Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1](Cl)(Cl)=O.[Br:5][C:6]1[CH:7]=[C:8]([NH2:17])[C:9]([NH2:16])=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13].C(N(CC)CC)C>ClCCl>[Br:5][C:6]1[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]2=[N:16][S:1][N:17]=[C:8]2[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: Nc1cc(Br)c(C(F)(F)F)cc1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: FC(F)(F)c1cc2nsnc2cc1Br
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.6 %

Procedure:
Thionyl chloride (373 mg, 3.1 mmol) in dichloromethane (0.8 mL) was added dropwise to a refluxing solution of diamine 18 (500 mg, 2.0 mmol) and triethylamine (794 mg, 7.8 mmol) in dichloromethane (8.0 mL). The mixture was refluxed with stirring for 4 h. The mixture was then cooled to room temperature, quenched with water (20 mL), and extracted with dichloromethane (3×75 mL). The combined extracts were dried with sodium sulfate and concentrated under reduced pressure. Flash chromatography (ISCO system, silica, 0-25% ethyl acetate in hexane) provided 19 (377 mg, 68%) as a solid: LRESIMS m/z 294.1.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[CH2:13]1[O:23][C:16]2([CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]2)[O:15][CH2:14]1.O>CCOCC.C1COCC1>[CH2:14]1[O:15][C:16]2([CH2:21][CH2:20][C:19]([OH:22])([C:7]3[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=3)[CH2:18][CH2:17]2)[O:23][CH2:13]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Brc1cccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: OC1(c2cccnc2)CCC2(CC1)OCCO2
Reaction time: 0.17 h
Yield: 47 %

Procedure:
To a solution of n-BuLi (1.59 M in Hexane, 45 mL. 71.6 mmol) in dry ether (150 mL) was added a solution of 3-Bromopyridine (11.24 g, 71.1 mmol) in dry ether (70 mL) dropwise at −78° C. After stirring for 10 min, a solution of cyclohexane-1,4-dione monoetylene acetal (9.25 g, 59.2 mmol) in THF (70 mL) was added over a period of 20 min at −78° C., and stirred for 3 h. To the reaction mixture was added with water. The aqueous layer was extracted with CH2Cl2, and the organic layer was washed with brine. The extracts were combined with the organic layer. After drying and concentration, the crude product was purified by column chromatography (Hexane/EtOAc=2/1) to yield 4-hydroxy-4-(3-pyridyl)cyclohexanone ethylene acetal (6.55 g, 47%) as a pale yellow powder.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:13]1([C:18]([C:20]2[CH:21]=[C:22]([C@@H:26]([CH3:30])[C:27](O)=[O:28])[CH:23]=[CH:24][CH:25]=2)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1.[CH3:31][S:32]([NH2:35])(=[O:34])=[O:33].C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[CH:13]1([C:18]([C:20]2[CH:21]=[C:22]([C@@H:26]([CH3:30])[C:27]([NH:35][S:32]([CH3:31])(=[O:34])=[O:33])=[O:28])[CH:23]=[CH:24][CH:25]=2)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: C[C@@H](C(=O)O)c1cccc(C(=O)C2CCCC2)c1
Reactant: CS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: C[C@@H](C(=O)NS(C)(=O)=O)c1cccc(C(=O)C2CCCC2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 790 %

Procedure:
1,1′-Carbonyldiimidazole (0.5 g, 3.06 mmol) was added to a solution of (R)-2-[3-cyclopentanoyl)phenyl]propionic acid (II) (0.68 g, 2.78 mmol) in dry CH2Cl2 (8 mL) and the resulting mixture was left stirring at room temperature for 90 min. Methanesulfonamide (0.26 g, 2.78 mmol) and DBU (0.43 mL, 2.78 mmol) were added and the mixture was left stirring fur further 16 h at room temperature. The organic phase was washed with 0.5N HCl (2×10 mL), with 5% NaH2PO4 (3×10 mL) and with water (2×10 mL). After drying with Na2SO4, solvent was removed under vacuum and the crude was purified by flash chromatography (eluent mixture CH2Cl2/MeOH 95:5). Pure N—[(R)-2-(3-cyclopentanecarbonylphenyl)propionyl]methanesulfonamide 22 was isolated as colourless oil (0.67 g, 2.09 mmol). Yield 790%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][NH:8][C:9]2[CH:14]=[C:13](Cl)[N:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[F:18][C:19]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:20]=1[OH:28].CCN(C(C)C)C(C)C.COCCOCCOC>CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][NH:8][C:9]2[CH:14]=[C:13]([O:28][C:20]3[CH:21]=[CH:22][C:23]([N+:25]([O-:27])=[O:26])=[CH:24][C:19]=3[F:18])[N:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CNc2cc(Cl)ncn2)cc1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Solvent: COCCOCCOC
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNc2cc(Oc3ccc([N+](=O)[O-])cc3F)ncn2)cc1
Temperature: 160 °C
Reaction time: 0.17 h
Yield: 51.4 %

Procedure:
A mixture of N-(4-methoxybenzyl)-6-chloropyrimidin-4-amine (2.3 g, 9.2 mmol), 2-fluoro-4-nitrophenol (1.45 g, 9.2 mmol), DIPEA (15 mL), and 2-methoxyethyl ether (75 mL) was heated at 160° C. in a sealed pressure bottle for 50 h. The mixture was cooled, poured onto crushed ice (200 g), treated with EtOAc (200 mL). After vigorously stirring for 10 min, the insoluble material was filtered off. The EtOAc phase was washed with saturated aq. Na2CO3 solution (100 mL), brine (3×100 mL), dried (MgSO4) and concentrated in vacuo. The gummy solid obtained was triturated with isopropyl ether to give the title compound (1.75 g, 76%) as a brown solid. 1H NMR (DMSO-d6) δ 8.32 (dd, 1H, J=10.2, 2.0 Hz), 8.15 (d, 2H, J=9.2 Hz), 8.05 (br s, 1H), 7.61 (dd, 1H, J=8.4, 8.4 Hz), 7.26 (d, 2H, J=8.5 Hz), 6.91 (d, 2H, J=8.5 Hz), 6.14 (br s, 1H), 4.48 (br s, 2H), 3.74 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.[F:11][CH:12]([F:23])[O:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1>>[F:11][CH:12]([F:23])[O:13][C:14]1[CH:19]=[C:18]([C:2]2[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1c(F)cc(Br)cc1F
Reactant: OB(O)c1cccc(OC(F)F)c1
Product: Nc1c(F)cc(-c2cccc(OC(F)F)c2)cc1F
Yield: 55.3 %

Procedure:
The title compound (144 mg) was prepared from 4-bromo-2,6-difluoroaniline (200 mg, 0.96 mmol) and 3-(difluoromethoxy)phenylboronic acid (234 mg, 1.25 mmol) as a white solid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 7.49 (d, J 7.9, 1H), 7.43-7.39 (m, 2H), 7.38-7.30 (m, 2H), 7.32 (t, J 74, 1H), 7.06 (dd, J 1.8, 7.9, 1H), 5.42 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][NH:11][CH:12]=2)=[CH:4][N:3]=1.[C:13](=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH2:21][CH2:22][CH2:23][N:24]1[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]2[C:25]1=[O:34]>CN(C=O)C>[F:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[N:9]=[CH:10][N:11]([CH2:13][CH2:20][CH2:21][CH2:22][CH2:23][N:24]3[C:28](=[O:29])[C:27]4[C:26](=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:25]3=[O:34])[CH:12]=2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(-c2c[nH]cn2)cn1
Reactant: O=C([O-])[O-]
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCCCn1cnc(-c2ccc(F)nc2)c1
Temperature: 80 °C
Reaction time: 24 h
Yield: 55 %

Procedure:
To a solution of 2-fluoro-5-(1H-imidazol-4-yl)-pyridine (1 eq) in DMF was added potassium carbonate (5 eq) at room temperature under dry conditions. After heating the reaction mixture in a 80° C. oil bath for 1 hour, N-(4-bromobutyl)phtalimide (4 eq) was added to the mixture. The solution was left stirring in a 80° C. oil bath for 24 hours. Upon cooling, the reaction was filtered and the solid was washed with ethyl acetate. The filterate was diluted with ethyl acetate and washed with NH4Cl (sat.), H2O, NaCl (sat.), dried over sodium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography using an initial solvent gradient of 97% DCM, 3% MeOH, and 0.1% TEA (1 L) to yield 2-{4-[4-(6-fluoro-pyridin-3-yl)-imidazol-1-ylmethyl]-butyl}-isoindole-1,3-dione (55%). MH+(365)
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[F:16][C:17]1[C:22](C=O)=[C:21]([F:25])[C:20]([F:26])=[C:19]([F:27])[C:18]=1[F:28]>CCCCCC.O1CCCC1>[OH:4][C:3]1[CH2:5][CH:8]([C:22]2[C:21]([F:25])=[C:20]([F:26])[C:19]([F:27])=[C:18]([F:28])[C:17]=2[F:16])[O:7][C:1](=[O:6])[CH:2]=1
Reactant: O=Cc1c(F)c(F)c(F)c(F)c1F
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1C=C(O)CC(c2c(F)c(F)c(F)c(F)c2F)O1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
The title compound was prepared as described in General Method 1 using 2.5 mL of methyl acetoacetate, 1.0 g of NaH 60% dispersion in oil, 12.5 mL of 2.0M n-butyl lithium in hexane, 3.4 mL of pentafluorobenzaldehyde and 75 mL of tetrahydrofuran. After addition of the aldehyde, the reaction was stirred for 10 minutes at 0° C. then allowed to warm to room temperature overnight. The crude product was triturated from diethyl ether to afford a solid (m.p. 176°-178° C.). 1H NMR (CDCl3) δ2.89 (dd, 1H), 3.15 (dd, 1H), 3.70 (dd, 2H), 6.02 (dd, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:5][C:4]=1[NH2:16])#[N:2].Cl.[N:18]([O-])=O.[Na+].C([O-])(=O)C.[Na+].[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O.C(O)C>[C:28]1([N:27]=[N:18][NH:16][C:4]2[CH:5]=[C:6]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:7]([O:9][CH3:10])=[CH:8][C:3]=2[C:1]#[N:2])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=N[O-]
Reactant: CCCCOc1cc(N)c(C#N)cc1OC
Reactant: Nc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCOc1cc(NN=Nc2ccccc2)c(C#N)cc1OC
Temperature: 0 °C
Reaction time: 8 h
Yield: 47.5 %

Procedure:
0.22 g (1 mmol) 2-cyano-4-methoxy-5-n-butoxyphenylamine and 3 mL (10 mol/L) hydrochloric acid were added into a round bottom flask. The solution was cooled to 0° C. and diazotized with sodium nitrite (0.072 g, 1 mmol) dissolved in water (1.0 mL), which was added dropwise to the solution. The mixture was stirred to react for 20 min. After adjusting the pH to 5˜6 with sodium acetate, the ethanol solution of aniline (0.093 g, 1 mmol) was added dropwise to the reaction mixture to react for 2 h under stirring, while maintaining the reaction temperature at between 0˜5° C., and using sodium acetate to keep the pH value at 5-6. The solution was kept overnight, filtered, and washed with water till colorless. The crude product was purified on a silica gel column with petroleum ether:ethyl acetate (v/v)=15:1 to yield 0.154 g of orange-yellow solid crystal product with a recovery rate of 47.5%.
Reaction SMILES: BrCC[C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([NH:9][C:10](=[O:11])[C:5]=12)=[O:8].[CH3:15][NH:16][CH2:17][C:18]#[CH:19].C(=O)([O-])[O-].[K+].[K+].[C:26]1(C)C=CC=C[CH:27]=1>>[CH3:15][N:16]([CH2:17][C:18]#[CH:19])[CH2:26][CH2:27][N:9]1[C:10](=[O:11])[C:5]2[C:6](=[CH:12][CH:13]=[CH:14][CH:4]=2)[C:7]1=[O:8]
Reactant: Cc1ccccc1
Reactant: C#CCNC
Reactant: O=C1NC(=O)c2c(CCBr)cccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C#CCN(C)CCN1C(=O)c2ccccc2C1=O

Procedure:
A mixture of bromoethylphthalimide (20.23 g, 0.080 mol), N-methyl-N-propargyl amine (5.0 g, 0.072 mol), potassium carbonate (17.5 g, 0.126 mol), and toluene (80 ml) was refluxed for 8 hours, filtered and the insoluble material washed with toluene. After removal of the solvent, the residue was purified by flash chromatography (Merck 60 silica gel, step gradient from pure dichloromethane to 4% methanol in dichloromethane). The pure fractions were combined, evaporated under reduced pressure, dried in vacuo to provide 16.24 g of title product.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:18][C@@H:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:20][OH:21])=[N:4][C:5]([C:8]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[N:13]3)=[CH:6][N:7]=1.NC1C(N[C@@H](C2C=CC=CC=2)[CH2:38][OH:39])=NC(Br)=CN=1.N1C2C=CC=C(B(O)O)C=2C=CC=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[OH:21][CH2:20][C@@H:19]([N:18]1[C:3]2=[N:4][C:5]([C:8]3[CH:17]=[CH:16][CH:15]=[C:14]4[C:9]=3[CH:10]=[CH:11][CH:12]=[N:13]4)=[CH:6][N:7]=[C:2]2[NH:1][C:38]1=[O:39])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Nc1ncc(Br)nc1N[C@H](CO)c1ccccc1
Reactant: Nc1ncc(-c2cccc3ncccc23)nc1N[C@H](CO)c1ccccc1
Agent: O=C([O-])[O-]
Agent: OB(O)c1cccc2ncccc12
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]c2ncc(-c3cccc4ncccc34)nc2n1[C@H](CO)c1ccccc1
Yield: 51 %

Procedure:
(S)-2-(3-Amino-6-(quinolin-5-yl)pyrazin-2-ylamino)-2-phenylethanol. (S)-2-(3-Amino-6-bromopyrazin-2-ylamino)-2-phenylethanol (0.882 g, 2.26 mmol), quinoline-5-boronic acid (0.544 g, 2.48 mmol) tetrakis(triphenylphosphine)-palladium (0.331 g, 0.287 mmol), potassium carbonate (1.25 g, 9.08 mmol), water (8 mL) and dimethylformamide (30 mL) were reacted according to General Procedure B. The crude material was purified via Biotage silica gel chromatography (0-10% methanol/dichloromethane, 40S column) to afford the title compound (0.524 g, 51% yield). MS (ESI) m/z 358.3 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[F:14][C:15]([F:25])([F:24])[C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1>>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:21][CH2:20][C:19]3[CH:18]=[CH:17][C:16]([C:15]([F:14])([F:24])[F:25])=[CH:23][CH:22]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: CSc1ncnc2cc(N)ncc12
Product: Nc1cc2ncnc(NCc3ccc(C(F)(F)F)cc3)c2cn1
Temperature: 140 °C
Reaction time: 1 h
Yield: 56.2 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (225 mg, 1.17 mmol) and 4-(trifluoromethyl)benzylamine (0.63 mL, 4.42 mmol) is stirred under N2 at 140° C. for 1 h. The resulting product is chromatographed on alumina (5-10% EtOH/CHCl3) then silica gel (2-10% EtOH/EtOAc) to give 7-amino-4-[(4-trifluoromethylphenyl) methylamino]pyrido[4,3-d]pyrimidine (0.21 g, 56%) as a light brown solid. 1H NMR (DMSO) δ 9.12 (1H, s), 8.94 (1H, t, J=5.8 Hz), 8.24 (1H, s), 7.69 (2H, d, J=8.1 Hz), 7.56 (2H, d, J=8.1 Hz), 6.48 (2H, brs), 6.38 (1H, s), 4.82 (2H, d, J=5.8 Hz).
Reaction SMILES: [C:1]12([CH:11]([NH:16][C:17]3[C:22]([F:23])=[CH:21][N:20]=[C:19]([C:24]4[C:32]5[C:27](=[N:28][CH:29]=[C:30](F)[CH:31]=5)[NH:26][CH:25]=4)[N:18]=3)[CH2:12][C:13]([OH:15])=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Cl:34]C1C=C2C(B3OC(C)(C)C(C)(C)O3)=CN(S(C3C=CC(C)=CC=3)(=O)=O)C2=NC=1.FC1C=C2C(B3OC(C)(C)C(C)(C)O3)=CN(S(C3C=CC(C)=CC=3)(=O)=O)C2=NC=1.C(O)=O>C(#N)C>[C:1]12([CH:11]([NH:16][C:17]3[C:22]([F:23])=[CH:21][N:20]=[C:19]([C:24]4[C:32]5[C:27](=[N:28][CH:29]=[C:30]([Cl:34])[CH:31]=5)[NH:26][CH:25]=4)[N:18]=3)[CH2:12][C:13]([OH:15])=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C(O)CC(Nc1nc(-c2c[nH]c3ncc(F)cc23)ncc1F)C12CC3CC(CC(C3)C1)C2
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(Cl)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(F)cnc32)cc1
Solvent: CC#N
Solvent: O=CO
Product: O=C(O)CC(Nc1nc(-c2c[nH]c3ncc(Cl)cc23)ncc1F)C12CC3CC(CC(C3)C1)C2

Procedure:
Compound 94 was synthesized in a manner similar to 3-(1-Adamantyl)-3-[[5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl]amino]propionic acid, 86, using 5-chloro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine instead of boronate ester, 7a: 1H NMR (400 MHz, CD3OD) δ 9.02 (d, J=2.3 Hz, 1H), 8.40-8.24 (m, 2H), 8.18 (d, J=5.0 Hz, 1H), 4.91 (d, J=11.6 Hz, 1H), 2.88 (dd, J=16.0, 2.8 Hz, 1H), 2.65 (dd, J=15.9, 11.0 Hz, 1H), 2.01 (s, 3H), 1.77 (dd, J=27.9, 11.9 Hz, 12H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time=2.60 minutes (M+H) 470.27.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([O:6][CH2:7][C@@H:8]2[O:12][C:11](=[O:13])[N:10]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][OH:28])[CH2:22][CH:21]=4)=[C:16]([F:29])[CH:15]=3)[CH2:9]2)=[N:2]1.C(N(CC)CC)C.[C:37](Cl)(=[O:39])[CH3:38].O>ClCCl>[O:1]1[CH:5]=[CH:4][C:3]([O:6][CH2:7][C@@H:8]2[O:12][C:11](=[O:13])[N:10]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][O:28][C:37](=[O:39])[CH3:38])[CH2:22][CH:21]=4)=[C:16]([F:29])[CH:15]=3)[CH2:9]2)=[N:2]1
Reactant: O=C1O[C@@H](COc2ccon2)CN1c1ccc(C2=CCN(CCO)CC2)c(F)c1
Reactant: CC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCCN1CC=C(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a stirred solution of Example 57(103 mg, 0.26 mmol) and triethylamine (77.4 mg, 0.77 mmol) in dichloromethane (10 ml) at 0° C. and under an atmosphere of nitrogen, was added dropwise acetyl chloride (60.2 mg, 0.77 mmol). The reaction was then allowed to warm to ambient temperature and stir for 1 hour. Water was added and the organic phase separated, washed with sat NaCl and then dried over MgSO4 and evaporated under reduced pressure. This yielded the title compound as a clear orange glass (110 mg, 97%). MS: ESP+ (M+H)+=446.
Reaction SMILES: [F:1][CH2:2][CH:3]([NH:14][O:15][CH3:16])[CH2:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:6]=1[Cl:13].N1C(C)=CC=CC=1C.[F:25][C:26]1[N:30]([CH3:31])[N:29]=[C:28]([CH3:32])[C:27]=1[C:33](F)=[O:34]>ClC1C=CC=CC=1.ClCCl>[F:1][CH2:2][CH:3]([N:14]([O:15][CH3:16])[C:33]([C:27]1[C:28]([CH3:32])=[N:29][N:30]([CH3:31])[C:26]=1[F:25])=[O:34])[CH2:4][C:5]1[C:6]([Cl:13])=[CH:7][C:8]([Cl:12])=[CH:9][C:10]=1[Cl:11]
Reactant: CONC(CF)Cc1c(Cl)cc(Cl)cc1Cl
Reactant: Cc1nn(C)c(F)c1C(=O)F
Solvent: Clc1ccccc1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CON(C(=O)c1c(C)nn(C)c1F)C(CF)Cc1c(Cl)cc(Cl)cc1Cl
Temperature: 130 °C
Yield: 6.7 %

Procedure:
To a stirred solution of N-[1-fluoromethyl-2-(2,4,6-trichloro-phenyl)-ethyl]-O-methylhydroxylamine (0.20 g; 0.70 mmol), prepared as described in example P6f2 in chlorobenzene (3.8 ml) was added 2,6-lutidine (85 μl; 0.74 mmol) and 5-fluoro-1,3-dimethyl-1H-pyrazole-4-carbonyl fluoride (0.11 g; 0.70 mmol). The yellow solution was stirred at reflux (130° C.) for 22 hours. The dark brown solution was dissolved in dichloromethane (20 ml), washed with 1 M sodium hydroxide solution (20 ml), 1 M hydrochloric acid solution (20 ml), brine (20 ml), dried over sodium sulfate and evaporated under reduced pressure. The crude was subject to flash chromatography (eluant: c-hexane/ethyl acetate 9:1 to 7:3) to afford 20 mg (7% of theory) of 5-fluoro-1,3-dimethyl-1H-pyrazole-4-carboxylic acid [1-fluoromethyl-2-(2,4,6-trichlorophenyl)-ethyl]-methoxy-amide as a brown oil.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[CH:5]=[CH:4][NH:3]1.Br[CH2:17][CH2:18]Br.C(=O)([O-])[O-:21].[Cs+].[Cs+]>C(#N)C>[OH:21][CH2:17][CH2:18][N:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:7]=2)[C:2]1=[O:1]
Reactant: COC(=O)c1ccc2cc[nH]c(=O)c2c1
Reactant: O=C([O-])[O-]
Reactant: BrCCBr
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)c1ccc2ccn(CCO)c(=O)c2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 65.2 %

Procedure:
To a solution of methyl 1-oxo-1,2-dihydroisoquinoline-7-carboxylate (1.26 g, 6.2 mmol) dissolved in acetonitrile (100 mL) was added 1,2-dibromoethane (5.3 mL, 62 mmol) and cesium carbonate (8.1 g, 24.8 mmol). The reaction mixture was stirred at rt for 1 d. The mixture was then concentrated, diluted with water and extracted with EtOAc (2×). The combined organic phases were then washed with water, and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (50% to 100% EtOAc/hexanes) to afford methyl 2-(2-hydroxyethyl)-1-oxo-1,2-dihydroisoquinoline-7-carboxylate (1.0 g, 65%). LC-MS: (FA) ES+ 248.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].C(N(CC)CC)C.[F:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1>C1COCC1.C1(C)C=CC=CC=1>[F:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:19])=[C:2]([C:1]#[N:5])[C:3]#[N:4])=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: N#CCC#N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: N#CC(C#N)=C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.1 %

Procedure:
To a solution of malononitrile (30 mmol) and triethylamine (36 mmol) in THF/toluene (40 mL, 1:1) at 0° C. was slowly added 4-fluorobenzoyl chloride (30 mmol). The resulting reaction mixture was stirred at room temperature for 2 hours. After concentration under reduced pressure, the crude residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio of 1:30), yielding the pure title compound (5.2 g, 93%) as a yellowish oil. MS (m/z) 189.2 [M+H]+ (100%). δH (300 MHz, CDCl3, 25° C.) 10.61 (br s, 1H), 7.80 (dd, J 8.7, 5.4 Hz, 2H), 7.06 (t, J 8.7 Hz, 2H).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@H:5]([C:7]([OH:9])=O)[CH2:4][S:3]1.Cl.[CH3:11][C@H:12]([NH2:18])[CH2:13][O:14][N+:15]([O-:17])=[O:16].C(N(CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>O1CCCC1>[CH3:11][C@H:12]([NH:18][C:7]([C@@H:5]1[CH2:4][S:3][C:2](=[O:1])[NH:6]1)=[O:9])[CH2:13][O:14][N+:15]([O-:17])=[O:16]
Reactant: O=C1N[C@H](C(=O)O)CS1
Reactant: C[C@H](N)CO[N+](=O)[O-]
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@@H](CO[N+](=O)[O-])NC(=O)[C@@H]1CSC(=O)N1
Yield: 94.2 %

Procedure:
In 60 ml of dry tetrahydrofuran were suspended 2.06 g of (4R)-2-oxothiazolidine-4-carboxylic acid and 2.00 g of (1S)-1-methyl-2-nitroxyethylamine hydrochloride, 4.5 ml of triethylamine and 3.00 ml of diphenylphosphoryl azide were added thereto with stirring under ice-cooling, and the mixture was stirred at room temperature for 5 hours. Then, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography employing cyclohexane-ethyl acetate (1:4) as an eluent to obtain 3.00 g of colorless crystals. The crystals were recrystallized from ethyl acetate to obtain 0.964 g of the desired compound as colorless needle crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH2:9])=[CH:4][CH:3]=1.[CH:10](=O)[CH2:11][CH2:12][CH3:13]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][CH2:10][CH2:11][CH2:12][CH3:13])=[CH:4][CH:3]=1
Reactant: CCCC=O
Reactant: NCc1ccc(Cl)cc1
Product: CCCCNCc1ccc(Cl)cc1
Yield: 40.2 %

Procedure:
Following a procedure analogous to that for the synthesis of Example 106, (4-chlorophenyl)methanamine (750 mg, 5.30 mmol) and butyraldehyde (480 μL, 5.30 mmol) were converted to the title compound (421 mg, 40%). 1H NMR (CDCl3) δ 7.55 (d, J=8.4 Hz, 2H), 7.41-7.34 (m, 2H), 3.98 (s, 2H), 2.78-2.70 (m, 2H), 1.79 (td, J=7.7, 15.6 Hz, 2H), 1.36 (qd, J=7.4, 15.1 Hz, 2H), 0.95-0.88 (m, 4H); MS(ESI+) m/z 198.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][C@H:12]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(Cl)Cl>C(N(CC)CC)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:11][C@H:12]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC[C@H](N)C(=O)OCC
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(Br)cc1)C(=O)OCC
Reaction time: 8 h

Procedure:
To a mixture of 0.92 g of of 4-bromobenzoyl chloride and 1.0 g of diethyl L-glutamate in 50 ml to dry methylene chloride is added 1.16 ml of triethylamine. The reaction mixture is stirred overnight under nitrogen. After a standard workup, the methylene chloride solution is concentrated under reduced pressure, and the residue recrystallized from hexanes to give 0.68 g (46%) of analytically pure diethyl N-(4-bromobenzoyl)-L-glutamate as a white solid: m.p. 82.5°-83.5° C.; NMR (CDCl3, 300 MHz) delta 1.26 (t, 3H, J=6.9 Hz), 1.33 (t, 3H, J=6.9 Hz), 2.11°-2.60 (m, 4H), 4.14 (q, 2H, J=6.9 Hz), 4.27 (q, 2H, J=6.9 Hz) 4.78 (m, 1H), 7.14 (d, 1H, J=7.2 Hz), 7.61 (d, 2H, J=8.4 Hz), 7.73 (d, 2H, J= 8.4 Hz); IR (KBr) 3320, 2980, 1745, 1720, 1635, 1520, 1375, 1300, and 1200 cm-1.