=O)=O)cn2)cc(-c2ccc(C3=N[C@H](C(=O)OCc4ccccc4)[C@H](C)O3)[nH]2)c1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 71.7 %

Procedure:
Benzyl N-{[5-(3-[(1S)-2-methoxy-1-methoxyethoxy]-5-{[5-(methylsulfonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrol-2-yl]carbonyl}-L-threoninate (13.5 g, 21.2 mmol) synthesized in Example (103b) was dissolved in methylene chloride (150 mL), and cooled to −78° C. Bis(2-methoxyethyl)amino sulfur trifluoride (5.47 mL, 29.7 mmol) was added dropwise, and stirring was carried out at −78° C. for 40 minutes. Potassium carbonate (5.86 g, 42.4 mmol) was added, and stirring was carried out for 1.5 hours with the temperature being raised gradually to room temperature. A saturated aqueous sodium hydrogencarbonate solution (100 mL) was added at 0° C., and extraction was carried out twice with methylene chloride (100 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=40%-70%) to afford the desired product (9.68 g, yield 74%) as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]2[O:13][C:14]3[CH:21]=[C:20]([N:22]([S:29]([C:32]4[CH:33]=[CH:34][CH:35]=[C:36]5[C:41]=4[NH:40][CH2:39][CH2:38][CH2:37]5)(=[O:31])=[O:30])[CH2:23][C:24]([O:26]CC)=[O:25])[CH:19]=[CH:18][C:15]=3[C:16]=2[CH3:17])=[CH:6][CH:5]=1)(=[NH:3])[NH2:2].[OH-].[Na+]>>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]2[O:13][C:14]3[CH:21]=[C:20]([N:22]([S:29]([C:32]4[CH:33]=[CH:34][CH:35]=[C:36]5[C:41]=4[NH:40][CH2:39][CH2:38][CH2:37]5)(=[O:31])=[O:30])[CH2:23][C:24]([OH:26])=[O:25])[CH:19]=[CH:18][C:15]=3[C:16]=2[CH3:17])=[CH:6][CH:5]=1)(=[NH:2])[NH2:3]
Reactant: CCOC(=O)CN(c1ccc2c(C)c(CNc3ccc(C(=N)N)cc3)oc2c1)S(=O)(=O)c1cccc2c1NCCC2
Agent: [Na+]
Agent: [OH-]
Product: Cc1c(CNc2ccc(C(=N)N)cc2)oc2cc(N(CC(=O)O)S(=O)(=O)c3cccc4c3NCCC4)ccc12

Procedure:
Prepared analogously to Example 3 from 2-[N-(4-amidinophenyl)-aminomethyl]-3-methyl-6-[N-(ethoxycarbonylmethyl)-1,2,3,4-tetrahydro-quinoline-8-sulphonylamino]-benzofuran and sodium hydroxide solution.
Reaction SMILES: [OH:1][C:2]([CH:5]1[CH2:10][NH:9][CH2:8][C:7]2([CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH3:28])[CH:19]=3)=[O:17])[CH2:12][CH2:11]2)[O:6]1)([CH3:4])[CH3:3].C([O-])(O)=O.[Na+].FC(F)(F)S(O[CH2:40][C:41]([F:44])([F:43])[F:42])(=O)=O>C(O)C>[OH:1][C:2]([CH:5]1[O:6][C:7]2([CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:26])[CH3:27])=[C:20]([CH3:28])[CH:19]=3)=[O:17])[CH2:12][CH2:11]2)[CH2:8][N:9]([CH2:40][C:41]([F:44])([F:43])[F:42])[CH2:10]1)([CH3:4])[CH3:3]
Reactant: Cc1cc(C(=O)N2CCC3(CC2)CNCC(C(C)(C)O)O3)ccc1OC(C)C
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(C(=O)N2CCC3(CC2)CN(CC(F)(F)F)CC(C(C)(C)O)O3)ccc1OC(C)C
Temperature: 80 °C
Yield: 52.9 %

Procedure:
(2-(2-Hydroxypropan-2-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)(4-isopropoxy-3-methylphenyl)methanone (25 mg, 0.06 mmol) was dissolved in dry ethanol (300 μL) and NaHCO3 (50 mg, 0.60 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (20 μL, 0.13 mmol) were added and the reaction mixture was heated at 80° C. for 16 hours. The reaction mixture was filtered, concentrated in vacuo and purified by silica gel column chromatography using 0-100% EtOAc/hexanes as eluent to give [10-(1-hydroxy-1-methyl-ethyl)-8-(2,2,2-trifluoroethyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone (15 mg, 53%) as a colorless oil. ESI-MS m/z calc. 472.5. Found 473.5 (M+1)+; Retention time: 1.93 minutes (3 min run).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[C:12](=[O:37])[N:13](CC4C=CC(OC)=CC=4)[C:14](=[O:27])[N:15]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([CH3:26])([CH3:25])[C:23]#[N:24])=[CH:18][CH:17]=4)[C:5]=3[C:4]=2[N:3]=1.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[Ce]>C(#N)C.O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[C:12](=[O:37])[NH:13][C:14](=[O:27])[N:15]([C:16]4[CH:17]=[CH:18][C:19]([C:22]([CH3:26])([CH3:25])[C:23]#[N:24])=[CH:20][CH:21]=4)[C:5]=3[C:4]=2[N:3]=1
Reactant: COc1ccc(Cn2c(=O)c3cnc4ccc(Cl)nc4c3n(-c3ccc(C(C)(C)C#N)cc3)c2=O)cc1
Agent: [Ce]
Solvent: CC#N
Solvent: O=[N+]([O-])O
Solvent: O
Product: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c(=O)c3cnc4ccc(Cl)nc4c32)cc1
Yield: 66.6 %

Procedure:
2-(4-(9-chloro-3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydropyrimidino[5,4-c][1,5]naphthyridine-1(2H)-yl)phenyl)-2-methylpropanenitrile (1.2 g, 2.3 mmol) was dissolved in acetonitrile (80 mL) and water (20 mL). Ammonium ceric nitrate (5.1 g, 9.4 mmol) was added in batch at room temperature. The reaction mixture was reacted at room temperature for 16 hrs, and then concentrated. 100 mL water was added. The mixture was filtered. The resulting solid was washed with EA and PE (1:1), and dried in vacuum to obtain a yellow solid (600 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]=[C:11]([Cl:13])[Cl:12])[CH:5]=[C:4]([Cl:14])[C:3]=1[OH:15].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:23][C:24](=[O:26])[CH3:25]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]=[C:11]([Cl:13])[Cl:12])[CH:5]=[C:4]([Cl:14])[C:3]=1[O:15][CH2:23][C:24](=[O:26])[CH3:25]
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)COc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
First, 8.64 g of 2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenol, 4.98 g of potassium carbonate, 3.36 g of chloroacetone, and 50 ml of N,N-dimethylformamide were placed in a reaction vessel. After stirring at room temperature for 24 hours, the reaction mixture was filtered. The filtrate was poured into diluted hydrochloric acid, and extracted twice with diethyl ether. The diethyl ether layers were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated, which afforded 10.12 g (yield, 98%) of (2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy-acetone, m.p., 83.8° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]([C:15]([O:17]C)=[O:16])=[C:13]([CH3:19])[NH:12][C:11]3[CH2:20][O:21][CH:22]([CH3:25])[C:23](=[O:24])[C:10]2=3)[CH:5]=[CH:6][C:7]=1[F:8].N1C=CC=CC=1.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.Cl>C(Cl)(Cl)Cl.ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[C:10]3[C:23](=[O:24])[C@@H:22]([CH3:25])[O:21][CH2:20][C:11]=3[NH:12][C:13]3[CH2:19][O:17][C:15](=[O:16])[C:14]2=3)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COC(=O)C1=C(C)NC2=C(C(=O)C(C)OC2)C1c1ccc(F)c(Br)c1
Agent: Cl
Agent: [Br-]
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: C[C@H]1OCC2=C(C1=O)[C@@H](c1ccc(F)c(Br)c1)C1=C(COC1=O)N2
Temperature: -10 °C
Reaction time: 0.33 h

Procedure:
The product from Example 84D (1.0 g, 2.5 mmol) was dissolved in chloroform (15 mL) under a nitrogen atmosphere, cooled to −10° C., treated with pyridine (0.24 mL, 3.0 mmol) and pyridinium tribromide (0.97 g, 3.0 mmol), stirred at −10° C. for 20 minutes, diluted with dichloromethane (100 mL) and treated with 1M HCl (10 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (50 mL). The combined organic layers were dried (MgSO4), filtered, concentrated, heated to 130° C. under nitrogen for 15 minutes and cooled to ambient temperature. The residue was purified by chromatography on silica gel eluting with 38:1:1:40 ethyl acetate:formic acid:water:hexane to provide the title compound as the faster moving diasteriomer which was crystallized from dichloromethane. 1H NMR (DMSO-d6) δ 1.22 (d, 3H), 4.12 (q, 1H), 4.48 (d, 1H), 4.65 (d, 1H), 4.68 (s, 1H), 4.86 (dd, 1H), 4.99 (d, 1H), 7.24-7.28 (m, 2H), 7.48 (dd, 1H), 10.42 (bs, 1H);
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=[O:9])[O:5][C:6]=1Br.O.CC(O)=O>C1(C)C=CC=CC=1.[Zn]>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=[O:9])[O:5][CH:6]=1
Reactant: O=C(O)c1cc(Br)c(Br)o1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(O)c1cc(Br)co1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A 500 mL three-necked round-bottom flask fitted with an overhead mechanical stirrer, and reflux condenser was charged with 4,5-dibromofuran-2-carboxylic acid (34.3 g, 127 mmol), H2O (100 mL), and HOAc (25 mL). The third neck of the flask was stoppered and the suspension was heated to reflux with a temperature controlled heating mantle held at 125-130° C. Zn dust (15.0 g, 229 mmol) (previously ground in a mortar and pestle to break up lumps) was added portionwise over 50 minutes. Subsequent portions are added after most of the previously added portion has disappeared. After the first portions of the Zn were added, all of the 4,5-dibromofuran-2-carboxylic acid dissolved to give a pale brown solution. Near the end of the Zn addition a white solid began to appear in the reaction flask. Ten minutes after the conclusion of the zinc addition a thick white slurry had formed. HPLC analysis of the reaction slurry after 15 minutes indicated nearly complete consumption of the starting 4,5-dibromofuran-2-carboxylic acid and conversion to the desired product. After 40 minutes, heating was discontinued, and the white slurry was allowed to cool to ambient temperature. After cooling to ambient temperature the reaction slurry was diluted with cold H2O (100 mL), cooled in an ice bath, and then filtered. The solids were rinsed with cold H2O, dried on the filter, and the resulting damp solids were dissolved in warm acetone (1.6 L). The resulting solution was filtered to remove residual zinc dust, and then concentrated under reduced pressure to afford a white solid. The resulting solid was broken up with a spatula and pumped down under high vacuum to afford an off-white powder. 1H NMR analysis of the material (DMSO-d6) showed it to be quite pure but to contain H2O. The solids were suspended in toluene (˜1 L) and heated to reflux in a flask fitted with a condenser and a Dean-Stark trap. The suspension was heated at reflux for ˜1 hour at which time less than 1 mL of H2O had collected in the trap. The suspension was cooled, and concentrated under reduced pressure to afford 4-bromo furan-2-carboxylic acid as a-white powdery solid. 1H-NMR (400 MHz, DMSOd6): δ 7.96 (1H, d, J=0.8 Hz), 7.04 (1H, d, J=0.8 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH:9]([CH2:11][N:12](CC2C=CC=CC=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[OH:10])=[CH:4][C:3]=1[Cl:38].Cl.C(O)C.[H][H].C(O)(=O)/C=C/C(O)=O>C(O)C.ClCCl.CO.[Pd]=O>[NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH:9]([CH2:11][NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[OH:10])=[CH:4][C:3]=1[Cl:38]
Reactant: [H][H]
Reactant: Nc1c(Cl)cc(C(O)CN(CCCCCCOCCOCCc2ccccn2)Cc2ccccc2)cc1Cl
Agent: O=[Pd]
Agent: Cl
Agent: O=C(O)/C=C/C(=O)O
Solvent: CO
Solvent: CCO
Solvent: ClCCl
Product: Nc1c(Cl)cc(C(O)CNCCCCCCOCCOCCc2ccccn2)cc1Cl
Yield: 65 %

Procedure:
A solution of 4-amino-3,5-dichloro-α-[[(phenylmethyl)[6-[2-[2(2-pyridinyl)ethoxy]ethoxy]hexyl]amino]methyl]benzenemethanol (1.1 g,) in ethanol (25 ml) was hydrogenated over pre-reduced 10% palladium oxide on charcoal catalyst (50% aqueous paste, 600 mg) in ethanol (10 ml) containing 1:9 conc. hydrochloric acid/ethanol, (1.78 ml,) until the uptake of hydrogen ceased (1 h). The mixture was filtered and evaporated in vacuo to give an oil which was dissolved in dichloromethane (100 ml) and washed with 8% sodium bicarbonate (50 ml). The aqueous phase was re-extracted with dichloromethane (50 ml) and the combined organic phases dried and evaporated in vacuo to give an oil. Purification by FCC eluting with System G (95:5:1) gave a colourless oil, which was dissolved in methanol (10 ml) and treated with fumaric acid (0.09 g), evaporated in vacuo and triturated with diethyl ether to give a white solid (0.75 g,). The solid was dissolved in dichloromethane (150 ml) and washed with 8% sodium bicarbonate (100 ml). The aqueous layer was re-extracted with dichloromethane (100 ml) and the combined organic fractions dried and evaporated in vacuo to give an oil. Trituration with System F (ca. 10:1) gave the title compound (0.60 g,) as a white solid m.p. 45.5°-46.5°. T.l.c. (System E 40:10:1) Rf 0.49.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][OH:16])[N:10]=[CH:9]2)C=CC=CC=1.Br[CH2:30][CH2:31][CH3:32]>>[CH2:30]([O:16][CH2:15][CH2:14][CH2:13][C:11]1[N:10]=[CH:9][NH:8][CH:12]=1)[CH2:31][CH3:32]
Reactant: OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CCCBr
Product: CCCOCCCc1c[nH]cn1

Procedure:
5 mmol of 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanol and 5 mmol of bromopropane are treated as described in Example 5. The title compound is crystallized in the form of hydrogen oxalate from ethanol and diethyl ether.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CN(C=O)C.[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([NH:29][C@H:30]([CH:34]([CH3:36])[CH3:35])[C:31]([OH:33])=O)(=[O:28])=[O:27])[CH2:22][CH2:21]2)=[N:17][CH:18]=1.C[Si](C)(C)[NH:39][O:40][Si](C)(C)C>C(Cl)Cl>[OH:40][NH:39][C:31](=[O:33])[C@H:30]([NH:29][S:26]([N:23]1[CH2:22][CH2:21][CH:20]([O:19][C:16]2[CH:15]=[CH:14][C:13]([Cl:12])=[CH:18][N:17]=2)[CH2:25][CH2:24]1)(=[O:28])=[O:27])[CH:34]([CH3:35])[CH3:36]
Reactant: CC(C)[C@@H](NS(=O)(=O)N1CCC(Oc2ccc(Cl)cn2)CC1)C(=O)O
Reactant: C[Si](C)(C)NO[Si](C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)[C@@H](NS(=O)(=O)N1CCC(Oc2ccc(Cl)cn2)CC1)C(=O)NO
Temperature: 25 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
Oxalyl chloride (0.58 ml, 6.7 mmol) and DMF (few drops) were added to a solution of (R)-2-{[4-(5-chloropyridin-2-yloxy)piperidine-1sulfonyl)amino}-3-methylbutyric acid (1.05 g, 2.7 mmol), [prepared as described in Step 1 above], in methylene chloride (85 ml) and the reaction mixture was stirred overnight at RT. After removal of the organics, the residue was redissolved in methylene chloride (40 ml) and N,O-bis-trimethylsilylhydroxylamine (1.7 g, 9.4 mmol) was added. After 3 h, the reaction was concentrated, methanol (20 ml) was added and after stirring for an additional 30 min., the solvent was removed in vacuo. The residue was dissolved in ethyl acetate and washed with water and brine, dried over MgSO4, and concentrated. Chromatography (SiO2, 1-2% methanol/methylene chloride) gave N-hydroxy-2-(R)-{[4-(5-chloropyridin-2-yl-oxy)piperidine-1-sulfonyl]amino}-3-methylbutyramide as a white solid (35%), mp 97.0-98.4° C.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:43][N:44]1[C:52]2[C:47](=[CH:48][C:49](B3OC(C)(C)C(C)(C)O3)=[CH:50][CH:51]=2)[CH:46]=[CH:45]1.[O:62]1[CH:66]=[CH:65][CH:64]=[C:63]1[C:67]1[O:71][C:70]([NH:72][C:73]([C:75]2[CH:80]=[CH:79][CH:78]=[C:77](I)[CH:76]=2)=[O:74])=[N:69][N:68]=1>C(O)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:62]1[CH:66]=[CH:65][CH:64]=[C:63]1[C:67]1[O:71][C:70]([NH:72][C:73]([C:75]2[CH:80]=[CH:79][CH:78]=[C:77]([C:49]3[CH:48]=[C:47]4[C:52](=[CH:51][CH:50]=3)[N:44]([CH3:43])[CH:45]=[CH:46]4)[CH:76]=2)=[O:74])=[N:69][N:68]=1
Reactant: O=C(Nc1nnc(-c2ccco2)o1)c1cccc(I)c1
Reactant: Cn1ccc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CCCCO
Product: Cn1ccc2cc(-c3cccc(C(=O)Nc4nnc(-c5ccco5)o4)c3)ccc21
Temperature: 100 °C
Reaction time: 8 h
Yield: 36.3 %

Procedure:
Palladium acetate (177 mg, 0.79 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (751 mg, 1.58 mmol), tripotassium phosphate (3.34 g, 15.7 mmol), and 1-methylindole-5-boronic acid pinacol ester (3.04 g, 11.8 mmol) were added to a solution of N-[5-(2-furyl)-1,3,4-oxadiazol-2-yl]-3-iodobenzenecarboxamide (3.00 g, 7.87 mmol) prepared in Reference Example 3 in 1-butanol (75 mL), followed by stirring at 100° C. overnight in an argon atmosphere. The reaction solution was concentrated. A saturated aqueous solution of sodium chloride was added to the residue, followed by extraction with methylene chloride and drying over anhydrous sodium sulfate. The solvent was distilled off, and methanol was added to the residue. The precipitated solid was filtered off. The residue obtained by distilling the solvent off was subjected to purification by silica gel column chromatography and recrystallization from methanol to obtain the title compound (1.10 g, 2.86 mmol) (yield: 36%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[BH4-].[Na+].Cl>O1CCCC1>[Cl:1][CH2:2][CH2:3][CH2:4][CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[OH:6]
Reactant: O=C(CCCCl)c1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OC(CCCCl)c1ccccc1
Reaction time: 36 h
Yield: 88.8 %

Procedure:
A mixture of 4-chloro-1-phenyl-1-butanone (7.35 g) and sodium tetrahydroborate (3.05 g) in tetrahydrofuran (40 ml) was stirred for 36 h. 2M Hydrochloric acid was added and the mixture was extracted three times with ethyl acetate. The combined organic extracts were dried (magnesium sulphate), evaporated and purified by chromatography on silica eluting with petrol-ether to give the sub-title compound as a colourless oil (6.60 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH:8]=[CH:7][C:4]=1[CH:5]=O.[N:18]1([CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1.S([O-])([O-])(=O)=O.[Mg+2].[BH4-].[Na+]>C(Cl)Cl.CO>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH:8]=[CH:7][C:4]=1[CH2:5][NH:32][C:29]1[CH:30]=[CH:31][C:26]([O:25][CH2:24][CH2:23][N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:27][CH:28]=1
Reactant: COc1cc(OC2CCCCO2)ccc1C=O
Reactant: Nc1ccc(OCCN2CCCC2)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CO
Product: COc1cc(OC2CCCCO2)ccc1CNc1ccc(OCCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.1 %

Procedure:
To a solution of 2-methoxy-4-(tetrahydro-pyran-2-yloxy)-benzaldehyde (1.62 g, 6.84 mmol) and 4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (1.345 g, 6.51 mmol) in 25 mL methylene chloride was added magnesium sulfate (2.74 g, 22.8 mmol). The reaction mixture was stirred at room temperature overnight, then was filtered and concentrated. The residue was dissolved in 25 mL of 2:1 (v/v) ethanol:methanol and was treated with sodium borohydride (1.48 g, 39.1 mmol) in portions added over 1 hr. The reaction mixture was stirred at room temperature for 2 hr. at which time it was concentrated to one-half of its original volume. To this mixture was added 25 mL water and 25 mL saturated aqueous sodium bicarbonate. The mixture was extracted with methylene chloride and the organic layer was dried (magnesium sulfate), filtered, and concentrated. Medium pressure silica gel chromatography of the residue (methylene chloride to 10% methanol/methylene chloride) afforded 1.225 g (47%) of the title compound. MS 427.2 (M+1)+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C@@H:12]([OH:13])[CH2:11][CH2:10][C:9]=2[C:14]([O:16]C)=[O:15])=[CH:4][CH:3]=1.C1COCC1.COCCO[AlH2-]OCCOC.[Na+].OS([O-])(=O)=O.[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[C@@H:12]([OH:13])[CH2:11][CH2:10][C@H:9]2[C:14]([OH:16])=[O:15])=[CH:6][CH:7]=1
Reactant: COC(=O)C1=C(c2ccc(F)cc2)[C@@H](O)CC1
Agent: COCCO[AlH2-]OCCOC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C(O)[C@@H]1CC[C@H](O)[C@H]1c1ccc(F)cc1
Temperature: -48 °C
Reaction time: 0.5 h

Procedure:
To a toluene stream containing methyl (3S)-2-(4-fluorophenyl)-3-hydroxycyclopent-1-enecarboxylate in 21 L toluene was added 12 Liters of dry THF and the reaction mixture was cooled to −48° C. To the cooled solution was added drop-wise over 45 min 3.8 Liters (13.46 mol) of 70% Red-Al in toluene. The reaction mixture was allowed to warm to −25° C. over 2.5 h and was added to a solution of 21 L of 2M NaHSO4. The mixture was stirred for 30 min and the layers separated. The toluene layer was then washed with 15 L of water. The toluene layer was then azeotropically dried (50° C., 25 inHg) to a final volume of 21 L (KF 130 ug/mL) and used in the next step. To the toluene solution was added 820 mL (3.6 mol) of 25 wt % NaOMe in MeOH at 50° C. and the mixture heated to 75° C. for 1 h. The mixture was then cooled to 50° C. and 17 L of water, 1 L of MeOH, and 4.5 L of 6N NaOH was added. The mixture was stirred at 20-25° C. overnight. The layers were separated, and the toluene layer discarded. The aqueous layer was then washed with 15 L of MTBE and the MTBE layer discarded. The aqueous layer was then made acidic with conc. HCl (2.1 L, pH 1). The mixture was extracted with 40 L of IPAC. The IPAC layer containing the product (1.35 kg, 69% assay) was then treated with 500 g of Darco for 30 min at 25° C. and filtered over a pad of solka floc, rinsing the pad with and additional 5 L of IPAC. The IPAC solution was then azeotropically dried (45° C., 25 inHg) to a final volume of 15 L (KF<200) and cooled to 20° C. To the IPAC solution was added 3.04 L of n-heptane and the mixture seeded with 5 g of (1R,2R,3S)-2-(4-fluorophenyl)-3-hydroxycyclopentane-1-carboxylic acid. After a good seed bed had been formed (30 min) the rest of the n-heptane (40.4 L) was added drop-wise over 1 hour. The slurry was cooled to 10° C. and filtered. The cake was washed with 2 L of 5:1 n-heptane/IPAC and then with 1 L of heptane. The cake was then dried under vacuum/N2 sweep at 20-25° C. overnight to provide (1R,2R,3S)-2-(4-fluorophenyl)-3-hydroxycyclopentane-1-carboxylic acid as a colorless solid.
Reaction SMILES: Cl.[N:2]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[N:5][CH:4]=[N:3]1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:38]=[CH:39][CH:40]=1)[CH2:15][C@H:16]1[CH2:20][NH:19][C@H:18]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)=[CH:26][CH:25]=2)=[O:22])[CH2:17]1>>[N:2]1([CH2:7][C:8]([N:19]2[CH2:20][C@H:16]([CH2:15][C:14]3[CH:38]=[CH:39][CH:40]=[C:12]([Cl:11])[CH:13]=3)[CH2:17][C@H:18]2[C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)=[CH:26][CH:25]=2)=[O:22])=[O:10])[CH:6]=[N:5][CH:4]=[N:3]1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2cccc(Cl)c2)CN1
Reactant: O=C(O)Cn1cncn1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2cccc(Cl)c2)CN1C(=O)Cn1cncn1
Yield: 60 %

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,4-triazol-1-yl)acetic acid hydrochloride and (2S,4R)-4-(3-chlorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 61, (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-(3-chlorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (65 mg, 60%). 1H-NMR (400 MHz, CDCl3): δ 9.00 (s, 1H), 8.20 (s, 1H), 8.00 (s, 1H), 7.40-7.20 (m, 6H), 6.90-6.80 (m, 6H), 5.00 (dd, 2H), 4.90 (d, 1H), 3.80 (m, 1H), 3.20 (m, 1H), 3.00-2.80 (m, 5H). MS (EI) for C28H25ClFN5O3 found 534 (MH+).