Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7]Br)(=[O:3])[CH3:2].[Na].[C:13]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:14][C:15]([CH3:17])=[O:16]>O1CCCC1>[C:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][CH:14]([C:15](=[O:16])[CH3:17])[C:13]([O:19][CH2:20][CH3:21])=[O:18])(=[O:3])[CH3:2]
Reactant: CC(=O)c1cccc(CBr)c1
Reactant: CCOC(=O)CC(C)=O
Agent: [Na]
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1cccc(C(C)=O)c1)C(C)=O
Yield: 49.1 %

Procedure:
A solution of 3-acetylbenzyl bromide (4 g) and ethyl acetoacetate sodium salt (3.42 g) in tetrahydrofuran (50 mL) was stirred for 12 hr. The insoluble material was filtered off and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound (2.42 g, 49%) as a colorless viscous oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[C:13](Cl)[N:12]=[C:11]([Cl:16])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]1([OH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)C(C)C)(C)C>ClCCl>[CH2:1]([O:8][C:9]1[N:10]=[C:11]([Cl:16])[N:12]=[C:13]([O:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccccc1
Reactant: Clc1nc(Cl)nc(OCc2ccccc2)n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Clc1nc(OCc2ccccc2)nc(Oc2ccccc2)n1
Yield: 94.1 %

Procedure:
Next, 5.70 mL of dichloromethane solution containing 896.2 mg (3.50 m mol) of 6-benzyloxy-2,4-dichloro-1,3,5-triazine, 2.00 mL of dichloromethane, 365.0 mg (3.88 m mol) of phenol and 0.738 mL (4.23 m mol) of N,N-diisopropylethylamine was added to a 30 mL eggplant flask, and reacted at 0 degree under a nitrogen atmosphere for 6 hours. After the reaction, 20 mL of dichloromethane was added, which was washed with 20 mL of 1 N hydrochloric acid, 20 mL of 1 N hydrochloric acid, 20 mL of water and 20 mL of saturated salt water. A resulting organic phase was dried by magnesium sulfate, from which dichloromethane was distilled away, and the residue was recrystallized to obtain 1033.2 mg of 6-benzyloxy-2-chloro-4-phenoxy-1,3,5-triazine (yield: 94%).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][CH:7]=[C:6]2[CH2:13][NH2:14]>CO.CC(O)=O.[Pd]>[CH3:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][CH2:7][CH:6]2[CH2:13][NH2:14]
Reactant: Cc1ccc2c(c1)C(CN)=CCO2
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccc2c(c1)C(CN)CCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.4 %

Procedure:
To a solution of 1-(6-methyl-2H-chromen-4-yl)methanamine hydrochloride (700 mg, 3.3 mmol) in MeOH (20 mL) and AcOH (2 mL) under N2 was added 10% Pd/C (70 mg) at rt. The suspension was stirred at rt overnight under 50 psi of H2. The reaction was filtered and concentrated. The residue was dissolved in EtOAc and washed with sat. Na2CO3, and the organics were concentrated to give 400 mg (68%) of the title compound as a yellow oil. 1H NMR (300 MHz, CDCl3): δ 1.98-2.09 (2H, m), 2.28 (3H, s), 2.80-2.83 (1H, m), 2.88-2.96 (1H, m), 3.09 (1H, dd, J=4.5, 12.6 Hz), 4.17 (2H, t, J=6.3 Hz), 6.73 (1H, d, J=8.4 Hz), 6.91-6.97 (2H, m).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH:19]=C)=[C:7]([CH3:18])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:9]2)=[CH:4][CH:3]=1.C[N+]1([O-])CC[O:25]CC1.S([O-])([O-])(=O)=S.[Na+].[Na+].I([O-])(=O)(=O)=O.[Na+]>CC(C)=O.O.[Os](=O)(=O)(=O)=O>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH:19]=[O:25])=[C:7]([CH3:18])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: C=Cc1c(C)c(-c2ccccn2)nc2cc(F)ccc12
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1C=O
Temperature: 23 °C
Reaction time: 18 h

Procedure:
To a solution of 7-fluoro-3-methyl-2-(pyridin-2-yl)-4-vinylquinoline (1.53 g, 5.79 mmol) in acetone (30 mL) and water (7.50 mL) were added N-methylmorpholine-N-oxide (2.034 g, 17.37 mmol) and osmium tetroxide (0.074 g, 0.289 mmol). The reaction was stirred at 23° C. for 18 h. Upon completion, 10% aqueous sodium thiosulfate was added and the reaction was stirred for an additional 10 minutes. The reaction mixture was then concd, and the dihydroxylated product was extracted with EtOAc (twice) and DCM (twice). The combined organics were dried over magnesium sulfate and concd, and the resulting residue was resolubilized in 30 mL 4:1 acetone:water and 3 mL dioxane. To this solution sodium periodate (3.10 g, 14.47 mmol) was added, and stirring continued at 23° C. for 2 h. Upon completion, the organic solvents were removed under vacuum, and the afforded crude material was partitioned between EtOAc and water. The organic phase was dried over magnesium sulfate and concd, and purification by column chromatography (silica; 0-70% EtOAc in hexanes yielded 7-fluoro-3-methyl-2-(pyridin-2-yl)quinoline-4-carbaldehyde as a white amorphous solid. Mass Spectrum (ESI) m/e=367.1 (M+1).
Reaction SMILES: [CH:1]1([C:4](=[O:27])[C:5](=[CH:23][N:24](C)C)[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=2[S:18][CH:19]([CH3:22])[CH2:20][CH3:21])=[O:7])[CH2:3][CH2:2]1.Cl.NO>C(O)C>[CH:1]1([C:4]2[O:27][N:24]=[CH:23][C:5]=2[C:6](=[O:7])[C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=2[S:18][CH:19]([CH3:22])[CH2:20][CH3:21])[CH2:3][CH2:2]1
Reactant: CCC(C)Sc1cc(C(F)(F)F)ccc1C(=O)C(=CN(C)C)C(=O)C1CC1
Agent: Cl
Agent: NO
Solvent: CCO
Product: CCC(C)Sc1cc(C(F)(F)F)ccc1C(=O)c1cnoc1C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.5 %

Procedure:
A mixture of 3-cyclopropyl-2-(N,N-dimethylaminomethylene)-1-[2-(1-methylpropylsulphenyl)-4-trifluoromethylphenyl]propan-1,3-dione (11.9 g) and hydroxylamine hydrochloride (2.3 g) in ethanol was stirred at room temperature overnight. The mixture was cooled (ice bath) and a solid filtered off, washed with a small amount of cold ethanol, then water, and dried to give 5-cyclopropyl-4-[2-(1-methylpropylsulphenyl)-4-trifluoromethylbenzoyl]isoxazole (3.8 g) as a white solid, m.p. 75.6°-76.4° C.
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[C:2]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:7]([CH3:1])[CH:6]=[CH:5][CH:4]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccccc1
Solvent: Cc1ccccc1
Product: Cc1cccc(Cc2ccccc2)c1Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.3 %

Procedure:
To a reaction vessel were added 2500 g of toluene and 50 g of FeCl3 and reaction was carried out for 3 hours by adding 1500 g of benzyl chloride with stirring at room temperature. After the reaction, the catalyst was deactivated and 660 g of dibenzyltoluene was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][N:14](C(OCC4C=CC=CC=4)=O)[C@H:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:33][C@H:34]([C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][C:40]=2[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:35]([F:38])([F:37])[F:36])[N:3]=1.[Si](I)(C)(C)C.Cl>C(#N)C.C(OCC)C>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][NH:14][C@H:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:33][C@H:34]([C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][C:40]=2[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:35]([F:38])([F:37])[F:36])[N:3]=1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(Cl)cc4-c4ccccc4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Agent: C[Si](C)(C)I
Agent: Cl
Solvent: CCOCC
Solvent: CC#N
Product: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(Cl)cc4-c4ccccc4)C(F)(F)F)nc(N)n3)CC2)CN1
Temperature: 25 °C

Procedure:
A solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (from Step 3, Example 34c, 315 mg, 0.43 mmol) in acetonitrile (300 mL) was added TMSI (0.13 mL, 0.9 mmol) [Method B]. The reaction mixture was then warmed to RT for an additional 30-40 min, then cooled to 0-5° C., and 2 M HCl in diethyl ether (0.5 mL) was added. The reaction mixture was the allowed to warm RT and then concentrated in vacuo. Normal phase silica gel chromatography provide the title compound as an off-white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@@H:8]1[C@@H:13]([N:14]=[N+]=[N-])[CH2:12][CH2:11][CH2:10][C:9]1([F:18])[F:17])([CH3:4])([CH3:3])[CH3:2]>CO>[C:1]([O:5][C:6](=[O:19])[NH:7][C@@H:8]1[C@@H:13]([NH2:14])[CH2:12][CH2:11][CH2:10][C:9]1([F:18])[F:17])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1[C@@H](N=[N+]=[N-])CCCC1(F)F
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H]1[C@@H](N)CCCC1(F)F
Reaction time: 48 h

Procedure:
A solution of tert-butyl[(1R,6S)-6-azido-2,2-difluorocyclohexyl]carbamate (18.84 g, 68.2 mmol) in methanol (400 mL) was degassed and purged (3× with N2) before the addition of Pd/C (1.45 g). The reaction was stirred for 2 d under 1 atm of hydrogen. Upon reaction completion, the reaction was filtered through a plug of celite and concentrated to dryness to afford the title compound as a white solid. 1H NMR (CDCl3, 500 MHz) 4.76-4.74 (d, 1H); 3.61-3.56 (m, 1H); 2.63-2.59 (dd, 1H); 2.2-2.0 (m, 2H); 1.8-1.68, (m, 2H); 1.53-1.42 (m, 11H); 1.29-1.21 (m, 2H). 19F NMR (CDCl3, 564 MHz) −101.7-−102.1 (d, 1F); −114.3-−114.9 (m, 1F).
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]2=[N:12][N:13]=[CH:14][N:4]2[N:3]=1.[NH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([CH3:24])[CH2:20][CH2:19]1>>[CH3:24][CH:21]1[CH2:22][CH2:23][N:18]([CH2:17][CH2:16][NH:15][C:2]2[C:11]3[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=3[C:5]3=[N:12][N:13]=[CH:14][N:4]3[N:3]=2)[CH2:19][CH2:20]1
Reactant: Clc1nn2cnnc2c2c1CCCC2
Reactant: CC1CCN(CCN)CC1
Product: CC1CCN(CCNc2nn3cnnc3c3c2CCCC3)CC1
Temperature: 0 °C

Procedure:
A solution of 5.0 g of 6-chloro-7,8,9,10-tetrahydro-1,2,4-triazolo[3,4-a]phthalazine in 25 ml of 1-(2-aminoethyl)-4-methylpiperidine was heated at reflux for 15 hours and then poured into ice water. The resulting off-white solid was separated by filtration and recrystallized from toluene to give 6-[2-(4-methyl-1-piperidinyl)ethylamino]-7,8,9,10-tetrahydro-1,2,4-triazolo[3,4-a]phthalazine melting at about 180°-181° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[CH2:3][NH:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[N:6]=1.[CH3:16][C:17]1[C:21]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=2)=[C:20]([CH3:34])[O:19][N:18]=1.C(N=C(N(C)C)N(C)C)(C)(C)C>N1C=CC=CC=1>[CH3:16][C:17]1[C:21]([CH2:22][O:23][C:24]2[CH:25]=[CH:26][C:27]([S:30]([N:4]([CH2:3][CH:2]([CH3:15])[CH3:1])[C:5]3[CH:10]=[CH:9][N:8]=[C:7]([C:11]([F:12])([F:14])[F:13])[N:6]=3)(=[O:32])=[O:31])=[CH:28][CH:29]=2)=[C:20]([CH3:34])[O:19][N:18]=1
Reactant: Cc1noc(C)c1COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)CNc1ccnc(C(F)(F)F)n1
Agent: CN(C)C(=NC(C)(C)C)N(C)C
Solvent: c1ccncc1
Product: Cc1noc(C)c1COc1ccc(S(=O)(=O)N(CC(C)C)c2ccnc(C(F)(F)F)n2)cc1
Temperature: 100 °C

Procedure:
To a solution of N-(2-methylpropyl)-2-(trifluoromethyl)-4-pyrimidinamine (100 mg, 0.456 mmol) and 4-{[(3,5-dimethyl-4-isoxazolyl)methyl]oxy}benzenesulfonyl chloride (151 mg, 0.502 mmol) in pyridine (1 mL) was added 2-(tert-butyl)-1,1,3,3-tetramethylguanidine (0.092 mL, 0.456 mmol). The reaction vessel was sealed and heated by microwaves to 100° C. for 30 minutes. The solvent was evaporated in vacuo to give the crude product, which was purified by solid phase extraction (SPE) using an aminopropyl (NH2) cartridge then a sulphonic acid (SCX) cartridge (both eluted with methanol). The appropriate fractions were combined and dried under a stream of nitrogen to give the crude product which was further purified by mass directed autoprep (formic acid modifier) to give the title product, 19.8 mg. LCMS (2 min, formic) Rt 1.32 min, m/z (ES+) 485 (M+H).
Reaction SMILES: Cl.[NH2:2][O:3][CH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1.C([O-])([O-])=O.[Na+].[Na+].[C:20](Cl)([O:22][CH2:23][CH:24]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:21].C(OCC)(=O)C>O1CCOCC1>[C:20]([NH:2][O:3][CH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)([O:22][CH2:23][CH:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:31]2[C:36]1=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:21]
Reactant: NOCc1ccc(C(=O)O)cc1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=C(NOCc1ccc(C(=O)O)cc1)OCC1c2ccccc2-c2ccccc21
Reaction time: 2 h

Procedure:
To a solution of 4-aminooxymethyl-benzoic acid, hydrochloride 111 (2.0 g, 0.010 mol) in dioxane (20 mL) and half saturated Na2CO3 solution (20 mL) was added Fmoc-Cl (2.8 g, 0.011 mol) and the mixture was stirred for 2 h. Ethyl acetate (100 mL) was added and the pH of the aqueous phase was adjusted to 1-3 by careful addition of HCl(conc.). The mixture was poured in to a separating funnel and the organic phase was isolated, washed once with water (100 mL), dried over Na2SO4 and the solvent was removed on a rotavap to give an oil that solidified upon standing. The crude product was purified by flash column chromatography (petroleum ether, ethyl acetate, AcOH 60:40:1). Yield: 3.5 g (92%) 1H-NMR (250 MHz, DMSO-d6) =4.05 (1H, t, J=6.3 Hz), 4.27 (2H, d, J=6.3 Hz), 4.51 (2H, s), 7.08-7.22 (6H, m), 7.46 (2H, d, J=7.4 Hz), 7.66 (2H, d, J=7.1 Hz), 7.72 (2H, d, J=8.4 Hz), 10.29 (1H, br. s), 12.78 (1H, br. s). 13C-NMR (63 MHz, DMSO-d6) =47.04, 66.03, 76.91, 120.51, 125.41, 127.45, 128.03, 128.89, 129.33, 129.63, 130.82, 141.19, 144.01, 157.12, 167.48. MS (ES) m/z=389 (MH+). 1The material was prepared as previously described: Deles, J. et al.; PJCHDQ; Pol. J. Chem.; EN; 53; 1979; 1025-1032
Reaction SMILES: [C:1]([C:5]1[CH:13]=[C:9]([C:10]([OH:12])=O)[C:8]([OH:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:15][C:16]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:17]=1[NH2:18].P(Cl)(Cl)Cl>C1(C)C(C)=CC=CC=1>[C:1]([C:5]1[CH:13]=[C:9]([C:10]([NH:18][C:17]2[CH:19]=[CH:20][C:21]([N+:23]([O-:25])=[O:24])=[CH:22][C:16]=2[CH3:15])=[O:12])[C:8]([OH:14])=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccc(O)c(C(=O)O)c1
Reactant: Cc1cc([N+](=O)[O-])ccc1N
Solvent: ClP(Cl)Cl
Solvent: Cc1ccccc1C
Product: Cc1cc([N+](=O)[O-])ccc1NC(=O)c1cc(C(C)(C)C)ccc1O
Yield: 70.1 %

Procedure:
A solution of 9.7 g of 5-tert-butylsalicylic acid and 7.6 g of 2-methyl-4-nitroaniline in 120 ml of xylene is heated at 65° to 70° C. To a reaction solution is added a solution of 2.6 g of phosphorus trichloride in 30 ml of xylene. The whole mixture is refluxed for 2 hours. The hot reaction solution is decanted. The supernatant solution is cooled on an ice bath. The crystalline precipitate is collected by filtration. Recrystallization from methanol gives 11.5 g of the title compound as pale yellow needles, melting at 202°-204° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=3)=[CH:9][N:10]=[C:4]2[CH:3]=1.[H-].[Na+].Br[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1.O>CN(C)C=O>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[CH:12]=3)=[CH:9][N:10]=[C:4]2[CH:3]=1
Reactant: Cc1ccn2c(-c3cccc(O)c3)cnc2c1
Reactant: Brc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccn2c(-c3cccc(Oc4ccccn4)c3)cnc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.7 %

Procedure:
3-(7-Methylimidazo[1,2-α]pyridin-3-yl)phenol (310 mg, 1.4 mmol) in anhydrous N,N-dimethylformamide (5 ml) was treated with sodium hydride (60% dispersion in mineral oil, 70 mg, 1.75 mmol) and then stirred at ambient temperature for 30 minutes. 2-Bromopyridine (0.16 ml, 1.67 mmol) was added and the reaction mixture heated at 120° C. for 4 days, poured into water (25 ml) and extracted with ethyl acetate (2×30 ml). The combined organic phases were washed with water (3×20 ml), dried over anhydrous magnesium sulphate and concentrated in vacuo. Purification by preparative TLC gave the title compound as a colourless oil (100 mg, 24%). 1H NMR (400 MHz, CDCl3) δH 2.64 (3H, s), 7.08-7.10 (1H, m), 7.14-7.17 (1H, m), 7.33-7.37 (2H, m), 7.50-7.55 (2H, m), 7.66-7.70 (1H, m), 7.78 (1H, s), 7.85-7.90 (1H, m), 8.07 (1H, s), 8.15-8.16 (1H, m), 8.65 (1H, d, J 7); m/z (ES+) 302 (M++H).
Reaction SMILES: C(OC(=O)[NH:7]/[C:8](/[NH:17][C:18]1[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[CH:19]=1)=[N:9]\C(=O)OC(C)(C)C)(C)(C)C.[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29]>ClCCl>[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29].[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29].[Cl:24][C:20]1[CH:19]=[C:18]([NH:17][C:8]([NH2:9])=[NH:7])[CH:23]=[CH:22][N:21]=1
Reactant: CC(C)(C)OC(=O)/N=C(\NC(=O)OC(C)(C)C)Nc1ccnc(Cl)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)Nc1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 110.8 %

Procedure:
To a solution of 43.67 g (0.117 mol) of di-tert-butyl{(Z)-[(2-chloropyridin-4-yl)amino]methylylidene}biscarbamate in dichloromethane (800 ml) at room temperature were added 81.64 ml of trifluoroacetic acid (1.06 mol). The reaction mixture was stirred at room temperature for 2 days, concentrated in vacuo, triturated with 100 ml of pentane, and upon standing crystallized to yield 51.68 g of 1-(2-chloropyridin-4-yl)guanidine bis(trifluoroacetate) (yield=99%).
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13](=O)[N:14]([CH2:16][C@H:17]([C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=1)[CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][C:27]2=[O:32])[CH2:22][CH2:21]1)C)(C)(C)C>ClCCl.[OH-].[Na+]>[Cl:40][C:35]1[CH:34]=[C:33]([C@@H:17]([CH2:16][NH:14][CH3:13])[CH2:18][CH2:19][N:20]2[CH2:21][CH2:22][CH:23]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][C:27]3=[O:32])[CH2:24][CH2:25]2)[CH:38]=[CH:37][C:36]=1[Cl:39]
Reactant: CN(C[C@@H](CCN1CCC(N2CCCCC2=O)CC1)c1ccc(Cl)c(Cl)c1)C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC[C@@H](CCN1CCC(N2CCCCC2=O)CC1)c1ccc(Cl)c(Cl)c1

Procedure:
Trifluoroacetic acid (13.1 mL) was added to a solution of (S)-[2-(3,4-dichloro-phenyl)-4-(2-oxo-[1,4′]bipiperidinyl-1′-yl)-butyl]-methyl-carbamic acid tert-butyl ester (8.73 g) in dichloromethane (300 mL). After stirring for 30 minutes additional trifluoroacetic acid (13.1 mL) was added. After 1.5 hours the reaction was diluted with aqueous sodium hydroxide, and the layers were separated. The organic layer was washed with water, dried and evacuated to a viscous oil which was not purified further. MS: m/z=412(M+1).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:19][CH2:20][O:21]S(C1C=CC(C)=CC=1)(=O)=O.[CH3:32][O:33][C:34](=[O:53])[CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40](O)=[CH:39][C:38]=1[CH2:44][CH2:45][NH:46][C:47]([O:49][CH:50]([CH3:52])[CH3:51])=[O:48].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH3:32][O:33][C:34](=[O:53])[CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:21][CH2:20][CH2:19][C:3]2[N:4]=[C:5]([C:7]3[CH:12]=[CH:11][C:10]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[CH:9][CH:8]=3)[O:6][C:2]=2[CH3:1])=[CH:39][C:38]=1[CH2:44][CH2:45][NH:46][C:47]([O:49][CH:50]([CH3:51])[CH3:52])=[O:48]
Reactant: COC(=O)CCc1ccc(O)cc1CCNC(=O)OC(C)C
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccc(N4CCOCC4)cc3)oc2C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCc1ccc(OCCc2nc(-c3ccc(N4CCOCC4)cc3)oc2C)cc1CCNC(=O)OC(C)C
Temperature: 65 °C
Reaction time: 16 h

Procedure:
A solution of toluene-4-sulfonic acid 2-[5-methyl-2-(4-morpholin-4-yl-phenyl)-oxazol-4-yl]-ethyl ester (44 mg, 0.10 mmol; Preparation 5) and 3-[4-hydroxy-2-(2-isopropoxycarbonylamino-ethyl)-phenyl]-propionic acid methyl ester (31 mg, 0.10 mmol) in DMF (1.0 mL) was treated with K2CO3 (30 mg). The resulting suspension was stirred at 65° C. for 16 h and diluted with water (10 mL). The mixture was extracted with EtOAc (3×10 mL). The combined organic layers were dried (Na2SO4), concentrated, and purified using silica gel chromatography (50% EtOAc/hexanes to yield 3-(2-(2-isopropoxycarbonylamino-ethyl)-4-{2-[5-methyl-2-(4-morpholin-4-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionic acid methyl ester.
Reaction SMILES: [O:1]=[O+][O-].[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[CH2:9][N:10]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH:21]=C)[CH:17]=2)[N:12]([CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:11]1=[O:29]>C(Cl)Cl>[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[CH2:9][N:10]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH:21]=[O:1])[CH:17]=2)[N:12]([CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:11]1=[O:29]
Reactant: C=Cc1ccc2c(c1)c(=O)n(Cc1ccc(OC)c(OC)c1)c(=O)n2C1CCOCC1
Reactant: O=[O+][O-]
Solvent: ClCCl
Product: COc1ccc(Cn2c(=O)c3cc(C=O)ccc3n(C3CCOCC3)c2=O)cc1OC
Temperature: -78 °C
Reaction time: 8 h

Procedure:
A stream of ozone is passed for 10 minutes through a solution of 1.4 g of the compound obtained in Step 14.1 in 100 ml of DCM cooled to −78° C. The reaction medium is degassed with nitrogen, 40 ml of dimethyl sulfide are added and the resulting mixture is stirred overnight at room temperature. The reaction medium is evaporated under reduced pressure. The residue is chromatographed on silica gel, eluting with a DCM/EtOAc mixture from (100/0, v/v) to (60/40, v/v) to give 0.58 g of the expected product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][NH2:16])[CH2:11][CH:12]=1>CO.[OH-].[Pd+2].[OH-]>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][NH2:16])[CH2:9][CH2:8]1
Reactant: NCCCN1CC=C(c2ccccn2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: NCCCN1CCC(c2ccccn2)CC1
Reaction time: 10 h

Procedure:
To a solution of 3-(3′,6′-dihydro-2′-H-[2,4′]bipyridinyl-1′-yl)-propylamine (3.48 g crude, 15.9 mmol) in MeOH (40 mL), was added 1.0 g of palladium hydroxide catalyst. The suspension was hydrogenated under 120 psi for 10 h after which the reaction mixture was filtered through a pad of Celite and the solvent was removed. The residue was purified by column chromatography over silica gel (30 g) [Note: If a large excess of silica gel is used the recovery of the product will be very low] using methylene chloridemethanol/2M ammonia in MeOH (90:8:4 to 90:40:40) as eluent. The product was obtained as a pale yellow oil.