Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:3][C@H:4]([OH:26])[C@@H:5]([NH:13][C:14]([C@@H:16]([NH:21][C:22](=[O:25])[O:23][CH3:24])[C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.FC(F)(F)C(O)=O.[CH3:41][C@@H:42]([CH2:65][CH3:66])[C@H:43]([N:47]1[CH2:51][CH2:50][N:49]([CH2:52][C:53]2[N:54]=[C:55]([C:58]3[CH:63]=[CH:62][CH:61]=CN=3)[S:56][CH:57]=2)[C:48]1=[O:64])[C:44]([OH:46])=O.CCOP(O[N:76]1N=NC2C=CC=CC=2[C:77]1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH2:6]([C@H:5]([NH:13][C:14]([C@@H:16]([NH:21][C:22](=[O:25])[O:23][CH3:24])[C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[C@@H:4]([OH:26])[CH2:3][C@@H:2]([NH:1][C:44](=[O:46])[C@@H:43]([N:47]1[CH2:51][CH2:50][N:49]([CH2:52][C:53]2[N:54]=[C:55]([C:58]3[CH:77]=[N:76][CH:61]=[CH:62][CH:63]=3)[S:56][CH:57]=2)[C:48]1=[O:64])[CH:42]([CH3:41])[CH2:65][CH3:66])[CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@@H](N)Cc1ccccc1)C(C)(C)C
Reactant: CC[C@H](C)[C@@H](C(=O)O)N1CCN(Cc2csc(-c3ccccn3)n2)C1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CCC(C)[C@@H](C(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)N1CCN(Cc2csc(-c3cccnc3)n2)C1=O
Temperature: 25 °C
Reaction time: 64 h
Yield: 83.1 %

Procedure:
A solution containing the product from Example 8B (0.275 g, 0.56 mmol) in THF (6 mL) was treated with the product from Example 3L (0.227 g, 0.61 mmol), DEPBT (0.275 g, 0.92 mmol), and N,N-diisopropylethylamine (0.55 mL, 3.16 mmol), stirred at 25° C. for 64 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-100% ethyl acetate/dichloromethane, followed by elution with 5% methanol in ethyl acetate to give the title compound (0.378 g, 77% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.67 (d, J=6.62 Hz, 3 H), 0.80 (m, 14 H), 0.94 (m, 1 H), 1.29 (m, 1 H), 1.49 (m, 2 H), 1.78 (m, 1 H), 2.42 (m, 1 H), 2.68 (m, 3 H), 2.86 (m, 1 H), 3.13 (m, 4 H), 3.58 (m, 4 H), 3.89 (m, 2 H), 4.12 (m, 2 H), 4.47 (s, 2 H), 4.79 (d, J=5.52 Hz, 1 H), 6.80 (d, J=9.19 Hz, 1 H), 7.07 (m, 7 H), 7.52 (m, 2 H), 7.57 (s, 1 H), 7.82 (d, J=8.82 Hz, 1 H), 8.29 (m, 1 H), 8.66 (dd, J=4.78, 1.84 Hz, 1 H), 9.13 (d, J=1.47 Hz, 1 H).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[NH2:10][CH2:11][CH2:12][C:13]1[N:17]=[CH:16][NH:15][CH:14]=1.[F:18][C:19]1[C:20]([C:43](O)=[O:44])=[CH:21][C:22]2[N:26]=[C:25]([C:27]3[CH:32]=[C:31]([C:33]4[C:34]([O:39][CH3:40])=[N:35][CH:36]=[CH:37][CH:38]=4)[CH:30]=[CH:29][C:28]=3[OH:41])[NH:24][C:23]=2[CH:42]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1.CN(C=O)C>[F:18][C:19]1[C:20]([C:43]([NH:10][CH2:11][CH2:12][C:13]2[N:17]=[CH:16][NH:15][CH:14]=2)=[O:44])=[CH:21][C:22]2[N:26]=[C:25]([C:27]3[CH:32]=[C:31]([C:33]4[C:34]([O:39][CH3:40])=[N:35][CH:36]=[CH:37][CH:38]=4)[CH:30]=[CH:29][C:28]=3[OH:41])[NH:24][C:23]=2[CH:42]=1
Reactant: NCCc1c[nH]cn1
Reactant: COc1ncccc1-c1ccc(O)c(-c2nc3cc(C(=O)O)c(F)cc3[nH]2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ncccc1-c1ccc(O)c(-c2nc3cc(C(=O)NCCc4c[nH]cn4)c(F)cc3[nH]2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N,N-Diisopropylethylamine (4.6 mL, 26.4 mmol) and histamine.2HCl (1.16 g, 6.3 mmol) were successively added to a solution of acid 9a (2.3 g, 6 mmol) and HBTU (2.5 g, 6.6 mmol) in THF (70 mL) and DMF (35 mL). The reaction mixture was stirred at room temperature for 18 h and the solvent was evaporated in vacuo. Water (35 mL) was added to the residue and the fine precipitate was collected by filtration and suspended in methanol/water (1/1, 100 mL). The suspension was stirred at room temperature for 14 h and the solid was collected by filtration and dried in vacuo at 40° C. for 14 h to afford the desired 6-fluoro-N-[2-(1H-imidazol-4-yl)ethyl]-2-[2-hydroxy-5-(2-methoxypyridin-3-yl)phenyl] 1H-benzimidazole-5-carboxamide (10a) as a colorless solid. 1H NMR (DMSO-d6) δ 13.79-11.28 (br s, 2H), 8.45-8.16 (m, 3H), 7.94-7.91 (m, 2H), 7.69-7.51 (m, 3H), 7.17-7.11 (m, 2H), 6.88 (s, 1H), 3.92 (s, 3H), 3.59-3.48 (m, 2H), 2.79 (t, J=6.6 Hz, 2H). ES-MS MH+ 473.48. EA was in agreement with the formula C25H21FN6O3.0.75H2O.
Reaction SMILES: [H-].[Na+].[CH2:3]([SH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CS(O)(=O)=O.[C:16]([C:20]1([CH2:28]O)[CH2:25][O:24][C:23]([CH3:27])([CH3:26])[O:22][CH2:21]1)([CH3:19])([CH3:18])[CH3:17].O>CN(C)C=O>[CH2:3]([S:10][CH2:28][C:20]1([C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:21][O:22][C:23]([CH3:27])([CH3:26])[O:24][CH2:25]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC1(C)OCC(CO)(C(C)(C)C)CO1
Reactant: SCc1ccccc1
Agent: CS(=O)(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)OCC(CSCc2ccccc2)(C(C)(C)C)CO1

Procedure:
Sodium hydride (1.25 g., 50% dispersion in oil) was added to a stirred solution of benzyl mercaptan (3.2 ml.) in dry dimethylformamide (75 ml) at 0°, under a current of nitrogen. Stirring was maintained for 30 minutes. 5-t-Butyl-2,2-dimethyl-5-hydroxymethyl-1,3-dioxane methanesulphonate (7.5 g.) was added and the mixture was maintained at 130°, with stirring for 7 hours. The reaction mixture was cooled and poured into water. The aqueous mixture was extracted with diethyl ether. The ethereal extracts were washed with water, dried over anhydrous magnesium sulphate and then evaporated in vacuo. 5-Benzylthiomethyl-5-t-butyl-2,2-dimethyl-1,3-dioxane (7.0 g.) was obtained as a mobile oil and was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:9])[CH2:4][CH2:5][CH:6]([CH3:8])[CH:7]=1.[Cl-].[Cl-].[Cl-].[Al+3].C=[CH:15][C:16](=[CH2:18])[CH3:17].[C:19]1(C)C=CC=CC=1>>[CH3:8][CH:6]1[CH:7]2[C:2]([CH3:19])([CH2:1][CH:15]=[C:16]([CH3:18])[CH2:17]2)[C:3](=[O:9])[CH2:4][CH2:5]1
Reactant: Cc1ccccc1
Reactant: CC1=CC(C)CCC1=O
Reactant: C=CC(=C)C
Agent: [Al+3]
Agent: [Cl-]
Product: CC1=CCC2(C)C(=O)CCC(C)C2C1

Procedure:
2,4-Dimethyl-2-cyclohexen-1-one (40 g, 0.32 mmol), Aluminium trichloride (10.7 g, 0.08 mmol), Isoprene (326 g, 4.8 mol), Toluene (500 ml)
Reaction SMILES: Br.[Br:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)=[O:5].[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O1CCCC1>[BrH:2].[O:5]=[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)[CH2:3][N+:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: c1ccncc1
Reactant: O=C(CBr)c1ccccn1
Agent: Br
Solvent: C1CCOC1
Product: O=C(C[n+]1ccccc1)c1ccccn1
Temperature: 25 °C

Procedure:
5 g of 2-bromoacetylpyridine hydrobromide and 7 cm3 of pyridine are introduced into a three-necked flask containing 50 cm3 of tetrahydrofuran. The stirring is maintained for 2 days at room temperature and then the precipitate formed is filtered, washed with 30 cm3 of tetrahydrofuran and then dried at 40° C. under reduced pressure (90 Pa) to give 6.9 g of 1-[2-oxo-2-(2-pyridyl)ethyl]pyridinium hydrobromide in the form of a beige solid which is used as it is.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:10]([NH2:16])=[CH:11][C:12]([Br:15])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C:19](OC)(OC)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[CH2:1]([N:8]1[C:9]2[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:10]=2[N:16]=[C:19]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(OC)(OC)c1ccccc1
Reactant: Nc1cc(Br)ccc1NCc1ccccc1
Solvent: ClCCl
Product: Brc1ccc2c(c1)nc(-c1ccccc1)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
p-TsOH-H2O (311.7 mg, 1.606 mmol) was added to a DCM (50 ml) solution of N1-benzyl-4-bromobenzene-1,2-diamine (4451 mg, 16.06 mmol) and trimethyl orthobenzoate (3096 μl, 17.66 mmol) and the resulting mixture was stirred at rt under an atmosphere of Nitrogen for 40 h. The reaction mixture was then concentrated in vacuo to give a yellow solid which was triturated with 40% MeOH/water (375 mL), filtered, washed with saturated NaHCO3 (20 ml)+H2O (80 ml) twice and 40% MeOH/H2O (2×50 ml), and dried to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm =5.44 (s, 2 H), 7.05-7.08 (m, 3 H), 7.30-7.36 (m, 4 H), 7.44-7.50 (m, 3 H), 7.66-7.68 (m, 2 H) and 7.99 (dd, 1 H, J=0.4 & 1.6 Hz). MS(ES+): m/z 363.20 and 365.26[MH+].
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:11]=[C:12]([O:20][C:21]3[C:28]([CH3:29])=[CH:27][C:24]([C:25]#[N:26])=[CH:23][C:22]=3[CH3:30])[C:13]3[N:18]([CH3:19])[CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:5][CH:4]=1)#[N:2].C1C(=O)N([Cl:38])C(=O)C1>C(Cl)Cl>[Cl:38][C:16]1[C:14]2[N:15]=[C:10]([NH:9][C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[N:11]=[C:12]([O:20][C:21]3[C:22]([CH3:30])=[CH:23][C:24]([C:25]#[N:26])=[CH:27][C:28]=3[CH3:29])[C:13]=2[N:18]([CH3:19])[CH:17]=1
Reactant: Cc1cc(C#N)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc2ccn(C)c12
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: Cc1cc(C#N)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc2c(Cl)cn(C)c12
Yield: 51.3 %

Procedure:
To a solution of 4-(2-(4-cyanophenylamino)-5-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-yloxy)-3,5-dimethylbenzonitrile (21.5 mg, 0.06 mmol) in CH2Cl2 (3 mL) was added NCS (7.3 mg, 0.06 mmol) and the resultant mixture was refluxed for 16 h. After completion of the reaction, the solvent was concentrated and purified by preparative TLC, eluting with Hexanes:Ethyl acetate (3:1), to give the product as a light yellow solid (13.2 mg, 56%).
Reaction SMILES: [CH2:1]([NH2:5])/[CH:2]=[CH:3]/[CH3:4].Cl.Br[CH2:8][C:9]([O:11][CH3:12])=[O:10].CCN(CC)CC>C(#N)C>[CH2:1]([NH:5][CH2:8][C:9]([O:11][CH3:12])=[O:10])/[CH:2]=[CH:3]/[CH3:4]
Reactant: C/C=C/CN
Reactant: COC(=O)CBr
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C/C=C/CNCC(=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.8 %

Procedure:
A suspension of (E)-2-buten-1-amine.HCl (5.37 g, 49.9 mmol) (Chem. Ber., 1984;117:1250) in acetonitrile (100 mL) was treated with methyl bromoacetate (4.72 mL, 49.9 mmol) and Et3N (14.0 mL, 99.8 mmol) and stirred at room temperature for 1 hour. The suspension was then heated at reflux overnight. Solution occurred at reflux temperature. After cooling, the precipitated Et3NHCl was filtered off and the solvent removed under reduced pressure leaving 5.0 g of the crude product. Chromatography on silica gel, eluting with CHCl3/MeOH (98:2) gave 1.41 g (19.8% yield) of the pure product as an oil.
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2].C(=O)(O)[O-].[Na+].Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18]>O.C(OCC)(=O)C>[C:1]([NH:4][CH:5]1[CH2:10][CH2:9][N:8]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)Cl
Reactant: CC(=O)NC1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)N1CCC(NC(C)=O)CC1
Temperature: 25 °C
Yield: 103.2 %

Procedure:
A solution of 4-acetamidopiperidine (20.7 g), sodium bicarbonate (10.6 g) and water (300 ml) was cooled to 0° C., and 17.7 g of ethyl chloroformate was added dropwise, with stirring. Upon completion of the addition, the reaction mixture was allowed to warm to ambient temperature and was diluted with water and ethyl acetate. The layers were separated, and the organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated to give 32.2 g (100%) of product.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH:19]=O)=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:21]=1.[CH2:23]1[CH:27]([OH:28])[CH2:26][NH:25][CH2:24]1>>[Br:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[CH:11]3[CH2:10][CH:9]([CH2:12]3)[N:8]3[C:13]([CH2:19][N:25]4[CH2:24][CH2:23][CH:27]([OH:28])[CH2:26]4)=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:21]=1
Reactant: NC(=O)c1nc2n(c1C=O)C1CC(C1)c1cc(F)c(Br)cc1-2
Reactant: OC1CCNC1
Product: NC(=O)c1nc2n(c1CN1CCC(O)C1)C1CC(C1)c1cc(F)c(Br)cc1-2

Procedure:
10-bromo-9-fluoro-3-formyl-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide (75 mg) was reacted with DL-3-hydroxypyrrolidine similarly to as described in the synthesis of 9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-3-[(4-methylpiperazin-1-yl)methyl]-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide to afford 10-bromo-9-fluoro-3((3-hydroxypyrrolidin-1-yl)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide which was directly reacted with 2-Methyl-3-butyne-ol via
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15]S(C3C=CC(C)=CC=3)(=O)=O)=[C:11]([C:26]3[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:36][C:37]([CH3:41])=[CH:38][CH2:39]O.N>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH2:39][CH:38]=[C:37]([CH3:41])[CH3:36])=[C:11]([C:26]3[CH:27]=[CH:28][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:30][CH:31]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2c(-c3ccc(S(C)(=O)=O)cc3)cnn(-c3ccc(F)cc3)c2=O)cc1
Reactant: CC(C)=CCO
Agent: N
Product: CC(C)=CCOc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)cc2)c1=O

Procedure:
The title compound was prepared according to the method of Example 335, substituting 2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-(3-chlorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting 3-methyl-2-buten-1-ol in place of isobutanol (yield: 0.1284 g, 88%). mp 128-132° C. 1H NMR (300 MHz, DMSO d6) δ 1.58 (s, 3H), 1.67 (s, 3H), 3.30 (s, 3H), 4.95 (d, J=7 Hz, 2H), 5.31 (m, 1H), 7.38 (m, 2H), 7.65 (m, 2H), 7.89 (m, 2H), 8.06 (m, 2H), 8.18 (s, 1H). MS (DCI/NH3) m/z 429 (M+H)+, 446 (M+NH4)+. Anal calc. for C22H21FN2O4S: C, 61.67; H, 4.94; N, 6.54. Found: C, 61.41; H, 4.95; N, 6.47.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4](C)[C:5](=O)OC(C)(C)C.N1C=CC=CC=1.[C:19]([Cl:26])(=[O:25])[O:20][CH2:21][CH2:22][O:23][CH3:24].O>C(OCC)(=O)C>[ClH:26].[C:19](=[O:25])([O:1][CH2:2][CH2:3][NH:4][CH3:5])[O:20][CH2:21][CH2:22][O:23][CH3:24]
Reactant: CN(CCO)C(=O)OC(C)(C)C
Reactant: COCCOC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CNCCOC(=O)OCCOC
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.1 %

Procedure:
To a mixture of tert-butyl 2-hydroxyethyl(methyl)carbamate (1.75 g) obtained in Reference Example 1 and ethyl acetate (20 mL) was added pyridine (1.62 mL) and a solution (5 mL) of 2-methoxyethyl chlorocarbonate (2.77 g) in ethyl acetate was dropwise added slowly, and the mixture was stirred overnight at room temperature. After concentration of the reaction mixture under reduced pressure, water (50 mL) was added, the mixture was extracted with ethyl acetate (50 mL). The mixture was washed with 5% aqueous citric acid solution (50 mL) and saturated brine (50 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in diethyl ether (2 mL), and a 4N hydrogen chloride-ethyl acetate solution (5 mL) was added. After stirring at room temperature for 30 min., diethyl ether (10 mL) was added, and the mixture was stirred overnight. The precipitated solid was collected by filtration, and dried under reduced pressure to give the title compound (1.56 g) as a white solid.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[F:25]C1N=C(F)N=C(F)N=1>C(Cl)Cl>[CH:1]1([CH2:6][C@@H:7]([C:8]([F:25])=[O:9])[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CC1CCCC1)C(=O)O
Reactant: Fc1nc(F)nc(F)n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C[C@@H](CC1CCCC1)C(=O)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (2R)-2-(cyclopentylmethyl)-4-[(1,1-dimethylethyl)oxy]-4-oxobutanoic acid (Tetrahedron, 2001, 57(36), 7675-7683) (4.0 g, 15.60 mmol) in DCM was added pyridine (1.38 ml, 17.2 mmol) and a solution of 2,4,6-trifluoro-1,3,5-triazine (2.3 g, 17.2 mmol) in DCM (10 mL). The reaction was stirred at room temperature for 2 h. The solution was then washed with citric acid (20 mL×2) and brine (20 mL), then concentrated to provide the crude product, 1,1-dimethylethyl (3R)-3-(cyclopentylmethyl)-4-fluoro-4-oxobutanoate, as a yellow oil (3.8 g, 57% yield), which was used directly in the next step. MS: 257 ([M−H]+).
Reaction SMILES: [CH:1]1[CH:9]=[CH:8][C:7]2[CH2:10][CH2:11][N:5]3[C:6]=2[C:2]=1[C@H:3]1[CH2:15][NH:14][CH2:13][CH2:12][C@H:4]13.[CH:16]1([C:19](Cl)=[O:20])[CH2:18][CH2:17]1>C(Cl)Cl.CCN(CC)CC>[CH:16]1([C:19]([N:14]2[CH2:13][CH2:12][C@H:4]3[N:5]4[CH2:11][CH2:10][C:7]5[CH:8]=[CH:9][CH:1]=[C:2]([C:6]4=5)[C@H:3]3[CH2:15]2)=[O:20])[CH2:18][CH2:17]1
Reactant: c1cc2c3c(c1)[C@H]1CNCC[C@H]1N3CC2
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(C1CC1)N1CC[C@@H]2[C@H](C1)c1cccc3c1N2CC3
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(±)-cis-4,5,6a,7,8,9,10,10a-octahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole from Example 3 (0.050 g, 0.25 mmol) was dissolved in CH2Cl2 (5 mL) with Et3N (0.75 mL) and cooled to 0° C. The cyclopropanecarbonyl chloride (0.026 g, 0.26 mmol) was then added dropwise. The solution was stirred at 0° C. for 1 h and then warmed to room temperature and stirred for 1 h. The reaction mixture was partitioned between water and CHCl3(3×15 mL) and the layers separated. The aqueous layer was extracted with CHCl3. The combined organics were washed with brine, H2O and dried (Na2SO4) and evaporated affording a light yellow liquid which was further purified by preparatory silica gel TLC (5% MeOH/CH2Cl2). The title compound was isolated as a clear colorless liquid (0.042 g, 65%). 1H NMR (CD3OD, 300 MHz) δ 7.22–7.58 (m, 3H), 4.62–4.75 (m, 1H), 3.85–4.30 (m, 5H), 3.55–3.62 (m, 2H), 1.9–2.18 (m, 3H), 0.75–0.9 (m, 4H) ppm.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:13][N:14]1[C:18](B2OC(C)(C)C(C)(C)O2)=[CH:17][CH:16]=[N:15]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>CO.O>[CH3:13][N:14]1[C:18]([C:2]2[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:3]=2[NH2:4])=[CH:17][CH:16]=[N:15]1
Reactant: Nc1ccc(C(F)(F)F)cc1Br
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: Cn1nccc1-c1cc(C(F)(F)F)ccc1N
Yield: 13.4 %

Procedure:
A round-bottom flask was charged with 2-bromo-4-(trifluoromethyl)aniline (4.115 g, 17.14 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (4.64 g, 22.29 mmol), potassium phosphate (10.92 g, 51.4 mmol), and Pd(AmPhos)2Cl2 (0.607 g, 0.857 mmol). Dioxane (30 mL) and water (10 mL) were added to give a thick suspension. The flask was fitted with a reflux condenser and placed in a 90° C. oil bath for 4 h. The mixture was removed from the heat, then diluted with water and extracted with EtOAc (3×). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The residue was partially purified twice by chromatography on silica gel, first with 25 to 75% EtOAc/Heptane, then with 20 to 70% EtOAc/Heptane. The partially purified material thus obtained was dissolved in methanol and loaded onto a 10 g SCX-2 ion exchange column. The column was eluted with methanol, then with 2N ammonia in methanol. The basic fractions were combined and concentrated to give 2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)aniline (0.5526 g, 2.291 mmol, 13.36% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ=7.52 (d, J=1.9 Hz, 1 H), 7.43 (ddd, J=0.5, 2.3, 8.6 Hz, 1 H), 7.26 (d, J=1.9 Hz, 1 H), 6.88 (d, J=8.5 Hz, 1 H), 6.32 (d, J=1.9 Hz, 1 H), 5.62 (s, 2 H), 3.64 (s, 3 H). m/z (ESI) 242.2 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[N:5]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][N:13]=2)[N:4]=1.C([Sn](CCCC)(CCCC)[C:24]1[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:32])[F:31])=[N:28][CH:29]=1)CCC.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>CN1C(=O)CCC1>[Cl:18][C:17]1[C:12]([N:5]2[C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:7][C:3]([CH2:2][C:24]3[CH:29]=[N:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[N:4]2)=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: COC(=O)c1cc(CBr)nn1-c1ncccc1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C(F)(F)F)nc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: CN1CCCC1=O
Product: COC(=O)c1cc(Cc2ccc(C(F)(F)F)nc2)nn1-c1ncccc1Cl
Reaction time: 1 h

Procedure:
Under argon, 0.8 g (2.36 mmol) of methyl 3-(bromomethyl)-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylate, 1.18 g (2.60 mmol) of 5-(tributylstannyl)-2-(trifluoromethyl)pyridine, 0.11 g (0.47 mmol) of tri-2-furylphosphine and 0.07 g (0.07 mmol) of tri(dibenzylideneacetone)dipalladium were stirred in NMP at 100° C. for 2 h. The solvent was distilled off under reduced pressure, and the residue was taken up in 80 ml of ethyl acetate and stirred vigorously with 70 ml of saturated potassium fluoride solution for 60 min. The organic phase was separated off, washed once with saturated sodium chloride solution, dried over sodium sulphate and concentrated using a rotary evaporator. The desired product was obtained by chromatographic purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([OH:9])[N:3]=1.S(=O)(=O)(O)O.[N+:15]([O-])([O-:17])=[O:16].[K+]>C(OCC)C>[CH3:1][C:2]1[C:7]([N+:15]([O-:17])=[O:16])=[C:6]([CH3:8])[N:5]=[C:4]([OH:9])[N:3]=1
Reactant: Cc1cc(C)nc(O)n1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCOCC
Product: Cc1nc(O)nc(C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.5 %

Procedure:
4,6-Dimethylpyrimidin-2-ol (10.0 g, 80.6 mmol) was added to sulfuric acid (80 mL) at 0° C. Then potassium nitrate (16.29 g, 161.1 mmol) was added to the reaction mixture at 0° C. The mixture was stirred at room temperature for 24 hr. The reaction mixture was poured slowly into diethyl ether at 0° C. The precipitated solid was collected by filtration and washed with diethyl ether. A suspension of the solid in ethanol (500 mL) was neutralized with sodium hydrogen carbonate at room temperature. The solid was removed by filtration and the filter cake was washed with ethanol. The filtrate was concentrated in vacuo to give the title compound (13.15 g) as a pale yellow solid.
Reaction SMILES: CN(C1C2C[C@@H]3C(C(=O)C=2C(O)=CC=1)=C(O)[C@@]1(O)[C@H]([C@H](N(C)C)C(O)=C(C(N)=O)C1=[O:18])C3)C.C[C@]1(O)[C@@H]2C(=C(O)[C@]3(O)C(=O)C(C(N)=O)=C(O)[C@@H](N(C)C)[C@@H]3C2)C(=O)C2C(O)=CC=C(Cl)C1=2.C[C@@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](NC(N)=N)[C@@H](O)[C@@H]2NC(N)=N)[C@H](O[C@@H]2O[C@@H](CO)[C@H](O)[C@@H](O)[C@@H]2NC)[C@@]1(O)C=O.CC[O:109][C:110]([C@@H:112]([NH:120]C(C1C=CC=CC=1)=O)[CH2:113][CH2:114][CH2:115][N:116]=[C:117](N)[NH2:118])=[O:111]>>[NH2:120][C@H:112]([C:110]([OH:109])=[O:111])[CH2:113][CH2:114][CH2:115][NH:116][C:117]([NH2:118])=[O:18]
Reactant: CCOC(=O)[C@H](CCCN=C(N)N)NC(=O)c1ccccc1
Reactant: CN(C)c1ccc(O)c2c1C[C@H]1C[C@H]3[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]3(O)C(O)=C1C2=O
Agent: CN(C)[C@@H]1C(O)=C(C(N)=O)C(=O)[C@@]2(O)C(O)=C3C(=O)c4c(O)ccc(Cl)c4[C@@](C)(O)[C@H]3C[C@@H]12
Agent: CN[C@@H]1[C@H](O[C@H]2[C@H](O[C@H]3[C@H](O)[C@@H](O)[C@H](NC(=N)N)[C@@H](O)[C@@H]3NC(=N)N)O[C@@H](C)[C@]2(O)C=O)O[C@@H](CO)[C@H](O)[C@H]1O
Product: NC(=O)NCCC[C@H](N)C(=O)O

Procedure:
Inhibition constants were determined for minocycline, chlortetracycline, and streptomycin using standard kinetic analyses. Briefly, the compounds were incubated in Reaction Buffer containing various concentrations of BAEE (0-20 mM) for 10 minutes at 37° C. PAD4 (0.2 μM) was then added to initiate the reaction and allowed to proceed for 6 additional minutes. Reactions were then quenched by flash freezing in liquid N2 and the amount of Cit produced was quantified. The data obtained for streptomycin, minocycline and chlortetracycline were fit to equations 2 and 3,