Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=2[NH:15][C:16](=[O:27])[NH:17][C:18]2[S:19][CH:20]=[C:21]([CH2:23][C:24]([OH:26])=[O:25])[N:22]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:28]N1C(=O)CCC1=O>C(#N)C>[Cl:28][C:20]1[S:19][C:18]([NH:17][C:16]([NH:15][C:9]2[CH:10]=[CH:11][C:12]([CH3:14])=[CH:13][C:8]=2[C:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:7])=[O:27])=[N:22][C:21]=1[CH2:23][C:24]([OH:26])=[O:25]
Reactant: Cc1ccc(NC(=O)Nc2nc(CC(=O)O)cs2)c(C(=O)C2CCCC2)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: Cc1ccc(NC(=O)Nc2nc(CC(=O)O)c(Cl)s2)c(C(=O)C2CCCC2)c1
Reaction time: 2 h
Yield: 23.5 %

Procedure:
To a suspension of {2-[3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid (0.50 g, 1.29 mmol) in 20 ml of acetonitrile was added N-chlorosuccinimide (0.19 g, 1.42 mmol). The reaction mixture was stirred under nitrogen, in a pressure bottle excluded from light, for 2 h at 80° C. The mixture was concentrated under reduced pressure, dissolved in DMSO and purified by preparative HPLC to afford the title compound (0.128 g, 24%).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[N:9][N:10]([CH2:12][C:13]([OH:15])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)C(C)C)(C)C.[Cl:25][C:26]1[CH:27]=[C:28]([CH:38]=[CH:39][C:40]=1[Cl:41])[CH2:29][N:30]1[CH2:35][CH2:34][O:33][C@@H:32]([CH2:36][NH2:37])[CH2:31]1>CN(C)C=O>[Cl:25][C:26]1[CH:27]=[C:28]([CH:38]=[CH:39][C:40]=1[Cl:41])[CH2:29][N:30]1[CH2:35][CH2:34][O:33][C@@H:32]([CH2:36][NH:37][C:13](=[O:15])[CH2:12][N:10]2[N:9]=[N:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:11]2)[CH2:31]1
Reactant: O=C(O)Cn1nnc(-c2ccccc2)n1
Reactant: NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Cn1nnc(-c2ccccc2)n1)NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Temperature: 22 °C
Reaction time: 4 h
Yield: 99.8 %

Procedure:
A solution of (5-phenyl-2H-tetraazol-2-yl)acetic acid (0.082 g) in N,N-dimethylformamide (2 ml) under nitrogen was treated with O-(7-azabenzotriazol-1-yl)-N,N,N′N′-tetramethylammonium hexafluorophosphate (0.152 g) and N,N-diisopropylethylamine (0.139 ml) followed by a solution of Intermediate 9 (0.110 g) in N,N-dimethylformamide (3 ml), and the mixture was stirred at 22° C. for 4 h. The solvent was removed in vacuo and the residue dissolved in ethyl acetate (20 ml). The solution was washed with 10% aqueous citric acid (20 ml), brine (20 ml), saturated aqueous sodium hydrogen carbonate (20 ml) and brine (20 ml), dried (MgSO4) and evaporated in vacuo. Purification by flash chromatography on silica gel (Merck 9385), eluting with ethyl acetate, followed by trituration of the resultant product with diethyl ether, gave the title compound as a white solid (0.184 g).
Reaction SMILES: [C@@H:1]12[CH2:7][C@@H:4]([CH2:5][CH2:6]1)[CH2:3][C@@H:2]2[NH:8][C:9]1[S:10][CH:11]([CH2:15][CH2:16][O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[C:12](=[O:14])[N:13]=1.[Li+].CC([N-]C(C)C)C.Br[CH2:33][C:34]([CH3:36])=[CH2:35]>C1COCC1>[C@@H:1]12[CH2:7][C@@H:4]([CH2:5][CH2:6]1)[CH2:3][C@@H:2]2[NH:8][C:9]1[S:10][C:11]([CH2:35][C:34]([CH3:36])=[CH2:33])([CH2:15][CH2:16][O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[C:12](=[O:14])[N:13]=1
Reactant: O=C1N=C(N[C@H]2C[C@@H]3CC[C@H]2C3)SC1CCOC1CCCCO1
Reactant: C=C(C)CBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C(C)CC1(CCOC2CCCCO2)SC(N[C@H]2C[C@@H]3CC[C@H]2C3)=NC1=O
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To the mixture of 2-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-ylamino)-5-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)thiazol-4(5H)-one (1160 mg, 3.43 mmol) in THF (8.0 mL) cooled in a −78° C. bath was added LDA (2.0 M, 17.15 mL). The resulting mixture was stirred for 10 min at −78° C., and then 3-bromo-2-methylprop-1-ene (1.6 ml, 17.15 mmol) was added. After the reaction mixture was allowed to warm to room temperature and stirred ca. 18 h. Saturated NaH2PO4 was added, and the aqueous phase was extracted with EtOAc. The organic layer was washed with sat'd NH4Cl, dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (4:1; Hexane:EtOAc) to give the title compound as yellow oil. MS (ES+): 393 (M+H)+.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][C:15]=1Br)[C:9]([O:11][CH3:12])=[O:10])(=[O:3])[CH3:2].[C:17]1([CH3:26])[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:4][CH2:5][C:6]1[CH:7]=[C:8]([C:9]([O:11][CH3:12])=[O:10])[CH:13]=[CH:14][C:15]=1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH3:26])(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(Br)c(COC(C)=O)c1
Reactant: Cc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2ccccc2C)c(COC(C)=O)c1
Temperature: 25 °C
Yield: 100.1 %

Procedure:
A mixture of methyl 3-[(acetyloxy)methyl]-4-bromobenzoate obtained in step 2 (4.7 g; 16.4 mmol), o-tolylboronic acid (2.45 g; 18 mmol), potassium carbonate (11.3 g; 82 mmol) and Pd(PPh3)4 (1.89 g; 1.64 mmol) in toluene (23.5 mL) and water (23.5 mL) was refluxed for 2 hours. After cooling to RT, the reaction mixture was filtered through a pad of Celite® which was further washed with toluene (50 mL). The filtrate was concentrated in vacuo, the residue taken up in EtOAc (250 mL) and washed with sat. aq. NaHCO3, water and brine, dried over magnesium sulphate and concentrated in vacuo to afford the title compound (4.9 g, quantitative) as a brown oil. HPLC (Method A) Rt 5.23 min (Purity 62.3%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:27][C:28]1[CH:51]=[C:50]([Cl:52])[CH:49]=[CH:48][C:29]=1[CH2:30][O:31][C:32]1[CH:47]=[CH:46][C:35]2[C:36]([O:42][CH2:43][O:44][CH3:45])=[C:37]([C:39](O)=[O:40])[S:38][C:34]=2[CH:33]=1>O.CN(C=O)C>[Cl:27][C:28]1[CH:51]=[C:50]([Cl:52])[CH:49]=[CH:48][C:29]=1[CH2:30][O:31][C:32]1[CH:47]=[CH:46][C:35]2[C:36]([O:42][CH2:43][O:44][CH3:45])=[C:37]([C:39]([NH:5][CH2:4][CH2:3][O:2][CH3:1])=[O:40])[S:38][C:34]=2[CH:33]=1
Reactant: COCCN
Reactant: COCOc1c(C(=O)O)sc2cc(OCc3ccc(Cl)cc3Cl)ccc12
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COCCNC(=O)c1sc2cc(OCc3ccc(Cl)cc3Cl)ccc2c1OCOC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2-methoxyethylamine (0.082 mL), EDCI (181 mg), HOBt (128 mg), 6-((2,4-dichlorobenzyl)oxy)-3-(methoxymethoxy)-1-benzothiophene-2-carboxylic acid (260 mg) and DMF (5 mL) was stirred at room temperature for 18 h. Water was added to the mixture, and the mixture was extracted with EtOAc. The EtOAc extract was washed successively with 1N HCl, saturated aqueous NaHCO3 and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (205 mg). The obtained crystals were recrystallized from EtOAc-hexane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.O[C:17]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH2:21][CH3:22])[C:18]([OH:20])=[O:19].B(F)(F)F.CCOCC>C(OCC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:15]=[CH:14][C:11]([CH:12]3[O:20][C:18](=[O:19])[C:17]([CH2:21][CH3:22])([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[O:13]3)=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCC(O)(C(=O)O)c1ccccc1
Reactant: O=Cc1ccc(-c2ccc(Cl)cc2)cc1
Agent: FB(F)F
Solvent: CCOCC
Product: CCC1(c2ccccc2)OC(c2ccc(-c3ccc(Cl)cc3)cc2)OC1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 45 %

Procedure:
To a stirred solution of 4-(4-chlorophenyl)benzaldehyde (2.16 g.) and 2-hydroxy-2-phenylbutyric acid (1.8 g.) in anhydrous diethyl ether (50 ml.) was added boron trifluoride etherate (2.2 g.). After stirring at room temperature for 12 hours, the solution was washed with 10% w/v sodium acetate solution (2×20 ml.) and then with water (2×20 ml.) and dried (Na2SO4). The solution was filtered and evaporated to give an oil which on crystallisation from methanol gave 2-[4-(4-chlorophenyl)phenyl]-5-ethyl-5-phenyl-1,3-dioxolan-4-one (1.7 g.) m.p. 80°-83° C.
Reaction SMILES: [OH-].[K+].[C:3]([O:7][C:8](=[O:15])[NH:9][C:10]([CH3:14])([CH3:13])[CH2:11][OH:12])([CH3:6])([CH3:5])[CH3:4].S(OC)(O[CH3:20])(=O)=O>O1CCOCC1>[C:3]([O:7][C:8](=[O:15])[NH:9][C:10]([CH3:14])([CH3:13])[CH2:11][O:12][CH3:20])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(CO)NC(=O)OC(C)(C)C
Reactant: COS(=O)(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COCC(C)(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 88 %

Procedure:
KOH (3.47 g, 61.82 mmol) was added to a solution of (2-Hydroxy-1,1-dimethyl-ethyl)-carbamic acid tert-butyl ester (Preparation 253, 3.9 g, 20.6 mmol) in 1,4-dioxane (30 mL) followed by the slow addition of dimethyl sulphate at room temperature. The mixture was further allowed to stir at room temperature for 48 hours. Reaction mass was filtered through a short pad of celite, washed with DCM (3×50 mL). The combined filtrate was washed with water (2×50 mL), brine (30 mL), dried over sodium sulphate and evaporated in vacuo to afford the title compound as yellow oil in 88% yield, 3.7 g.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.[F:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][C:42](O)=[O:43])=[CH:37][CH:36]=1.Cl.CN(C)CCCN=C=NCC>CC#N>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:42](=[O:43])[CH2:41][C:38]3[CH:39]=[CH:40][C:35]([F:34])=[CH:36][CH:37]=3)[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C(Cc1ccc(F)cc1)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.17 h
Yield: 68.7 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.70 g, 2.2 mmol) in CH3CN (60 ml), was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.82 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzenetriazole (0.35 g, 2.6 mmol) and 4-fluorophenylacetic acid (0.37 g, 2.4 mmol) were added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.62 g, 3.2 mmol). After stirring at room temperature overnight and was then concentrated in vacuo, and the residue was dissolved in CH2Cl2 (50 mL). The CH2Cl2 solution was washed with water (2×30 mL) and brine (30 mL), and dried over MgSO4. The organic solvent was removed in vacuo, and the resulting oil was purified by ISCO silica gel flash chromatography (eluent: 0% MeOH in CH2Cl2 to 5% MeOH in 10 min then stay at this ratio for 15 min) to afford N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-2-(4-fluoro-phenyl)-acetamide as a white solid (0.64 g, 65%): mp, 214-216° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=3.0 min (99%); 1H NMR (DMSO-d6): δ 2.03-2.08 (m, 1H), 2.51-2.63 (m, 2H), 2.86-2.91 (m, 1H), 3.53 (s, 2H), 4.72 (d, J=6.0 Hz, 2H), 5.12-5.18 (dd, J=5, 12 Hz, 1H), 7.10-7.16 (m, 2H), 7.29-7.34 (m, 2H), 7.62-7.65 (m, 1H), 7.78-7.81 (m, 2H), 8.67 (t, J=5.9 Hz, 1H), 11.14 (s, 1H). 13C NMR (DMSO-d6) δ: 21.95, 30.90, 37.83, 41.17, 48.82, 114.77, 115.05, 121.89, 127.12, 130.81, 130.92, 131.51, 132.24, 132.28, 133.19, 134.67, 139.09, 159.42, 162.62, 166.90, 167.42, 169.78, 170.51, 172.73. Anal Calcd for C22H18FN3O5: C, 62.41; H, 4.29; N, 9.92; F, 4.49. Found: C, 62.05; H, 4.18; N, 9.85; F, 4.48.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[C@H:7]([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[NH2:8])([CH3:4])([CH3:3])[CH3:2].[C:18](N1C=CN=C1)([N:20]1[CH:24]=[CH:23][N:22]=[CH:21]1)=[O:19]>CN(C)C=O>[C:1]([O:5][C:6](=[O:17])[C@H:7]([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[NH:8][C:18]([N:20]1[CH:24]=[CH:23][N:22]=[CH:21]1)=[O:19])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)C[C@H](N)C(=O)OC(C)(C)C
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C[C@H](NC(=O)n1ccnc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
L-aspartic acid di-tert-butyl ester (0.84 g, 3.0 mmol) and 1,1′-carbonyldiimidazole (2.4 g, 15 mmol) were dissolved in N,N-dimethylformamide (10 ml), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added, and the mixture was washed with 1N hydrochloric acid (15 mL) and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (0.72 g, 2.1 mmol).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[CH2:12][CH2:11]3)=[CH:4][CH:3]=1.Br[CH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[CH:20]1([CH2:19][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:9]=[C:10]4[C:14](=[CH:15][CH:16]=3)[C:13](=[O:17])[CH2:12][CH2:11]4)=[CH:6][CH:7]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C1CCc2cc(-c3ccc(O)cc3)ccc21
Reactant: BrCC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C1CCc2cc(-c3ccc(OCC4CCCCC4)cc3)ccc21
Yield: 393.5 %

Procedure:
A solution of 5-(4-hydroxyphenyl)-1-indanone (0.52 g, 0.23 mmol, from Step A), bromomethylcyclohexane (0.53 g, 0.30 mmol) and potassium carbonate (0.58 g, 0.42 mmol) in acetonitrile (2.5 mL) was stirred at 80° C. for 16 h. The reaction mixture was cooled, diluted with ethyl acetate and washed with water. Silica gel chromatography eluting with 10% ethyl acetate/hexane yielded 0.29 g of product. 1H NMR (500 MHz, CDCl3): δ 7.83 (d, J=7.8 Hz, 1H), 7.67 (s, 1H), 7.60 (d, J=8.3 Hz, 3H), 7.03 (d, J=8.2 Hz, 2H), 3.85 (s, 2H), 3.21 (s, 2H), 2.78 (s, 2H), 2.08 (s, 1H), 1.90–1.98 (m, 2H), 1.80–1.86 (m, 2H), 1.20–1.42 (m, 4H), 1.07–1.18 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[NH:11][C:10](=[O:12])[C:9]([O:13]C)=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[C:19]([Cl:24])[CH:18]=1)[C:7]2=[O:15]>Br.C(O)(=O)C>[Br:1][C:2]1[NH:11][C:10](=[O:12])[C:9]([OH:13])=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[C:19]([Cl:24])[CH:18]=1)[C:7]2=[O:15]
Reactant: COc1c2c(c(Br)[nH]c1=O)CCN(Cc1ccc(F)c(Cl)c1)C2=O
Agent: Br
Solvent: CC(=O)O
Product: O=C1c2c(c(Br)[nH]c(=O)c2O)CCN1Cc1ccc(F)c(Cl)c1

Procedure:
A solution of 5-bromo-2-(3-chloro-4-fluorobenzyl)-8-methoxy-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione (1.40 g, 3.37 mmol) in 33% HBr in acetic acid (20 mL) was stirred at room temperature for 1 hour. The product mixture was concentrated under vacuum. The residue was dissolved in methanol, concentrated under vacuum, and triturated with anhydrous diethyl ether. The solid precipitated was filtered to provide the titled compound.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[N:8]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[S:21]([NH2:24])(=[O:23])=[O:22])[N:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[C:6]=2[CH2:5][CH2:4][N:3]1[C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]2=[O:37])=[CH:27][CH:26]=1.[C:38](OC(=O)C)(=[O:40])[CH3:39]>>[C:38]([NH:24][S:21]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[N:8]1[C:7]2[C:2](=[O:1])[N:3]([C:25]3[CH:30]=[CH:29][C:28]([N:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]4=[O:37])=[CH:27][CH:26]=3)[CH2:4][CH2:5][C:6]=2[C:10]([C:11]([F:12])([F:14])[F:13])=[N:9]1)(=[O:22])=[O:23])(=[O:40])[CH3:39]
Reactant: NS(=O)(=O)c1ccccc1-n1nc(C(F)(F)F)c2c1C(=O)N(c1ccc(-n3ccccc3=O)cc1)CC2
Reactant: CC(=O)OC(C)=O
Product: CC(=O)NS(=O)(=O)c1ccccc1-n1nc(C(F)(F)F)c2c1C(=O)N(c1ccc(-n3ccccc3=O)cc1)CC2

Procedure:
The sulfonamide of Example 121 was acetylated with acetic anhydride to afford the title compound. MS (ES+): 572.1 (M+H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]2[C:11](I)=[CH:12][N:13]=[C:7]2[CH:6]=1)=O.O.[NH2:16][NH2:17]>C(O)C>[N:13]1[CH:12]=[CH:11][N:8]2[CH:9]=[CH:10][C:5]([C:3]([NH:16][NH2:17])=[O:2])=[CH:6][C:7]=12
Reactant: COC(=O)c1ccn2c(I)cnc2c1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)c1ccn2ccnc2c1
Reaction time: 1 h
Yield: 69.8 %

Procedure:
To a suspension of methyl-3-Iodo-imidazo[1,2-a]pyridine-7-carboxylate (0.3 g, 1.7 mmol, 1.0 equiv) in ethanol (3 ml) was added hydrazine hydrate (0.414 ml, 8.52 mmol). The mixture was heated to 70 deg C. for 1 h then allowed to cool. The solid was filtered off and washed with ethyl acetate and ether then dried to afford 0.209 g of product. 1H NMR (400 MHz, DMSO-d6): 9.95 (1H, s), 8.60 (1H, d), 8.05 (2H, d), 7.70 (1H, d), 7.30 (1H, dd), 4.58 (2H, s).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20](O)=O)=[CH:15][CH:14]=1)([O-:12])=[O:11].[OH-].[Na+]>>[Cl:9][C:3]1[C:2]2[NH:1][C:20]([CH2:19][C:16]3[CH:15]=[CH:14][C:13]([N+:10]([O-:12])=[O:11])=[CH:18][CH:17]=3)=[N:8][C:7]=2[CH:6]=[CH:5][N:4]=1
Reactant: Nc1ccnc(Cl)c1N
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])c1ccc(Cc2nc3ccnc(Cl)c3[nH]2)cc1
Temperature: 0 °C
Yield: 76 %

Procedure:
2.1 A solution of 1.44 g of 3,4-diamino-2-chloropyridine and 9.06 g of (4-nitrophenyl)acetic acid in 10 ml of polyphosphoric acid is stirred at 80° for 16 hours. The mixture is subsequently poured into ice-water, neutralised using NaOH, the deposited crystals are separated off and subjected to conventional work-up. The organic phase yields 2.2 g of 4-chloro-2-(4-nitrophenylmethyl)-3H-imidazo[4,5-c]pyridine (“4”).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[O:4][N:3]=1.C(N(CC)CC)C.[CH3:18][CH:19]([CH2:23][CH2:24][Cl:25])[C:20](Cl)=[O:21]>C(OCC)(=O)C>[Cl:25][CH2:24][CH2:23][CH:19]([CH3:18])[C:20]([NH:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[O:4][N:3]=1)=[O:21]
Reactant: CC(CCCl)C(=O)Cl
Reactant: CC(C)(C)c1cc(N)no1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(CCCl)C(=O)Nc1cc(C(C)(C)C)on1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.2 %

Procedure:
To a stirred solution of 7 g of 3-amino-5-(1,1-dimethylethyl)isoxazole and 5.05 g triethylamine dissolved in 100 ml ethyl acetate was added 7.75 g of 2-methyl-4-chlorobutyric acid chloride dropwise. The mixture was stirred for about 16 hours at room temperature and the precipitated salt was collected by filtration and washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the residue was chromatographed over silica gel while eluting with a 1:1 (v/v) mixture of toluene:diethyl ether. Fractions containing the major component as indicated by thin layer chromatography were combined and concentrated under vacuum to provide 7 g of 4-chloro-N-[5-(1,1-dimethylethyl)-3-isoxazolyl]-2-methylbutanamide. Yield 54%. This material was used in the following reaction without additional purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]([O:23][CH2:24][C:25]2([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)[CH2:30][CH2:29][N:28]([C:31](OC(C)(C)C)=O)[CH2:27][CH2:26]2)[CH3:22])[C:5]2[N:9](COCC[Si](C)(C)C)[C:8](=[O:18])[N:7]([CH3:19])[C:6]=2[CH:20]=1.C([BH3-])#N.[Na+].C(O)(=O)C.[F:53][C:54]([F:59])([F:58])[C:55]([OH:57])=[O:56]>>[F:53][C:54]([F:59])([F:58])[C:55]([OH:57])=[O:56].[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]([O:23][CH2:24][C:25]2([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]2)[CH3:22])[C:5]2[NH:9][C:8](=[O:18])[N:7]([CH3:19])[C:6]=2[CH:20]=1
Reactant: CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2c1n(COCC[Si](C)(C)C)c(=O)n2C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CC(OCC1(c2ccc(F)cc2)CCN(C)CC1)c1cc(Cl)cc2c1[nH]c(=O)n2C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 4-((1-(6-chloro-1-methyl-2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzo[d]imidazol-4-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (16.5 mg, 0.025 mmol) was dissolved in trifluoroacetic acid (40% in dichloromethane, 1 mL) and stirred at room temperature for 1 h. The reaction was concentrated and loaded onto a strong cation exchange cartridge in methanol. The cartridge was flushed with several volumes of methanol which were discarded. The crude piperidine was eluted with 2M ammonia in methanol and concentrated. The crude product was dissolved in acetonitrile (1 mL) and treated with formalin (50 μL) followed quickly by sodium cyanoborohydride (3.2 mg, 0.05 mmol). To this was added two small drops of acetic acid over 5 minutes. The reaction was concentrated and the residue taken up in ethyl acetate, washed with saturated sodium bicarbonate, then brine, dried over magnesium sulfate, and concentrated. The crude product was dissolved in ethanol (10 mL) and heated at reflux overnight. The reaction was concentrated and purified by preparative HPLC (28% B isocratic method, TFA/ACN) to give 9.0 mg (64%) as a colorless film. 1H-NMR (CD3OD, 500 MHz) δ 7.43 (dd, J=8.9, 4.9 Hz, 1.5H), 7.33 (dd, J=8.9, 5.2 Hz, 0.5H), 7.13 (m, 1.5H), 7.04 (m, 1.5H), 6.72 (d, J=1.8 Hz, 0.7H), 6.67 (d, J=1.8 Hz, 0.3H), 4.5 1 (q, J=6.4 Hz, 1H), 3.15-3.52 (m, 9H), 2.40-3.00 (m, 7H), 2.08 (m, 2H), 1.38 (d, J=6.4 Hz, 3H). Mass spec.: 432.1 (MH)+.
Reaction SMILES: [N+:1]([NH:4][C:5]([NH2:7])=[NH:6])([O-:3])=[O:2].[Na].[CH2:9]([CH:13]([C:19]([CH3:21])=O)[C:14](OCC)=[O:15])[CH:10]([CH3:12])[CH3:11]>CO>[CH2:9]([C:13]1[C:14](=[O:15])[NH:6][C:5]([NH:4][N+:1]([O-:3])=[O:2])=[N:7][C:19]=1[CH3:21])[CH:10]([CH3:12])[CH3:11]
Reactant: CCOC(=O)C(CC(C)C)C(C)=O
Reactant: N=C(N)N[N+](=O)[O-]
Agent: [Na]
Solvent: CO
Product: Cc1nc(N[N+](=O)[O-])[nH]c(=O)c1CC(C)C
Yield: 63.4 %

Procedure:
Nitroguanidine (53.1 g) was added to a solution of sodium (17.6 g) in methanol (500 ml). The mixture was heated under reflux for 45 minutes. Ethyl α-isobutylacetoacetate (95.0 g) was then added dropwise to the refluxing mixture over 30 minutes. Refluxing was continued for a further 61/2 hours. Most of the methanol was removed and the residue was dissolved in water. Unreacted β-keto-ester was removed by extraction with chloroform and the solution was acidified with concentrated hydrochloric acid. The separated solid was washed with water and dried, giving 5-isobutyl-6-methyl-2-nitraminopyrimid-4(3H)-one (formula IV, R1 = CH3, R = isobutyl) (73.2 g). A sample recrystallised from ethanol had a melting point of 179°-181° (decomp.).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH2:8][CH2:9][CH3:10])[N:5]=[C:4]([CH3:11])[C:3]=1[C:12]#[N:13].[F:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18]>ClCCl.N1C=CC=CC=1>[CH2:7]([N:6]1[C:2]([NH:1][C:17](=[O:18])[C:16]2[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=2[F:14])=[C:3]([C:12]#[N:13])[C:4]([CH3:11])=[N:5]1)[CH2:8][CH2:9][CH3:10]
Reactant: CCCCn1nc(C)c(C#N)c1N
Reactant: O=C(Cl)c1ccccc1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCn1nc(C)c(C#N)c1NC(=O)c1ccccc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 24.7 %

Procedure:
5-Amino-1-butyl-3-methyl-1H-pyrazole-4-carbonitrile (10.0 g, 56 mmole) was dissolved in a mixture of dichloromethane/pyridine (45 ml/15 ml) and cooled to 0° C. 2-fluorobenzoyl chloride (8.87 g, 56 mmole) was added dropwise and the reaction mixture was stirred for 1 hour at 0° C., and at room temperature overnight. The solvent was removed under vacuum. The residue was taken up in ethyl acetate, washed with diluted hydrochloric acid, 0.1 M sodium hydroxide, and water, and dried over sodium sulfate (anh). The solvent was removed and the solid triturated in 30% ethyl acetate/hexanes. The product was filtered to obtain 4.16 g product (yield: 24%).