Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([OH:10])=O)=[C:4]([CH3:15])[CH:3]=1.CN(C=O)C.[Cl-].[Al+3].[Cl-].[Cl-].[Cl-]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH3:15])[C:5]2[O:6][C:7]([CH3:12])([CH3:11])[C:8](=[O:10])[C:13]=2[CH:14]=1
Reactant: Cc1cc(F)ccc1OC(C)(C)C(=O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1cc(F)cc2c1OC(C)(C)C2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(4-fluoro-2-methylphenoxy)-2-methylpropanoic acid (658) (5 g, 23.6 mmol) in tetrahydrofuran (50 mL) at 0° C. was added cat. DMF and oxayl chloride (2.5 mL, 28.3 mmol). The reaction was warmed to room temperature, stirred for 1 hour, and concentrated in vacuo. The oil was dissolved in dichloromethane (50 mL), cooled to −78° C. and AlCl3 (7.6 g, 56.6 mmol) was added. The reaction was allowed to warm to room temperature overnight. Ice water was added and the dichloromethane was removed in vacuo. The aqueous phase was extracted with ethyl acetate (3×50 mL) and washed with saturated sodium bicarbonate dried over sodium sulfate, filtered and concentrated in vacuo. The crude compound was purified by flash column chromatography on silica gel with hexanes and EtOAc (20%) to provide 5-fluoro-2,2,7-trimethylbenzofuran-3(2H)-one (659).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[CH3:17][N:18]=[C:19]=[S:20]>>[CH3:17][NH:18][C:19](=[S:20])[NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6]
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Reactant: CN=C=S
Product: CNC(=S)Nc1cccc(C(=O)C2CCN(C)CC2)c1
Yield: 65.6 %

Procedure:
Following the example above and beginning with 4-[3-aminobenzoyl]-1-methylpiperidine (25 mg, 0.115 mmol) and methyl isothiocyanate (124 μL, 1.813 mmol), 22.0 mg (66%) of the title compound were recovered.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][S:14][CH2:15][CH2:16][CH2:17][C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>>[F:24][C:18]([F:23])([C:19]([F:20])([F:21])[F:22])[CH2:17][CH2:16][CH2:15][S:14][CH2:13][C@@H:9]1[CH2:10][CH2:11][CH2:12][NH:8]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CSCCCC(F)(F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)C(F)(F)CCCSC[C@@H]1CCCN1
Temperature: 0 °C
Reaction time: 16 h
Yield: 96.1 %

Procedure:
2.55 g of N-tert-butyloxycarbonyl-(2S)-2-(4,4,5,5,5-pentafluoropentylthiomethyl)-pyrrolidine is added to 5.4 ml of trifluoroacetic acid, cooled to 0° C., and the mixture is stirred for 1.5 hours at 0° C. and for 16 hours at room temperature. The reaction mixture is poured onto 10% sodium bicarbonate solution, extracted with ethyl acetate, washed with saturated common salt solution, dried on sodium sulfate and concentrated by evaporation. 1.8 g of the title compound is obtained as oily crude product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C@H:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17]CC2C=CC=CC=2)=[CH:13][C:12]=1[O:25][CH3:26])[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6](=[O:27])[NH:7][C@H:8]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=1[O:25][CH3:26])[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(OCc2ccccc2)ccc1[C@H](CO)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: COc1cc(O)ccc1[C@H](CO)NC(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
A mixture of [(R)-1-(4-benzyloxy-2-methoxy-phenyl)-2-hydroxy-ethyl]-carbamic acid tert-butyl ester (136 mg, 0.365 mmol) and Pd/C (˜10 mg) in MeOH (4 ml) was stirred under H2 (1 atm) for overnight. The mixture was filtered and the filtrate was concentrated to give the titled compound (100 mg, 100%).
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].CN(C)C(=O)C.[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:31]2[C:39](SC)=[N:38][C:37]3[C:32]2=[N:33][CH:34]=[N:35][CH:36]=3)=[CH:26][CH:25]=1>O>[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:31]2[C:39]([O:14][CH:11]3[CH2:12][CH2:13][N:8]([CH2:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH2:9][CH2:10]3)=[N:38][C:37]3[C:32]2=[N:33][CH:34]=[N:35][CH:36]=3)=[CH:26][CH:25]=1
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: CSc1nc2cncnc2n1Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Fc1ccc(Cn2c(OC3CCN(Cc4ccccc4)CC3)nc3cncnc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.1 %

Procedure:
A mixture of 12.6 parts of 1-(phenylmethyl)-4-piperidinol, 3.2 parts of a sodium hydride dispersion 50% and 200 parts of N,N-dimethylacetamide was stirred for 1 hour at room temperature. 18 Parts of 9-[(4-fluorophenyl)methyl]-8-(methylthio)-9H-purine were added portionwise and upon completion, stirring was continued for 4 hours at room temperature. The reaction mixture was poured into water. The product was filtered off and taken up in trichloromethane. The organic layer was washed with water and filtered over diatomaceous earth. The filtrate was dried, filtered and evaporated. After crystallization from acetonitrile, the product was filtered off and dried, yielding 16.75 parts (61.1%) of 9-[(4-fluorophenyl)methyl]-8-[[1-(phenylmethyl)-4-piperidinyl]oxy]-9H-purine; mp. 117.0° C. (compound 5).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1[N:6]=[CH:7][N:8](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:9]=1.Br[C:31]1[CH:36]=[C:35]([C:37]#[N:38])[CH:34]=[CH:33][C:32]=1[CH3:39]>C(#N)C>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1[N:6]([CH2:39][C:32]2[CH:33]=[CH:34][C:35]([C:37]#[N:38])=[CH:36][CH:31]=2)[CH:7]=[N:8][CH:9]=1
Reactant: COC(=O)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: Cc1ccc(C#N)cc1Br
Solvent: CC#N
Product: COC(=O)Cc1cncn1Cc1ccc(C#N)cc1
Temperature: 55 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(triphenylmethyl)-1H-imidazol-4-ylacetic acid methyl ester (8.00 g, 20.9 mmol) in acetonitrile (70 ml) was added bromo-p-toluonitrile (4.10 g, 20.92 mmol) and heated at 55° C. for 3 hr. After this time, the reaction was cooled to room temperature and the resulting imidazolium salt (white precipitate) was collected by filtration. The filtrate was heated at 55° C. for 18 hr. The reaction mixture was cooled to room temperature and evaporated in vacuo. To the residue was added EtOAc (70 ml) and the resulting white precipitate collected by filtration. The precipitated imidazolium salts were combined, suspended in methanol (100 ml) and heated to reflux for 30 min. After this time, the solvent was removed in vacuo, the resulting residue was suspended in EtOAc (75 ml) and the solid isolated by filtration and washed (EtOAc). The solid was treated with sat aq NaHCO3 (300 ml) and CH2Cl2 (300 ml) and stirred at room temperature for 2 hr. The organic layer was separated, dried (MgSO4) and evaporated in vacuo to afford the title compound as a white solid:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:14]=[CH:13][NH:12][N:11]=2)[CH:7]=[C:6]([F:15])[C:3]=1[C:4]#[N:5].O[CH2:17][C@H:18]([NH:20]C(=O)OC(C)(C)C)[CH3:19]>>[NH2:20][C@H:18]([CH3:19])[CH2:17][N:12]1[CH:13]=[CH:14][C:10]([C:8]2[CH:7]=[C:6]([F:15])[C:3]([C:4]#[N:5])=[C:2]([Cl:1])[CH:9]=2)=[N:11]1
Reactant: N#Cc1c(F)cc(-c2cc[nH]n2)cc1Cl
Reactant: C[C@H](CO)NC(=O)OC(C)(C)C
Product: C[C@@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Yield: 70.5 %

Procedure:
(R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile was prepared using the method of Example 202 starting from 2-chloro-6-fluoro-4-(1H-pyrazol-3-yl)benzonitrile (5.0 g, 22.56 mmol) and (R)-tert-butyl (1-hydroxypropan-2-yl)carbamate (7.91 g, 45.1 mmol). The product was evaporated to dryness. Yield 70.5%. 1H-NMR (400 MHz; DMSO): δ 0.96 (d, 3H), 3.20-3.30 (m, 1H), 4.00-4.10 (m, 2H), 7.03 (d, 1H), 7.85-7.91 (m, 2H), 7.99 (m, 1H).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[C:9](=[O:25])[N:10]([CH:17]1[CH2:22][CH2:21][C:20](=[O:23])[NH:19][C:18]1=[O:24])[C:11]2=[O:16])=[O:4].[N-:26]=[N+:27]=[N-:28].[Na+].[I-].[Na+]>CC(C)=O>[N:26]([CH2:2][C:3]([NH:5][CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[C:9](=[O:25])[N:10]([CH:17]1[CH2:22][CH2:21][C:20](=[O:23])[NH:19][C:18]1=[O:24])[C:11]2=[O:16])=[O:4])=[N+:27]=[N-:28]
Reactant: O=C(CCl)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: [N-]=[N+]=[N-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: [N-]=[N+]=NCC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Yield: 90.8 %

Procedure:
A mixture of 2-chloro-N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}acetamide (1.3 g, 3.57 mmol), sodium azide (0.3 g, 4.65 mmol) and sodium iodide (0.54 g, 3.57 mmol) in acetone (50 ml) was refluxed for 17 hours. The solvent was removed in vacuo and the residue was dissolved in EtOAc (60 ml). The EtOAc solution was washed with H2O (30 ml), brine (30 ml), and dried (MgSO4). The solvent was removed in vacuo to give 2-azido-N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}acetamide (1.2 g, 90%) as a white solid: 1H NMR (CDCl3) δ d 8.48 (s, 1H), 7.84-7.68 (m, 31), 7.51 (t, J=6.3 Hz, 1H), 5.04-4.97 (dd, J=4.7 and 11.8 Hz, 1H), 4.80 (d, J=6.5 Hz, 2H), 3.97 (s, 2H), 2.95-2.74 (m, 3H) 2.20-2.15 (m, 1H).
Reaction SMILES: C(=O)(O)[O-].[Na+].[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)=O.O>C(O)C>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([C:15]2[N:6]=[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]3[CH:14]=2)=[CH:18][CH:19]=1
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: Nc1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2cn3ccccc3n2)cc1

Procedure:
A mixture of 25.2 g. of sodium bicarbonate, 12.3 g. of 2-aminopyridine and 30 g. of α-bromo-p-methoxyacetophenone in 100 ml. of water and 550 ml. of absolute ethanol is heated at reflux temperatures for 1.5 hrs. The reaction mixture is concentrated under reduced pressure to a yellow solid, which is partitioned between chloroform and water. The organic layer is separated, dried over sodium sulfate. Removal of the chloroform in vacuo leaves the crude intermediate as a yellow solid. Recrystallization from ethanolwater give 15.2 g. of the desired material, m.p. 131-134° C.
Reaction SMILES: [C:1]([OH:8])(=O)[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].C(N(CC)CC)C.CC(C)(C)C(Cl)=O.[Cl-].[Li+].[CH2:25]([C@H:32]1[CH2:36][O:35][C:34](=[O:37])[NH:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCCC1>[CH2:25]([C@H:32]1[CH2:36][O:35][C:34](=[O:37])[N:33]1[C:1](=[O:8])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: C#CCCCC(=O)O
Agent: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C#CCCCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
To a solution of 10 g (89 mmol) of 5-hexynoic acid and 31.0 mL (223 mmol) of triethylamine in 450 mL of anhydrous tetrahydrofuran at −25° C. under an atmosphere of nitrogen was added 12 mL (98 mmol) of trimethylacetyl chloride over 20 min. Upon addition a white precipitate formed and the resulting suspension was stirred for 2 h. Next, 4.2 g (98 mmol) of anhydrous lithium chloride and 17 g (94 mmol) of (S)-(−)-4-benzyl-2-oxazolidinone were added sequentially and the mixture was allowed to gradually warm to ambient temperature over 12 h. All volatiles were removed in vacuo and the residue was diluted with water (500 mL) and extracted with ether (3×200 mL). The combined organic layers were washed with brine (100 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography eluting with a 10-25% ethyl acetate in hexanes gradient to afford the title compound as a colorless solid (22 g, 93%). 1H NMR (500 MHz, CDCl3): δ7.35-7.31 (m, 2H), 7.28-7.25 (m, 1H), 7.19-7.21 (m, 2H), 4.69-4.64 (m, 1H), 4.22-4.15 (m, 2H), 3.28 (dd, J=13.4, 3.3 Hz, 1H), 3.13-3.01 (m, 2H), 2.78 (dd, J=13.4, 9.6 Hz, 1H), 2.34-2.30 (m, 2H), 1.99 (t, J=2.7 Hz, 1H), 1.96-1.88 (m, 2H). LC-MS: m/z (ES) 272.2 (MH)+, 294.3 (MNa)+.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[C:17]([OH:19])=O)[CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:22])=O.CN(C)C=O>C(Cl)Cl>[CH2:1]([S:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[C:17]([Cl:22])=[O:19])[CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(C(=O)O)c(SCc2ccccc2)c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=Cc1ccc(C(=O)Cl)c(SCc2ccccc2)c1

Procedure:
To a solution containing 23.2 g of 3-benzylmercapto-4-carboxy benzaldehyde in 250 ml of methylene chloride is added 15 ml of thionyl chloride and 0.5 ml of dimethylformamide. The reaction mixture is refluxed for 6-7 hours, then evaporated to dryness. Crystallization from 100 ml of ether yielded 27.0 g of 3-benzylmercapto-4-chlorocarbonyl benzaldehyde (a).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:16]([OH:18])=[O:17])=[CH:10][CH:9]=2)[CH:5]=[C:4]([O:27][C@@H:28]([C:33]2[CH:38]=[CH:37][C:36](Br)=[CH:35][CH:34]=2)[C:29]([F:32])([F:31])[F:30])[N:3]=1.CC1(C)C(C)(C)OB([C:48]2[CH:49]=[N:50][O:51][CH:52]=2)O1.C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:16]([OH:18])=[O:17])=[CH:10][CH:9]=2)[CH:5]=[C:4]([O:27][C@@H:28]([C:33]2[CH:38]=[CH:37][C:36]([C:48]3[CH:49]=[N:50][O:51][CH:52]=3)=[CH:35][CH:34]=2)[C:29]([F:32])([F:31])[F:30])[N:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cc(O[C@@H](c3ccc(Br)cc3)C(F)(F)F)nc(N)n2)cc1)C(=O)O
Reactant: CC1(C)OB(c2cnoc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cc(O[C@@H](c3ccc(-c4cnoc4)cc3)C(F)(F)F)nc(N)n2)cc1)C(=O)O
Temperature: 150 °C
Yield: 14.5 %

Procedure:
A microwave vial (2 ml) was charged with (S)-3-(4-{2-amino-6-[(S)-1-(4-bromo-phenyl)-2,2,2-trifluoro-ethoxy]-pyrimidin-4-yl}-phenyl)-2-tert-butoxycarbonylamino-propionic acid (139 mg, 0.23 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-isoxazole (57.5 mg, 0.3 mmol), 1 ml of acetonitrile, and 0.7 ml of water. To this mixture was added 0.4 ml of aqueous sodium carbonate (1M), followed by 14 mg of dichlorobis-(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated to 150° C. for 5 minutes with microwave irradiation. After cooling, the reaction mixture was evaporated to dryness, the residue was dissolved in 2.5 ml of methanol and was purified by preparative HPLC to give 20 mg of (S)-3-(4-{2-amino-6-[(S)-2,2,2-trifluoro-1-(4-isoxazol-4-yl-phenyl)-ethoxy]-pyrimidin-4-yl}-phenyl)-2-tert-butoxycarbonylamino propionic acid.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH:5]([O:8][C:9]([N:11]1[CH2:17][CH2:16][CH2:15][CH:14]([NH:18][CH2:19][C:20]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=2)[C:13]2[CH:34]=[CH:35][C:36]([Cl:39])=[C:37]([CH3:38])[C:12]1=2)=[O:10])([CH3:7])[CH3:6].N1C=CC=CC=1>ClCCl>[CH:5]([O:8][C:9]([N:11]1[CH2:17][CH2:16][CH2:15][CH:14]([N:18]([C:1](=[O:3])[CH3:2])[CH2:19][C:20]2[CH:21]=[C:22]([C:30]([F:33])([F:31])[F:32])[CH:23]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:25]=2)[C:13]2[CH:34]=[CH:35][C:36]([Cl:39])=[C:37]([CH3:38])[C:12]1=2)=[O:10])([CH3:7])[CH3:6]
Reactant: CC(=O)Cl
Reactant: Cc1c(Cl)ccc2c1N(C(=O)OC(C)C)CCCC2NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2c1ccc(Cl)c2C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.6 %

Procedure:
Inject titanium isopropoxide (0.176 mL, 0.60 mmol) to a mixture of 8-chloro-9-methyl-5-oxo-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid isopropyl ester (90 mg, 0.30 mmol) and 3,5-bis(trifluoromethyl)benzylamine (137 mg, 0.45 mmol) at room temperature under an atmosphere of nitrogen and stir the solution for 14 h. Add methanol (1.3 mL) and sodium borohydride (28 mg, 0.75 mmol) and stir the mixture under nitrogen at room temperature for 2 h. Add 0.1M NaOH, stir for 30 min. Filter through celite and wash the residue with AcOEt. Separate organic layer, extract aqueous with AcOEt. Wash organic layer with brine and dry the organic layers over anhydrous sodium sulfate. Filter and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to afford (+/−)-5-(3,5-Bis-trifluoromethyl-benzylamino)-8-chloro-9-methyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid isopropyl ester (90 mg, 57%). Add acetyl chloride (0.025 mL, 0.34 mmol) dropwise to a solution of the amine (90 mg, 0.17 mmol) and pyridine (0.025 mL, 0.34 mmol) in dichloromethane (1.2 mL) at 0° C. Stir under nitrogen at room temperature for 1 h 30 min. Add water and extract with dichloromethane. Dry the organic layer over anhydrous magnesium sulfate, filter and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to afford the title compound (40 mg, 42%); MS (ES+): 565 (M+H).
Reaction SMILES: [S:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3](=[O:11])[CH2:2]1.[H-].[Na+].[CH3:14][N:15]([CH3:20])[CH2:16][CH2:17][CH2:18]Cl.[I-].[Na+]>C1(C)C=CC=CC=1.CN(C=O)C>[CH3:14][N:15]([CH3:20])[CH2:16][CH2:17][CH2:18][N:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[S:1][CH2:2][C:3]1=[O:11]
Reactant: CN(C)CCCCl
Reactant: O=C1CSc2ccccc2N1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CN(C)CCCN1C(=O)CSc2ccccc21

Procedure:
The title product is prepared by reacting sixty grams (0.36 mole) of 1,4-benzothiazin-3(4H)-one in 360 of DMF with 18 g (0.37 mole) of 50% NaH, 260 ml (0.55 mole) of a 2.1 N toluene solution of 3-dimethylaminopropyl chloride, and 4 g of sodium iodide according to the procedure described in Example 1, part A; yield, 57.7 g; bp 157°-160°/0.2 mm.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:6][CH:7]=1.[CH2:15]([N:22]1[CH2:26][CH2:25][C@@H:24]([NH2:27])[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CCN(CC)CC>CN(C=O)C>[CH2:15]([N:22]1[CH2:26][CH2:25][C@@H:24]([NH:27][C:2]2[N:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:6][CH:7]=2)[CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: N[C@@H]1CCN(Cc2ccccc2)C1
Reactant: CCOC(=O)/C=C/c1cnc(Cl)cn1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCN(Cc3ccccc3)C2)cn1
Temperature: 100 °C
Reaction time: 3 h
Yield: 46.3 %

Procedure:
To a solution of ethyl (2E)-3-(5-chloro-2-pyrazinyl)acrylate (1.50 g) in DMF (21 mL) was added (3R)-1-benzyl-3-pyrrolidinamine (2.24 g) and Et3N (3.44 mL). After stirring for 3 hours at 100° C., the reaction mixture was partitioned between ethyl acetate and H2O. The organic layer was washed with brine, dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give ethyl (2E)-3-(5-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylate (1.15 g)
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][NH:16][CH2:15][C:14]3=[O:19])=[CH:10][C:5]=2[CH2:4][O:3]1.Br[CH2:21][CH2:22][C:23]1[CH:32]=[CH:31][C:26]2[C:27](=[O:30])[O:28][CH2:29][C:25]=2[CH:24]=1>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][N:16]([CH2:21][CH2:22][C:23]4[CH:32]=[CH:31][C:26]5[C:27](=[O:30])[O:28][CH2:29][C:25]=5[CH:24]=4)[CH2:15][C:14]3=[O:19])=[CH:10][C:5]=2[CH2:4][O:3]1
Reactant: O=C1OCc2cc(CCBr)ccc21
Reactant: O=C1OCc2cc(CCN3CCNCC3=O)ccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Product: O=C1OCc2cc(CCN3CCN(CCc4ccc5c(c4)COC5=O)C(=O)C3)ccc21
Temperature: 55 °C

Procedure:
To a solution of 1-[2-(1-Oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-2-one (30 mg, 0.12 mmol) and 5-(2-Bromoethyl)-2-benzofuran-1(3H)-one (56 mg, 0.23 mmol) in DMF (2 ml) was added TEA (0.048 ml, 0.35 mmol) and tetrabutylammonium iodide (4.3 mg, 0.012 mmol). The mixture was heated to 55° C. for 16 hours. LC showed formation of the desired product, which was purified by mass-directed reverse phase HPLC (AcCN-Water with 0.1% TFA). LC-MS (IE, m/z): 421 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C@@H:11]([CH2:13][N:14]3C(=O)C4C(=CC=CC=4)C3=O)[O:10][C:9]2=[O:25])[CH:5]=[CH:6][CH:7]=1.O.NN>C(O)C>[NH2:14][CH2:13][C@@H:11]1[O:10][C:9](=[O:25])[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH2:12]1
Reactant: O=C1c2ccccc2C(=O)N1C[C@@H]1CN(c2cccc(F)c2)C(=O)O1
Agent: NN
Solvent: O
Solvent: CCO
Product: NC[C@H]1CN(c2cccc(F)c2)C(=O)O1
Temperature: 25 °C
Yield: 96.5 %

Procedure:
A solution of phthalimide 110 (3.0 g, 8.82 mmol) in ethanol (EtOH, 30 mL) was treated with hydrazine monohydrate (2.20 g, 2.2 mL, 44.12 mmol, 5.0 equiv) at 25° C., and the resulting reaction mixture was warmed to reflux for 2 h. White precipitates formed as the reaction mixture was refluxed. When TLC and HPLC showed the reaction was complete, the reaction mixture was cooled to room temperature before being quenched with H2O (20 mL). The aqueous solution was then extracted with CH2Cl2 (3×40 mL), and the combined organic extracts were washed with H2O (2×20 mL) and saturated aqueous NaCl (20 mL), dried over MgSO4, and concentrated in vacuo. The residue was further dried in vacuo to afford the desired (5S)-5-aminomethyl-3-(3-fluoro-phenyl)-oxazolidin-2-one 111 (1.79 g, 96.6% yield) as a white powder. This product was directly used in the subsequent reactions without further purification. C10H11FN2O2, LCMS (EI) m/e 211 (M++H).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:21]=[CH:20][C:9]2[NH:10][C:11]([CH2:16][C:17]([OH:19])=O)=[N:12][S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1)(=[O:4])=[O:3].[CH2:22]([O:24][C:25]([CH:27]1[CH2:31][CH2:30][CH2:29][CH:28]1[NH:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)=[O:26])[CH3:23].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.Cl>CN(C)C=O>[CH2:22]([O:24][C:25]([CH:27]1[CH2:31][CH2:30][CH2:29][CH:28]1[N:32]([CH2:33][C:34]1[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=1)[C:17](=[O:19])[CH2:16][C:11]1[NH:10][C:9]2[CH:20]=[CH:21][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:7][C:8]=2[S:13](=[O:14])(=[O:15])[N:12]=1)=[O:26])[CH3:23]
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Reactant: CCOC(=O)C1CCCC1NCc1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCCC1N(Cc1ccc(Cl)cc1)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
(7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 0.1665 g, 0.5 mmol) was dissolved in anhydrous N,N-dimethylformamide (3 mL). 2-(4-Chloro-benzylamino)-cyclopentanecarboxylic acid ethyl ester (0.1406 g, 0.5 mmol) was added followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.1003 g, 0.525 mmol). Then N-methylmorpholine (115 μL, 1.05 mmol) was added. The mixture was stirred at 25° C. for 5 h. The solution was poured into 1.0 M aqueous hydrochloric acid solution (100 mL). The aqueous layer was extracted with ethyl acetate (2×100 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to afford the crude product, 2-{(4-chloro-benzyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-cyclopentanecarboxylic acid ethyl ester, as a yellow oil. LC-MS (ESI) calcd for C25H29ClN4O7S2 596.12, found 597.2 [M+H+].