Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]([OH:5])([OH:4])(=[O:3])=[O:2].[NH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]([NH2:16])=[NH:15].CC(C)=O.O.[CH3:22][C:23]1([CH3:31])[C:27](=[O:28])[O:26][C:25]([CH:29]=[CH2:30])=[N:24]1.[OH-].[Na+:33]>>[S:1]([O-:5])([O-:4])(=[O:3])=[O:2].[Na+:33].[C:25]([NH:24][C:23]([CH3:31])([CH3:22])[C:27]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]([NH2:16])=[NH2+:15])=[O:28])(=[O:26])[CH:29]=[CH2:30]
Reactant: O=S(=O)(O)O
Reactant: C=CC1=NC(C)(C)C(=O)O1
Reactant: N=C(N)NCCCCCCN
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: C=CC(=O)NC(C)(C)C(=O)NCCCCCCNC(N)=[NH2+]
Product: O=S(=O)([O-])[O-]
Temperature: 10 °C
Reaction time: 1 h

Procedure:
Aminohexylguanidine sulfate (32.4 g, 127 mmol) was dissolved in 120 mL of aqueous 1.00 N NaOH. Acetone (60 mL) was then added and the stirred mixture was cooled to about 10° C. in a cold water bath. An additional 60 mL of H2O was added to keep the aminohexylguanidine sulfate in solution. 4,4-dimethyl-2-vinyl-1,3-oxazol-5(4H)-one (17.6 g, 137 mmol) was then added to the reaction mixture, via an addition funnel, over a period of 10 min. After stirring an additional 60 min, the reaction mixture was placed on a rotary evaporator at ambient temperature. After pulling off most of the acetone, the reaction mixture was transferred to a separatory funnel and washed with ethyl acetate (2×75 mL) and methylene chloride (2×25 mL). The remaining aqueous solution was brought to pH 7 by addition of dilute sulfuric acid and then placed on a rotary evaporator at ambient temperature to draw off any remaining volatiles. Lyophilization yielded the title compound (49 g) as a white powder 1H NMR (500 MHz, D2O) δ 6.37 (m, 1H), 6.25 (m, 1H), 5.84 (m, 1H), 3.26-3.24 (m, 4H), 1.68-1.38 (m, 14H). This monomer (0.71 grams), MBA (0.07 grams), PEG400MA (0.28 grams), and photoinitiator (31.2 μL of the photoinitiator solution of Example 14) were dissolved in enough methanol to provide 5 grams of coating solution. Primed membranes were coated, grafted, washed and dried as described in Example 1. Static and dynamic capacities for the grafted membrane were 110 and 71 mg/mL, respectively.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]1[C:16](=[O:17])[C:15]2[CH:18]=[C:19]([CH2:21][CH3:22])[S:20][C:14]=2[NH:13][C:12]1=[O:23])(C(C)(C)C)(C)C.Br[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:38]2[N:42]=[C:41](C(Cl)(Cl)Cl)[O:40][N:39]=2)=[CH:28][CH:27]=1.CN(C)C=[O:50].[H-].[Na+]>C(OCC)(=O)C>[CH2:21]([C:19]1[S:20][C:14]2[N:13]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[C:38]4[NH:42][C:41](=[O:50])[O:40][N:39]=4)=[CH:28][CH:27]=3)[C:12](=[O:23])[N:11]([CH2:10][CH2:9][OH:8])[C:16](=[O:17])[C:15]=2[CH:18]=1)[CH3:22]
Reactant: ClC(Cl)(Cl)c1nc(-c2ccccc2-c2ccc(CBr)cc2)no1
Reactant: CCc1cc2c(=O)n(CCO[Si](C)(C)C(C)(C)C)c(=O)[nH]c2s1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCc1cc2c(=O)n(CCO)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 50 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
To a mixture of 3-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-6-ethylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.14 g), 3-[4′-(bromomethyl)biphenyl-2-yl]-5-(trichloromethyl)-1,2,4-oxadiazole (0.22 g) and N,N-dimethylformamide (10 mL) was added sodium hydride (0.02 g), and the mixture was stirred at 50° C. for 1 hr. The reaction mixture was diluted with ethyl acetate, washed successively with 5% aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. To the obtained residue was added 1N aqueous sodium hydroxide solution (50 mL), and the mixture was stirred at 60° C. for 1 hr. The reaction mixture was adjusted to pH 4 with 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography, and dissolved in tetrahydrofuran (10 mL). Tetrabutylammonium fluoride (1.0M tetrahydrofuran solution, 0.6 mL) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.07 g, 37%).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:14]=[N:15][CH:16]=[C:11]2[C:10]([CH2:25][OH:26])=[C:9]1[CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.[C:43](O)(=[O:45])[CH3:44].C(=O)([O-])O.[Na+]>O1CCCC1.O>[C:43]([O:26][CH2:25][C:10]1[C:11]2[C:12](=[C:13]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:14]=[N:15][CH:16]=2)[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]=1[CH3:27])(=[O:45])[CH3:44]
Reactant: Cc1c(CO)c2cnnc(OCc3ccccc3)c2n1Cc1ccccc1
Reactant: CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)OCc1c(C)n(Cc2ccccc2)c2c(OCc3ccccc3)nncc12

Procedure:
A solution of 1.65 g (4.59 mmol) of 1-benzyl-7-benzyloxy-3-hydroxymethyl-2-methylpyrrolo [2,3-d]pyridazine, 3.8 g (18.6 mmol) of dicyclohexylcarbodiimide and 1.6 ml (27.4 mmol) of glacial acetic acid in 50 ml of anhydrous tetrahydrofuran is stirred at room temperature for 18 h. The solution is then treated with 50 ml of water, rendered neutral with saturated sodiumhydrogen carbonate solution and extracted with 3×50 ml of dichloromethane. The organic extracts are washed with 50 ml of water, dried over magnesium sulfate and concentrated. The residue which remains is chromatographed on silica gel (eluent: ethyl acetate). After crystallization from diisopropyl ether, 1.3 g (71%) of the title compound are isolated. M.p.: 121°-122° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH:21](OCC)(OCC)OCC>C(O)=O>[C:15]1([CH2:14][CH2:13][N:12]2[C:11]3[C:10]4[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=4[N:4]=[CH:3][C:2]=3[N:1]=[CH:21]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Nc1cnc2ccccc2c1NCCc1ccccc1
Reactant: CCOC(OCC)OCC
Solvent: O=CO
Product: c1ccc(CCn2cnc3cnc4ccccc4c32)cc1

Procedure:
Using the method of Example 31, 3-amino-4-[2-(phenyl)ethylamino]quinoline was reacted with triethyl orthoformate and formic acid to provide 1-[2-(phenyl)ethyl]-1H-imidazo[4,5-c]quinoline, m.p. 105°-108° C.
Reaction SMILES: [NH2:1][CH:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:3]1([N:8]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1.[CH3:29][C:30]1[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[C:31]=1[C:32](Cl)=[O:33].C(N(CC)CC)C>C(Cl)Cl>[C:10]1([CH2:9][N:8]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:3]2([CH:2]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[NH:1][C:32](=[O:33])[C:31]3[C:35]([CH3:39])=[CH:36][CH:37]=[CH:38][C:30]=3[CH3:29])[CH2:7][CH2:6][CH2:5][CH2:4]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NC(c1ccccc1)C1(N(Cc2ccccc2)Cc2ccccc2)CCCC1
Reactant: Cc1cccc(C)c1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(C)c1C(=O)NC(c1ccccc1)C1(N(Cc2ccccc2)Cc2ccccc2)CCCC1
Yield: 80 %

Procedure:
The title compound (2.51 g; 80%) was prepared from (±)-{1-[amino(phenyl)methyl]cyclopentyl}bis(phenylmethyl)amine D33 (2.31 g; 6.23 mmol), 2,6-dimethyl benzoyl chloride (1.15 g; 6.85 mmol), triethylamine (1.73 ml; 12.5 mmol) in DCM (70 ml) in a similar manner to that described in E13. 1H NMR (CDCl3) δ: 1.40-2.05 (8H, m), 2.28 (6H, s), 3.68 (4H, s), 5.37 (1H, d), 6.78 (1H, m), 6.95-7.36 (16H, m), 7.45 (2H, m); Mass Spectrum (Electrospray LC/MS), API+: Found 503 (MH+). C35H38N2O requires 502. Ret. time 3.77 min.
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][CH3:17])[C:11]=2[C:18]#[C:19][C:20]2[C:21]([CH2:27][CH3:28])=[N:22][C:23]([NH2:26])=[CH:24][CH:25]=2)=[CH:6][C:5]=1[F:29].[OH-].[Na+]>C1COCC1.O>[NH2:26][C:23]1[N:22]=[C:21]([CH2:27][CH3:28])[C:20]([C:19]#[C:18][C:11]2[C:12]([CH2:16][CH3:17])=[N:13][CH:14]=[CH:15][C:10]=2[C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:30])=[O:2])=[C:5]([F:29])[CH:6]=2)=[CH:25][CH:24]=1
Reactant: CCc1nc(N)ccc1C#Cc1c(-c2ccc(C(=O)OC)c(F)c2)ccnc1CC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCc1nc(N)ccc1C#Cc1c(-c2ccc(C(=O)O)c(F)c2)ccnc1CC

Procedure:
The title compound is synthesized according to general procedure GP4 starting from 944 mg (2.34 mmol) 4-[3-(6-Amino-2-ethyl-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-fluoro-benzoic acid methyl ester (A-43) using 3.5 mL (3.5 mmoL) 1N NaOH in 25 mL THF. The reaction mixture is diluted with water and the product extracted with DCM. The organic phase is separated and the solvent removed under reduced pressure. The crude product is used without further purification. Yield: 945 mg (>100%).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:29])[CH2:15][C@@H:16]([C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)[C:17]1[CH:21]=[CH:20][O:19][N:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrC[CH2:32][CH2:33][Br:34].[C:35](=O)([O-])[O-].[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:29])[CH2:15][C@@H:16]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:35][CH:33]([Br:34])[CH3:32])=[CH:24][CH:23]=1)[C:17]1[CH:21]=[CH:20][O:19][N:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(C[C@@H](c1ccc(O)cc1)c1ccon1)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: O=C([O-])[O-]
Reactant: BrCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: O
Product: CC(Br)COc1ccc([C@H](CC(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)c2ccon2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.1 %

Procedure:
A mixture of 7.5 (200 mg, 0.51 mmol), 1,3-dibromopropane (1.00 mL, 10 mmol), potassium carbonate (210 mg, 1.500 mmol) and tetrabutylammonium bromide (16 mg, 0.051 mmol) in water (6.0 mL) was heated to reflux and stirred for two hours. The mixture was then cooled to room temperature and extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine and dried over magnesium sulfate. The filtrate was concentrated under reduced pressure and the residue was recrystallized with EtOAc and hexanes to obtain 48.1 (160 mg). MS ESI (pos.): m/e 514.0 (M+H).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:11][CH:12]=[C:13]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)=[CH:6][CH:5]=1.S(C1C=[CH:29][C:27](C)=[CH:26]C=1)([O-])(=O)=O.[OH2:31]>CN(C)C=O>[CH:27]1([NH:11][CH2:10][CH:7]([OH:31])[CH2:6][O:3][C:4]2[CH:5]=[CH:6][C:7]([C:10]3[NH:11][CH:12]=[C:13]([C:15]4[S:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)=[CH:8][CH:9]=2)[CH2:26][CH2:29]1
Reactant: Oc1ccc(-c2nc(-c3cccs3)c[nH]2)cc1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OC(CNC1CC1)COc1ccc(-c2nc(-c3cccs3)c[nH]2)cc1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
A solution of IV (6.80 g., 0.031 m.) in pyridine (12 ml.) is cooled to 10° C. and p-toluenesulfonyl chloride (5.91 g., 0.031 m) is added over 30 minutes, keeping temperature below 25° C. After stirring at 25° C. for 3 hours, a cold solution of K2CO3 (4.28 g., 0.031 m.) in H2O (28 ml.) is added and the mixture is extracted with CHCl3 (3×50 ml.). The extracts are washed with H2O, dried and concentrated under reduced pressure below 50° C., initially using water aspiration and finally high vacuum to yield the tosylate a (11.27 g., 97%). Sodium hydride (1.39 g., 0.029 m., 50% dispersion in mineral oil) is added to a solution of 2-(p-hydroxyphenyl)-4-(2-thienyl)imidazole (7.00 g., 0.029 m.) in dimethylformamide (50 ml.) under nitrogen and the mixture is heated at 60° C. for 30 minutes. A solution of the tosylate (11.27 g., 0.030 m.) in dimethylformamide (45 ml.) is added and the mixture is refluxed for 16 hours. The reaction mixture is poured into H2O (300 ml.) and extracted with ether (3×150 ml.). The combined organic layers are extracted with cold 1N HCl (3×75 ml.) and the acid layer added to sodium acetate (18.5 g., 0.23 m.) an stirred at 25° C. for 5 hours. The solution is extracted with ether (2X), basified with saturated Na2CO3 solution, extracted with 10% MeOH-CHCl3 (3×150 ml.), 150 ml.), dried and concentrated under reduced pressure. The residue is chromatographed on silica gel and eluted with 5% MeOH-CHCl3 saturated with NH3. The product VII is crystallized from CH3CN (0.43 g., mp 169°-171.5° C.).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[CH3:11][N+:12]([CH3:14])=[CH2:13].[I-]>C1COCC1.CCOC(C)=O>[CH3:11][N:12]([CH2:14][C:8]1[N:6]2[CH:7]=[C:2]([I:1])[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1)[CH3:13]
Reactant: Ic1ccc2nccn2c1
Reactant: C=[N+](C)C
Agent: [I-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C)Cc1cnc2ccc(I)cn12
Yield: 135.3 %

Procedure:
A stirred solution of 6-iodoimidazo[1,2-a]pyridine (2.0 g, 8.2 mmol) and Eschenmoser's salt (5.0 g, 2.7 mmol) in THF (50 mL) was heated to reflux for 24 h. The reaction mixture was then diluted with EtOAc (50 mL), washed with water (3×20 mL), dried (MgSO4), filtered and concentrated in vacuo. The residual solid was triturated from Et2O, collected by filtration and dried to give the title compound (1.1 g, 45%) as a brown powder. δH (DMSO-d6) 8.67 (1H, m), 7.45 (1H, s), 7.43-7.41 (2H, m), 3.72 (2H, s), 2.14 (6H, s). LCMS (ES+) 302.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:19]2[N:23]=[C:22]([C:24]([NH:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=3)=[O:25])[O:21][N:20]=2)[CH:5]=[C:6]([Cl:18])[C:7]=1[O:8]CC1C=CC(OC)=CC=1.[F:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][C:37]=1[C:45]([F:48])([F:47])[F:46].N1C=CC=CC=1>ClCCl.CC([O-])=O.CC([O-])=O.[Cu+2]>[Cl:1][C:2]1[CH:3]=[C:4]([C:19]2[N:23]=[C:22]([C:24]([NH:26][CH2:27][C:28]3[CH:29]=[CH:30][C:31]([O:34][C:39]4[CH:40]=[CH:41][C:36]([F:35])=[C:37]([C:45]([F:48])([F:47])[F:46])[CH:38]=4)=[CH:32][CH:33]=3)=[O:25])[O:21][N:20]=2)[CH:5]=[C:6]([Cl:18])[C:7]=1[OH:8]
Reactant: COc1ccc(COc2c(Cl)cc(-c3noc(C(=O)NCc4ccc(O)cc4)n3)cc2Cl)cc1
Reactant: OB(O)c1ccc(F)c(C(F)(F)F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(NCc1ccc(Oc2ccc(F)c(C(F)(F)F)c2)cc1)c1nc(-c2cc(Cl)c(O)c(Cl)c2)no1
Temperature: 25 °C
Reaction time: 24 h
Yield: 70.8 %

Procedure:
3-(3,5-Dichloro-4-(4-methoxybenzyloxy)phenyl)-N-(4-hydroxybenzyl)-1,2,4-oxadiazole-5-carboxamide (compound G, 60 mg, 0.12 mmol), 4-fluoro-3-(trifluoromethyl)phenylboronic acid (50 mg, 0.24 mmol), Cu(OAc)2 (44 mg, 0.24 mmol) and 3 Å powdered molecular sieves (70 mg) were stirred in an open tube in dichloromethane (3 mL). Pyridine (57 mg, 0.72 mmol) was added and the dark green suspension stirred vigorously at room temperature in an open tube for 1 d. The molecular sieves were filtered, washed with dichloromethane and the filtrate concentrated in vacuo. The residue was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (0.3 mL) was added. The dark solution was stirred at room temperature for 5 h, then methanol (1 mL) was added and the solution concentrated in vacuo. The residue was purified by preparative HPLC providing the title compound (46 mg, 0.085 mmol, 71%). 1H NMR δ (ppm) (DMSO-d6): 4.53 (2H, d, J=6.20 Hz), 7.06-7.13 (2H, m), 7.36-7.48 (4H, m), 7.53-7.60 (1H, m), 8.01 (2H, s), 10.03 (1H, t, J=6.20 Hz), 11.20 (1H, s). LCMS (10 cm_esci_Bicarb_MeCN) tR 3.48 min; m/z 540/542/544 [M−H]−.
Reaction SMILES: Cl[C:2]1[NH:3][CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[Br:10][C:11]1[CH:12]=[CH:13][C:14]2[O:18][C:17](=[O:19])[N:16]([CH2:20][C:21]3([CH3:24])[CH2:23][O:22]3)[C:15]=2[CH:25]=1.C([O-])(=O)C.[Na+].[H-].[Na+]>C(O)C>[Br:10][C:11]1[CH:12]=[CH:13][C:14]2[O:18][C:17](=[O:19])[N:16]([CH2:20][C:21]3([CH3:23])[O:22][C:2]4=[N:6][C:5]([N+:7]([O-:9])=[O:8])=[CH:4][N:3]4[CH2:24]3)[C:15]=2[CH:25]=1
Reactant: O=[N+]([O-])c1c[nH]c(Cl)n1
Reactant: CC1(Cn2c(=O)oc3ccc(Br)cc32)CO1
Agent: CC(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CC1(Cn2c(=O)oc3ccc(Br)cc32)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 75 °C
Reaction time: 17 h
Yield: 21.1 %

Procedure:
A mixture of 2-chloro-4-nitro-1H-imidazole (3.22 g, 21.8 mmol), 5-bromo-3-(2-methyloxiran-2-ylmethyl)-3H-benzoxazol-2-one (6.2 g, 21.8 mmol); sodium acetate (1.97 g, 24 mmol) and ethanol (50 ml) was stirred under reflux for 8 hours. The reaction mixture was allowed to return to room temperature and concentrated under reduced pressure. To the residue, water was added, and the resulting solution was extracted with methylene chloride. The organic phase was dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was dissolved in 1,4-dioxane (60 ml). To the solution, sodium hydride (528 mg, 13.21 mmol) was added followed by stirring at 70-80° C. for 17 hours. The reaction mixture was allowed to return to room temperature and concentrated under reduced pressure. To the residue, water was added, extracted with methylene chloride. The organic phase was dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=30/1) to afford 5-bromo-3-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)-3H-benzoxazol-2-one (1.82 g, yield 37%) as a white powder.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([OH:11])=[CH:8][C:7]([CH3:12])=[N:6][C:5]=2[N:4]([CH2:13][CH3:14])[N:3]=1.[CH2:15]=O.[ClH:17].[CH3:18][NH:19][CH3:20]>CN(C)C=O>[ClH:17].[CH3:18][N:19]([CH2:15][C:8]1[C:7]([CH3:12])=[N:6][C:5]2[N:4]([CH2:13][CH3:14])[N:3]=[C:2]([CH3:1])[C:10]=2[C:9]=1[OH:11])[CH3:20]
Reactant: CNC
Reactant: CCn1nc(C)c2c(O)cc(C)nc21
Reactant: C=O
Agent: Cl
Solvent: CN(C)C=O
Product: CCn1nc(C)c2c(O)c(CN(C)C)c(C)nc21
Yield: 70.9 %

Procedure:
28.7 g. of 3,6-dimethyl-1-ethyl-1H-pyrazolo[3,4-b]pyridin-4-ol (0.15 mol.), 6.75 g. of paraformaldehyde (0.22 mol.) and 13.5 g. of dimethylamine hydrochloride (0.165 mol.) suspended in 400 ml. dimethylformamide is reacted and worked up according to the procedure of Example 6 to obtain 5-[(dimethylamino)methyl]-3,6-dimethyl-1-ethyl-1H-pyrazolo[3,4-b]pyridin-4-ol, hydrochloride (1:1) yield 30.3 g. (71%), m.p. 242°-245°.
Reaction SMILES: C[CH2:2][N:3]=[C:4]=NCCCN(C)C.Cl.[NH2:13][C:14]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](O)=[O:17].CNC.C1COCC1>ClCCl.ON1C2C=CC=CC=2N=N1>[NH2:13][C:14]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([N:3]([CH3:4])[CH3:2])=[O:17]
Reactant: Nc1c(C(=O)O)cccc1[N+](=O)[O-]
Reactant: CCN=C=NCCCN(C)C
Agent: CNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)C(=O)c1cccc([N+](=O)[O-])c1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.8 %

Procedure:
EDC.HCl (2.47 g, 12.88 mmol) was added to a stirred mixture of 2-amino-3-nitrobenzoic acid (2.18 g, 11.98 mmol) (Mickelson, J. Med. Chem., 39(23) 4662 (1996)), 2M dimethylamine in THF (6.45 ml, 12.9 mmol) and 1-hydroxybenzotriazole (0.1 g, 0.74 mmol) in dichloromethane (100 ml). The reaction mixture was stirred at room temperature for 18 h, washed with saturated aqueous sodium bicarbonate and the organic layer dried (Na2SO4) and evaporated in vacuo to afford the title compound as a pale orange gum (2.5 g, 100%).
Reaction SMILES: [F:1][C:2]([F:37])([CH3:36])[C@H:3]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[N:19]([CH3:27])[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])[CH3:4].FC(F)(F)C(O)=O.C(N)CN>ClCCl>[F:37][C:2]([F:1])([CH3:36])[C@H:3]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[N:19]([CH3:27])[N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])[CH3:4]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)C(C)(F)F
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)C(C)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 0.1 %

Procedure:
In a round-bottomed flask, 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-2,2-difluoro-1-methyl-propyl)-amide (105 mg, 197 mmol) was dissolved in dichloromethane (1 ml) and trifluoroacetic acid (0.6 ml, 7.9 mmol) was added. The reaction mixture was stirred at room temperature for 2 h then concentrated. The residue was dissolved in dichloromethane (1 ml) and ethylenediamine (0.8 ml, 11.8 mmol) was added. The reaction was stirred at room temperature for 1 h then quenched with water and diluted with ethyl acetate. The resulting suspension was filtered, washed with hot water and ethyl acetate and dried under high vacuum to provide 48 mg (61%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-2,2-difluoro-1-methyl-propyl)-amide as an off-white powder. MS: (M+H)+=403; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.85 (br. s., 1H), 9.12 (s, 1H), 8.51 (s, 1H), 8.45 (dd, J=8.9, 5.5 Hz, 1H), 8.32 (d, J=9.8 Hz, 1H), 7.69 (dd, J=9.8, 2.3 Hz, 1H), 7.10 (td, J=9.1, 1.9 Hz, 1H), 4.56-4.80 (m, 1H), 4.15 (s, 3H), 1.72 (t, J=19.3 Hz, 3H), 1.37 (d, J=6.8 Hz, 3H).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:14])[CH:12]=2)[N:7]([NH:15][C:16]([C:18]2[C:19]([CH3:30])=[N:20][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[N:22][CH:23]=2)=[O:17])[CH:6]=1)=[O:4].[OH-].[K+]>CO.O.CCOC(C)=O>[F:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]([NH:15][C:16]([C:18]1[C:19]([CH3:30])=[N:20][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[N:22][CH:23]=1)=[O:17])[CH:6]=[C:5]2[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1cn(NC(=O)c2cnc(-c3ccccn3)nc2C)c2ccc(F)cc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1nc(-c2ccccn2)ncc1C(=O)Nn1cc(C(=O)O)c2cc(F)ccc21
Yield: 19.2 %

Procedure:
A solution of 5-fluoro-1-[(4-methyl-2-pyridin-2-yl-pyrimidine-5-carbonyl)-amino]-1H-indole-3-carboxylic acid methyl ester (2.6 mmol) in MeOH (10 mL) is treated with an aqueous solution of KOH (500 mg, 8.9 mmol) in H2O (200 mL) and heated at reflux for 2 h. The mixture is diluted with EtOAc (50 mL) and extracted with 1% aqueous KOH (3×50 mL). The combined aqueous layer is neutralized with HCl (conc.), and the precipitate is collected by filtration and dried in vacuo to afford 5-fluoro-1-[(4-methyl-2-pyridin-2-yl-pyrimidine-5-carbonyl)-amino]-1H-indole-3-carboxylic acid (195 mg, 19%, 3 steps). MS: 392 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 12.44 (s, OH, 1H), 12.31 (s, NH, 1H), 9.31 (s, 1H), 8.81 (d, 1H), 8.48 (d, 1H), 8.35 (s, 1H), 8.03 (m, 1H), 7.77 (m, 1H), 7.62 (m, 2H), 7.19 (m, 1H), 2.79 (s, 3H).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([CH2:20][O:21][CH3:22])[N:16]=2)[CH2:11][C:12](O)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:36][OH:37]>O1CCCC1>[NH3:16].[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([CH2:20][O:21][CH3:22])[N:16]=2)[CH2:11][C:12]([NH:36][OH:37])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COCc1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Reactant: NO
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COCc1noc([C@H](CCCC2CCCCC2)CC(=O)NO)n1
Product: N
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.9 %

Procedure:
A solution of (3R)-6-cyclohexyl-3-[3-(methoxymethyl)-1,2,4-oxadiazol-5-yl]hexanoic acid (Preparation 49) (250 mg, 0.81 mmol) in anhydrous tetrahydrofuran (10 ml) was treated with 1,1′-carbonyldiimidazole (130 mg, 0.81 mmol) and the mixture stirred at room temperature under a nitrogen atmosphere for 2 hours. Hydroxylamine hydrochloride (56 mg, 0.81 mmol) was then added and the mixture stirred for 18 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol:0.88 ammonia (95:5:0.5) to afford the title compound as an oil (75 mg).