Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:11](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[CH3:11][O:9][C:8]([C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=1)=[O:10]
Reactant: O=C([O-])[O-]
Reactant: Cc1cccnc1C(=O)O
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)c1ncccc1C
Yield: 57.1 %

Procedure:
Heat a mixture of 3-methylpicolinic acid (1.0 g, 7.3 mmol), potassium carbonate (4.1 g, 29.7 mmol), and iodomethane (4.4 g, 31.0 mmol) in acetone (35 mL) overnight under reflux. Filter, wash the residue with EtOAc, and concentrate in vacuo. Pass through a short plug of silica gel eluting with hexane/EtOAc (1:1) to provide 2-methoxycarbonyl-3-methylpyridine as a pale yellow liquid (630 mg, 57%). To a solution of 2-methoxycarbonyl-3-methylpyridine in anhydrous THF (10 mL) at 0° C., add with stirring a solution of 1M lithium aluminum hydride in THF (5 mL, 5 mmol), and continue stirring for 30 min at 0° C. Allow the mixture to warm to ambient temperature and quench cautiously with 0.5M aqueous NaOH. Heat the mixture at 60° C. for 40 min, cool to ambient temperature, extract with EtOAc, dry over anhydrous Na2SO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (4:3) to give the desired intermediate (90 mg, 18%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH3:21])[CH:7]=[N:6][CH:5]=1.Br[C:24]1[CH:25]=[N:26][N:27]([CH:29]([CH3:31])[CH3:30])[CH:28]=1>>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[N:13]([C:24]3[CH:25]=[N:26][N:27]([CH:29]([CH3:31])[CH3:30])[CH:28]=3)[C:12]=2[CH3:21])[CH:7]=[N:6][CH:5]=1
Reactant: COC(=O)c1cncc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Reactant: CC(C)n1cc(Br)cn1
Product: COC(=O)c1cncc(Sc2c(C)n(-c3cnn(C(C)C)c3)c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 3, Step 1, using the following starting materials: 5-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-nicotinic acid methyl ester and 4-bromo-1-isopropyl-1H-pyrazole.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:27]2[C:32](=[O:33])[NH:31][C:30](=[O:34])[CH:29]=[N:28]2)[CH:5]=[C:6]([CH3:26])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15]C)=[C:11]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH:10]=1.B(Cl)(Cl)Cl>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([N:27]2[C:32](=[O:33])[NH:31][C:30](=[O:34])[CH:29]=[N:28]2)[CH:5]=[C:6]([CH3:26])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([S:17]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)(=[O:19])=[O:18])[CH:10]=1
Reactant: COc1ccc(Oc2c(C)cc(-n3ncc(=O)[nH]c3=O)cc2Cl)cc1S(=O)(=O)c1ccccc1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: Cc1cc(-n2ncc(=O)[nH]c2=O)cc(Cl)c1Oc1ccc(O)c(S(=O)(=O)c2ccccc2)c1
Reaction time: 4 h

Procedure:
To a stirred solution of 2-{3-chloro-4-[3-(benzenesulfonyl)-4-methoxy-phenoxy]-5-methyl-phenyl}-2H-[1,2,4]triazine-3,5-dione (0.66 9) in dichloromethane (12 mL) was added boron trichloride (8 mL, 1M in dichloromethane) and the resulting solution was stirred for 4 h. The reaction solution was poured onto ice, allowed to stir for 1 h, the phases separated and the aqueous layer washed with dichloromethane. The combined organic layers were dried (Na2SO4) and concentrated to afford the title compound of this EXAMPLE as a tan foam, 0.52 g. m.p. 78-81° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7](Cl)(=[O:9])=[O:8])[CH:2]=1.[NH2:11][C:12]1[CH:13]=[C:14]([CH:18]2[CH2:27][C:26]([CH3:29])([CH3:28])[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:30]#[N:31])[CH:24]=3)[NH:19]2)[CH:15]=[CH:16][CH:17]=1.N1C=CC=CC=1>ClCCl>[C:30]([C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[NH:19][CH:18]([C:14]1[CH:13]=[C:12]([NH:11][S:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)(=[O:9])=[O:8])[CH:17]=[CH:16][CH:15]=1)[CH2:27][C:26]2([CH3:29])[CH3:28])#[N:31]
Reactant: CC1(C)CC(c2cccc(N)c2)Nc2ccc(C#N)cc21
Reactant: O=S(=O)(Cl)c1cccnc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)CC(c2cccc(NS(=O)(=O)c3cccnc3)c2)Nc2ccc(C#N)cc21
Reaction time: 8 h
Yield: 44.2 %

Procedure:
Pyridine-3-sulfonyl chloride (144 mg, 0.81 mmol) was added dropwise to a mixture of 2-(3-amino-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonitrile (150 mg, 0.54 mmol) and pyridine (77 mg, 0.97 mmol) in dichloromethane (5 mL). The resultant mixture was allowed to stir overnight. The reaction mixture was washed by water, dried over magnesium sulfate. Filtered and concentrated to provide the crude product. It was purified by column chromatography (silica gel, petroleum ether:ethyl acetate=3:1) to afford pyridine-3-sulfonic acid [3-(6-cyano-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-amide as off-white solid (100 mg, yield: 44.2%). MS (ESI+APCI) M+1=419.1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Cl)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([SH:26])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:26][C:23]2[CH:24]=[CH:25][C:20]([NH2:19])=[CH:21][CH:22]=2)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(S)cc1
Reactant: O=[N+]([O-])c1cc(OCc2ccccc2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1ccc(Sc2ccc(OCc3ccccc3)cc2[N+](=O)[O-])cc1
Temperature: 0 °C
Yield: 82.1 %

Procedure:
A solution of the compound prepared in Example 214A (1.0 g, 3.80 mmol), 4-aminothiophenol (0.5 g, 4.00 mmol), cesium carbonate (1.3 g, 4 mmol) in dimethylformamide (10 ml) was heated at 40° C. for 16 hours. Afterwards, ice water (50 mL) was added to the solution and the resultant slurry was treated with ethyl acetate (100 ml). The layers were separated and the organic layer was washed with 10% sodium bicarbonate and 10% sodium chloride, then dried over anhydrous sodium sulfate. The drying agent was filtered and solvent was removed under vacuum leaving an orange oil as the title compound, (1.1 g, 83%).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.Br[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].O>CN(C=O)C>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:5]=1
Reactant: Oc1cccnc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)COc1cccnc1
Yield: 32.5 %

Procedure:
To a suspension of 0.22 g of sodium hydride (60% oil dispersion, 5.5 mmol) in 2 mL of DMF was added dropwise a solution of 0.48 g of 3-hydroxypyridine (5.0 mmol) in 2 mL of DMF at room temperature, and the mixture was stirred for an hour. The resulting brown solution was ice-cooled, 0.81 mL of tert-butyl bromoacetate (5.5 mmol) was added, and the mixture was stirred under ice-cooling for an hour followed by stirring at room temperature for 2 hours. After addition of water, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and evaporated. The residue was purified by column chromatography on silica gel (eluent: chloroform:ethyl acetate=5:1), to give 0.34 g of tert-butyl 3-pyridyloxyacetate (Yield: 32.5%) as a clear oil.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].[CH3:13][N:14](C=O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C-]#N.[C-]#N.[Zn+2]>[C:13]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12])#[N:14]
Reactant: CN(C)C=O
Reactant: COC(=O)c1ccc(Br)c(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COC(=O)c1ccc(C#N)c(C)c1

Procedure:
To a microwave tube, was added methyl 4-bromo-3-methylbenzoate (100 mg, 0.437 mmol), Pd(Ph3P)4 (25.2 mg, 0.022 mmol), Zn(CN)2 (51.3 mg, 0.437 mmol) and DMF (2 mL). The mixture was flushed with N2 and capped tightly. The reaction mixture was exposed to microwave irradiation at 150° C. for 5 min. The mixture was diluted with EtOAc and washed with water. The organic layer was dried (Na2SO4), filtered and the solvent was evaporated in vacuo. The residue was purified by flash chromatography on silica gel to give methyl 4-cyano-3-methylbenzoate. LCMS calc.=176.1; found=176.1 (M+1)+. 1H NMR (500 MHz, CDCl3) δ 8.02 (s, 1 H); 7.95 (d, J=8.1 Hz, 1 H); 7.71 (d, J=8.0 Hz, 1 H); 7.29 (s, 1H); 3.98 (s, 3 H); 2.64 (s, 3 H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:16]2[C:29]3[C:30]4=[C:31]5[C:26](=[CH:27][CH:28]=3)[CH:25]=[CH:24][CH:23]=[C:22]5[CH:21]=[CH:20][C:19]4=[CH:18][CH:17]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[CH:10]=2)=[CH:4][CH:3]=1.I[C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:16]2[C:29]3[C:30]4=[C:31]5[C:26](=[CH:27][CH:28]=3)[CH:25]=[CH:24][CH:23]=[C:22]5[CH:21]=[CH:20][C:19]4=[CH:18][CH:17]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N:15]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)[C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=3)[CH:10]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(N(c2cccc(N)c2)c2ccc3ccc4cccc5ccc2c3c45)cc1
Reactant: Cc1ccc(I)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(N(c2ccc(C)cc2)c2cccc(N(c3ccc(C)cc3)c3ccc4ccc5cccc6ccc3c4c56)c2)cc1
Reaction time: 10 h

Procedure:
A mixture of 2.79 g (7.00 mmol) of N-(4-methylphenyl)-N-(3-aminophenyl)-1-pyrenylamine synthesized in Synthesis Example 2, 15.3 g (70.0 mmol) of 4-iodotoluene, 3.87 g of potassium carbonate, and 0.44 g of copper powder was subjected to azeotropic dehydration in a stream of nitrogen, using an ester tube, with stirring, at 209° to 212° C. for 10 hours.
Reaction SMILES: [CH2:1]([C:5]1=[CH:6][N:7]([C:18]([CH3:21])([CH3:20])[CH3:19])[S:8]/[C:9]/1=[N:10]\[C:11]([CH:13]1[CH2:17][CH2:16][NH:15][CH2:14]1)=[O:12])[CH2:2][CH2:3][CH3:4].F[C:23]1[N:30]=[CH:29][CH:28]=[CH:27][C:24]=1[C:25]#[N:26].C(N(CC)CC)C>C(#N)C>[CH2:1]([C:5]1=[CH:6][N:7]([C:18]([CH3:20])([CH3:19])[CH3:21])[S:8]/[C:9]/1=[N:10]\[C:11]([CH:13]1[CH2:17][CH2:16][N:15]([C:23]2[C:24]([C:25]#[N:26])=[CH:27][CH:28]=[CH:29][N:30]=2)[CH2:14]1)=[O:12])[CH2:2][CH2:3][CH3:4]
Reactant: N#Cc1cccnc1F
Reactant: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)C1CCNC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)C1CCN(c2ncccc2C#N)C1
Temperature: 60 °C
Yield: 75.8 %

Procedure:
To a 20-mL scintillation vial were added the product from Example 104B (54.2 mg, 0.175 mmol), the 2-fluoronicotin-onitrile (Aldrich, 32.1 mg, 0.263 mmol), and anhydrous acetonitrile (2 mL). Neat triethylamine (53.1 mg, 0.525 mmol) was added. The reaction mixture was heated to 60° C. in a heated shaker block and mixed for 24 hours. After cooling to room temperature, the volatiles were removed by rotary evaporator. The product was purified by flash chromatography (silica gel: 20-65% ethyl acetate in hexanes) to give 54.6 mg (76%) of the title compound. 1H NMR (DMSO-d6) δ 0.88 (t, J=7.3 Hz, 3H), 1.21-1.34 (m, 3H), 1.52-1.62 (m, 1H), 1.57 (s, 9H), 2.20-2.27 (m, 2H), 2.59-2.64 (m, 2H), 3.35-3.43 (m, 1H), 3.69-3.78 (m, 2H), 3.88-3.95 (m, 1H), 4.04-4.09 (m, 1H), 6.69 (dd, J=7.5, 4.8 Hz, 1H), 7.93 (dd, J=7.9, 2.0 Hz, 1H), 8.31 (dd, J=4.8, 2.0 Hz, 1H), 8.57 (s, 1H). MS (ESI+) m/z 412 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].C([Li])CCC.[CH3:17][N:18]([CH3:29])[CH2:19][CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:22].[Cl-].[NH4+]>CCCCCC.O1CCCC1>[CH3:29][N:18]([CH3:17])[CH2:19][CH2:20][C:21]([OH:22])([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5]
Reactant: CNC(=O)c1ccccc1C
Reactant: CN(C)CCC(=O)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CNC(=O)c1ccccc1CC(O)(CCN(C)C)c1ccccc1
Temperature: 5 °C

Procedure:
To a flask equipped with a stirrer, dropping funnel, condenser and gas inlet tube maintained under a nitrogen atmosphere there is added at room temperature 40.0 g. (0.28 mole) of o-methyl-N-methyl benzamide and 250 ml. of anhydrous tetrahydrofuran. The reaction flask is immersed in an ice bath and cooled to an internal temperature of 5° C. Stirring is initiated and 360 ml. of 1.6 M. n-butyllithium (0.616 mole) in hexane is added dropwise for about 1 hour maintaining the temperature below 8° C. The resulting red dilithio salt (compound VIII) is stirred at 5° C. for 1 additional hour and the reaction flask is then immersed in a dry-ice acetone bath and cooled to an internal temperature of -30° C. To the cold reaction mixture a solution of 49.7 g. (0.28 mole) 3-dimethylaminopropiophenone in 140 ml. anhydrous tetrahydrofuran is added dropwise in ca. 45 minutes maintaining the temperature between -30° C. and -20° C. The resulting reaction mixture is stirred at -25° C. for 1 hour, allowed to warm to -10° C. in ca. 1 hour, and then treated with 200 ml. of saturated aqueous ammonium chloride while maintaining the temperature below 0° C. The resulting solid is filtered, washed thoroughly with water and recrystallized from methylene chloride-ether (1:1) to give 2-(β-[2-dimethylaminoethyl]-β-hydroxyphenethyl)-N-methylbenzamide; m.p. 139.5 to 140.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([F:12])[CH:3]=1.C([Li])CCC.CN([CH:21]=[O:22])C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([F:12])[C:3]=1[CH:21]=[O:22]
Reactant: CC(=O)Nc1ccc(Cl)cc1F
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(Cl)c(C=O)c1F
Temperature: -78 °C
Reaction time: 2.5 h
Yield: 47.9 %

Procedure:
A −78° C. solution of N-(4-chloro-2-fluorophenyl)acetamide (2.00 g, 10.66 mmol) in THF (40 mL), under Ar, was treated with butyl lithium (16.66 mL, 26.7 mmol), stirred at −78° C. for 2.5 h, treated slowly with DMF (1.651 mL, 21.32 mmol), stirred for 15 min at −78° C. and slowly warmed to RT. The mixture was stirred for 2 h, treated with satd. NH4Cl, the layers separated and the aqueous layer extracted with EtOAc (1×). The combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford N-(4-chloro-2-fluoro-3-formylphenyl)acetamide (1.1 g, 48% yield) as an off-white solid. MS (ESI) m/z: 216.0 [M+H]+.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C@H:10]2[C@@H:16]([OH:17])[C:15](=[O:18])[N:14]([CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])[C:13]3[C:24]([CH3:29])=[C:25]([CH3:28])[CH:26]=[CH:27][C:12]=3[S:11]2)=[CH:6][CH:5]=1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>C(O)(=O)C>[ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([C@H:10]2[C@@H:16]([O:17][C:30](=[O:32])[CH3:31])[C:15](=[O:18])[N:14]([CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])[C:13]3[C:24]([CH3:29])=[C:25]([CH3:28])[CH:26]=[CH:27][C:12]=3[S:11]2)=[CH:8][CH:9]=1
Reactant: COc1ccc([C@@H]2Sc3ccc(C)c(C)c3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CC(=O)O
Product: COc1ccc([C@@H]2Sc3ccc(C)c(C)c3N(CCN(C)C)C(=O)[C@@H]2OC(C)=O)cc1
Temperature: 105 °C

Procedure:
A mixture of 0.618 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-6,7-dimethyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride, 6 ml of acetic anhydride and 6 ml of acetic acid is heated at 105° C. for 18 hours. After the reaction is completed, the mixture is evaporated under reduced pressure to remove solvent. Benzene is added to the residue, and the mixture is evaporated under reduced pressure to remove solvent. The residue is recystallized from a mixture of ethanol and ether. 0.44 g of (±)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(dimethylamino)ethyl]-6,7-dimethyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride 3/2 H2O is obtained.
Reaction SMILES: C(OC(/[N:8]=[C:9](\[NH:32]C(OC(C)(C)C)=O)/[NH:10][C@H:11]1[CH2:16][C:15]([C:17]([OH:19])=[O:18])=[CH:14][C@@H:13]([O:20][CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C@@H:12]1[NH:26][C:27](=[O:31])[CH:28]([F:30])[F:29])=O)(C)(C)C>FC(F)(F)C(O)=O.C(Cl)Cl>[F:29][CH:28]([F:30])[C:27]([NH:26][C@@H:12]1[C@@H:11]([NH:10][C:9]([NH2:32])=[NH:8])[CH2:16][C:15]([C:17]([OH:19])=[O:18])=[CH:14][C@H:13]1[O:20][CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[O:31]
Reactant: CCC(CC)O[C@@H]1C=C(C(=O)O)C[C@H](N/C(=N/C(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)[C@H]1NC(=O)C(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(CC)O[C@@H]1C=C(C(=O)O)C[C@H](NC(=N)N)[C@H]1NC(=O)C(F)F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (3R,4R,5S)-ethyl 5-((Z)-2,3-bis(tert-butoxycarbonyl)guanidino-4-(2,2-difluoroacetamido)-3-(pentan-3-yloxy)cyclohex-1-enecarboxylate 6b (250 mg) in dioxane (5 ml) 5% solution of lithium hydroxide (2.5 ml) was added and the reaction mixture was stirred at room temperature for 45 min. Then lithium hydroxide was passivated by adding acetic acid (300 mcl), the solvents were evaporated in vacuo. The solid was extracted with isopropyl alcohol, the extract was dried over Na2SO4 and evaporated in vacuo. It gives (3R,4R,5S)-5-((Z)-2,3-bis(tert-butoxycarbonyl)guanidino)-4-(2,2-difluoroacetamido)-3-(pentan-3-yloxy)cyclohex-1-enecarboxylic acid 8b (200 mg, 84%). LCMS (M+H): found 563; calculated 562.62. The obtained acid 8b (200 mg) was dissolved in 10% solution of trifluoroacetic acid in methylene chloride (2 ml) and stirred at room temperature for 12 h. Then the solvents were evaporated in vacuo. (3R,4R,5S)-4-(2,2-Difluoroacetamido)-5-guanidino-3-(pentan-3-yloxy)cyclohex-1-enecarboxylic acid 1.4 was separated by HPLC method. LCMS (M+H): found 363; calculated 362.28. 1H NMR (DMSO-d6), 400 MHz: 8.68 (d, J=8.4 Hz, 1H), 7.6 (d, J=10 Hz, 1H), 7.26 (br, 2H), 6.91 (br, 2H), 6.63 (s, 1H), 6.27 (t, J=53.6 Hz, 1H), 4.18 (d, J=8 Hz, 2H), 4.09 (m, 1H), 3.54 (q, J=10 Hz, 1H), 3.39 (m, 2H), 2.57 (dd, J1=18 Hz, J2=6 Hz, 1H), 2.31 (m, 1H), 1.44 (m, 4H), 0.85 (t, J=8 Hz, 3H), 0.795(t, J=7.6 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=2)=[O:10])=[CH:4][C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1.[NH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[C:11]2[CH:12]=[CH:13][C:14]([C:15]([NH:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[O:16])=[CH:18][CH:19]=2)=[CH:4][C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1
Reactant: NCc1ccccn1
Product: O=C(NCc1ccccn1)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1

Procedure:
50 mg of 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 2-(aminomethyl)pyridine via Procedure G. The product was purified on reverse phase HPLC to yield N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(pyridin-2-ylmethyl)terephthalamide. MS (Q1) 443 (M)+.
Reaction SMILES: C[NH:2][C:3](=[O:22])[CH:4]([C:17](=[O:21])[CH2:18][NH:19][CH3:20])[CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1>CO.[OH-].[Na+].CO.O.[H][H]>[CH3:20][NH:19][CH2:18][C:17]([CH:4]([CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1)[C:3]([NH2:2])=[O:22])=[O:21]
Reactant: [H][H]
Reactant: CNCC(=O)C(CCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21)C(=O)NC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CNCC(=O)C(CCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21)C(N)=O
Reaction time: 1 h
Yield: 90 %

Procedure:
N-Methylglycylbiotinamide methyl ester was hydrolyzed in a mixture of 31 mL MeOH and 10 mL of 1N NaOH at room temperature with stirring for 1 hour. The mixture was diluted with 50 mL 50% MeOH/water and neutralized with cation exchange resin, hydrogen form (AG MP-50, BioRad). The solution was filtered, the resin washed (3×50 mL) with 50% MeOH/water, and the solvents removed by rotary evaporation to yield 1.6 g (90%) of N-methylglycylbiotinamide acid as an off-white solid. 1H-NMR. (Ref. Wilbur, D. S., Bioconj. Chem., v8 pp572-584)
Reaction SMILES: [Br:1][C:2]1[C:3]([O:22][CH3:23])=[C:4]([C:8]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2F)(=[O:14])=[O:13])=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].C(N(CC)CC)C.[CH3:31][N:32]([CH3:39])[CH2:33][C:34]([CH3:38])([CH3:37])[CH2:35][NH2:36]>C(#N)C>[Br:1][C:2]1[C:3]([O:22][CH3:23])=[C:4]([C:8]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH:36][CH2:35][C:34]([CH3:38])([CH3:37])[CH2:33][N:32]([CH3:39])[CH3:31])(=[O:14])=[O:13])=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: COc1c(Br)ccc(NS(=O)(=O)c2ccccc2F)c1C(=O)O
Reactant: CN(C)CC(C)(C)CN
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1c(Br)ccc(NS(=O)(=O)c2ccccc2NCC(C)(C)CN(C)C)c1C(=O)O
Temperature: 65 °C
Reaction time: 144 h

Procedure:
A mixture of Example 371A (150 mg, 0.37 mmol), acetonitrile (2.5 mL), triethylamine (0.26 mL, 1.86 mmol), and N,N,2,2-tetramethyl-1,3-propanediamine (381 mg, 3.0 mmol) was sealed in a vial and shaken at 65° C. for 144 hours and heated to 80° C. for 18 hours. The mixture was concentrated and the residue was purified by preparative HPLC on a; Waters Symmetry C8 column (25 mm×100 mm, 7 μm particle size) using a gradient of 10% to 100% acetonitrile/10 mmol aqueous ammonium acetate over 8 minutes (10 minute run time) at a flow rate of 40 mL/min to provide the desired product. MS (ESI(+)) m/e 514, 516 (M+H)+; (ESI(−)) m/e 512, 514 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 12.07 (br s, 1H), 7.61 (d, 1H), 7.38 (d, 1H), 7.31 (t, 1H), 7.01 (d, 1H), 6.85 (t, 1H), 6.63 (t, 1H), 5.75 (s, 1H), 3.68 (s, 3H), 3.26 (br s, 1H), 3.09 (m, 4H), 2.79 (br s, 6H), 1.07 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:7]=1[C:8](O)=[O:9]>C1COCC1>[Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:7]=1[CH2:8][OH:9]
Reactant: O=C(O)c1cc(F)ccc1OCc1ccccc1Cl
Solvent: C1CCOC1
Product: OCc1cc(F)ccc1OCc1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5.50 g (20 mmol) of 2-(2-chlorobenzyloxy)-5-fluorobenzoic acid are dissolved in 25 ml of THF, heated to reflux and then 20 ml of 1 M borane-dimethyl sulfide complex are added dropwise. The mixture is then cooled to room temperature and stirred at this temperature for 1 h. The solvent is distilled out in vacuo, and water is added to the residue. Acidification is then carried out cautiously (copious gas evolution) with 1 N hydrochloric acid. 1 N sodium hydroxide solution is then added to make slightly basic, and the aqueous phase is extracted three times with dichloromethane. The organic phases are dried over magnesium sulfate, filtered and washed with dichloromethane, and concentrated. Petroleum ether is added to the residue, and the crystals which have separated out are filtered off with suction and dried on a clay dish. 3.65 g (13.6 mmol, 68% of theory) of the title compound are obtained.