Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N:14]2[CH2:18][CH2:17][NH:16][C:15]2=[O:19])[CH:9]=1)(=O)=O.[CH3:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][C:27]=2[N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[N:22]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[CH3:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][C:27]=2[N:31]2[CH2:36][CH2:35][N:34]([CH2:6][CH2:7][C:8]3[CH:9]=[C:10]([N:14]4[CH2:18][CH2:17][NH:16][C:15]4=[O:19])[CH:11]=[CH:12][CH:13]=3)[CH2:33][CH2:32]2)[N:22]=1
Reactant: Cc1ccc2c(N3CCNCC3)cccc2n1
Reactant: CS(=O)(=O)OCCc1cccc(N2CCNC2=O)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2c(N3CCN(CCc4cccc(N5CCNC5=O)c4)CC3)cccc2n1
Temperature: 75 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
2-[3-(2-Oxo-1-imidazolidinyl)phenyl]ethyl methanesulfonate (1.32 wt) and 2-methyl-5-(1-piperazinyl)quinoline (1 wt.) were suspended in acetonitrile (5 vol) at room temperature under nitrogen. Diisopropylethylamine (1.53 vol) was added dropwise over 30 minutes, and the mixture was then stirred at 75° C. for 4 hours. The reaction mixture was cooled to room temperature, concentrated to 2 vol, and diluted with ethyl acetate (7 vol). The organic layer was washed with saturated aqueous ammonium chloride solution (2×3 vol), followed by water (1×3 vol). The organic layer was evaporated to dryness, yielding the title compound as a brown foam (70% th).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[O:10]COCC[Si](C)(C)C)[CH3:2].[Li]C(C)(C)C.[C:24](=[O:26])=[O:25]>C1COCC1.CCOCC>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:24]([OH:26])=[O:25])[C:5]=1[OH:10])[CH3:2]
Reactant: O=C=O
Reactant: CCOc1ccncc1OCOCC[Si](C)(C)C
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOc1ccnc(C(=O)O)c1O
Reaction time: 0.75 h

Procedure:
A stirred solution of 11 (2.9 g) in THF (50 mL) under an argon atmosphere was cooled to ≦−70° C. To this was slowly added t-BuLi (8 mL, 1.5M pentane solution) while keeping the reaction temperature at ≦−66° C. After the addition was complete, the mixture was stirred at ≦−70° C. for 45 minutes and then poured into a slurry of crushed dry ice in ether. The resulting mixture was stirred until it reached room temperature, then the solvents were evaporated. THF (25 mL) and 4N HCl (15 mL) were added to the residue and the resulting mixture was stirred at room temperature for two hours. At the end of this period, the insoluble material was filtered, washed with a small volume of THF and air dried to give the title compound as a white solid (1.05 g). Preparation of 6-Bromo-3-Benzyloxy-4-Methoxypyridine-2-Carboxylic Acid (16) and its Acid Chloride (3) (See Scheme 4). a. Preparation of Methyl 4,6-Dibromo-3-Hydroxypyridine-2-Carboxylate (14).
Reaction SMILES: [S:1]([Cl:5])(Cl)(=[O:3])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:25][Si:26]([CH3:34])([CH3:33])[CH2:27][CH2:28]S([O-])(=O)=O.[Na+]>C(Cl)Cl>[CH3:25][Si:26]([CH3:34])([CH3:33])[CH2:27][CH2:28][S:1]([Cl:5])(=[O:3])=[O:2]
Reactant: C[Si](C)(C)CCS(=O)(=O)[O-]
Reactant: O=S(=O)(Cl)Cl
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C[Si](C)(C)CCS(=O)(=O)Cl
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Sulfuryl chloride (43 ml, 539 mmol) was added in 3 min to a clear solution of triphenylphosphine (129 g, 490 mmol) in methylene chloride (200 mL) at 0° C. in a flame-dried three-neck round bottom flask. After stirring at 0° C. for 5 min, the ice-water bath was removed and sodium 2-trimethylsilylethanesulfonate (50 g, 245 mmol) was added in portions over 10 min. The resulting white suspension was stirred at room temperature for 16 h, then it was filtered through a pad of celite. The filtrate was concentrated to ca 50 mL, ethyl acetate/hexanes (1:3, 1000 mL) and celite (40 g) were added. The mixture was stirred at room temperature for 15 min and filtered through a pad of celite. Solvents were removed in vacuo and the residue was loaded onto a pre-wetted column with silica gel (300 mL) using 1:3 ethyl acetate/hexanes as the eluent. Solvents were removed and the title compound was obtained as a light tan liquid (41.9 g, 85%). If not used immediately, the final product should be stored under nitrogen in the freezer or refrigerator to minimize decomposition. 1H-NMR (CDCl3, 500 MHz) δ 3.61–3.57 (m, 2H), 1.32–1.27 (m, 2H), 0.10 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.C([C:11]1[CH:15]=[CH:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:12]=1B(O)O)C>>[NH2:1][C:2]1[N:3]=[C:4]([C:12]2[N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:14]=[CH:15][CH:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCc1ccn(C(=O)OC(C)(C)C)c1B(O)O
Reactant: Nc1cccc(Cl)n1
Product: CC(C)(C)OC(=O)n1cccc1-c1cccc(N)n1

Procedure:
The title compound was prepared following procedure described for intermediate A1 step a), but starting from 2-amino-6-chloropyridine (2.05 g; 16.0 mmol; 1.0 eq.) and ethyl 1-(t-butoxycarbonyl)pyrrole-2-boronic acid (5.06 g; 24.0 mmol; 1.5 eq.) as a beige powder (1.15 g, 27%). HPLC, Rt: 2.65 min. (purity 97.0%). LC/MS, M+(ESI): 204.3.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl>[CH2:14]([NH:21][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Solvent: ClCCl
Product: O=C(O)c1cccc(S(=O)(=O)NCc2ccccc2)c1
Yield: 99.7 %

Procedure:
3-Chlorosulfonyl-benzoic acid (300 mg, 1.36 mmol), and benzylamine (0.60 mL, 5.49 mmol) were stirred at room temperature in anhydrous CH2Cl2 (10 mL) overnight under N2. The reaction mixture was concentrated in vacuo. Purification of the residue on IR-120 ion exchange resin column (elution with methanol) afforded the title compound (395 mg, 100%) as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]([CH3:7])[CH3:6])=[O:4].[C:8]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:13]=[CH:12][C:11]([CH2:14][C@@H:15]([NH:24]C(OC(C)(C)C)=O)[CH2:16][C@:17]([CH2:22][OH:23])([CH3:21])[C:18]([OH:20])=[O:19])=[CH:10][CH:9]=1.CCN(CC)CC>CC(C)=O>[CH3:6][N:5]([CH3:7])[C:3]([CH2:2][O:20][C:18](=[O:19])[C@@:17]([CH2:22][OH:23])([CH3:21])[CH2:16][C@H:15]([NH2:24])[CH2:14][C:11]1[CH:12]=[CH:13][C:8]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:9][CH:10]=1)=[O:4]
Reactant: CN(C)C(=O)CCl
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(-c2ccccc2)cc1)C[C@@](C)(CO)C(=O)O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CN(C)C(=O)COC(=O)[C@](C)(CO)C[C@H](N)Cc1ccc(-c2ccccc2)cc1

Procedure:
2-Chloro-N,N-dimethylacetamide (40 μL, 387 μmol) was added to a mixture of (2S,4R)-5-biphenyl-4-yl-4-t-butoxycarbonylamino-2-hydroxymethyl-2-methyl-pentanoic acid (100 mg, 242 μmol) and Et3N (35 μL, 254 μmol) in acetone (10 mL). The mixture was refluxed for 24 hours and the reaction monitored for completion. When the reaction was complete, the product was purified ((Interchim reverse phase chromatography column) the solvent was removed under vacuum to yield (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid dimethylcarbamoylmethyl ester.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[CH:15]=[C:14](B3OC(C)(C)C(C)(C)O3)[CH:13]=[C:12]([CH3:25])[N:11]=2)=[O:9])[S:5][CH:6]=1.I[C:27]1[CH:32]=[CH:31][N:30]=[C:29]([CH3:33])[CH:28]=1>>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[CH:15]=[C:14]([C:27]3[CH:32]=[CH:31][N:30]=[C:29]([CH3:33])[CH:28]=3)[CH:13]=[C:12]([CH3:25])[N:11]=2)=[O:9])[S:5][CH:6]=1
Reactant: Cc1cc(I)ccn1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C(=O)Nc2nc(C)cs2)n1
Product: Cc1cc(-c2cc(C)nc(C(=O)Nc3nc(C)cs3)c2)ccn1

Procedure:
The title compound, was prepared from 6-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-2-carboxylic acid (4-methyl-thiazol-2-yl)-amide in accordance with the general method of example 131, step 2 using 4-Iodo-2-methyl-pyridine instead of 3-Trifluoromethyl-5-bromopyridine to yield the final compound as a white solid, MS (ISP): m/e=325.2 (M+H)+.
Reaction SMILES: [CH:1]1([CH:6]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([N:28]([CH3:36])[CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])=[O:27])=[CH:22][CH:21]=2)[C:7]2[O:8][C:9]3[C:16]([F:17])=[CH:15][C:14]([F:18])=[CH:13][C:10]=3[C:11]=2[CH3:12])[CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)C.O1CCCC1.[OH-].[Na+]>[CH:1]1([CH:6]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]([N:28]([CH3:36])[CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:27])=[CH:24][CH:25]=2)[C:7]2[O:8][C:9]3[C:16]([F:17])=[CH:15][C:14]([F:18])=[CH:13][C:10]=3[C:11]=2[CH3:12])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3c(F)cc(F)cc3c2C)C2CCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(C(Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)C2CCCC2)oc2c(F)cc(F)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.7 %

Procedure:
Ethyl 3-{[(4-{[cyclopentyl(5,7-difluoro-3-methyl-1-benzofuran-2-yl)methyl]amino}phenyl)carbonyl](methyl)amino}propanoate (240 mg) synthesized in Example A207 was dissolved in ethanol (1.0 mL)-tetrahydrofuran (1.0 mL), 1N aqueous sodium hydroxide solution (0.96 mL) was added to the solution, and the mixture was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure, water (4 mL) was added to the residue, and the mixture was neutralized with 1N hydrochloric acid (0.96 mL) under ice-cooling, and stirred for 15 min. The resulting precipitate was collected by filtration, and dried to give the title compound (185 mg, 82%) as a colorless amorphous form.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]2[N:22]=[C:21]([N:23]3[C:27]([C:28]([F:31])([F:30])[F:29])=[C:26]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:25]=[N:24]3)[CH:20]=[CH:19][CH:18]=2)=[CH:5][CH:4]=1.[H][H]>CCOC(C)=O.CCO.[Pt](=O)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]2[N:22]=[C:21]([N:23]3[C:27]([C:28]([F:31])([F:29])[F:30])=[C:26]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:25]=[N:24]3)[CH:20]=[CH:19][CH:18]=2)=[CH:5][CH:4]=1
Reactant: [H][H]
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3ccccc3C#Cc3ccc(OC)cc3)n2)c1C(F)(F)F
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2cccc(-c3ccccc3CCc3ccc(OC)cc3)n2)c1C(F)(F)F
Reaction time: 2 h

Procedure:
To a degassed solution of the title compound from Example 236 Step A (255 mg, 0.519 mmol) in EtOAc (3 mL) and EtOH (3 mL) was added platinum(IV) oxide (175 mg). The reaction mixture was fitted with a hydrogen balloon attached to a 3-way adapter. The reaction flask was then evacuated and back-filled with hydrogen. After this process was repeated three times, the reaction mixture was placed under a hydrogen atmosphere, and was stirred vigorously. After 2 h, the reaction mixture was filtered through Celite, rinsing with EtOAc. The mixture was then concentrated in vacuo, and used without further purification: LCMS m/z 496.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:5]([OH:7])=[O:6].[H-].[Na+].[CH3:30]I>CN(C)P(N(C)C)(N(C)C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:5]([O:7][CH3:30])=[O:6]
Reactant: CI
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OC)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 7.20 g of 3-fluoro-4-(hexadecylamino)-benzoic acid in 25 ml of hexamethylphosphoramide is added to a stirred mixture of 0.800 g of sodium hydride (57% in mineral oil) and 25 ml of hexamethylphosphoramide. The solution which forms after one hour is treated with 11.0 g of methyl iodide and is then stirred at 25° C. for 18 hours. Dilution with water followed by filtration affords a white solid which is crystallized from ethanol to yield methyl 3-fluoro-4-(hexadecylamino)-benzoate as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][C:13]([Br:17])=[C:12]([OH:16])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1oc2cccc(O)c2c1C
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1oc2ccc(Br)c(O)c2c1C
Temperature: 0 °C
Reaction time: 3 h
Yield: 59 %

Procedure:
To 2 g (0.81 mmol) of 4-hydroxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester was added 20 mL of carbon tetrachloride, and the mixture was cooled with a water/ice bath while 1 equivalent of N-bromosuccinimide was added in small portions. After stirring at 0° C. for 3 h, the reaction mixture was filtered and the filtrate was loaded onto a column and purified by column chromatography to give 1.6 mg (59% yield) of 5-bromo-4-hydroxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester as a white solid.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1.[N:15]12[CH2:22][CH2:21][CH:18]([CH2:19][CH2:20]1)[C@@H:17]([NH:23][C:24]([C:26]1[O:27][C:28]3[CH:34]=[C:33](Br)[CH:32]=[CH:31][C:29]=3[CH:30]=1)=[O:25])[CH2:16]2.[OH-].[Na+]>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].CN(C=O)C>[N:15]12[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22]1)[C@@H:17]([NH:23][C:24]([C:26]1[O:27][C:28]3[CH:34]=[C:33]([C:7]4[CH:8]=[CH:9][C:4]([O:3][C:2]([F:14])([F:13])[F:1])=[CH:5][CH:6]=4)[CH:32]=[CH:31][C:29]=3[CH:30]=1)=[O:25])[CH2:16]2
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2ccc(Br)cc2o1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2ccc(-c3ccc(OC(F)(F)F)cc3)cc2o1
Temperature: 82.5 °C

Procedure:
A mixture of 180 mg (0.86 mmol) of 4-(trifluoromethoxy)phenylboronic acid, 200 mg (0.57 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-bromo-1-benzofuran-2-carboxamide (Example 2A), 1.72 ml (1.72 mmol) of 1N sodium hydroxide solution, 40 mg (0.06 mmol) of 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) chloride and 2 ml of DMF is heated at 80-85° C. for 18 h. The solvent is removed under reduced pressure. The crude product is purified on silica gel 60 (Merck, Darmstadt; eluent: dichloromethane, dichloromethane/methanol 20:1, dichloromethane/methanol/ammonia 80:20:2). The solvent is removed under reduced pressure. Finally, the last residues of solvent are removed under high vacuum. 155 mg (68% of theory) of the title compound are isolated.
Reaction SMILES: [BH4-].[Na+].B(F)(F)F.CC[O:9]CC.[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH:27]=2)=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+].OO.Cl>C1COCC1.C(O)C.C(Cl)Cl.O>[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23]([C@@H:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][C@H:27]2[OH:9])=[CH:22][CH:21]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(OCc3ccccc3)cc2)CC1
Reactant: CCOCC
Agent: Cl
Agent: FB(F)F
Agent: OO
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@@H](c2ccc(OCc3ccccc3)cc2)[C@H](O)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88.5 %

Procedure:
Sodium borohydride (15.5 g, 410 mmol) was dissolved in THF, and the solution was chilled to 0° C. Boron trifluoride etherate (52.3 mL, 424 mmol) was added to the solution and the mixture was allowed to warm to rt and stirred for 30 min. Then a solution of tert-butyl 4-(4-(benzyloxy)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (50 g, 137 mmol, intermediate A) in 500 mL of THF was added and the reaction mixture was stirred for 2 h at rt. A 100 mL portion of water was then added slowly to the mixture (Caution: effervescence is observed). The mixture was diluted with 100 mL of ethanol, and sodium hydroxide (228 mL, 10% solution in water, 0.684 mol) and hydrogen peroxide (20.5 mL, 0.684 mol) were added. The reaction mixture was heated to reflux temperature and stirred for 16 h. The mixture was cooled to 10° C. and diluted with 1 L of DCM. Then the pH was adjusted to 7 with 1.5 L of 1.5 N HCl. The layers were then separated, and the aqueous layer was extracted with an addition two 500 mL portions of DCM. The organic layers were combined, washed with 2×1 L of water and 200 mL of brine, dried over sodium sulfate, and evaporated in vacuo to provide an off-white solid. The solid was triturated with 500 mL of pet ether, and isolated by filtration to yield 46.5 grams of product (88%, 99.0% purity by HPLC). LC/MS RT (conditions A)=2.372 min, (M+H)+=382.0. 1H NMR (400 MHz, DMSO-d6) δ 7.47-7.42 (m, 2H), 7.42-7.36 (m, 2H), 7.36-7.28 (m, 1H), 7.14 (d, J=9.0 Hz, 2H), 6.92 (d, J=9.0 Hz, 2H), 5.07 (s, 2H), 4.74 (d, J=5.5 Hz, 1H), 4.10 (br. s., 1H), 3.94 (br. s., 1H), 3.46-3.35 (m, 1H), 2.47-2.31 (m, 2H), 1.70-1.61 (m, 1H), 1.55-1.45 (m, 2H), 1.42 (s, 9H).
Reaction SMILES: C([N:3](CC)CC)C.P(N=[N+]=[N-])(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.[CH3:27][O:28][C:29]1[C:30]([N+:38]([O-:40])=[O:39])=[C:31]([CH:35]=[CH:36][CH:37]=1)C(O)=O.O>C1(C)C=CC=CC=1>[CH3:27][O:28][C:29]1[C:30]([N+:38]([O-:40])=[O:39])=[C:31]([NH2:3])[CH:35]=[CH:36][CH:37]=1
Reactant: COc1cccc(C(=O)O)c1[N+](=O)[O-]
Reactant: CCN(CC)CC
Agent: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cccc(N)c1[N+](=O)[O-]
Yield: 35 %

Procedure:
Triethylamine (6.29 mL) and diphenyl azidophosphate (6.66 mL, 30.1 mmol) were added to a suspension of 3-methoxy-2-nitrobenzoic acid (3.00 g, 15.2 mmol) in toluene (50 mL). The reaction mixture was stirred under reflux for 2 hours, water (10 mL) was added and it was stirred overnight under reflux. After evaporation of the solvent, the residue was dissolved in AcOEt and the resulting solution was filtered through celite. The organic phase was washed with saturated solution of NaHCO3, brine, dried over MgSO4, filtered and evaporated. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 900 mg (5.35 mmol, 35%) of 3-methoxy-2-nitrophenylamine as a yellow solid.
Reaction SMILES: C1C=C(O[C:8](OC2N=CC=CC=2)=[S:9])N=CC=1.[C:17]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C>C(Cl)Cl>[C:17]([C:21]1[CH:22]=[CH:23][C:24]([CH2:25][N:26]=[C:8]=[S:9])=[CH:27][CH:28]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)c1ccc(CN)cc1
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)c1ccc(CN=C=S)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.3 %

Procedure:
Di-2-pyridyl thionocarbonate (45 mg) was dissolved in methylenechloride (2 ml) and to the solution were added 4-t-butylbenzylamine (29 mg) and triethylamine (20 μl), followed by stirring at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure and the obtained residue was chromatographed on a silica gel column eluting with ethyl acetate/hexane (1/10) to yield 4-t-butylbenzylisothiocyanate (26 mg, 71%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8](Cl)=[O:9])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([NH:19][C:20](=[O:34])[C:21]2[CH:26]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:24]=[C:23]([F:33])[CH:22]=2)[CH:15]=[CH:16][C:17]=1[Cl:18]>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:11][C:12]2[CH:13]=[C:14]([NH:19][C:20](=[O:34])[C:21]3[CH:26]=[C:25]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[CH:24]=[C:23]([F:33])[CH:22]=3)[CH:15]=[CH:16][C:17]=2[Cl:18])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: Nc1cc(NC(=O)c2cc(F)cc(N3CCOCC3)c2)ccc1Cl
Product: O=C(Nc1ccc(Cl)c(NC(=O)c2ccc(Cl)nc2)c1)c1cc(F)cc(N2CCOCC2)c1
Yield: 48 %

Procedure:
Using an analogous procedure to that described in Example 2, 6-chloropyridine-3-carbonyl chloride was reacted with N-(3-amino-4-chlorophenyl)-3-fluoro-5-morpholinobenzamide to give the title compound in 48% yield; NMR Spectrum: (DMSOd6) 3.23 (m, 4H0m 3.74 (m, 4H0, 6.97 (d, 1H), 7.12 (d, 1H, 7.26 (s, 1H), 7.54 (d, 1H), 7.71 (d, 2H), 8.07 (s, 1H), 8.35 (d, 1H), 8.95 (s, 1H), 10.37 (m, 2H); Mass Spectrum: M+H+487.
Reaction SMILES: [ClH:1].[CH3:2][O:3][N:4]=[C:5]([NH2:7])[NH2:6].[F:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[C:16]1[S:20][C:19]([CH2:27][CH2:28]NC#N)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:18]([C:32](=[O:37])[C@@H:33]([O:35][CH3:36])[CH3:34])[N:17]=1.Cl.CON.C(N(CC)CC)C>C(O)C.C(OCC)(=O)C>[ClH:1].[F:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[C:16]1[S:20][C:19]([CH2:27][CH2:28][NH:6][C:5]([NH2:7])=[N:4][O:3][CH3:2])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:18]([C:32](=[O:37])[C@@H:33]([O:35][CH3:36])[CH3:34])[N:17]=1
Reactant: CO[C@@H](C)C(=O)N1N=C(c2cc(F)ccc2F)SC1(CCNC#N)c1ccccc1
Reactant: CON=C(N)N
Agent: CON
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCO
Product: CON=C(N)NCCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1C(=O)[C@H](C)OC
Temperature: 70 °C
Yield: 62 %

Procedure:
Preparation of 1-(2-(2,5-difluorophenyl)-3-((S)-2-methoxypropanoyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)ethyl)-2-methoxyguanidine hydrochloride: To a solution of crude (2-(5-(2,5-difluorophenyl)-3-((S)-2-methoxypropanoyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)ethyl)cyanamide (31 mg, 0.072 mmol) and methoxyamine hydrochloride (151 mg, 1.80 mol) in ethanol (3 mL) was added triethylamine (182 mg, 1.80 mmol). After heating to 70° C. in a sealed vessel for 16 hours, additional methoxyamine hydrochloride (151 mg, 1.80 mol) and triethylamine (182 mg, 1.80 mmol) was added, and the reaction mixture was heated to 70° C. in a sealed vessel for an additional 24 hours. The mixture was cooled to room temperature and diluted with ethyl acetate. The salts were removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was chromatographed (4% methanol in dichloromethane with 0.5% NH4OH), and the isolated material was treated with excess HCl in MeOH then concentrated to afford the product as a mixture of diastereomers (23 mg, 62% yield). MS APCI (+) m/z 478 (M+1) detected; 1H NMR (400 MHz, CD3OD) δ 7.69-7.64 (m, 2H), 7.50-7.38 (m, 8H), 7.37-7.29 (m, 6H), 4.83-4.78 (m, 2H), 3.80-3.67 (m, 2H), 3.73 (s, 6H), 3.54-3.45 (m, 2H), 3.45-3.33 (m, 2H), 3.39 (s, 3H), 3.31 (s, 3H), 3.04-2.92 (m, 2H), 1.49 (d, 3H, J=7.1 Hz), 1.45 (d, 3H, J=7.1 Hz).
Reaction SMILES: [CH2:1]([CH:11]([CH2:24][CH2:25][CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:12]([OH:23])[CH2:13][CH2:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Br:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40](O)=[O:41].CCN=C=NCCCN(C)C.Cl.C(N(C(C)C)CC)(C)C>ClCCl.CN(C1C=CC=CN=1)C>[Br:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]([O:23][CH:12]([CH:11]([CH2:1][CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:24][CH2:25][CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:13][CH2:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:41]
Reactant: O=C(O)CCCCCBr
Reactant: CCCCC/C=C\CCCC(O)C(CCC/C=C\CCCCC)CCC/C=C\CCCCC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCC/C=C\CCCC(CCC/C=C\CCCCC)C(CCC/C=C\CCCCC)OC(=O)CCCCCBr
Temperature: 25 °C
Yield: 93.5 %

Procedure:
To a solution of (6Z,16Z)-12-((Z)-dec-4-enyl)docosa-6,16-dien-11-ol 8 (2.4 g, 5.2 mmol), 6-bromohexanoic acid (1.5 g, 7.8 mmol), EDCI hydrochloride (1.5 g, 7.8 mmol), diisopropylethylamine (2.0 g, 15.6 mmol) in anhydrous dichloromethane (25 mL) was added dimethylaminopyridine (15 mg). The solution was refluxed for 2 hours, cooled to room temperature and concentrated in vacuo to dryness. The reaction mixture was purified by column chromatography on silica gel 60 (2″ W×10″ L; eluted with 5% EtOAc/Hex) to afford (6Z,16Z)-12-((Z)-dec-4-enyl)docosa-6,16-dien-11-yl 6-bromohexanoate 10 as a colorless oil (3.1 g, 94%). Rf 0.5 (10% EtOAc-Hexanes).