Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:23])[CH2:21]Cl)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:24][N:25]1[C:29]([SH:30])=[N:28][N:27]=[N:26]1>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:23])[CH2:21][S:30][C:29]3[N:25]([CH3:24])[N:26]=[N:27][N:28]=3)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CCl)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Reactant: Cn1nnnc1S
Product: Cn1nnnc1SCC(=O)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Yield: 87 %

Procedure:
Following a procedure similar to that described in Example 33, but using N-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]-2-chloroacetamide (prepared as described in Preparation 1) and 1-methyl-5-mercaptotetrazole as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a white powder, melting at 58°-62° C., in an 87% yield.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3[O:22][C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][C:24]=3[F:32])[CH:14]=2)=[CH:9][CH:8]=1)[CH3:5].Cl[Sn]Cl>CO>[Cl:1][CH2:2][CH2:3][N:4]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[S:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3[O:22][C:23]3[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][C:24]=3[F:32])[CH:14]=2)=[CH:11][CH:12]=1)[CH3:5]
Reactant: CN(CCCl)Cc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)cc1
Agent: Cl[Sn]Cl
Solvent: CO
Product: CN(CCCl)Cc1ccc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)cc1
Temperature: 25 °C
Yield: 99.7 %

Procedure:
To a solution of 86 (375 mg, 0.79 mmol) in MeOH (15 ml) was added SnCl2×2H2O (891 mg, 5, eq, 3.95 mmol) and the reaction mixture was heated to reflux for 3 hours. The mixture was cooled to RT and poured onto ice/water then basified to pH 9. The mixture was filtered and the aqueous solution was extracted with EtOAc and the EtOAc was washed with brine solution. The organic phase was collected, dried over Na2SO4, filtered and concentrated and the 4-(2-(4-(((2-chloroethyl)(methyl)amino)methyl)phenyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorobenzenamine (87) (348 mg, 100% yield) was used immediately in the next step with no additional purification.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][N:9]=[CH:10][C:11]=3[NH:12]2)=[CH:4][CH:3]=1.O.[N+:16]([O-])([OH:18])=[O:17]>>[Cl:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][N:9]=[CH:10][C:11]=3[N:12]2[N+:16]([O-:18])=[O:17])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: Clc1ccc2c(c1)[nH]c1cnccc12
Solvent: O
Product: O=[N+]([O-])n1c2cnccc2c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A mixture of the product from example 12 (500 mg, 2.48 mmol) in concentrated nitric acid (20 ml) was stirred at RT for 22 h. The reaction mixture was carefully poured into cold (3° C. to 5° C.) water (50 ml), and after stirring for 2 h the precipitate was collected. The solid was suspended in saturated aqueous NaHCO3 (50 ml) and stirred at RT for 12 h. The product was filtered and washed with water to provide 550 mg of 7-chloro-9-nitro-β-carboline
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][OH:7].[N+](=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N-]>ClCCl.CCCCCCC.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][O:7][CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:18]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: COc1cccc(CO)c1
Agent: [Rh]
Solvent: CC(=O)O
Solvent: CCCCCCC
Solvent: ClCCl
Product: CCOC(=O)COCc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
To a solution of 3-methoxybenzyl alcohol (1.24 g, 10.0 mmol) in dichloromethane (20 mL) is added rhodium (II) acetate dimer (10 mg) followed by ethyl diazoacetate (0.95 mL, 9.0 mmol). The reaction mixture is stirred at RT for 30 min. The reaction mixture is diluted with heptane, filtered through Celite, and the filtrate is evaporated and the residue is vacuum distilled at 150° C. to give 2.00 g of the product 398. 1H NMR (CDCl3) δ 7.26 (t, 1H), 6.93 (m, 2H), 6.85 (m, 1H), 4.62 (s, 2H), 4.23 (q, 2H), 4.09 (s, 2H), 3.81 (s, 3H), 1.29 (t, 3H); MS: m/z 224 (M++1).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[C:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:8][C:9]2[C:14]([C:15]=1[C:16]([OH:18])=O)=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:4])=[O:3].C1C=C2N=NN(O)C2=CC=1.O.CN1CCOCC1.CCN=C=NCCCN(C)C.[C:54]1([C@@H:60]([NH2:63])[CH2:61][CH3:62])[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>O1CCCC1>[CH3:1][S:2]([NH:5][C:6]1[C:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:8][C:9]2[C:14]([C:15]=1[C:16]([NH:63][C@H:60]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[CH2:61][CH3:62])=[O:18])=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:4])=[O:3]
Reactant: CC[C@H](N)c1ccccc1
Reactant: CS(=O)(=O)Nc1c(-c2ccccc2)nc2ccccc2c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC[C@H](NC(=O)c1c(NS(C)(=O)=O)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 15.2 %

Procedure:
A solution of 3-[(methylsulfonyl)amino]-2-phenylquinoline-4-carboxylic acid (1c) (342 mg, 1.0 mmol), HOBT hydrate (231 mg, 1.5 mmol), 4-methylmorpholine (276 μL, 1.5 mmol) in tetrahydrofuran (50 ml) was added EDCI (289 mg, 1.5 mmol) at RT under N2. (S)-1-Phenyl propylamine (135 mg, 1.0 mmol) was then added and the reaction mixture stirred at RT for 12 h. All solvent was removed in vacuo and the residue was partitioned between ethyl acetate and 10% aqueous sodium bicarbonate solution, dried over sodium sulfate and then concentrated in vacuo. The residue was purified by chromatography eluting with 15-25% ethyl acetate/hexane to give the title compound (70 mg, 15%) as a solid. 1H NMR (300 MHz, CDCl3) δ 0.94 (t, 3H), 1.97 (m, 2H), 3.44 (s, 3H), 5.17 (q, 1H), 5.47 (m, 2H), 7.32 (d, 2H), 7.34 (d, 2H), 7.39 (m, 1H), 7.78 (m, 2H), 7.84 (m, 2H), 8.08 (m, 1H), 8.30 (m, 2H), 8.42 (m, 2H). MS APCI, m/z=460 (M+1). LCMS: 2.51 min.
Reaction SMILES: [Cl:1][C:2](=[O:7])[CH2:3][C:4]([O-:6])=O.[NH2:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]1.CCN(C(C)C)C(C)C.[Li+].[OH-]>O.C(Cl)Cl>[Cl:1][C:2](=[O:7])[CH2:3][C:4]([NH:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]1)=[O:6]
Reactant: CC(C)(C)OC(=O)N1CCC(N)C1
Reactant: O=C([O-])CC(=O)Cl
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)CC(=O)Cl)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.7 %

Procedure:
A mixture of 3-chloro-3-oxopropanoate (0.235 mL, 2.2 mmol), tert-butyl 3-aminopyrrolidine-1-carboxylate (410 mg, 2.2 mmol), DCM (4.4 mL) and DIPEA (0.766 mL, 4.4 mmol) was stirred for 2 h at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was re-dissolved in THF (2.2 mL), treated with LiOH×H2O (0.185 g, 4.4 mmol) in water (2.2 mL) for 2 h at room temperature and concentrated under reduced pressure to remove the THF. The remaining aqueous solution was extracted with EtOAc, acidified with 2N HCl (until pH˜5), extracted again with EtOAc. The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the title compound 35 (286 mg, 48% yield) as a light brown foam which was used in the next step without further purification. MS (m/z): 273.1 (M+H).
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH2:9][CH3:10])[N:7]=[C:6]([NH:11][C:12]([N:14]3[C:22]4[C:17](=[CH:18][C:19]([O:23][C:24]5[CH:29]=[CH:28][N:27]=[C:26]([CH2:30][N:31](C)[C:32](=O)OC(C)(C)C)[N:25]=5)=[CH:20][CH:21]=4)[CH:16]=[CH:15]3)=[O:13])[CH:5]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([C:4]2[N:8]([CH2:9][CH3:10])[N:7]=[C:6]([NH:11][C:12]([N:14]3[C:22]4[C:17](=[CH:18][C:19]([O:23][C:24]5[CH:29]=[CH:28][N:27]=[C:26]([CH2:30][NH:31][CH3:32])[N:25]=5)=[CH:20][CH:21]=4)[CH:16]=[CH:15]3)=[O:13])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: CCn1nc(NC(=O)n2ccc3cc(Oc4ccnc(CN(C)C(=O)OC(C)(C)C)n4)ccc32)cc1C1CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCn1nc(NC(=O)n2ccc3cc(Oc4ccnc(CNC)n4)ccc32)cc1C1CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl (4-(1-(5-cyclopropyl-1-ethyl-1H-pyrazol-3-ylcarbamoyl)-1H-indol-5-yloxy)pyrimidin-2-yl)methyl(methyl)carbamate (33 mg, 0.062 mmol) in DCM (2 mL) at 0° C. is added TFA (0.7 mL, 9.1 mmol). The reaction is stirred for 30 minutes at 0° C. and is then placed at room temperature for an additional 20 minutes. The reaction mixture is then concentrated in vacuo to near dryness and then diluted with DCM and water. The mixture is neutralized by the addition of saturated aqueous NaHCO3 and the resulting layers are separated. The aqueous layer is extracted two additional times with DCM. The organic layers are combined, dried over anhydrous Na2SO4, filtered, and concentrated. The resulting residue is purified via FCC (0-20% MeOH)/DCM) to give the title compound. MS (ESI) m/z 432.2 (M+1). (DMSO-d6) δ ppm 0.62-0.71 (m, 2 H) 0.93-1.02 (m, 2 H) 1.37 (t, J=7.20 Hz, 3 H) 1.86-1.99 (m, 1 H) 2.30 (s, 3 H) 3.71 (s, 2 H) 4.15 (q, J=7.24 Hz, 2 H) 6.16 (s, 1 H) 6.71 (d, J=4.29 Hz, 1 H) 6.87 (d, J=5.56 Hz, 1 H) 7.12 (dd, J=9.09, 2.27 Hz, 1 H) 7.46 (d, J=2.27 Hz, 1 H) 8.17 (d, J=3.79 Hz, 1 H) 8.31 (d, J=9.09 Hz, 1 H) 8.61 (d, J=5.56 Hz, 1 H) 10.64 (s, 1 H).
Reaction SMILES: [C:1]1(=[O:21])[N:5]([CH2:6][C:7]2[S:8][C:9]([C:12](=[O:15])[CH2:13][CH3:14])=[CH:10][CH:11]=2)[C:4](=[O:16])[C:3]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:2]12.[Br:22]Br>C(Cl)Cl>[Br:22][CH:13]([CH3:14])[C:12]([C:9]1[S:8][C:7]([CH2:6][N:5]2[C:4](=[O:16])[C:3]3=[CH:17][CH:18]=[CH:19][CH:20]=[C:2]3[C:1]2=[O:21])=[CH:11][CH:10]=1)=[O:15]
Reactant: CCC(=O)c1ccc(CN2C(=O)c3ccccc3C2=O)s1
Reactant: BrBr
Solvent: ClCCl
Product: CC(Br)C(=O)c1ccc(CN2C(=O)c3ccccc3C2=O)s1
Temperature: 25 °C

Procedure:
2-Phthalimidomethyl-5-propionylthiophene (39.3 g., 0.13 mole) is dissolved in methylene chloride 300 ml.) and bromine (20.8 g., 0.13 mole) is added dropwise with stirring over 3/4 hours at room temperature. The solution is partially evaporated in vacuo to remove the hydrogen bromide. Then it is washed with saturated sodium carbonate solution and with water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. This affords 5-(2-bromopropionyl)-2-(phthalimidomethyl) thiophene as a pale beige solid (46.7 g.), m.p. 127°-130° C.
Reaction SMILES: [N:1]1([C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22](O)=[O:23])=[CH:16][CH:15]=2)=[O:13])[CH2:7][CH2:6][CH2:5][CH2:4][C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.S(Cl)(Cl)=O.[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(N(CC)CC)C>ClCCl>[CH2:29]([NH:36][C:22](=[O:23])[CH2:21][CH2:20][C:17]1[CH:16]=[CH:15][C:14]([C:12]([N:1]2[CH2:7][CH2:6][CH2:5][CH2:4][C:11]3[CH:10]=[CH:9][CH:8]=[CH:3][C:2]2=3)=[O:13])=[CH:19][CH:18]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(O)CCc1ccc(C(=O)N2CCCCc3ccccc32)cc1
Reactant: NCc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCc1ccc(C(=O)N2CCCCc3ccccc32)cc1)NCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
A mixture of 3-[4-(2,3,4,5-tetrahydro-benzo[b]azepine-1-carbonyl)-phenyl]-propionic acid from Example E65.4 (57 mg, 0.18 mmol) and thionyl chloride (0.2 ml, 2.74 mmol) in dichloromethane (6 ml) was heated at reflux for 2 h then volatiles were removed in vacuo. The residue was dissolved in dichloromethane (8 ml) then benzylamine (0.022 ml, 0.20 mmol) and triethylamine (0.05 ml, 0.36 mmol) were added. The mixture was stirred for 3 h at room temperature then concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 30% pet. ether:70% EtOAc) to give a white fluffy solid identified as the title compound (36.5 mg, 50%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:12])[CH2:9][CH:10]=[CH2:11])[CH:5]=[CH:6][CH:7]=1.N1C=CN=C1.[C:18]([Si:22]([CH3:25])([CH3:24])Cl)([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C.ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([O:12][Si:22]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:25])[CH3:24])[CH2:9][CH:10]=[CH2:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=CCC(O)c1cccc(Br)c1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=CCC(O[Si](C)(C)C(C)(C)C)c1cccc(Br)c1

Procedure:
A solution of 1-(3-bromophenyl)but-3-en-1-ol (17.0 g, 74.9 mmol), 1H-imidazole (11.8 g, 172.2 mmol) and tert-butyldimethylchlorosilane (13.9 g, 89.8 mmol) in DMF (40 mL) is stirred at room temperature for 2 hours. The mixture is diluted with dichloromethane and is washed sequentially with water and saturated ammonium chloride aqueous solution. The organic layer is dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The crude product is purified by silica gel chromatography eluting with 5% ethyl acetate in hexanes to give the title compound as racemic mixture (23.9 g, 94%). 1H NMR (400 MHz, CDCl3) δ 7.44 (s, 1H), 7.34 (d, 1H, J=7.5 Hz), 7.24-7.14 (m, 2H), 5.78-5.70 (m, 1H), 5.02-4.97 (m, 2H), 4.65-4.62 (m, 1H), 2.45-2.31 (m, 2H), 0.87 (s, 9H), 0.02 (s, 3H), 0.12 (s, 3H).
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([C@@H:8]2[CH2:13][C@@H:12]3[C@@H:10]([CH2:11]3)[N:9]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[NH:5][C:6]=1I.S([O-])([O-])=O.[Na+].[Na+]>CCO.O>[I:1][C:2]1[N:3]=[C:4]([C@@H:8]2[CH2:13][C@@H:12]3[C@@H:10]([CH2:11]3)[N:9]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[NH:5][CH:6]=1.[NH:3]1[CH:2]=[CH:6][N:5]=[C:4]1[C@@H:8]1[CH2:13][C@@H:12]2[C@@H:10]([CH2:11]2)[N:9]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1nc(I)c(I)[nH]1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1nc(I)c[nH]1
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1ncc[nH]1
Temperature: 90 °C
Yield: 62 %
Yield: 13 %

Procedure:
A 250 mL pressure flask equipped with a stir bar was charge with a solution of (1R,3S,5R)-tert-butyl 3-(4,5-diiodo-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (8.3 g, 17 mmol) in EtOH (83 mL) and water (83 mL). Then, sodium sulfite (20.88 g, 166 mmol) was added and the mixture was heated at 90° C. for 16 h. The reaction mixture was extracted with EtOAc and the combined organic layers were dried over Na2SO4 and evaporated under vacuum. The residue was purified by flash column chromatography (BIOTAGE®), eluting with a gradient of 0 to 15% EtOAc/DCM to afford (1R,3S,5R)-tert-butyl 3-(4-iodo-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (3.84 g, 10.2 mmol, 62% yield) as yellow solid along with the fully reduced product (1R,3S,5R)-tert-butyl 3-(1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (550 mg, 2.21 mmol, 13% yield). LC-MS retention time 0.932 min; m/z 376.22 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters Sunfire 5u C18 4.6×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where Solvent A was 10% MeOH/90% H2O/0.1% TFA and Solvent B was 10% H2O/90% MeOH/0.1% TFA. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (500 MHz, MeOD) δ ppm 7.12 (br s, 1H), 4.59 (br s, 1H), 3.44-3.64 (br s, 1H), 2.40-2.52 (m, 1H), 2.17-2.30 (m, 1H), 1.65-1.73 (m, 1H), 1.27 (br s, 9H), 0.84 (dt, J=8.5, 5.7 Hz, 1H), 0.58 (br s, 1H).
Reaction SMILES: [CH:1]1([N:4]([CH2:39][C:40]2[CH:45]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:43]=[C:42]([OH:51])[CH:41]=2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:15][CH:14]=3)[CH2:11][CH2:10][N:9]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:8]2)=[O:6])[CH2:3][CH2:2]1.CS(O[CH2:57][C:58]1([CH2:61][C:62]([O:64][CH3:65])=[O:63])[CH2:60][CH2:59]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOCC>[CH:1]1([N:4]([CH2:39][C:40]2[CH:45]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:43]=[C:42]([O:51][CH2:57][C:58]3([CH2:61][C:62]([O:64][CH3:65])=[O:63])[CH2:60][CH2:59]3)[CH:41]=2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:17][CH:18]=3)[CH2:11][CH2:10][N:9]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:8]2)=[O:6])[CH2:3][CH2:2]1
Reactant: COCCCc1cc(O)cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)c1
Reactant: COC(=O)CC1(COS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COCCCc1cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OCC2(CC(=O)OC)CC2)c1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of tert-butyl (3R,4S)-3-({cyclopropyl[3-hydroxy-5-(3-methoxy-propyl)benzyl]amino}carbonyl)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]-phenyl}piperidine-1-carboxylate (1 eq.) from Example 1/Step 2 in DMF (0.1 M) was added methyl (1-{[(methylsulfonyl)oxy]methyl}cyclopropyl)acetate (appendage 3) (2 eq.) and cesium carbonate (2 eq.). The reaction was heated to 80° C. and stirred for 18 h. After cooling to rt, the reaction was diluted with ether. The organic extract was washed with water, brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 20% EtOAc in toluene) to afford the title compound as an oil.
Reaction SMILES: [C:1]([C:4]1[CH:16]=[C:15]2[C:7]([C:8]3[CH:9]=[CH:10][C:11]([O:18][CH2:19][C@H:20]4[N:24]([CH2:25][CH2:26][CH2:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[C:23](=[O:34])[C@H:22]([CH2:35][C:36]([OH:38])=[O:37])[CH2:21]4)=[CH:12][C:13]=3[C:14]2=[O:17])=[CH:6][CH:5]=1)(=[NH:3])[NH2:2].[H][H]>C(O)(=O)C.[Pd]>[C:1]([C:4]1[CH:16]=[C:15]2[C:7]([C:8]3[CH:9]=[CH:10][C:11]([O:18][CH2:19][C@H:20]4[N:24]([CH2:25][CH2:26][CH2:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[C:23](=[O:34])[C@H:22]([CH2:35][C:36]([OH:38])=[O:37])[CH2:21]4)=[CH:12][C:13]=3[CH:14]2[OH:17])=[CH:6][CH:5]=1)(=[NH:2])[NH2:3]
Reactant: N=C(N)c1ccc2c(c1)C(=O)c1cc(OC[C@@H]3C[C@@H](CC(=O)O)C(=O)N3CCCc3ccccc3)ccc1-2
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: N=C(N)c1ccc2c(c1)C(O)c1cc(OC[C@@H]3C[C@@H](CC(=O)O)C(=O)N3CCCc3ccccc3)ccc1-2

Procedure:
0.77 g of (3S,5S)-5-[(7-amidino-9-keto-2-fluorenyl)oxymethyl]-3-carboxymethyl-1-(3-phenylpropyl)-2-pyrrolidinone are dissolved in 15 ml of glacial acetic acid, 0.4 g of 10% palladium/charcoal are added and the mixture is hydrogenated for 24 hours at ambient temperature under 3 bars of hydrogen pressure. The catalyst is filtered off, the filtrate is evaporated down and purified by chromatography over silica gel (eluant:methylene chloride/methanol/glacial acetic acid =3:1:0.1). The crude product obtained is triturated with ether, filtered off and taken up in 50 ml of a mixture of glacial acetic acid and water (1:2). This solution is concentrated until crystallisation begins (about 5 ml). The crystals precipitated are washed with water, acetone and ether.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.C(N(CC)CC)C.[CH:19]1([C:22]#[CH:23])[CH2:21][CH2:20]1>C1COCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH:19]1([C:22]#[C:23][C:2]2[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=2)[CH2:21][CH2:20]1
Reactant: C#CC1CC1
Reactant: COC(=O)c1ccc(Br)cn1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(C#CC2CC2)cn1
Temperature: 40 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
To a sealed tube were added methyl 5-bromopyridine-2-carboxylate (450 mg, 2.083 mmol) in THF (4 ml) followed by tetrakis(triphenylphosphine)palladium (193 mg, 0.167 mmol), copper(i) iodide (20 mg, 0.104 mmol), triethylamine (2.3 ml, 16.66 mmol) under N2. Finally cyclopropylacetylene (275 mg, 4.17 mmol) was added. The yellow mixture was stirred at 40° C. for overnight. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine and dried over MgSO4. The solution was filtered and concentrated to give the crude material as an orange oil. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 15% to 30% to 45% EtOAc in Heptane, to provide methyl 5-(cyclopropylethynyl)picolinate (390 mg, 1.938 mmol, 93% yield) as an orange solid. MS m/z=202.2 (M+H).
Reaction SMILES: [H-].[Na+].[CH3:3]I.[Br:5][C:6]1[CH:7]=[C:8]([CH2:11][OH:12])[S:9][CH:10]=1>O1CCCC1>[Br:5][C:6]1[CH:7]=[C:8]([CH2:11][O:12][CH3:3])[S:9][CH:10]=1
Reactant: CI
Reactant: OCc1cc(Br)cs1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1cc(Br)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Add sodium hydride (737 mg, 29.23 mmol, 1.10 equivalents, 95%) to a solution containing methyl iodide (1.65 mL, 26.57 mmol, 1.00 equivalents) and (4-bromo-thiophen-2-yl)-methanol (5.13 g, 26.57 mmol, 1.00 equivalents) in tetrahydrofuran (dry, 25 mL). Stir the resulting mixture at room temperature overnight and evaporate. Partition the residue between water (100 mL) and dichloromethane (100 mL). Extract the aqueous layer with dichloromethane (100 mL), combine the organic layers, dry over magnesium sulfate, filter and evaporate to yield the desired product as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:17])[C:10]([C:14]([OH:16])=[O:15])=CNC=2)=[CH:4][CH:3]=1.F[C:19]1C=CC(CC(Cl)=O)=C[CH:20]=1.CC1(C)OC(=O)CC(=O)O1.N1C=CC=CC=1>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9](=[O:17])[CH2:10][C:14]([O:16][CH2:19][CH3:20])=[O:15])=[CH:6][CH:7]=1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Reactant: O=C(O)c1c[nH]cc(-c2ccc(F)cc2)c1=O
Agent: CC1(C)OC(=O)CC(=O)O1
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)CC(=O)Cc1ccc(F)cc1

Procedure:
The intermediate, 5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (8) can be obtained using the chemistry described in Scheme 2. Thus, 2-(4-fluorophenyl)acetyl chloride (10) can be treated with 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum's acid) in the presence of pyridine and the resulting adduct can be refluxed in ethanol to afford ethyl 4-(4-fluorophenyl)-3-oxobutanoate (12). Treatment of intermediate 12 with triazine and sodium ethoxide in ethanol can furnish the requisite ester intermediate, which can be readily hydrolyzed in the presence of sodium hydroxide at elevated temperature to furnish intermediate 8.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][CH:8]=1)OC)#[N:2].[C:15]1([CH2:21][CH2:22][NH2:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(OCC)C>CO>[C:1]([NH:3][C:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][CH:8]=1)=[N:23][CH2:22][CH2:21][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)#[N:2]
Reactant: NCCc1ccccc1
Reactant: COC(=NC#N)c1ccc(C#N)cc1
Solvent: CO
Solvent: CCOCC
Product: N#CNC(=NCCc1ccccc1)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.5 %

Procedure:
Methyl N-cyano-4-cyanobenzenecarboximidate (0.37 g, 2.0 mmol) was suspended in methanol (4 ml), and 2-phenylethylamine (0.25 g, 2.1 mmol) was added. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, methanol (6 ml) and diethyl ether (10 ml) were added to the reaction solution, and deposited crystals were collected by filtration to give the title compound (0.51 g, 1.87 mmol, yield: 94%) as colorless crystals.