Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C2OC3C=CC=CC=3NCC=2C=CC=1.FC1C=C(F)C=CC=1C(Cl)=O.[F:27][C:28]1[CH:33]=[C:32](F)[CH:31]=[CH:30][C:29]=1[C:35]([N:37]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[O:41][C:40]2[N:48]=[CH:49][CH:50]=[CH:51][C:39]=2[CH2:38]1)=[O:36].[Na].[CH3:53][C:54]1[CH:58]=[CH:57][NH:56][N:55]=1>>[F:27][C:28]1[CH:33]=[C:32]([N:56]2[CH:57]=[CH:58][C:54]([CH3:53])=[N:55]2)[CH:31]=[CH:30][C:29]=1[C:35]([N:37]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[O:41][C:40]2[N:48]=[CH:49][CH:50]=[CH:51][C:39]=2[CH2:38]1)=[O:36]
Reactant: O=C(c1ccc(F)cc1F)N1Cc2cccnc2Oc2ccccc21
Reactant: Cc1cc[nH]n1
Agent: O=C(Cl)c1ccc(F)cc1F
Agent: [Na]
Agent: c1cnc2c(c1)CNc1ccccc1O2
Product: Cc1ccn(-c2ccc(C(=O)N3Cc4cccnc4Oc4ccccc43)c(F)c2)n1

Procedure:
The title compound may be prepared in a manner analogous to that of the 2-chloro analog of Example 16, by reacting 6H-pyrido[2,3-b][1,5]benzoxazepine of Example 16, Step A with 2,4-difluoro benzoylchloride of Example 9, Step A. Subsequent reaction of the intermediate (2,4-difluoro-phenyl)-(11H-5-oxa-4,10-diaza-dibenzo[a,d]cyclohepten-10-yl)-methanone with the sodium salt of 3-methylpyrazole in a manner analogous to that of Example 16, Step C will provide the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[CH2:3][CH2:4][NH:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([OH:28])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][CH:17]=2)=[CH:11][C:10]=1[F:29])=[O:7].C(=O)([O-])[O-].[K+].[K+].Br[CH2:39][CH2:40][Cl:41]>CN(C)C=O>[Cl:41][CH2:40][CH2:39][O:28][C:22]1[CH:21]=[C:20]2[C:25]([C:16]([O:15][C:12]3[CH:13]=[CH:14][C:9]([NH:8][C:6]([NH:5][CH2:4][CH2:3][C:2]([CH3:31])([CH3:30])[CH3:1])=[O:7])=[C:10]([F:29])[CH:11]=3)=[CH:17][CH:18]=[N:19]2)=[CH:24][C:23]=1[O:26][CH3:27]
Reactant: COc1cc2c(Oc3ccc(NC(=O)NCCC(C)(C)C)c(F)c3)ccnc2cc1O
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(NC(=O)NCCC(C)(C)C)c(F)c3)ccnc2cc1OCCCl
Temperature: 25 °C
Reaction time: 20 h
Yield: 74 %

Procedure:
A crude product of 1-(3,3-dimethyl-butyl)-3-[2-fluoro-4-(7-hydroxy-6-methoxy-quinolin-4-yloxy)-phenyl]-urea was dissolved in dimethylformamide (100 ml) to prepare a solution. Potassium carbonate (18 g) and 1-bromo-2-chloroethane (11 g) were added to the solution, and the mixture was stirred at room temperature for 20 hr. The mixture was extracted with ethyl acetate, was then washed with saturated brine, and was dried over anhydrous sodium sulfate. The solvent was removed by evaporation under the reduced pressure. The residue was washed with a mixed solvent of n-hexane: ethyl acetate (2:1) and was then collected by filtration to give 1-{4-[7-(2-chloroethoxy)-6-methoxy-quinolin-4-yloxy]-2-fluorophenyl}-3-(3,3-dimethyl-butyl)urea (7.7 g, yield 74%).
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:7]=[N:8][C:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[N:10][CH:11]=1)=[O:5].C([Mg]Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1>[C:4]([C:6]1[CH:11]=[N:10][C:9]([N:12]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH2:16][CH2:17]2)=[N:8][CH:7]=1)(=[O:5])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CON(C)C(=O)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Reactant: Br[Mg]Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(C(=O)c3ccccc3)cn2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73 %

Procedure:
To a solution of tert-butyl 4-(5-(methoxy(methyl)carbamoyl)pyrimidin-2-yl)piperazine-1-carboxylate (2.6 g, 7.4 mmol) in dry THF (30 mL) was added benzylmagnesium bromide (1 M in THF, 29.6 mL) at 0° C. under N2, and the mixture was stirred at room temperature for 3 hours. LCMS showed the reaction was completed. The reaction mixture was quenched with 1 M HCl and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=5:1) to get tert-butyl 4-(5-benzoylpyrimidin-2-yl)piperazine-1-carboxylate (2 g, 73%) as a yellow solid. MS (ES+) C20H24N4O3 requires: 368, found: 313 [M-56+H]+.
Reaction SMILES: C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[CH2:25]([O:32][C:33]([NH:35][C@H:36]([C:52](O)=[O:53])[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[CH:40][CH:39]=1)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Br.[CH3:56][O:57][C:58](=[O:63])[C@@H:59]([CH3:62])[NH:60][CH3:61]>O1CCCC1>[CH3:56][O:57][C:58](=[O:63])[C@@H:59]([CH3:62])[N:60]([C:52](=[O:53])[C@H:36]([CH2:37][C:38]1[CH:39]=[CH:40][C:41]([O:44][CH2:45][C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)=[CH:42][CH:43]=1)[NH:35][C:33]([O:32][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:34])[CH3:61]
Reactant: O=C(N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O)OCc1ccccc1
Reactant: CN[C@H](C)C(=O)OC
Agent: Br
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)[C@@H](C)N(C)C(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OCc1ccccc1
Temperature: -20 °C
Reaction time: 0.17 h

Procedure:
Diisopropylethylamine (1.29 g.), then diphenylphosphinic chloride (2.37 g.), were added to a solution of N-benzyloxycarbonyl-O-benzyl-L-tyrosine (4.05 g.) in tetrahydrofuran (30 ml.) maintained at -20° C., and the mixture was stirred at that temperature for 10 minutes. A solution of N-methyl-D-alanine methyl ester hydrobromide (1.98 g.) in tetrahydrofuran (20 ml.) was then added, followed by diisopropylethylamine (1.29 g.). The mixture was stirred for two hours at 0° C., then overnight at room temperature, then filtered, stripped of volatiles and distributed between ethyl acetate and aqueous citric acid (5%). The ethyl acetate layer was washed with water, saturated aqueous sodium bicarbonate, water again and saturated aqueous sodium chloride, then dried over magnesium sulfate and concentrated to a yellow gum (about 6 g.). Purification of the yellow gum by high pressure liquid chromatography on silica gel (350 g.) using hexane-ethyl acetate (7:3) as the eluant afforded (N-benzyloxycarbonyl-O-benzyl-L-tyrosyl)-N-methyl-D-alanine methyl ester as a clear gum (3.2 g.) containing about a one-sixth molar amount of ethyl acetate as shown by NMR spectral analysis.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:12]=[C:11]([Cl:23])[C:10]=1[CH2:24][CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.Cl[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33]>C1COCC1>[CH2:16]([O:15][C:13]1[N:12]=[C:11]([Cl:23])[C:10]([CH2:24][CH3:25])=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:14]=1[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCc1c(OCc2ccccc2)cc(OCc2ccccc2)nc1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1c(Cl)nc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 64.9 %

Procedure:
To a solution of the intermediate obtained in Step 2 (7.7 g, 21.8 mmol) in THF (80 mL), at −78° C. was added n-BuLi (21.8 mL, 54.4 mmol) dropwise, and stirred for additional 15 min. at −78° C. after the addition. Benzyl chloroformate (4.7 mL, 32.6 mmol) was then added and the resulting mixture was stirred for 10 min before the cooling bath was removed. The mixture was allowed to warm to room temperature while stirring. The reaction was quenched with a solution of NH4Cl (5 mL), diluted with ethyl ether (150 mL), washed with water (2×30 mL) and brine (30 mL). After drying with Na2SO4, the solvent was removed and the residue was chromatographed (silica gel, ethylacetate in hexanes, 0-5%) to provide product as white crystalline material (6.9 g, yield: 65%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[C:15](Cl)(=[O:18])[CH2:16][CH3:17]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([O:8][C:15](=[O:18])[CH2:16][CH3:17])[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(F)c1
Reactant: CCC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(=O)Oc1cccc(F)c1
Reaction time: 0.5 h
Yield: 100.5 %

Procedure:
To a solution of 3-fluorophenol (22.4 g, 0.2 mol), pyridine (24 ml, 0.3 mol) and dichloromethane (200 ml) at room temperature was added 20 ml (0.225 mol) propionyl chloride over a period of 5 min. The reaction was exothermic. The solution was stirred for another 30 min. After addition of dichloromethane, the organic phase was washed with sat. NaHCO3 solution and water, dried over MgSO4 and concentrated in vacuo. 33.8 g (100%) of 3-fluoro-1-propionyloxybenzene was obtained. This compound was reacted with 33.3 g (0.25 mol) AlCl3 at 150° C. for a period of 10 min. After careful quenching with water, the reaction mixture was extracted three times with ether. The ether phase was dried (MgSO4) and evaporated to give 29.5 g (0.176 mol, 88%) rearranged product. This intermediate was dissolved in 200 ml of acetone and K2CO3 (42, 0.3 mol) and MeI (25 ml, 0.4 mol) were added. The reaction mixture was heated at 40° C. for a period of 12 h. The reaction mixture was filtered and the acetone was evaporated. The residue was dissolved in ether and the ether phase washed with a 0.5 M NaOH solution and water. Drying (MgSO4) and evaporation gave 31.2 g (0.17 mol, 86% yield for three steps) of 4-fluoro-2-methoxypropiophenone.
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[N:3]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[CH2:28][NH:27][CH2:26][CH2:25][NH:24]2)=[C:19]([O:29][CH3:30])[CH:18]=1.C(N(CC)CC)C>CN(C)C=O>[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[CH2:28][N:27]([C:2]3[N:7]([CH3:8])[C:6](=[O:9])[CH:5]=[C:4]([C:10]4[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=4)[N:3]=3)[CH2:26][CH2:25][NH:24]2)=[C:19]([O:29][CH3:30])[CH:18]=1
Reactant: COc1cc(F)ccc1C1CNCCN1
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(F)ccc1C1CN(c2nc(-c3ccncc3)cc(=O)n2C)CCN1
Temperature: 0 °C
Reaction time: 1 h
Yield: 62.2 %

Procedure:
2-Chloro-3-methyl-6-(4-pyridyl)-pyrimidin-4-one (222 mg, 1.0 mmol) was added to an ice-cooled solution of 2-(4-fluoro-2-methoxyphenyl)piperazine (210 mg, 1.0 mmol), triethylamine (0.15 ml, 1.1 mmol) in N,N-dimethylformamide (10 ml) and stirred at that temperature for 1 hr and then at room temperature for 2 hr. Next day, reaction was quenched by ice-water and the filtrate was washed with water and dried to give 2-(2-(4-fluoro-2-methoxyphenyl)piperazin-4-yl)-3-methyl-6-(4-pyridyl)-pyrimidin-4-one (246 mg, 62%).
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[CH:37][C:5]2[NH:6][C:7]([C@@H:9]([NH:11][C:12](=[O:36])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([N:21]4[CH2:25][CH2:24][CH2:23][C@@H:22]4[CH2:26][NH:27]C(OC(C)(C)C)=O)=[O:20])=[C:15]([Cl:35])[CH:14]=3)[CH3:10])=[N:8][C:4]=2[CH:3]=1.FC(F)(F)C(O)=O.ClCCl.CO.N.ClCl>>[Cl:1][C:2]1[CH:38]=[CH:37][C:5]2[NH:6][C:7]([C@@H:9]([NH:11][C:12](=[O:36])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([N:21]4[CH2:25][CH2:24][CH2:23][C@@H:22]4[CH2:26][NH2:27])=[O:20])=[C:15]([Cl:35])[CH:14]=3)[CH3:10])=[N:8][C:4]=2[CH:3]=1
Reactant: C[C@H](NC(=O)c1ccc(C(=O)N2CCC[C@@H]2CNC(=O)OC(C)(C)C)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Agent: N
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](NC(=O)c1ccc(C(=O)N2CCC[C@@H]2CN)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 86 %

Procedure:
Prepared analogously to Example 17 from N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)ethyl]-3-chloro-4-[(2R)-2-(N-tert-butoxycarbonylaminomethyl)pyrrolidin-1-ylcarbonyl]benzamide and trifluoroacetic acid. Yield: 86%; Rf value: 0.10 (silica gel; dichloromethane/methanol/ammonia=9:1:0.1); C22H23Cl2N5O2 (460.36); mass spectrum: (M+H)+=460/462 (chlorine isotope) and (M−H)−=458/460 (chlorine isotope).
Reaction SMILES: Br[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[NH:20][C:19]4[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=4[N:17]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[O:25]1[CH2:30][CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH2:27][CH2:26]1.C([O-])(=O)C.[K+]>C(#N)C.O>[O:25]1[CH2:26][CH:27]=[C:28]([C:2]2[C:3]([O:8][C:9]3[CH:14]=[CH:13][C:12]([NH:15][C:16]4[NH:17][C:18]5[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=5[N:20]=4)=[CH:11][CH:10]=3)=[N:4][CH:5]=[CH:6][CH:7]=2)[CH2:29][CH2:30]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: Brc1cccnc1Oc1ccc(Nc2nc3ccccc3[nH]2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: C1=C(c2cccnc2Oc2ccc(Nc3nc4ccccc4[nH]3)cc2)CCOC1
Temperature: 25 °C

Procedure:
To a round bottomed flask was added N-(4-(3-bromopyridin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amine (0.5674 g, 1.488 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.938 g, 4.47 mmol), PdCl2(PPhtBu2)2 (0.093 g, 0.149 mmol), and potassium acetate (0.698 mL, 11.16 mmol) in ACN (3.72 mL) and water (1.240 mL) at 100° C. to stir. Upon completion, reaction allowed to cool to room temperature. Solvent was evaporated. The crude product was purified by reverse-phase preparative HPLC using a Phenomenex Synergi column, 4 micron, MAX-RP, 80 Å, 150×30 mM, 0.1% TFA in ACN/H2O, gradient 25% to 90% over 20 min to provide N-(4-(3-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amine. MS (ESI, pos. ion) m/z: 385.0 (M+1).
Reaction SMILES: BrCCBr.[CH2:5](I)[C:6]([CH3:9])([CH3:8])[CH3:7].Br[C:12]1[C:17]([O:18][CH2:19][C:20]2[N:21]([CH3:25])[N:22]=[CH:23][N:24]=2)=[N:16][N:15]2[C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[F:35])=[N:27][N:28]=[C:14]2[CH:13]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>CN(C=O)C.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH3:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:12]1[C:17]([O:18][CH2:19][C:20]2[N:21]([CH3:25])[N:22]=[CH:23][N:24]=2)=[N:16][N:15]2[C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[F:35])=[N:27][N:28]=[C:14]2[CH:13]=1
Reactant: Cn1ncnc1COc1nn2c(-c3ccccc3F)nnc2cc1Br
Reactant: CC(C)(C)CI
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: O
Solvent: BrCCBr
Product: Cn1ncnc1COc1nn2c(-c3ccccc3F)nnc2cc1CC(C)(C)C
Reaction time: 0.08 h
Yield: 58.1 %

Procedure:
1,2-Dibromoethane (0.03 ml, 10 mol %) was added to a stirred suspension of acid washed zinc dust (0.45 g, 7.0 mmol) in anhydrous DMF (3 ml) at 50° C. under nitrogen. After 5 min, neopentyl iodide (1.0 ml, 7.5 mmol) was added. The mixture was stirred for 2.5 h to give a grey-green milky solution. A mixture of 7-bromo-3-(2-fluorophenyl)-6-(2-methyl2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4,3-b]pyridazine (0.35 g, 0.866 mmol), tri-2-furylphosphine (0.08 g. 40 mol %) and tris(dibenzylideneacetone)dipalladium(0) (0.04 g, 5 mol %) in anhydrous DMF (2 ml) was stirred at 50° C. under nitrogen for 15 min followed by addition of the solution of organozinc reagent via syringe. After 2.5 h, the mixture was cooled, poured into water (100 ml) and extracted with dichloromethane (2×50 ml). The extracts were dried (Na2SO4), filtered and concentrated. Flash column chromatography on silica gel, eluting with 2% methanol-dichloromethane, gave a brown solid that was recrystallised from ethyl acetate-diethyl ether to give 7-(2,2-dimethylpropyl)-3-(2-fluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4,3-b]pyridazine (0.199 g, 58%) as a beige powder; 1H NMR (360 MHz, CDCl3) δ0.96 (9H, s), 2.61 (2H, s), 3.83 (3H, s), 5.47 (2H, s), 7.28 (1H, dd, J=10 and 10 Hz), 7.36 (1H, dd, J=8 and 8 Hz), 7.56-7.62 (1H, m), 7.83 (1H, s), 7.86 (1H, dd, J=8 and 8 Hz), 7.90 (1H, s); MS (ES+) m/e 396 [MH]+. Anal. Found C, 59.66; H, 5.69; N. 24.41%. C20H22FN7O.0.4H2O requires C, 59.66; H, 5.71; N, 24.35%.
Reaction SMILES: C(OC([NH:8][C@H:9]1[C@H:14]([CH2:15][CH:16]2[CH2:19][CH2:18][CH2:17]2)[CH2:13][CH2:12][N:11]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:10]1)=O)(C)(C)C.[OH-].[Na+]>Cl.C(#N)C>[NH2:8][C@H:9]1[C@H:14]([CH2:15][CH:16]2[CH2:19][CH2:18][CH2:17]2)[CH2:13][CH2:12][N:11]([C:20]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:21])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1CC1CCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: N[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1CC1CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.1 %

Procedure:
(±)-trans-benzyl 3-(tert-butoxycarbonylamino)-4-(cyclobutylmethyl)piperidine-1-carboxylate (14 mg, 0.035 mmol)) was dissolved in 1:1 2N aq HCl/acetonitrile (8 mL) and stirred overnight at rt. The reaction mixture was basified with 5% aq NaOH solution to about pH=9. The acetonitrile was removed under vacuum. The aqueous residue was extracted with CH2Cl2 (3×20 mL). The combined organic layers were washed with brine (10 mL) and dried over Na2SO4. Concentration afforded (±)-trans-benzyl 3-amino-4-(cyclobutylmethyl)piperidine-1-carboxylate (8.9 mg, 85% yield). The crude product was used in the next step without further purification. MS ESI +ve m/z 303 (M+Na).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[C:10](Cl)=[CH:9][C:8]([Cl:12])=[N:7][CH:6]=1)[CH3:2].[CH2:14]([O:16][C:17](=[O:30])[CH2:18][CH2:19][NH:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[CH2:26][CH2:25][CH2:24]2)[CH3:15].C(N(CC)CC)C>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[C:10]([N:20]([CH2:19][CH2:18][C:17]([O:16][CH2:14][CH3:15])=[O:30])[C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[CH2:26][CH2:25][CH2:24]3)=[CH:9][C:8]([Cl:12])=[N:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cnc(Cl)cc1Cl
Reactant: CCOC(=O)CCNc1ccc2c(c1)CCC2
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CCN(c1ccc2c(c1)CCC2)c1cc(Cl)ncc1C(=O)OCC
Temperature: 100 °C
Reaction time: 48 h
Yield: 42.6 %

Procedure:
To a solution of 4,6-dichloro-nicotinic acid ethyl ester (2 g, 9 mmol) and 3-(indan-5-ylamino)-propionic acid ethyl ester (from Example 1 (A), 2.3 g, 10 mmol) in 5 mL of DMF was added triethylamine (2 g, 20 mmol). The mixture was stirred at 100° C. for 48 hours. The reaction was cooled, quenched with water, and extracted 3 times with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuo. Flash chromatography (EtOAc/Hexanes, 2:10 v/v) afforded the title compound as a white solid (1.6 g, 44%). 1H NMR (400 MHz, CDCl3) δ (ppm): 8.22 (s, 1H), 7.15 (d, J=8.0 Hz, 1H), 6.92 (s, 1H), 6.85 (m, 2H), 4.03-4.15 (m, 4H), 3.74 (q, J=7.1 Hz, 2H), 2.85 (t, J=7.4 Hz, 4H), 2.64 (m, 2H), 2.07 (m, 2H), 1.23 (t, J=7.1 Hz, 3H), 1.08 (t, J=7.1 Hz, 3H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][C:30]=1[CH2:31][OH:32])[CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:27])=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:23])[CH2:21][CH3:22])=[CH:16][C:15]=2[CH2:24][CH2:25][CH3:26])[CH:13]=1.[CH2:33]([Mg]Br)[CH3:34].[Cl-].[NH4+]>C1COCC1>[CH2:21]([C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:12]2[C:11]([CH3:27])=[CH:10][CH:9]=[C:8]([O:7][CH2:6][C:5]3[CH:28]=[CH:29][C:30]([CH2:31][OH:32])=[C:3]([CH2:2][OH:1])[CH:4]=3)[CH:13]=2)=[C:15]([CH2:24][CH2:25][CH3:26])[CH:16]=1)([OH:23])[CH2:33][CH3:34])[CH3:22]
Reactant: CCCc1cc(C(=O)CC)ccc1-c1cc(OCc2ccc(CO)c(CO)c2)ccc1C
Reactant: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCc1cc(C(O)(CC)CC)ccc1-c1cc(OCc2ccc(CO)c(CO)c2)ccc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.4 %

Procedure:
890 mg (2 mmol) of 1-{5′-[3,4-bis(hydroxymethyl)benzyloxy]-2′-methyl-2-propylbiphenyl-4-yl}-1-propanone are placed in 40 ml of dry THF in a round-bottomed flask and under a stream of nitrogen. At 0° C., 4.1 ml (12 mmol) of ethylmagnesium bromide are added. The reaction medium is stirred at room temperature for 1 hour 30 minutes and then poured into saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and then evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a mixture of heptane and ethyl acetate (50/50) to give 550 mg (64%) of {5-[4′-(1-ethyl-1-hydroxypropyl)-6-methyl-2′-propylbiphenyl-3-yloxymethyl]-2-hydroxymethylphenyl}methanol in the form of white crystals with a melting point of 97° C.
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(OO)(C)(C)C.[OH:13][N:14]1[C:19]([CH3:21])([CH3:20])[CH2:18][C:17](=[O:22])[CH2:16][C:15]1([CH3:24])[CH3:23]>[Mo](=O)(=O)=O.O>[CH:1]1([O:13][N:14]2[C:19]([CH3:20])([CH3:21])[CH2:18][C:17](=[O:22])[CH2:16][C:15]2([CH3:24])[CH3:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCCCC1
Reactant: CC1(C)CC(=O)CC(C)(C)N1O
Agent: O=[Mo](=O)=O
Agent: CC(C)(C)OO
Solvent: O
Product: CC1(C)CC(=O)CC(C)(C)N1OC1CCCCC1
Reaction time: 5 h
Yield: 98.7 %

Procedure:
A mixture of cyclohexane (215 ml, 2.0 moles), t-butyl hydroperoxide, 70% aqueous (77.1 g, 0.6 moles), molybdenum trioxide (1.44 g, 0.01 moles) and 1-oxyl-2,2,6,6-tetramethyl-4-piperidone (34 g, 0.2 moles) is charged into a 500 ml flask equipped with a Barrett trap. The mixture is stirred at reflux (80° C.) for two hours until no more water is collected. Then, the mixture is filtered by gravity into a pressure bottle and molybdenum trioxide (1.44 g, 0.01 mole) are added. Subsequently, the mixture is heated under stirring to 105° C. (2.34 bar) and held for 5 hours, until the color changes from deep orange to pale yellow. The mixture is filtered and the clear solution is washed with 10% aqueous sodium sulfite (100 ml) and subsequently with water (2×50 ml). The obtained clear solution is dried over sodium sulfate and then concentrated to give 50 g of the desired material as a clear yellow oil (Mass spectrum: m/e=253)
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:13]([C:14]([O:16]C)=O)=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][C:19](C)([O-:21])C.[K+]>C(OCCCC)(=O)C>[OH:16][C:14]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:19](=[O:21])[CH:18]=1
Reactant: COC(=O)c1cccnc1Nc1ccccc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCCOC(C)=O
Product: O=c1cc(O)c2cccnc2n1-c1ccccc1

Procedure:
To a stirred solution of 1 kg. of methyl 2-phenylamino-3-pyridine carboxylate in 3.97 liters of n-butyl acetate there is added portionwise, 1.1 kg. of potassium tertiary butoxide. After the addition of the potassium tertiary butoxide, there is added an additional 1.32 liters of n-butyl acetate. The reaction mixture is heated to reflux for 20 hours during which the internal temperature of the reaction mixture rose from 90° C. to 122° C. During this period, 1.8 liters of liquid is removed from the reaction mixture via a Dean-Stark trap. Xylene (3.0 liters) is added to the reaction mixture and the remainder of the n-butyl acetate is removed via the Dean-Stark trap. The reaction mixture is cooled and the potassium salt is collected by filtration, washed with toluene and air dried. The crude potassium salt is dissolved in 12 liters of water, the aqueous solution is extracted with toluene, acidified to pH 2 and the product filtered and dried; weight 937 g., m.p. 311°-313° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=1.[CH3:13][N:14]([CH3:18])[C:15](Cl)=[S:16].C(N(CC)CC)C>O1CCOCC1>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:15](=[S:16])[N:14]([CH3:18])[CH3:13])[CH:6]=1
Reactant: COC(=O)Cc1cccc(O)c1
Reactant: CN(C)C(=S)Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COC(=O)Cc1cccc(OC(=S)N(C)C)c1

Procedure:
A mixture of (3-Hydroxy-phenyl)-acetic acid methyl ester (5.5 g, 33.1 mmol), N,N-dimethyl thiocarbamoyl chloride (5.11 g, 41.38 mmol), triethylamine (9.2 mL, 66.2 mmol), N,N-dimethylamino pyridine (0.4 g, 3.31 mmol) and dioxane (50 mL) is stirred at reflux 18 hr. The mixture is concentrated, partioned between 1M aqueous hydrochloric acid (200 mL) and ethyl acetate (3×75 mL). The combined organic extracts are dried over anhydrous magnesium sulfate, filtered, concentrated, and purified via silica chromatography eluting the product with dichloromethane to afford the title compound as a brown oil, 6.8 g, 81%. MS M++1 254. The structure is confirmed by 1H NMR spectroscopy.