Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:19]=[CH:18][C:6]2[CH2:7][C@@H:8]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:9](=[O:12])[NH:10][CH2:11][C:5]=2[CH:4]=1.B(Br)(Br)Br.CO>C(Cl)(Cl)Cl.O.CO>[OH:2][C:3]1[CH:19]=[CH:18][C:6]2[CH2:7][C@@H:8]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:9](=[O:12])[NH:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COC(=O)C[C@@H]1Cc2ccc(OC)cc2CNC1=O
Agent: BrB(Br)Br
Solvent: CO
Solvent: O
Solvent: ClC(Cl)Cl
Product: COC(=O)C[C@@H]1Cc2ccc(O)cc2CNC1=O
Temperature: -8 °C
Reaction time: 0.5 h
Yield: 68.3 %

Procedure:
A solution of methyl (S)-(−)-8-methoxy-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate (15.0 g, 0.057 mole) in CHCl3 (160 mL) was added dropwise over 30 min to a solution of boron tribromide (20.53 mL, 0.217 mole) in CHCl3 (160 mL) at −8° C. under argon, maintaining the temperature between −5° C. and 0° C. The reaction mixture was stirred at ca. −8° C. for 30 min and then MeOH (200 mL) was added, dropwise initially, maintaining the temperature at ca. 0° C. The reaction mixture was concentrated to give a viscous oil which was reconcentrated from MeOH (100 mL). The oil was dissolved in H2O/MeOH and a small amount of dark solid was removed by filtration. The filtrate was neutralized (to pH 7) with 50% sodium hydroxide, depositing a white solid. The suspension pH was adjusted to 4.5 by the addition of a small amount of acetic acid and the solid was collected and dried in vacuum to give afford the title compound (9.7 g, 68%). The product was assayed for chiral purity by HPLC: Chiralpak AS® column (4.6×50 mm), 100% EtOH mobile phase, 0.5 mL/min flow rate, uv detection at 215 nm; tR=7.5 min (S-enantiomer, 99%); tR=4.4 min (R-enantiomer, 1%).
Reaction SMILES: [Cu]C#N.[C:4]([C:6](=[C:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])#[N:5].O1[CH2:29][CH2:28][CH2:27][CH2:26]1>>[C:4]([CH:6]([C:12]1([C:26]2[CH:4]=[CH:6][C:12]([CH3:13])=[C:28]([CH3:29])[CH:27]=2)[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:16][CH2:17]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])#[N:5]
Reactant: C1CCOC1
Reactant: CCOC(=O)C(C#N)=C1CCN(C(=O)OC(C)(C)C)CC1
Agent: N#C[Cu]
Product: CCOC(=O)C(C#N)C1(c2ccc(C)c(C)c2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -50 °C
Reaction time: 0.17 h

Procedure:
3,4-Dimethylmagnesium bromide (250 mL of a 0.5 M solution in tetrahydrofuran, 125 mmol, Rieke Metals, Inc., 3045) was added to a suspension of copper (I) cyanide (5.48 g, 61.2 mmol) in anhydrous tetrahydrofuran (400 mL) under nitrogen at approximately −50° C. After stirring at approximately −50° C. for 10 minutes, the reaction mixture was allowed to warm to ambient temperature over 1 h then recooled to approximately −50° C. A solution of tert-butyl 4-(1-cyano-2-ethoxy-2-oxoethylidene)piperidine-1-carboxylate 8-2 (15.0 g, 51.0 mmol) in tetrahydrofuran (50 mL) was added. After stirring at −50° C. for 3 h, the reaction mixture was warmed to 0° C. and quenched with saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate and the organic layer was washed with brine, dried (magnesium sulfate) and concentrated in vacuo to give compound 8-3 as light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]([Cl:23])[C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([C@@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]2[CH3:16])[C:6]1=[O:17].CCN(CC)CC.[O:31](S(C(F)(F)F)(=O)=O)[S:32]([C:35]([F:38])([F:37])[F:36])(=O)=[O:33].O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:36][C:35]([F:38])([F:37])[S:32]([O:22][C:20]1[CH:19]=[C:18]([Cl:23])[C:3]([CH2:4][CH:5]2[CH2:9][CH2:8][N:7]([C@@H:10]3[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]3[CH3:16])[C:6]2=[O:17])=[C:2]([Cl:1])[CH:21]=1)(=[O:33])=[O:31]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: C[C@H]1CCCC[C@H]1N1CCC(Cc2c(Cl)cc(O)cc2Cl)C1=O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H]1CCCC[C@H]1N1CCC(Cc2c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc2Cl)C1=O
Temperature: 0 °C
Yield: 87.4 %

Procedure:
Dissolve 3-(2,6-dichloro-4-hydroxybenzyl)-1-(cis-2-methylcyclohexyl)pyrrolidin-2-one (1.0 g, 2.81 mmol) in DCM (100 mL) and cool to 0° C. under N2. Add DMAP (0.069 g, 0.56 mmol), Et3N (2.84 g, 28.01 mmol), and Tf2O (0.83 g, 2.95 mmol) at the same temperature. Stir the reaction for six hour and then add water (100 mL). Extract the aqueous layer with dichloromethane (3×100 mL). Combine the organic layers and dry with Na2SO4, filter, concentrate and purify by flash column chromatography (silica gel, 20-50% of EtOAc-Hexane) to give 1.2 g (88%) of the title compound as a colorless oil. 1H NMR (CDCl3) δ 7.28 (s, 2H), 4.02 (m, 1H), 3.46 (m, 2H), 3.38 (m, 1H), 3.02 (m, 1H), 2.91 (m, 1H), 2.35 (m, 1H), 2.02 (m, 1H), 1.31-1.87 (m, 9H), 0.92 (d, 3H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Br[C:9]1[S:10][C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:12]([CH3:14])[N:13]=1.C(N(C(C)C)CC)(C)C>>[NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:9]2[S:10][C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:12]([CH3:14])[N:13]=2)[CH2:4][CH2:3]1
Reactant: NC1CCNCC1
Reactant: CCOC(=O)c1sc(Br)nc1C
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1sc(N2CCC(N)CC2)nc1C
Yield: 87.6 %

Procedure:
The same operation as in Example (237a) was performed using 4-aminopiperidine (0.19 mL, 1.80 mmol), ethyl 2-bromo-4-methylthiazole-5-carboxylate (300 mg, 1.20 mmol) and diisopropylethylamine (0.42 mL, 2.40 mmol), to obtain 283 mg of the title compound as a pale yellow oily substance (88%).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[Cl:9][C:10]1[CH:11]=[C:12]([CH:28]=[CH:29][CH:30]=1)[C:13]([C@@H:15]1[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]1)=[O:14]>C1COCC1>[Cl:9][C:10]1[CH:11]=[C:12]([C:13]2([C@@H:15]3[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])[CH2:16]3)[CH2:4][O:14]2)[CH:28]=[CH:29][CH:30]=1
Reactant: C[S+](C)(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2cccc(Cl)c2)C1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C2(c3cccc(Cl)c3)CO2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
A flame dried 250 mL round bottom flask was charged with sodium hydride (60% in oil, 1.45 g, 36.2 mmol) and trimethyloxosulfonium iodide (8.05 g, 36.5 mmol). The flask was evacuated and refilled with N2. Dry DMSO (50 mL) was added and the mixture was stirred at rt for 1 h. A portion of this solution (14.5 mL, 10.5 mmol, 1.5 equiv) was added by syringe to a 150 mL round bottom flask which had been charged with (R)-tert-butyl 3-(3-chlorobenzoyl)-piperidine-1-carboxylate (2.27 g, 7 mmol) and THF (30 mL) and placed under N2. The resulting mixture was stirred for 1 h at rt. The reaction mixture was quenched with brine and extracted with EtOAc (3×). The combined organic phase was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give (3R)-tert-butyl 3-(2-(3-chlorophenyl)oxiran-2-yl)piperidine-1-carboxylate as a mixture of two isomers (2.32 g, 6.9 mmol, 99% yield), which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3): 1.40 (s, 9H), 1.55-1.72 (m, 3H), 1.85 (m, 1H), 2.01 (m, 1H), 2.35-2.60 (m, 2H), 2.65 (d, 1H), 3.063 (d, 1H), 4.05 (m, 1H), 4.15 (m, 1H), 7.26 (m, 3H), 7.34 (s, 1H); MS (E/Z): 338 (M+H+)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:30](=[O:31])[C:29]3[C:24](=[C:25]([CH3:32])[CH:26]=[CH:27][CH:28]=3)[NH:23][C:22]2=[O:33])[CH2:17][CH2:16]1.[CH3:34]OC1C=C2C(=CC=1OC)N=CN=C2N1CCC(N2C(=O)C3C(=CC=C([N+]([O-])=O)C=3)NC2=O)CC1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:16][CH2:17][CH:18]([N:21]2[C:30](=[O:31])[C:29]3[C:24](=[C:25]([CH3:32])[CH:26]=[CH:27][CH:28]=3)[N:23]([CH3:34])[C:22]2=[O:33])[CH2:19][CH2:20]1
Reactant: COc1cc2ncnc(N3CCC(n4c(=O)[nH]c5c(C)cccc5c4=O)CC3)c2cc1OC
Reactant: COc1cc2ncnc(N3CCC(n4c(=O)[nH]c5ccc([N+](=O)[O-])cc5c4=O)CC3)c2cc1OC
Product: COc1cc2ncnc(N3CCC(n4c(=O)c5cccc(C)c5n(C)c4=O)CC3)c2cc1OC
Yield: 61 %

Procedure:
The procedure similar to that described in Example 1 was repeated, except that 300 mg (0.67 mmol) of 3-[1-(6,7-dimethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-8-methyl-2,4-dioxoquinazoline (Compound 101) obtained in Reference Example 12 was used in place of Compound 24. As a result, 185.2 mg (yield: 61%) of Compound 59 was obtained as white crystals.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:23])[N:4]2[C:8](=[C:9]([C:20](O)=[O:21])[C:10]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=1[F:19])[CH2:7][CH2:6][CH2:5]2.CC1(C)[O:29][C@@H:28]([CH2:30][O:31][NH2:32])[CH2:27][O:26]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.C(N(CC)CC)C.O.CN(C=O)C>[OH:29][C@H:28]([CH2:27][OH:26])[CH2:30][O:31][NH:32][C:20]([C:9]1[C:10]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])=[C:2]([F:1])[C:3](=[O:23])[N:4]2[C:8]=1[CH2:7][CH2:6][CH2:5]2)=[O:21]
Reactant: O=C(O)c1c(Nc2ccc(I)cc2F)c(F)c(=O)n2c1CCC2
Reactant: CC1(C)OC[C@H](CON)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: O
Product: O=C(NOC[C@H](O)CO)c1c(Nc2ccc(I)cc2F)c(F)c(=O)n2c1CCC2
Reaction time: 16 h
Yield: 48.5 %

Procedure:
Example 1 (82 mg, 0.19 mmol), (R)-(2,2-dimethyl-1,3-dioxolan-4-yl)methoxyamine (see Bailey et al., J. Med. Chem., 34, 1991, 51-65; 56 mg, 0.38 mmol), and HOBt (28 mg, 0.21 mmol) were stirred in CH2Cl2 (4 mL) with DMF (0.5 mL) at r.t. EDC (47 mg, 0.25 mmol) and then triethylamine (40 μL, 0.29 mmol) were added, and the reaction stirred for 16 h. The solution was washed with 0.1N HCl and brine, dried (MgSO4), and concentrated in vacuo. The residue was stirred in MeOH (2.0 mL) and water (200 μL) with p-toluensulfonic acid (16 mg, 0.08 mmol) for 4 h. Triethylamine (50 μL) was added, and the solution was concentrated in vacuo. Purification by prep-HPLC gave 48 mg (48%) of the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.50 (s, 1H), 8.04 (s, 1H), 7.57 (d, 1H, J=8.8 Hz), 7.40 (d, 1H, J=8.8 Hz), 6.79 (t, 1H, J=8.8 Hz), 4.00 (t, 2H, J=7.6 Hz), 3.77-3.84 (m, 1H), 3.63-3.68 (m, 2H), 3.28-3.36 (m, 2H), 3.17 (t, 2H, J=7.6 Hz), 2.01-2.09 (m, 2H). MS (ES) [m+H] calc'd for C18H18F2IN3O5, 522. found 522.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-].[CH2:11]([N:14]1[C:20]2=[C:21]3[C:26](=[N:27][C:28]4=[CH:29][CH:30]=[CH:31][C:18](=[C:19]24)[O:17][CH2:16][C:15]1=O)[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH2:12][CH3:13]>O1CCCC1>[CH2:11]([N:14]1[C:20]2=[C:21]3[C:26](=[N:27][C:28]4=[CH:29][CH:30]=[CH:31][C:18](=[C:19]24)[O:17][CH2:16][CH2:15]1)[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH2:12][CH3:13]
Reactant: CCCN1C(=O)COc2cccc3nc4c(c1c23)CCCC4
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CCCN1CCOc2cccc3nc4c(c1c23)CCCC4
Reaction time: 0.08 h
Yield: 71.2 %

Procedure:
To a solution of lithium aluminum hydride in tetrahydrofuran (1.0M, 14.2 ml) and dry tetrahydrofuran (30 ml) was added aluminum chloride (1.89 g) in portions. The mixture was stirred for five mins, 1,3,9,10,11,12-hexahydro-1-propyl-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one (4.2 g) was added, and stirring was continued overnight. The reaction mixture was quenched with ethyl acetate (200 ml), 10% sodium hydroxide solution (200 ml) was added, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was recrystallized from pentane/diethyl ether to yield 2.85 g (71%) of product, mp 74.5°-75.5° C.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].B.C1COCC1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.C(OCC)C>C1COCC1.C(Cl)Cl>[CH2:7]([O:6][P:4]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([CH:14]=[O:15])=[CH:17][CH:18]=1)([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOP(=O)(Cc1ccc(C(=O)O)cc1)OCC
Agent: O=[Cr](=O)([O-])Cl
Agent: B
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOP(=O)(Cc1ccc(C=O)cc1)OCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.5 %

Procedure:
Triethylphosphite (9.28 mL, 53.3 mmol) and α-bromo-p-toluic acid (10.4 g, 48.4 mmol) were suspended in toluene (25 mL) and the mixture was heated to reflux for 18 h. The mixture was cooled to room temperature. After 12 h, the resulting white solid was collected by suction filtration, washed with petroleum ether and dried to yield 4-(diethoxyphosphorylmethyl)benzoic acid as a white solid (10.2 g, 77%): mp 117-120° C.; 1H NMR δ 1.26 (t, J=6.8 Hz, 6H), 3.24 (d, J=25.6 Hz, 2H), 4.06 (m, 4H), 7.38-7.40 (m, 2H), 8.02 (d, J=7.6 Hz, 2H), 11.4 (br s, 1H); 13C NMR δ 16.5, 16.6, 33.4, 34.8, 62.8, 62.9, 129.1, 129.2, 130.00, 130.05, 130.10, 130.48, 130.51, 137.3, 137.4, 170.1; FABMS obsd 273.0896, calcd 273.0892; Anal. Calcd. for C12H17O5P: C, 52.94; H, 6.29. Found: C, 52.92; H, 6.28. A suspension of 4-(diethoxyphosphorylmethyl)benzoic acid (9.99 g, 36.7 mmol) in anhydrous THF (40 mL) at 0° C. was treated dropwise over 10 min with borane-THF complex (40.3 mL, 40.3 mmol, 1.0 M in THF). The reaction mixture was stirred at room temperature for 4 h. The reaction was quenched by slow addition of water. The mixture was concentrated and the residue was partitioned between water (100 mL) and CH2Cl2 (100 mL). The aqueous layer was washed with CH2Cl2. The combined organic layers were washed with water, dried (MgSO4), and concentrated to give a yellow oil. Analysis by TLC and 1H NMR spectroscopy showed starting material (˜10%) and the desired benzyl alcohol. The latter (9.56 g) was dissolved in CH2Cl2 and rapidly added to a sample of PCC (10.8 g, 50.1 mmol) in CH2Cl2 (50 mL) with rapid stirring. After 2 h, ethyl ether (150 mL) was added and the organic solution was decanted from the tarry residue. The residue was washed with ethyl ether (3×50 mL). The combined organic solution was filtered through Florisil and concentrated to a brown oil. Kugelrohr distillation (190° C. @ 0.05 Torr) afforded a clear, colorless oil (6.54 g, 77%): 1H NMR δ 1.24 (t, J=7.2 Hz, 6H), 3.21 (d, J=22.4 Hz, 2H), 4.03 (m, 4H), 7.45-7.48 (m, 2H), 7.83 (d, J=7.6 Hz, 2H), 9.99 (s, 1H); 13C NMR δ 16.1, 16.2, 33.0, 34.9, 62.1, 62.2, 77.2, 129.49, 129.53, 129.6, 129.66, 129.71, 130.2, 130.2, 138.8, 138.9, 191.61, 191.63; 31P NMR δ 25.4, 25.9; FABMS obsd 257.0949, calcd 257.0943 (C12H17PO4).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=4[N:19]([CH3:26])[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O.C1CCCCC1>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=4[N:19]([CH3:26])[N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c2c1CCCC2
Solvent: C1CCCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)c2c1CCCC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 0 %

Procedure:
To a pale yellow solution of N-tert-butyl-2-(1-methyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (25 mg, 51.8 mmol) in dichloromethane (2.00 mL) was added TFA (2.96 g, 2.00 mL, 26.0 mmol, Eq: 501), the reaction mixture turned brown and was stirred at 25° C. for 18 h. The mixture was concentrated and the residue was re-dissolved in 5 mL of a solution of (dichloromethane/MeOH/ammonium hydroxide; 60:10:1) and stirred at 25° C. for 3 h, then evaporated to a light yellow solid, dissolved in dichloromethane (containing a few drops of MeOH) and purified by chromatography (spherical silica 20-45 μm, 23 g, Versaflash Supelco) eluting with 0 to 5% over 15 min (MeOH containing 10% ammonium hydroxide)/dichloromethane. Product isolated as an off-white solid which was sonicated with cyclohexane decanted and then sonicated again with MeOH, decanted and dried to give clean N-tert-butyl-2-(1-methyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (8 mg, 22.7 μmol, 43.8%). MS (M+H)+=353.1; 1H NMR (DMSO-d6) δ: 8.91 (s, 1H), 8.26 (s, 1H), 7.74 (s, 1H), 3.76 (s, 3H), 2.91 (br. s., 2H), 2.64 (br. s., 2H), 1.65-1.84 (m, 4H), 1.45 (s, 9H); LCMS ESI+ TIC MS showed 100% purity, [M+H]+=353.1, [MNa]+=375.0.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][Cl:15])=[CH:7][C:6]=1[F:16])=O.[NH2:17][C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=1>C(O)C>[Cl:15][CH2:14][CH2:13][CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:17]=[C:18]3[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]3[CH:2]=2)=[C:6]([F:16])[CH:7]=1
Reactant: Cc1ccnc(N)c1
Reactant: O=C(CBr)c1ccc(OCCCCl)cc1F
Solvent: CCO
Product: Cc1ccn2cc(-c3ccc(OCCCCl)cc3F)nc2c1
Temperature: 25 °C

Procedure:
A solution of the product of Step B (1.0 g) and 2-amino-4-picoline (0.357 g) in ethanol (4 mL) was heated at 73° C. for 18 hours. The reaction mixture was cooled to ambient temperature and the solvent evaporated in vacuo. A portion of the residue was purified via silica gel chromatography (ethyl acetate/hexane) directly. The remainder of the residue was dissolved in methanol/dichloromethane and treated with Dowex® 550A basic resin (Aldrich, Milwaukee, Wis.) for 10 minutes. The resin was removed via filtration and the filtrate evaporated prior to silica gel chromatography (ethyl acetate/hexane). The combined material (0.42 g) containing the title compound was used without further purification.
Reaction SMILES: [ClH:1].[CH2:2]([N:9]1[C:15](=[O:16])[CH:14]2[N:17](CC3C=CC=CC=3)[CH:11]([CH2:12][CH2:13]2)[C:10]1=[O:25])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N#N>CO.[Pd]>[ClH:1].[CH2:2]([N:9]1[C:10](=[O:25])[CH:11]2[NH:17][CH:14]([CH2:13][CH2:12]2)[C:15]1=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C1C2CCC(C(=O)N1Cc1ccccc1)N2Cc1ccccc1
Agent: [Pd]
Agent: Cl
Agent: N#N
Solvent: CO
Product: O=C1C2CCC(N2)C(=O)N1Cc1ccccc1
Reaction time: 8 h
Yield: 96.5 %

Procedure:
3,8-Dibenzyl-3,8-diazabicyclo[3.2.1]octan-2,4-dione hydrochloride (39 g, 0.11 mol; from step (c) above) was added to a suspension of 10% Pd/C (500 mg) in methanol (500 mL) under a blanket of N2. The N2 atmosphere was exchanged for H2 (one atmosphere of pressure). The reaction was stirred vigorously overnight. The catalyst was removed by filtration and the filtrate concentrated in vacuo to afford 28.3 g (96%) of the sub-title compound as a light tan solid.
Reaction SMILES: ClC(OCC(C)C)=O.[C:9]([OH:22])(=O)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].Cl.[NH2:24][C@H:25]([C:27]([NH:29][C@@H:30]([C:43](=[O:45])[NH2:44])[CH2:31][CH2:32][C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])=[O:28])[CH3:26].C(OCC)(=O)C>C1(C)C=CC=CC=1.C(N(CC)CC)C.O>[C:9]([NH:24][C@H:25]([C:27]([NH:29][C@@H:30]([C:43](=[O:45])[NH2:44])[CH2:31][CH2:32][C:33]([O:35][CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[O:34])=[O:28])[CH3:26])(=[O:22])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: C[C@H](N)C(=O)N[C@H](CCC(=O)OCc1ccccc1)C(N)=O
Reactant: CCCCCCCCCCCC(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCC(=O)N[C@@H](C)C(=O)N[C@H](CCC(=O)OCc1ccccc1)C(N)=O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 15.7 %

Procedure:
Isobutyl chloroformate (2.54 cc) is added to a solution, kept at 0° C., of lauric acid (3.9 g) in anhydrous toluene (156 cc) and triethylamine (2.7 cc). The mixture is stirred for 20 minutes at 0° C. and a solution, cooled to 0° C., of benzyl L-alanyl-D-isoglutaminate hydrochloride (6.7 g) in water (52 cc) and triethylamine (2.7 cc) is then added. The reaction mixture is stirred for 65 hours at a temperature of the order of 20° C. This yields a reaction mixture of gelatinous appearance, to which ethyl acetate (150 cc) is added. The precipitate is filtered off, washed with water (30 cc) and then dried. This yields benzyl N-lauroyl-L-alanyl-D-isoglutaminate (7.6 g) in the form of a white powder. The aqueous phase of the above filtrate is extracted twice with ethyl acetate (100 cc in total), this ethyl acetate phase is combined with the organic phase of the filtrate and the combined phase is washed with 0.1N hydrochloric acid (125 cc) and water (120 cc), dried over magnesium sulphate and then concentrated to dryness under reduced pressure (20 mm Hg) at 50° C. This yields a further amount of benzyl N-lauroyl-L-alanyl-D-isoglutaminate (1.5 g). The product (7.6 g and 1.5 g) is recrystallised from methanol (120 cc). This yields benzyl N-lauroyl-L-alanly-D-isoglutaminate (6.6 g) which melts at 169° C.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.[N:10]([C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1)=[N+:11]=[N-:12].[OH-].[Na+]>C(O)C.O>[N:10]([C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[C:7]2[CH2:8][CH:3]([O:2][CH3:1])[CH2:4][C:5](=[CH:17][C:16]3[CH:19]=[CH:20][C:13]([N:10]=[N+:11]=[N-:12])=[CH:14][CH:15]=3)[C:6]2=[O:9])=[CH:15][CH:14]=1)=[N+:11]=[N-:12]
Reactant: COC1CCC(=O)CC1
Reactant: [N-]=[N+]=Nc1ccc(C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COC1CC(=Cc2ccc(N=[N+]=[N-])cc2)C(=O)C(=Cc2ccc(N=[N+]=[N-])cc2)C1
Yield: 15.6 %

Procedure:
In 100 ml of ethanol were dissolved 10 g of 4-methoxycyclohexanone and 30 g of para-azidobenzaldehyde, after which a solution of 1 g of sodium hydroxide in 1 ml of water was added, and the resulting mixture was subjected to reaction in a brown flask at room temperature for 2 days. The crystals formed were separated by suction filtration, washed with ethanol, and then recrystallized from methyl Cellosolve to obtain 4.7 g of yellow crystals having a decomposition point of 145° to 150° C. (differential thermal analysis, the rate of heating: 5° C./min).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Br[C:7]1[CH:8]=[N:9][C:10]([NH2:13])=[N:11][CH:12]=1.CNC1CCCCC1NC.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[Cu]I>[N:1]1([C:7]2[CH:8]=[N:9][C:10]([NH2:13])=[N:11][CH:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: Nc1ncc(Br)cn1
Reactant: c1cn[nH]c1
Agent: [Cu]I
Agent: CNC1CCCCC1NC
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Nc1ncc(-n2cccn2)cn1

Procedure:
A suspension of 1H-pyrazole (0.42 g, 0.0061 mol), 5-bromopyrimidin-2-amine (1.3 g, 7.3 mmol), copper(I) iodide (58.2 mg, 0.306 mmol), N,N′-dimethylcyclohexane-1,2-diamine (0.193 mL, 1.22 mmol), potassium carbonate (1.77 g, 12.8 mmol) in N,N-dimethylformamide (5.00 mL) was irradiated under microwave at 180° C. for 1 h. After cooling, the mixture was purified by chromatography on silica gel with methanol in methylene chloride (0-10%) to afford the desired product. LCMS: (M+H)=162.1.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C:13]2[S:14][C:15]([C:19]([OH:21])=O)=[C:16]([CH3:18])[N:17]=2)[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6]C=CC=1.C1(CN2CCN(C3SC(C(O)=O)=C(C)N=3)C2=O)CC1.[CH2:42]([NH2:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>>[CH2:42]([NH:49][C:19]([C:15]1[S:14][C:13]([N:10]2[CH2:11][CH2:12][N:8]([CH2:1][CH:2]3[CH2:7][CH2:6]3)[C:9]2=[O:22])=[N:17][C:16]=1[CH3:18])=[O:21])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Reactant: NCc1ccccc1
Agent: Cc1nc(N2CCN(CC3CC3)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(CC3CC3)C2=O)sc1C(=O)NCc1ccccc1
Yield: 26 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with benzylamine, the title compound was obtained as a white powder in 26% yield: mp 142-143° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.36-7.25 (m, 5H), 5.90 (s, 1H), 4.54 (d, J=5.7 Hz, 2H), 4.09 (t, J=8.4 Hz, 2H), 3.67 (t, J=8.4 Hz, 2H), 3.15 (d, J=7.2 Hz, 2H), 2.60 (s, 3H), 0.97-0.86 (m, 1H), 0.58-0.49 (m, 2H), 0.25-0.19 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ 162.4, 157.4, 155.2, 153.0, 137.9, 128.7, 127.8, 127.6, 117.0, 48.6, 44.0, 42.2, 42.1, 17.1, 8.9, 3.4; MS (ES+) m/z 371.1 (M+1).