Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][CH:9]([N:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15])[CH2:8][CH2:7]2.C([Li])CCC.CCCCCC.[CH3:30][S:31]SC>O1CCCC1.O>[CH2:13]([N:12]([CH2:16][CH2:17][CH3:18])[CH:9]1[CH2:8][CH2:7][C:6]2[C:11](=[C:2]([S:31][CH3:30])[CH:3]=[CH:4][CH:5]=2)[CH2:10]1)[CH2:14][CH3:15]
Reactant: CCCN(CCC)C1CCc2cccc(Br)c2C1
Reactant: CSSC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCN(CCC)C1CCc2cccc(SC)c2C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 80.3 %

Procedure:
To a solution of 8-bromo-2-di-n-propylamino-1,2,3,4-tetrahydronaphthalene (600 mg, 1.93 mMol) in tetrahydrofuran (20 mL) at -78° C. was added a solution of n-butyllithium in hexane (1.6 M, 1.9 mL, 3.04 mMol). The solution was stirred at -78° C. for one hour, forming a light orange solution. Dimethyl disulfide (0.24 mL, 3.00 mMol) was added, and the reaction mixture was allowed to warm gradually to room temperature. The colorless solution was diluted with water and extracted with dichloromethane. The dichloromethane extracts were combined, dried (Na2SO4), and concentrated in vacuo to give the crude product as a light yellow oil. Purification by flash chromatography (3% methanol in dichloromethane+ tr. NH4OH) gave the product as a colorless, viscous oil (430 mg, 80%). The hydrochloride salt was formed. Recrystallization (ethanol/diethyl ether) gave a colorless, crystalline solid (m.p.=185° C.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[CH2:10]([O:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCc1ccccc1
Reactant: O=c1ccc(Br)c[nH]1
Solvent: Cc1ccccc1
Product: Brc1ccc(OCc2ccccc2)nc1
Temperature: 100 °C
Yield: 92.6 %

Procedure:
To a solution of 5-bromopyridin-2(1H)-one (1.28 g, 7.36 mmol) and Ag2CO3 (3 g, 11.04 mmol) in toluene (50 mL) was added (bromomethyl)benzene (1.25 g, 7.36 mmol) dropwise and the reaction mixture was stirred at 100° C. over night. The reaction mixture was filtered through a short pad of silica gel and washed with DCM. The filtrate was concentrated to yield the title compound as light yellow oil (1.8 g, 95%).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:13](=[N:15][O:16][CH2:17][CH2:18][OH:19])[CH3:14])=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[C:21]1[CH:53]=[CH:52][C:24]([CH2:25][CH:26]2[S:30][C:29](=[O:31])[N:28]([C:32]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]2=[O:51])=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:13](=[N:15][O:16][CH2:17][CH2:18][O:19][C:21]3[CH:53]=[CH:52][C:24]([CH2:25][CH:26]4[S:30][C:29](=[O:31])[N:28]([C:32]([C:45]5[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=5)([C:39]5[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=5)[C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[C:27]4=[O:51])=[CH:23][CH:22]=3)[CH3:14])=[N:11][CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=NOCCO)c1ccc(-c2ccccc2)cn1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(=NOCCOc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1)c1ccc(-c2ccccc2)cn1
Yield: 99.4 %

Procedure:
Following a procedure similar to that described in Example 1(a), but using 513 mg of 2-[1-(5-phenyl-2-pyridyl)ethylideneaminooxy]ethanol (prepared as described in Preparation 39), 1.02 g of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione, 577 mg of triphenylphosphine and 383 mg of diethyl azodicarboxylate, 1.40 g of the title compound were obtained as a foam-like solid.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][N+:12]([O-])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:18])=O.[OH-].[Na+]>O>[C:1]([C:9]1[CH:14]=[CH:13][N:12]=[C:11]([Cl:18])[CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1cc[n+]([O-])cc1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(c1ccccc1)c1ccnc(Cl)c1

Procedure:
A mixture of 2.5 g 4-benzoylpyridine N-oxide m.p. 127°-30° C. (obtained according to T. KATO et. al., Yakugaku Zasshi 86, 1022-26, 1966), and 6 ml phosphorus oxychloride is refluxed for 2 hrs. After cooling, the reaction mixture is very slowly added to ice:water, basified (10N NaOH) and extracted with methylene chloride. The organic layer is washed with water, dried and solvent removed in a rotary evaporator. Yield: 2.4 g of title product, identical with that described in Ex. 4.
Reaction SMILES: Br[C:2]1[C:3]([CH3:9])=[C:4]([C:7]#[N:8])[S:5][CH:6]=1.[CH:10]([B-](F)(F)F)=[CH2:11].[K+]>CCO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:10]([C:2]1[C:3]([CH3:9])=[C:4]([C:7]#[N:8])[S:5][CH:6]=1)=[CH2:11]
Reactant: Cc1c(Br)csc1C#N
Reactant: C=C[B-](F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [K+]
Solvent: CCO
Product: C=Cc1csc(C#N)c1C

Procedure:
A mixture of 4-bromo-3-methylthiophene-2-carbonitrile (3.00 g, 14.8 mmol), potassium vinyltrifluoroborate (2.40 g, 17.8 mmol) and Pd(dppf)Cl2 (0.5 g) in 30 mL of EtOH and 30 mL of TEA was refluxed under Ar for 4 hours. The reaction mixture was concentrated, and the residue was purified by column chromatography (petrol ether: EtOAc=50:1) to afford 4-ethenyl-3-methylthiophene-2-carbonitrile.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([F:19])[C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=3)=[CH:7][C:6]=2[CH:18]=1.Cl.N1C=CC=CC=1>O>[F:1][C:2]1[CH:3]=[C:4]([F:19])[C:5]2[O:9][C:8]([C:10]3[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=3)=[CH:7][C:6]=2[CH:18]=1
Reactant: COc1ccc(-c2cc3cc(F)cc(F)c3o2)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: Oc1ccc(-c2cc3cc(F)cc(F)c3o2)cc1
Temperature: 200 °C
Reaction time: 1 h
Yield: 13 %

Procedure:
Compound 86 was treated with Pyridine HCl (5 g) and heated to 200° C. After 1 hr, the reaction was cooled and diluted with water. The aqueous layer was extracted with EtOAc, dried, and the product was purified by column chromatography (eluent 25% EtOAc/hex) to give a solid (0.12 g, 13%): Mp=152–154° C.; 1H NMR (DMSO-d6) δ 10.01 (br s, 1 H), 7.77 (d, 2 H, J=8.9 Hz), 7.32–7.25 (m, 3 H), 6.91 (d, 2 H, J=8.9 Hz); MS 245 [M−H]−
Reaction SMILES: Cl.[C:2]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][O:13][Si](C(C)(C)C)(C)C)=[CH:8][C:7]=1[NH:21][C:22](=[O:40])[CH2:23][CH:24]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][C:31]=1[O:38][CH3:39])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])([CH3:5])([CH3:4])[CH3:3]>CO.C(Cl)Cl.C(OCC)C>[C:2]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][OH:13])=[CH:8][C:7]=1[NH:21][C:22](=[O:40])[CH2:23][CH:24]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][C:31]=1[O:38][CH3:39])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])([CH3:3])([CH3:4])[CH3:5]
Reactant: CCCCCC(CC(=O)Nc1cc(CO[Si](C)(C)C(C)(C)C)ccc1C(C)(C)C)c1ccc(OC)cc1OC
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: CCOCC
Product: CCCCCC(CC(=O)Nc1cc(CO)ccc1C(C)(C)C)c1ccc(OC)cc1OC
Reaction time: 0.67 h
Yield: 96.5 %

Procedure:
0.1 ml of concentrated aqueous hydrochloric acid was added, with stirring and ice-cooling, to a solution of 460 mg (0.828 mmol) of N-[2-t-butyl-5-(t-butyldimethylsilyloxymethyl)phenyl]-3-(2,4-dimethoxyphenyl)octanamide (prepared as described in Preparation 8) in a mixture of 9 ml of methanol and 1 ml of methylene chloride, and the resulting mixture was allowed to stand at the same temperature for 40 minutes, after which it was diluted with diethyl ether. The diluted solution was washed twice with water and once with a saturated aqueous solution of sodium chloride, after which it was dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was recrystallized from a mixture of hexane and ethyl acetate to give 353 mg (yield 96%) of the title compound as crystals, melting at 125-126° C.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[F:27][C:28]([F:46])([F:45])[CH2:29][S:30][CH2:31][C:32]1([O:44][CH2:43][CH2:42][O:41]1)[C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH2:38])=[CH:35][CH:34]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:13])([F:15])[F:14])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:38][CH2:37][C:36]1[CH:35]=[CH:34][C:33]([C:32]2([O:41][CH2:42][CH2:43][O:44]2)[CH2:31][S:30][CH2:29][C:28]([F:27])([F:45])[F:46])=[CH:40][CH:39]=1
Reactant: NCc1ccc(C2(CSCC(F)(F)F)OCCO2)cc1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: O=C(N1CCc2ccc(Cl)c(NCc3ccc(C4(CSCC(F)(F)F)OCCO4)cc3)c2CC1)C(F)(F)F
Yield: 41.6 %

Procedure:
Use a method similar to the General Procedure 1-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (173 mg, 0.4 mmol) with 4-[2-(2,2,2-trifluoroethylthio)-1,1-(ethylenedioxy)ethyl]-benzylamine (250 mg, 0.8 mmol) using tris(dibenzylideneacetone)dipalladium(0) (73.2 mg, 0.08 mmol), BINAP (106 mg, 0.16 mmol) and cesium carbonate (182 mg, 0.6 mmol) in toluene (20 mL). Purify by chromatography on silica gel eluting with hexane/EtOAc (75:25) to give 7-chloro-3-(2,2,2-trifluoroacetyl)-6-{4-[2-(2,2,2-trifluoroethylthio)-1,1-(ethylenedioxy)ethyl]-benzylamino}-2,3,4,5-tetrahydro-1H-benzo[d]azepine (97 mg, 41%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:7][C:8]([NH:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]([F:24])([F:23])[F:22])[CH:19]=2)[N:14]=[CH:13][CH:12]=1)=[O:9].[H-].[Na+].[CH3:27]I>CN(C)C=O>[CH3:27][N:7]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][N:1]=1)[C:8]([NH:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]([F:24])([F:22])[F:23])[CH:19]=2)[N:14]=[CH:13][CH:12]=1)=[O:9]
Reactant: O=C(Nc1cnccn1)Nc1ccnc2ccc(C(F)(F)F)cc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)Nc1ccnc2ccc(C(F)(F)F)cc12)c1cnccn1
Reaction time: 16 h
Yield: 21.2 %

Procedure:
A solution of 145 mg (0.44 mmol) of 1-pyrazin-2-yl-3-(6-trifluoromethyl-quinolin-4-yl)-urea (Example 14) and 16 mg (0.65 mmol) of sodium hydride in 10 ml of dimethylformamide was stirred at 0° C. for 10 min. Methyl iodide (93 mg, 0.65 mmol) was added and the solution was allowed to reach RT and stirred for a further 16 h. The solution was concentrated in vacuo, and partitioned between dichloromethane and water. The organic layer was washed 3 times with water, concentrated in vacuo and the material purified by chromatography. White solid. Amount 32 mg. Yield 21.2%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[NH:10][CH2:11][C:12]([OH:14])=O)[CH:5]=[CH:6][CH:7]=1.[NH:16]([CH:23]([C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.S(Cl)(Cl)=O>>[Cl:37][C:34]1[CH:33]=[CH:32][C:31]([CH:23]([N:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:12](=[O:14])[CH2:11][NH:10][C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)=[O:15])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)C(Nc1ccccc1)c1ccc(Cl)cc1
Reactant: Cc1cccc(NC(=O)NCC(=O)O)c1
Solvent: O=S(Cl)Cl
Product: Cc1cccc(NC(=O)NCC(=O)N(c2ccccc2)C(C(=O)OC(C)(C)C)c2ccc(Cl)cc2)c1
Yield: 51.1 %

Procedure:
The procedure is as in Example 8, but using 2.1 g of 2-[3-(3-methylphenyl)ureido]acetic acid, 3.18 g of tert-butyl (RS)-2-anilino-2-(4-chlorophenyl)acetate and 0.72 cm3 of thionyl chloride as starting materials. The product obtained is purified by chromatography on 250 g of silica (0.04-0.063 mm) contained in a column 4.2 cm in diameter [eluent: ethyl acetate/cyclohexane (30/70 by volume)], using an excess pressure of 40 kPa of nitrogen and collecting 10-cm3 fractions. Fractions 8 to 17 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. and the residue obtained is recrystallized from diisopropyl ether. 2.6 g of tertbutyl (RS)-2-(4-chlorophenyl)-2-{2-[3-(3-methylphenyl)ureido]-N-phenylacetamido}acetate melting at 167° C. are then obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1O)[C:6]#[N:7].[CH3:12][CH2:13]N(C(C)C)C(C)C.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.C([Sn](CC)(CC)CC)C.[Li+].[Cl-]>C(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[CH2:12][CH3:13])[C:6]#[N:7]
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1cc(C#N)ccc1O
Agent: CC[Sn](CC)(CC)CC
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCc1ccc(C#N)cc1OC
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of 3-methoxy-4-hydroxybenzonitrile (9-1, 2.0 g, 13.4 mmol) in DCM (67 mL) at −78 deg was added DIPEA (3.0 mL, 17.4 mmol) followed by Triflic Anhydride (2.7 mL, 16.0 mmol) and stirred at −78 deg for 1 h. The mixture was poured into a separatory funnel containing a few pieces of ice and then partitioned between ice water and ether. The organic phase was washed with 1N HCl and then 10% Na2CO3, dried over Na2SO4, filtered and concentrated to yield a pale yellow oil. To a solution of this oil (2.7 g, 9.60 mmol) in DMF (96.0 mL) was added tetraethyl tin (3.80 mL, 19.2 mmol), bis-tri-t-butylphosphine palladium (0.491 g, 0.960 mmol) and LiCl (1.22 g, 28.8 mmol) and the system was heated to 80° C. for 1 h in an oil bath. The mixture was partitioned between saturated NaHCO3 and EtOAc. The organic phase was washed with water, brine, dried over Na2SO4, filtered and concentrated. The crude material was purified by gradient elution on silica gel (0 to 20% EtOAc in hexanes) to afford the desired compound (9-2) as a pale yellow crystalline solid. ESI+ MS [M+H]+ C10H11NO: 162.1 found, 162.2 required.
Reaction SMILES: [OH:1][C:2]([CH3:22])([CH3:21])[CH:3]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:10][CH:9]=1)[S:4]([NH2:7])(=[O:6])=[O:5].[C:23](OC)(OC)(OC)[O:24][CH3:25]>C(O)(=O)C>[CH3:23][O:24][C:25]1[O:1][C:2]([CH3:22])([CH3:21])[CH:3]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][N:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[CH:10][CH:9]=2)[S:4](=[O:5])(=[O:6])[N:7]=1
Reactant: COC(OC)(OC)OC
Reactant: CC(C)(O)C(c1ccc(CN2CCOCC2)cc1)S(N)(=O)=O
Solvent: CC(=O)O
Product: COC1=NS(=O)(=O)C(c2ccc(CN3CCOCC3)cc2)C(C)(C)O1

Procedure:
2-Hydroxy-2-methyl-1-(4-morpholin-4-ylmethylphenyl)propane-1-sulfonamide (350 mg) was stirred with tetramethyl orthocarbonate (5 ml) and glacial acetic acid (1 ml) at 80° C. for 16 hours. The solvents were removed under reduced pressure and the residue was used further without further purification.
Reaction SMILES: Cl[C:2]1[C:3]([CH:8]2[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[OH:27].C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.O>[C:15]([O:14][C:12]([N:10]1[CH2:11][CH:8]([C:3]2[C:2]([O:27][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[O:20][CH3:19])=[N:7][CH:6]=[CH:5][N:4]=2)[CH2:9]1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CC(c2nccnc2Cl)C1
Reactant: COc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccccc1Oc1nccnc1C1CN(C(=O)OC(C)(C)C)C1
Temperature: 90 °C
Reaction time: 8 h
Yield: 59.5 %

Procedure:
A mixture of 3-(3-chloro-pyrazin-2-yl)-azetidine-1-carboxylic acid tert-butyl ester (7) (100 mg, 0.37 mmol), 2-methoxy-phenol (47 mg, 0.37 mmol) and Cs2CO3 (242 mg, 0.74 mmol) in DMSO (10 mL) was stirred at 90° C. overnight. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated to give the crude compound, which was purified by column chromatography to afford pure product (13) (80 mg, 0.22 mmol, yield 61%) as solid. ESI-MS (M+1): 358 calc. for C19H23N3O4 357.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Br:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([CH:15]=1)[C:12]([NH2:14])=O>>[Br:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:12]#[N:14])[CH:15]=1
Reactant: NC(=O)c1cncc(Br)c1
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1cncc(Br)c1
Temperature: 25 °C
Yield: 82 %

Procedure:
Phosphorus oxychloride (5 ml) was added to 5-bromonicotinamide (2 g, 10 mmol, Avocado Research Chemicals, Ltd.) and the mixture was heated to gentle reflux for 3 hours. The mixture was allowed to cool to room temperature, poured onto ice (100 g) and extracted with ethyl acetate (3×100 mL). The combined extracts were washed successively with aqueous ammonium hydroxide and water, dried (MgSO4), filtered and the filtrate concentrated under reduced pressure. The residue was purified by chromatography (SiO2, ethyl acetate:hexanes, 1:1) to provide the title compound (1.5 g, 82% yield). MS (DCI/NH3) m/z 184 (M+H)+.
Reaction SMILES: [NH2:1][OH:2].[F:3][CH2:4][CH:5]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=O)=[CH:8][CH:7]=1>C(O)C>[C:17]([O:16][C:15](=[O:21])[NH:14][CH:5]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[N:1][OH:2])=[CH:8][CH:7]=1)[CH2:4][F:3])([CH3:20])([CH3:19])[CH3:18]
Reactant: NO
Reactant: CC(C)(C)OC(=O)NC(CF)c1ccc(C=O)cc1
Solvent: CCO
Product: CC(C)(C)OC(=O)NC(CF)c1ccc(C=NO)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 107.7 %

Procedure:
Hydroxylamine (459.6 μL of 50% w/v, 6.958 mmol) was added to a stirred solution of tert-butyl N-[2-fluoro-1-(4-formylphenyl)ethyl]carbamate (930 mg, 3.479 mmol) in ethanol (100 mL) and the reaction mixture stirred at ambient temperature for 4 hours. The reaction mixture was concentrated in vacuo and the residue taken up in water and extracted with ethyl acetate (×3). The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to give tert-butyl(2-fluoro-1-(4-((hydroxyimino)methyl)phenyl)ethyl)carbamate as an impure white solid (1058.2 mg, >100%). 1H NMR (400.0 MHz, DMSO-d6) 1.37 (s, 9H), 4.38-4.41 (m, 1H), 4.49-4.53 (m, 1H), 4.83-4.92 (m, 1H), 7.38 (d, 2H), 7.56 (d, 2H), 7.70 (d, 1H), 8.11 (d, 1H) and 11.24 (s, 1H) ppm; LC/MS m/z 227.0 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[OH-].[Na+].S(OCC)(O[CH2:19][CH3:20])(=O)=O>O>[CH2:19]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1)[CH3:20]
Reactant: O=C(O)CCc1ccc(O)cc1
Reactant: CCOS(=O)(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOc1ccc(CCC(=O)O)cc1
Temperature: 100 °C

Procedure:
16.62 g (100 mmol) of 3-(4-hydroxyphenyl)-propionic acid is dissolved with stirring and covering with argon in 45 ml (225.0 mmol) of 5N sodium hydroxide solution, and 15.73 g (100 mmol), (98%) of diethyl sulfate is instilled quickly so that the temperature does not exceed 40° C. (water cooling). After completion of the addition, it is heated for 30 more minutes to 100° C. After the cooling, it is extracted with diethyl ether, then acidified with sulfuric acid to pH 4 and the precipitated compound in ether is taken up. After drying on sodium sulfate, it is evaporated to dryness in a vacuum. The title compound is obtained as solid. Yield: 15.21 g (78.3% of theory) Elementary analysis: Cld: C 68.02 H 7.26 Fnd: C 68.13 H 7.34
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:11])=[N:4][C:5]([O:9][CH3:10])=[CH:6][C:7]=1[CH3:8].C1C(=O)N([Br:19])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[C:3]([CH2:11][Br:19])=[N:4][C:5]([O:9][CH3:10])=[CH:6][C:7]=1[CH3:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc(C)c(Br)c(C)n1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(C)c(Br)c(CBr)n1
Temperature: 25 °C

Procedure:
A mixture of 3-bromo-6-methoxy-2,4-dimethylpyridine obtained in Preparation Example 22 (200 mg), NBS (165 mg) and benzoyl peroxide (6.73 mg) was heated under reflux in a carbon tetrachloride solvent (4 mL) for two hours. The reaction mixture was cooled to room temperature and then filtered. The resulting filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 0% to 5%) to give the title compound (126 mg).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH2:15])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Cl:16][C:17]1[N:22]=[C:21]([Cl:23])[C:20]([Cl:24])=[C:19](Cl)[C:18]=1[Cl:26].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:19]2[C:18]([Cl:26])=[C:17]([Cl:16])[N:22]=[C:21]([Cl:23])[C:20]=2[Cl:24])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: Clc1nc(Cl)c(Cl)c(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CNc2c(Cl)c(Cl)nc(Cl)c2Cl)CC1
Yield: 62.4 %

Procedure:
A mixture of 1-Boc-4-(aminomethyl)piperidine (2.0 g, 9.33 mmol), pentachloropyridine (2.58 g, 10.3 mmol) and potassium carbonate (2.58 g, 18.7 mmol) was heated at 60° C. in DMF (22 mL) for 2 h. Excess DMF was removed in vacuo and the residue taken in to water/ethyl acetate. The aqueous solution was extracted with ethyl acetate (×3) and the combined organic solution dried (MgSO4) and concentrated in vacuo. Flash chromatography (SiO2, hexane/diethyl ether 30% to 60% gave the product as a white solid (2.5 g, 62%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C@H:5]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:6][C@@H:7]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[NH:8][C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.[Cl:49][C:50]1[CH:55]=[C:54]([Cl:56])[CH:53]=[C:52]([Cl:57])[C:51]=1[S:58](Cl)(=[O:60])=[O:59].O>ClCCl>[Cl:49][C:50]1[CH:55]=[C:54]([Cl:56])[CH:53]=[C:52]([Cl:57])[C:51]=1[S:58]([O:1][CH2:2][CH2:3][CH2:4][C@H:5]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:6][C@@H:7]([C:28]([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29])[NH:8][C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)(=[O:60])=[O:59]
Reactant: O=S(=O)(Cl)c1c(Cl)cc(Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)[C@@H](CCCO)C[C@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)[C@@H](CCCOS(=O)(=O)c1c(Cl)cc(Cl)cc1Cl)C[C@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 66.2 %

Procedure:
To a solution of di-tert-butyl (4S)-4-(3-hydroxypropyl)-N-trityl-L-glutamate (438 mg, 0.78 mmol) and triethylamine (327 μL, 2.35 mmol) in dichloromethane (7.0 mL) was added 2,4,6-trichlorobenzenesulfonyl chloride (328.6 mg, 1.17 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 h and then water was added. The organic layer was separated, and aqueous layer was extracted with dichloromethane. Combined organic solution was dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography (ethyl acetate/n-hexane=10/90) to give the desired product (415 mg, 66%) as a white solid.