Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([NH:9][C:10](=[O:13])[O:11][CH3:12])=[N:6][C:7]=1[Br:8].N([O-])=O.[Na+].[ClH:18]>O.Cl[Cu]>[Br:8][C:7]1[N:6]=[C:5]([NH:9][C:10](=[O:13])[O:11][CH3:12])[CH:4]=[CH:3][C:2]=1[Cl:18]
Reactant: Cl
Reactant: COC(=O)Nc1ccc(N)c(Br)n1
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)Nc1ccc(Cl)c(Br)n1
Temperature: 25 °C
Yield: 75 %

Procedure:
To a mixture of methyl 5-amino-6-bromopyridin-2-ylcarbamate (100 mg, 0.41 mmol) and CuCl (120 mg, 1.6 mmol) in HCl (28%, 10 mL) was added and NaNO2 (29 mg, 0.41 mmol) at 0° C. The mixture was stirred at room temperature for 2Hr. The reaction mixture was diluted with water and extracted with ethyl acetate (20 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum to give methyl 6-bromo-5-chloropyridin-2-ylcarbamate (80 mg, 75%). 1H NMR (400 MHz, CDCl3) δ 7.93 (d, J=8.8 Hz, 1H), 7.69 (d, J=8.8 Hz, 1H), 7.38 (brs, 1H), 3.82 (s, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([F:13])=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].C(=O)(O)[O-:15].[Na+]>CS(C)=O>[F:13][C:4]1[C:3]([CH:2]=[O:15])=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cccc(CBr)c1F
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)c1cccc(C=O)c1F
Yield: 64.4 %

Procedure:
A mixture of methyl 3-(bromomethyl)-2-fluorobenzoate (11.5 g, 46.4 mmol) from Step B above and solid sodium bicarbonate (33.0 g, 398.7 mmol) in DMSO (150 mL) was refluxed until the reaction was complete by TLC (2-3 h). The mixture was cooled in an ice bath immediately and then partitioned between brine and ethyl acetate. The combined organics were concentrated and purified by column chromatography (silica gel, 9:1 hexanes/ethyl acetate) to afford methyl 2-fluoro-3-formylbenzoate as a white solid (5.44 g, 64%): 1H NMR (300 MHz, CDCl3) δ 10.43 (s, 1H), 8.21 (t, J=7.8 Hz, 1H), 8.07 (t, J=6.0 Hz, 1H), 7.35 (t, J=7.8 Hz, 1H), 3.93 (s, 3H).
Reaction SMILES: [S:1]([O:11][C:12]1[CH:28]=[CH:27][CH:26]=[C:14]([O:15][S:16]([C:19]2[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[C:13]=1[NH:29][C:30](=[O:32])[CH3:31])([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[N+:33]([O-])([OH:35])=[O:34].S(=O)(=O)(O)O>C(OC(=O)C)(=O)C>[S:1]([O:11][C:12]1[CH:28]=[C:27]([N+:33]([O-:35])=[O:34])[CH:26]=[C:14]([O:15][S:16]([C:19]2[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[C:13]=1[NH:29][C:30](=[O:32])[CH3:31])([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=1)(=[O:3])=[O:2]
Reactant: CC(=O)Nc1c(OS(=O)(=O)c2ccc(C)cc2)cccc1OS(=O)(=O)c1ccc(C)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1c(OS(=O)(=O)c2ccc(C)cc2)cc([N+](=O)[O-])cc1OS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Yield: 76.1 %

Procedure:
A solution of 2-acetamidoresorcinol ditosylate (11.9 g, 0.025 mole) in acetic anhydride (75 ml) was cooled to below 15° C. Meanwhile, nitric acid (1.9 ml, 0.029 mole) was slowly added to cold acetic anhydride (20 ml) with stirring so that the temperature did not exceed 25° C. The nitric acid solution was then added to the cold acetanalide solution. Finally, the sulfuric acid (0.75 ml) was added. The mixture was stirred an additional six hours, during which time the reaction temperature rose to 30° C. The mixture was pured into ice water (1500 ml) and stirred one hour. The resulting precipitate was collected, air dried, and recrystalllized from isopropyl alcohol (100 ml) to yield a tan crystallline solid (9.9 g, 76.0 percent). TLC showed the product to be pure.
Reaction SMILES: C(N[C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][CH:11]=1)[NH2:8])(=O)C.[C:12](NC1C=C(C=CC=1)N)(=[O:15])CC.C(NC1C=C(C=CC=1)N)(=O)CCC.C(NC1C=C(C=CC=1)N)(=O)C1C=CC=CC=1>>[NH2:8][C:7]1[CH:6]=[C:5]([O:15][CH3:12])[CH:11]=[CH:10][CH:9]=1
Reactant: CC(=O)Nc1cccc(N)c1
Reactant: CCC(=O)Nc1cccc(N)c1
Agent: CCCC(=O)Nc1cccc(N)c1
Agent: Nc1cccc(NC(=O)c2ccccc2)c1
Product: COc1cccc(N)c1

Procedure:
m-acetylaminoaniline, m-propionylaminoaniline, m-butyrylaminoaniline or m-benzoylaminoaniline;
Reaction SMILES: [C:1]([Si:5]([CH3:22])([CH3:21])[O:6][C@@H:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C@H:8]1[NH:16][S:17]([CH3:20])(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].[C:23]([O-])([O-])=O.[Cs+].[Cs+].CI.[OH-].[Na+]>CN(C=O)C.C(Cl)Cl>[C:1]([Si:5]([CH3:22])([CH3:21])[O:6][C@@H:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C@H:8]1[N:16]([CH3:23])[S:17]([CH3:20])(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1Cc2ccccc2[C@H]1NS(C)(=O)=O
Agent: [Cs+]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CI
Product: CN([C@@H]1c2ccccc2C[C@H]1O[Si](C)(C)C(C)(C)C)S(C)(=O)=O
Reaction time: 2 h

Procedure:
N-[(1R,2R)-2-(tert-butyl-dimethyl-silanyloxy)-indan-1-yl]-methanesulphonamide (0.50 g) is dissolved in 2 mL DMF and mixed with Cs2CO3 (0.96 g, 2.93 mmol) and MeI (0.10 mL). The reaction mixture is stirred for 2 h and, once the reaction has ended, combined with DCM and NaOH (1 N). The organic phase is dried on MgSO4 and freed from the solvent using the rotary evaporator. After dissolving in acetonitrile water is added. The precipitate formed is filtered off, washed with water and taken up in DCM. After drying on MgSO4 the solvent is eliminated using the rotary evaporator.
Reaction SMILES: N(OC(C)(C)C)=O.N[C:9]1[S:10][C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][C:13]=1[C:14]([O:16][CH3:17])=[O:15]>CN(C)C=O.O>[C:18]1([C:11]2[S:10][CH:9]=[C:13]([C:14]([O:16][CH3:17])=[O:15])[CH:12]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)c1cc(-c2ccccc2)sc1N
Agent: CC(C)(C)ON=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1csc(-c2ccccc2)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of tert-butyl nitrite (428 μL, 3.6 mmol) in N,N-dimethylformamide (5 mL) at 60° C. was dropwise added a solution of methyl 2-amino-5-phenylthiophene-3-carboxylate (11a) (420 mg, 1.8 mmol) in N,N-dimethylformamide (2.5 mL). The mixture was stirred at 60° C. for 1 hour, poured in water (15 mL) and extracted with ethyl acetate (2×20 mL). The organic layer was washed with brine (2×10 mL), dried over sodium sulfate and concentrated in vacuo. The residue was dissolved in toluene (5 mL) and concentrated in vacuo to provide the desired product (11b) (390 mg, 1.8 mmol, 99%) which was used without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:16]=[N:17][C:18]([NH:21][C:22]3[N:27]=[C:26]([C:28]4[CH:40]=[C:39]([F:41])[C:31]5[N:32]=[C:33]([CH3:38])[N:34]([CH:35]([CH3:37])[CH3:36])[C:30]=5[CH:29]=4)[C:25]([F:42])=[CH:24][N:23]=3)=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(Cl)Cl.CO.O1CCOCC1>[F:42][C:25]1[C:26]([C:28]2[CH:40]=[C:39]([F:41])[C:31]3[N:32]=[C:33]([CH3:38])[N:34]([CH:35]([CH3:37])[CH3:36])[C:30]=3[CH:29]=2)=[N:27][C:22]([NH:21][C:18]2[CH:19]=[CH:20][C:15]([CH2:14][N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[CH:16][N:17]=2)=[N:23][CH:24]=1
Reactant: Cc1nc2c(F)cc(-c3nc(Nc4ccc(CN5CCN(C(=O)OC(C)(C)C)CC5)cn4)ncc3F)cc2n1C(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1nc2c(F)cc(-c3nc(Nc4ccc(CN5CCNCC5)cn4)ncc3F)cc2n1C(C)C
Reaction time: 0.17 h
Yield: 96.7 %

Procedure:
To a mixture of 4-{6-[5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-3H-benzoimidazol-5-yl)-pyrimidin-2-ylamino]-pyridin-3-ylmethyl}-piperazine-1-carboxylic acid tert-butyl ester (150 mg) in DCM (10 mL) and methanol (10 mL) add hydrogen chloride 4M in dioxane (194 μL). Stir 10 min and remove the solvent under vacuum. Purify by strong cation exchange cartridge (SCX) eluting with methanol and then methanol-NH3 2M followed by silica gel column chromatography eluting with DCM/methanol-NH3 2M (3%) to afford 120 mg of the title compound. MS (ES+): m/z=479 (M+H)+.
Reaction SMILES: [C:1](OC(OC(C)(C)C)=O)(OC(C)(C)C)=[O:2].[CH:16]([C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22])([CH3:18])[CH3:17].[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][C:37]=1[O:38][CH3:39])[N:34]=[CH:33][N:32]=[C:31]2[N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>ClCCl.CN(C1C=CN=CC=1)C>[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][C:37]=1[O:38][CH3:39])[N:34]=[CH:33][N:32]=[C:31]2[N:40]1[CH2:41][CH2:42][N:43]([C:1]([NH:22][C:21]2[CH:23]=[CH:24][CH:25]=[C:19]([CH:16]([CH3:18])[CH3:17])[CH:20]=2)=[O:2])[CH2:44][CH2:45]1
Reactant: CC(C)c1cccc(N)c1
Reactant: COc1cc2ncnc(N3CCNCC3)c2cc1OC
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1cc2ncnc(N3CCN(C(=O)Nc4cccc(C(C)C)c4)CC3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 63 %

Procedure:
To a solution of 2.05 g (9.39 mmol) of di-tert-butyl dicarbonate in 30 ml of dichloromethane was added 108 mg (0.88 mmol) of 4-(N,N-dimethylamino)pyridine. After the mixture was stirred at room temperature for 5 minutes, 1.26 ml (8.95 mmol) of 3-isopropylaniline was added thereto, followed by further stirring at room temperature for 30 minutes. To the reaction mixture was added 548 mg (2.00 mmol) of 6,7-dimethoxy-4-piperazinylquinazoline obtained by the method described in South African Patent No. 67 06512 (1968), followed by stirring at room temperature for 30 minutes. After the solvent was evaporated, the residue was purified by silica gel chromatography and recrystallized from ethyl acetate to give the desired compound as colorless crystals.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][C@@H:12]([N:14]2[CH2:21][C:20]3[C:16](=[N:17][N:18]([S:22]([CH3:25])(=[O:24])=[O:23])[CH:19]=3)[CH2:15]2)[CH2:11][N:10]([CH2:26][C@@H:27]([OH:29])[CH3:28])[C@@H:9]1[C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[F:37])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C@H:8]1[CH2:13][C@@H:12]([N:14]2[CH2:21][C:20]3[C:16](=[N:17][N:18]([S:22]([CH3:25])(=[O:23])=[O:24])[CH:19]=3)[CH2:15]2)[CH2:11][N:10]([CH2:26][C@@H:27]([OH:29])[CH3:28])[C@@H:9]1[C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[F:37]
Reactant: C[C@H](O)CN1C[C@H](N2Cc3cn(S(C)(=O)=O)nc3C2)C[C@H](NC(=O)OC(C)(C)C)[C@H]1c1cc(F)ccc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](O)CN1C[C@H](N2Cc3cn(S(C)(=O)=O)nc3C2)C[C@H](N)[C@H]1c1cc(F)ccc1F
Reaction time: 1 h

Procedure:
To the product from Step A (18 mg, 0.032 mmol) was added a 1:1 mixture of dichloromethane and trifluoroacetic acid (0.5 mL). The mixture was stirred for 1 h, and the solvent removed in vacuo. The residue was purified by preparative thin layer chromatography (Analtech 1000 μm) and eluted with methanol containing 10% ammonium hydroxide in dichloromethane (10:90) to afford the title compound as a colorless solid. LC/MS 456.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:16]2[CH2:18][CH2:17]2)(O)[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[Cl-].[In+3].[Cl-].[Cl-].[CH3:23][S:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]2[C:34]=1[NH:33][CH:32]=[CH:31]2>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:16]2[CH2:18][CH2:17]2)([C:31]2[C:30]3[C:34](=[C:26]([CH2:25][S:24][CH3:23])[CH:27]=[CH:28][CH:29]=3)[NH:33][CH:32]=2)[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(O)(c1ccc(Cl)cc1)C1CC1
Reactant: CSCc1cccc2cc[nH]c12
Agent: [Cl-]
Agent: [In+3]
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(c1ccc(Cl)cc1)(c1c[nH]c2c(CSC)cccc12)C1CC1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
700 mg (2.61 mmol) of the compound from Example 90A and 576 mg (2.61 mmol) of indium(III) chloride were added to 462 mg (2.61 mmol) of the compound from Example 8A in 11 ml of toluene. The reaction mixture was stirred at 80° C. for 5 h. After cooling to RT, the solid was filtered off through silica gel, and the solvents were removed in a rotary evaporator. Purification of the crude product by preparative HPLC (mobile phase: acetonitrile/water gradient) resulted in 69 mg (6% of theory) of the title compound.
Reaction SMILES: C[C:2]1([C:17](O)=O)[CH2:7][CH2:6][CH:5]([O:8][CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH2:4][CH2:3]1.C1C=CC(P([N:34]=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.[C:37]([OH:41])(C)(C)C>>[N:34]([C:2]1([CH3:17])[CH2:3][CH2:4][CH:5]([O:8][CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:14])([CH3:15])[CH3:16])[CH2:6][CH2:7]1)=[C:37]=[O:41]
Reactant: CC(C)(C)O
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC1(C(=O)O)CCC(OCOCC[Si](C)(C)C)CC1
Product: CC1(N=C=O)CCC(OCOCC[Si](C)(C)C)CC1
Temperature: 25 °C
Yield: 49 %

Procedure:
To a solution of 1-methyl-4-[[2-(trimethylsilyl)ethoxy]methoxy]cyclohexane-1-carboxylic acid (3.1 g, 10.75 mmol, 1.00 equiv) in tert-butanol (40 mL) was added DPPA (5.33 g, 19.37 mmol, 1.80 equiv) and TEA (3.28 g, 32.41 mmol, 3.02 equiv) at room temperature. The resulting solution was heated to reflux overnight and cooled down to room temperature. The reaction was quenched with water and extracted with 3×100 mL of ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/100) to give (2-[[(4-isocyanato-4-methylcyclohexyl)oxy]methoxy]ethyl)trimethylsilane (1.5 g, 49%) as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:12]2[C@H:21]3[C@H:16]([CH2:17][CH:18]=[CH:19][CH2:20]3)[C:15](=[O:22])[NH:14][N:13]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:29](I)[CH3:30].O.CN1C[CH2:37][CH2:36][C:35]1=O>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:12]2[C@H:21]3[C@H:16]([CH2:17][CH:18]=[CH:19][CH2:20]3)[C:15](=[O:22])[N:14]([CH:30]3[CH2:29][CH2:37][CH2:36][CH2:35]3)[N:13]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CCI
Reactant: CCOc1cc(C2=NNC(=O)[C@H]3CC=CC[C@@H]23)ccc1OC
Reactant: CN1CCCC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOc1cc(C2=NN(C3CCCC3)C(=O)[C@H]3CC=CC[C@@H]23)ccc1OC
Temperature: 25 °C

Procedure:
A solution of 0.5 g of compound 6, 0.8 g of K2CO3 and 0.3 g of ethyliodide was stirred in 20 ml of N-methyl-pyrrolidinone for 4 h at 70° C. After cooling to room temperature, the reaction mixture was poured into 200 ml of water and this mixture was extracted with diethyl ether. After drying over magnesium sulfate, the solvent was evaporated and the compound crystallized from methanol, M.p. 124-127° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[NH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[C:35]2[C:39]=1[C:38](=[O:40])[N:37]([CH3:41])[CH:36]2[CH3:42].C([O-])(O)=O.[Na+]>>[CH3:42][CH:36]1[C:35]2[C:39](=[C:31]([NH:30][C:2]3[C:7]([C:8]([F:9])([F:11])[F:10])=[CH:6][N:5]=[C:4]([NH:12][C:13]4[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=4[O:28][CH3:29])[N:3]=3)[CH:32]=[CH:33][CH:34]=2)[C:38](=[O:40])[N:37]1[CH3:41]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Reactant: CC1c2cccc(N)c2C(=O)N1C
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3cccc4c3C(=O)N(C)C4C)n2)c(OC)c1)OCC
Yield: 34.3 %

Procedure:
The title compound was prepared according to the procedure from Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (230.1 mg, 0.5071 mmol) and 7-amino-2,3-dimethyl-2,3-dihydro-1H-isoindol-1-one (Compound 157A, 95.1 mg, 0.540 mmol) in TFE (5 mL). The reaction mixture poured into a separatory funnel containing saturated NaHCO3 and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude was adsorbed onto a pre-filled solid loading cartridge [RediSepRf 2.5 gram] and purified using an ISCO Combiflash unit [RediSepRf 4 gram silica], eluting first with 40-100% EtOAc:Heptane and then 0-15% MeOH:CH2Cl2. The product was purified again by MDP [under basic conditions; ammonium bicarbonate buffer (pH 9)] to afford title product as a white solid (103.1 mg, 34%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.57 (s, 1H), 9.13 (s, 1H), 8.39 (s, 1H), 7.64-8.90 (m, 1H), 7.41 (br s, 2H), 7.18 (d, J=7.3 Hz, 1H), 7.05 (s, 1H), 6.91 (d, J=7.8 Hz, 1H), 4.55 (q, J=6.5 Hz, 1H), 3.91-4.06 (m, 4H), 3.74 (s, 3H), 3.29 (d, J=22.5 Hz, 2H), 2.99 (s, 3H), 1.40 (d, J=6.6 Hz, 3H), 1.20 (t, J=7.1 Hz, 6H). MS (ES+): m/z 594.17 (100) [MH+]. HPLC: tR=1.59 min (TOF, polar—3 min).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([C:6]([OH:8])=O)[CH2:2]1.C(Cl)(=O)[C:10]([Cl:12])=O.[N+](=C)=[N-].Cl>ClCCl.CCOCC>[Cl:12][CH2:10][C:6]([CH:3]1[CH2:4][CH2:5][O:1][CH2:2]1)=[O:8]
Reactant: O=C(O)C1CCOC1
Reactant: O=C(Cl)C(=O)Cl
Agent: C=[N+]=[N-]
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(CCl)C1CCOC1
Yield: 88.1 %

Procedure:
(RS)-3-Tetrahydrofuroic acid (3.48 g) in dichloromethane (40 ml) was treated with oxalyl chloride (11.43 g) as described in Example 1(a). The resultant acid chloride in dichloromethane (40 ml) was then treated with excess diazomethane (60 mM) in ether (100 ml), followed by hydrogen chloride. The solution was washed once with brine, dried and concentrated. Flash chromatography on silica gel, eluting with 40% ethyl acetate/hexane afforded the title compound as a pale yellow oil, (3.924 g, 88%); νmax (CH2Cl2) 1735 and 1716 cm-1 ; 2.17 (2H, dt, J 7.0, 7.5 Hz), 3.47-3.58 (1H, m), 3.77-4.04 (4H, m) and 4.18 (2H, s); [mass spectrum: +ve ion (ammonia) MNH4+ (166)].
Reaction SMILES: [CH2:1]1[C@H:6](N)[C@@H:5](O[C@H]2O[C@H](CN)[C@@H](O)[C@H](O)[C@H]2O)[C@H:4](O)[C@@H:3](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](N)[C@H]2O)[C@@H:2]1[NH2:33].[CH:34]1[C:39]([C@@H:40](O)[C@H:41]([NH:44]C(C(Cl)Cl)=O)[CH2:42][OH:43])=CC=C([N+]([O-])=O)C=1.CC(S[C@@H]1[O:63][C@H](CO)[C@H](O)[C@H](O)[C@H]1O)C>>[NH2:44][C@H:41]([C:42]([OH:63])=[O:43])[CH2:40][C:39]1[C:3]2[C:2](=[CH:1][CH:6]=[CH:5][CH:4]=2)[NH:33][CH:34]=1
Reactant: CC(C)S[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Reactant: O=C(N[C@H](CO)[C@H](O)c1ccc([N+](=O)[O-])cc1)C(Cl)Cl
Reactant: NC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O[C@H]3O[C@H](CO)[C@@H](O)[C@H](N)[C@H]3O)[C@H](N)C[C@@H]2N)[C@H](O)[C@@H](O)[C@@H]1O
Product: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reaction time: 2 h

Procedure:
An overnight culture with the pET30Trp racemase construct was subcultured into fresh LB medium with the appropriate antibiotics (50 μg/mL kanamycin and 20 μg/mL chloramphenicol) and grown to an OD600˜0.6 (37° C. with aeration). Expression was induced with 100 μM IPTG and incubation was continued at 37° C. with aeration for 2 hours. The cells were harvested by centrifugation and stored at −80° C. until use. The cell pellet was thawed on ice and cells were lysed using BugBuster Primary Amine Free Cell Lysis Reagent and Benzonase Nuclease (Novagen, Madison, Wis.). Cell debris was removed by centrifugation and the supernatant was used as the crude protein extract. The crude protein extract was filtered using a 0.45 μm syringe filter and applied to a HisBind column (Novagen, Madison, Wis.) that had been pre-equilibrated according to the manufacturer's instructions. The column was washed and the protein was eluted as directed in the manufacturer's protocol. The purified protein was desalted with a PD-10 column (GE Healthcare, Piscataway, N.J.) using 50 mM potassium phosphate pH 8.0, 10 μM pyridoxal-5′-phosphate (“PLP”) as the eluent. The desalted protein was concentrated using Amicon centrifugal concentrators (Millipore, Billerica, Mass.). Wild-type alanine racemase was purified as described above.
Reaction SMILES: [CH2:1]([N:8]([CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[C:9](=[O:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:19]1[N:24]=[CH:23][C:22]([C:25]2[NH:34][C:33](=[O:35])[C:32]3[C:27](=[CH:28][C:29]([O:38][CH3:39])=[CH:30][C:31]=3[O:36][CH3:37])[N:26]=2)=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([N:8]([CH:12]1[CH2:17][CH2:16][N:15]([C:19]2[CH:20]=[CH:21][C:22]([C:25]3[NH:34][C:33](=[O:35])[C:32]4[C:27](=[CH:28][C:29]([O:38][CH3:39])=[CH:30][C:31]=4[O:36][CH3:37])[N:26]=3)=[CH:23][N:24]=2)[CH2:14][CH2:13]1)[C:9](=[O:11])[CH3:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)N(Cc1ccccc1)C1CCNCC1
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(Cl)nc3)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCC(N(Cc5ccccc5)C(C)=O)CC4)nc3)nc2c1
Yield: 30.4 %

Procedure:
To a solution of N-benzyl-N-(piperidin-4-yl)acetamide (1.5 g, 6.3 mmol) and 2-(6-chloropyridin-3-yl)-5,7-dimethoxyquinazolin-4(3H)-one (1.0 g, 3.2 mmol) in DMF (15 mL) was added K2CO3 (0.875 g, 6.3 mmol) and the reaction was heated at reflux temperature overnight. The resulting mixture was concentrated in vacuo and purified by flash chromatography on silica gel, eluting with 1% to 10% MeOH/CH2Cl2, to afford the title compound (0.500 g, 30%) as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 11.84 (s, 1H), 8.86 (s, 1H), 8.22 (d, J=9.2 Hz, 1H), 7.33-7.37 (m, 1H), 7.14-7.27 (m, 4H), 6.88-6.96 (m, 1H), 6.66 (d, J=1.5 Hz, 1H), 6.46 (d, J=1.5 Hz, 1H), 4.44-4.58 (m, 4.5H), 4.10-4.20 (m, 0.5H), 3.87 (s, 3H), 3.83 (s, 3H), 2.86-2.98 (m, 2H), 2.25 (s, 1.5H), 1.95 (s, 1.5H), 1.45-1.77 (m, 4H). ESI/APCI MS m/z 514 [M+H]+.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:16]2[N:15]=[C:14]([NH2:17])[N:13]3[N:18]=[C:19]([C:21]4[O:22][CH:23]=[CH:24][CH:25]=4)[N:20]=[C:12]3[C:11]=2[CH:10]=[CH:9]1)(=O)=O.Cl.[F:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[C:35]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)=[O:36].CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:17][C:14]1[N:13]2[N:18]=[C:19]([C:21]3[O:22][CH:23]=[CH:24][CH:25]=3)[N:20]=[C:12]2[C:11]2[CH:10]=[CH:9][N:8]([CH2:7][CH2:6][N:40]3[CH2:39][CH2:38][N:37]([C:35]([C:29]4[CH:30]=[CH:31][C:32]([F:34])=[CH:33][C:28]=4[F:27])=[O:36])[CH2:42][CH2:41]3)[C:16]=2[N:15]=1
Reactant: O=C(c1ccc(F)cc1F)N1CCNCC1
Reactant: CS(=O)(=O)OCCn1ccc2c1nc(N)n1nc(-c3ccco3)nc21
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc2c(ccn2CCN2CCN(C(=O)c3ccc(F)cc3F)CC2)c2nc(-c3ccco3)nn12
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To a solution of the title D compound of Example 1, 2-{5-amino-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-7-yl}ethyl methanesulfonate (0.06 g, 0.165 mmol) in dry DMF (5 mL), the title B compound, (2,4-difluorophenyl)piperazin-1-yl-methanone hydrochloride (0.33 mmol) and 0.06 mL of DIEA are added, and the solution is stirred at 100° C. for 5 h. The reaction mixture is cooled to RT, and the solvent is removed under reduced pressure. To the residue, acetonitrile is added and the solution is stirred at 60° C. for 0.5 h. The solution is then cooled to RT, and the resulting solids are collected by filtration to give (4-(2-(5-amino-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-7-yl)ethyl)piperazin-1-yl)(2,4-difluorophenyl)methanone: LC/MS (M+1=493.1). 1H NMR (DMSO-d6, 400 MHz) δ 2.42 (m, 2H), 2.72 (t, 2H, J=6.0 Hz), 3.17 (m, 2H), 3.34 (m, 2H), 3.60 (m, 2H), 4.25 (t, 2H, J=6.0 Hz), 6.59 (d, 1H, J=3.2 Hz), 6.72 (m, 1H), 7.18 (m, 3H), 7.38 (m, 1H), 7.46 (m, 1H), 7.54 (brs, 2H, NH2), 7.93 (s, 1H). Anal. calculated for (C24H22F2N8O2+0.5H2O): C, 57.48; H, 4.62; F, 7.58; N, 22.34; 0, 7.98. Found C, 57.40; H, 4.46; N, 22.29.