Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:4]1[CH:9]=[C:8]([NH:10][C:11](=[O:21])[C:12]2[C:17]([Cl:18])=[CH:16][C:15]([Cl:19])=[CH:14][C:13]=2[Cl:20])[CH:7]=[CH:6][N:5]=1)=[N+]=[N-].O.O.Cl[Sn]Cl>C(O)C>[NH2:1][C:4]1[CH:9]=[C:8]([NH:10][C:11](=[O:21])[C:12]2[C:13]([Cl:20])=[CH:14][C:15]([Cl:19])=[CH:16][C:17]=2[Cl:18])[CH:7]=[CH:6][N:5]=1
Reactant: [N-]=[N+]=Nc1cc(NC(=O)c2c(Cl)cc(Cl)cc2Cl)ccn1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Nc1cc(NC(=O)c2c(Cl)cc(Cl)cc2Cl)ccn1
Temperature: 25 °C
Yield: 99.6 %

Procedure:
To a solution of N-(2-azidopyridin-4-yl)-2,4,6-trichlorobenzamide (90 mg, 0.26 mmol) in ethanol (5 mL) was added SnCl2.2H2O (300 mg, 1.31 mmol). The mixture was heated at reflux for 1 hour and then cooled to room temperature. The reaction was concentrated under reduced pressure and the residue was diluted with water (10 mL). The mixture was extracted with ethyl acetate (3×5 mL). The combined organic extracts were dried over MgSO4 and concentrated under reduced pressure to give N-(2-aminopyridin-4-yl)-2,4,6-trichlorobenzamide (82 mg, yield: 100%). LCMS (ESI) m/z: 316.0 [M+H+].
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].[CH2:10]([O:14][CH2:15][CH2:16][O:17][CH:18]=[CH2:19])[CH:11]1[O:13][CH2:12]1>>[CH2:10]([O:14][CH2:15][CH2:16][O:17][CH:18]([O:6][C:5](=[O:7])[CH2:4][CH2:3][CH2:2][C:1]([O:9][CH:18]([O:17][CH2:16][CH2:15][O:14][CH2:10][CH:11]1[O:13][CH2:12]1)[CH3:19])=[O:8])[CH3:19])[CH:11]1[O:13][CH2:12]1
Reactant: C=COCCOCC1CO1
Reactant: O=C(O)CCCC(=O)O
Product: CC(OCCOCC1CO1)OC(=O)CCCC(=O)OC(C)OCCOCC1CO1
Reaction time: 2 h

Procedure:
Glutaric acid (1.32 g; 0.01 moles) was added slowly over about 20 minutes to a stirred reaction flask containing 2-vinyloxyethyl glycidyl ether (prepared as described by Sawamoto et. Al in J. Polym. Sci., Part A 1987, V. 25, 2717) at 80° C. After all the acid was added, heating and stirring was continued for a further 2 hours. On cooling, the product, bis-[α-(2-glycidoxyethoxy)ethyl]glutarate, was obtained in quantitative yield. The structure of the product was confirmed by 1H NMR and IR analysis. Previous synthesis of polyepoxides by addition of 2-vinyloxyethyl glycidyl ether to polycarboxylic acids has previously been reported to occur in the presence of acid catalysts by Tofimov et. al (Review Heteroatom Chem. 1993, V.9, 205). Such catalysts are undesirable as they tend to reduce the storage stability of the epoxide monomer and reduce the degradation temperature of the cured adhesive polymer.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:32]=[CH:31][C:30]([Br:33])=[CH:29][C:10]=1[CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]1>C(Cl)Cl>[F:8][C:9]1[CH:32]=[CH:31][C:30]([Br:33])=[CH:29][C:10]=1[CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCCC(CCCOCc2cc(Br)ccc2F)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc(Br)cc1COCCCC1CCCNC1
Temperature: 0 °C

Procedure:
In a 100 ml round bottom flask, 1-[2-fluoro-5-bromobenzyloxy]-3-[1-(t-butoxycarbonyl)piperidin-3-yl]propane (0.395 g) was dissolved in methylene chloride (4.2 ml). The solution was cooled to 0° C. and trifluoroacetic acid (0.8 ml) was slowly added dropwise. The resulting mixture was stirred at 0° C. for thirty minutes, followed by stirring at ambient temperature for thirty minutes. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was partitioned between 1 M potassium carbonate and methylene chloride. The aqueous fraction was back extracted with methylene chloride. The organic fractions were combined, and dried over sodium sulfate. The solvents were removed in vacuo. The desired title intermediate was further purified by liquid chromatography.
Reaction SMILES: [C:1]([C:3](=[C:10]1[CH2:17][C@H:16]2[C@H:12]([CH2:13][CH:14]([OH:28])[C@@H:15]2/[CH:18]=[CH:19]/[C@@H:20]([OH:27])[CH:21]([CH3:26])[CH2:22][CH2:23][CH2:24][CH3:25])[O:11]1)[CH2:4][CH2:5][CH2:6][C:7](O)=[O:8])#[N:2].[CH2:29]([CH2:31][NH2:32])O>>[OH:28][CH:14]1[CH2:13][C@H:12]2[C@H:16]([CH2:17]/[C:10](=[C:3](/[CH2:4][CH2:5][CH2:6][C:7]3[O:8][CH2:29][CH2:31][N:32]=3)\[C:1]#[N:2])/[O:11]2)[C@H:15]1/[CH:18]=[CH:19]/[C@@H:20]([OH:27])[CH:21]([CH3:26])[CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCC(C)[C@H](O)/C=C/[C@H]1C(O)C[C@@H]2OC(=C(C#N)CCCC(=O)O)C[C@@H]21
Reactant: NCCO
Product: CCCCC(C)[C@H](O)/C=C/[C@H]1C(O)C[C@@H]2O/C(=C(/C#N)CCCC3=NCCO3)C[C@@H]21

Procedure:
Analogously to Example 4 from 78 mg (0.2 mmol) of 5-cyano-5-{(1S,5R,6R)-7-hydroxy-6-[(E)-(3S,4RS)-3-hydroxy-4-methyl-1-octenyl]-2-oxabicyclo[3.3.0]octan-3-ylidene}-pentanoic acid and ethanolamine. Yield: 60 mg (72% of theory).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:17]O>>[NH2:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:17])=[O:5]
Reactant: CO
Reactant: Cc1ccc(C(=O)O)c(N)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(C)cc1N

Procedure:
A mixture of 2-amino-4-methylbenzoic acid (15.0 g) and concentrated sulphuric acid (20 ml) was heated under reflux with methanol for 18 hours. After removal of the solvent the residue was dissolved in dichloromethane, basified with sodium carbonate solution and the organic phase was washed with water, dried (anhydrous magnesium sulphate) and the solvent evaporated to give methyl 2-amino-4-methylbenzoate, m.p. 41-43° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH2:24]1[O:33][C:32]2[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][C:26]=2[O:25]1.Cl>C(O)(C)C>[O:33]1[C:32]2[CH:31]=[CH:30][C:28]([NH:29][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]5[CH2:23][CH2:22][O:21][CH2:20][CH2:19]5)=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][N:3]=3)=[CH:27][C:26]=2[O:25][CH2:24]1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Reactant: Nc1ccc2c(c1)OCO2
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2c(Nc3ccc4c(c3)OCO4)ncnc2cc1OCCCN1CCOCC1
Temperature: 25 °C
Yield: 81.3 %

Procedure:
A solution of 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (74 mg, 0.23 mmol), (prepared as described for the starting material in Example 1), and 3,4-(methylenedioxy)aniline (53 mg, 0.24 mmol) in a solution of isopropanol (3.5 ml) containing 5.5M hydrogen chloride in isopropanol (42 μl) was heated for 3 hours. After cooling to ambient temperature, the reaction mixture was cooled to 0° C. and maintained at this temperature overnight. The precipitate was collected by filtration, washed with ethyl acetate and dried under vacuum to give 4-(1,3-benzodioxol-5-ylamino)-6-methoxy-7-(3-morpholinopropoxy)quinazoline (82 mg, 76%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:23]([OH:25])=O)=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([Br:22])[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][C:32]=1[N:33]1[CH2:38][C@H:37]([CH3:39])[C@H:36]([NH:40][C:41](=[O:44])[O:42][CH3:43])[C@H:35]([NH:45][C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49])[CH2:34]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:23]([NH:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][C:32]=2[N:33]2[CH2:38][C@H:37]([CH3:39])[C@H:36]([NH:40][C:41](=[O:44])[O:42][CH3:43])[C@H:35]([NH:45][C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49])[CH2:34]2)=[O:25])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([Br:22])[CH:16]=2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1cc2ccc(Br)cc2nc1C(=O)O)OCc1ccccc1
Reactant: COC(=O)N[C@H]1[C@@H](C)CN(c2ccncc2N)C[C@H]1NC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)N[C@H]1[C@@H](C)CN(c2ccncc2NC(=O)c2nc3cc(Br)ccc3cc2NC(=O)OCc2ccccc2)C[C@H]1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 183.8 %

Procedure:
To a mixture of 3-{[(benzyloxy)carbonyl]amino}-7-bromoquinoline-2-carboxylic acid (360 mg, 0.897 mmol), tert-butyl methyl [(3R,4S,5S)-1-(3-aminopyridin-4-yl)-5-methylpiperidine-3,4-diyl]biscarbamate (303 mg, 0.799 mmol) and HATU (914.8 mg, 2.406 mmol) in DMF (5.0 mL), DIPEA (539 mg, 4.17 mmol) was added. The mixture was stirred at room temperature for 3 h. The volatile solvents were removed under reduced pressure, and the residue was purified by flash chromatography (40 g, 0-100% EtOAc in hexanes) to give the sub-title compound as a red viscous oil (1.120 g, 184%). The product was used in the next step without further purification. LCMS calc. for C36H41BrN7O7 (M+H)+: m/z=762.2. Found: 762.3.
Reaction SMILES: [CH:1]1([C:4]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=2[CH3:19])([C:6]2[S:7][CH:8]=[CH:9][C:10]=2[CH3:11])O)[CH2:3][CH2:2]1.[Br:20][Si](C)(C)C.O>ClCCl>[Br:20][CH2:3][CH2:2][CH:1]=[C:4]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=1[CH3:19])[C:6]1[S:7][CH:8]=[CH:9][C:10]=1[CH3:11]
Reactant: C[Si](C)(C)Br
Reactant: Cc1ccc(C(O)(c2sccc2C)C2CC2)c(C)c1
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(C(=CCCBr)c2sccc2C)c(C)c1
Temperature: 10 °C

Procedure:
A solution of cyclopropyl(2,4-dimethylphenyl)(3-methyl-2-thienyl)methanol (7.0 g, 0.026 mole; obtained by the method described in Example 7) in dichloromethane (125 ml) was cooled to 10° C. and bromotrimethylsilane (4.0 g, 0.026 mole) in dichloromethane (50 ml) was added dropwise keeping the temperature at about 10° C. When addition was complete, water was added (250 ml) and the phases were separated. The aqueous phase was extracted with dichloromethane (25 ml). The combined organic phases was washed with a saturated sodium bicarbonate solution, brine and dried over sodium sulphate. The solvent was removed in vacuo leaving 1-bromo-4-(2,4-dimethylphenyl)-4-(3-methyl-2-thienyl)but-3-ene (8.7 g) as an oil. This bromide was converted by the method described in Example 7 into the title acid hydrochloride, M.p.=200°-201° C. (i-Propanol).
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]2[C:14](=[O:22])[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:16][N:7]3[C:8]=2[C:3]=1[CH:4](C(O)=O)[CH2:5][N:6]3[CH3:23].O>CN1CCCC1=O>[F:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]2[C:14](=[O:22])[CH:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:16][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][N:6]3[CH3:23]
Reactant: CCOC(=O)c1cn2c3c(c(F)c(F)c(F)c3c1=O)C(C(=O)O)CN2C
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOC(=O)C1CN2c3c(c(F)c(F)c(F)c3C1=O)CCN2C
Temperature: 160 °C
Yield: 48.1 %

Procedure:
300 mg of the compound (197) obtained in Example 68 was dissolved in 6 ml of N-methylpyrrolidone, and the solution was heated at 160° C. for 3 hours. After air-cooling, the water was added to the reaction solution, and the solution was extracted with chloroform three times. After drying over magnesium sulfate, the solvent was removed by distillation. The residue was separated by column chromatography (silica gel, eluent solvent; chloroform) to obtain 128 mg of the subject compound (198) in a 49% yield.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([NH2:9])=[CH:4][N:3]=1.[CH:10]1[CH:15]=[CH:14][C:13]([O:16][C:17](OC2C=CC=CC=2)=[N:18][C:19]#[N:20])=[CH:12][CH:11]=1>COCCOC>[NH2:8][C:7]1[CH:6]=[C:5]([NH:9][C:17](=[N:18][C:19]#[N:20])[O:16][C:13]2[CH:14]=[CH:15][CH:10]=[CH:11][CH:12]=2)[CH:4]=[N:3][C:2]=1[Cl:1]
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Reactant: Nc1cnc(Cl)c(N)c1
Solvent: COCCOC
Product: N#CN=C(Nc1cnc(Cl)c(N)c1)Oc1ccccc1
Yield: 60.1 %

Procedure:
A stirred solution of the product from Step 1 (1.80 g, 0.0125 mol) in ethylene glycol dimethyl ether (DME, 50 ml) was treated with diphenylcyanocarbonimidate (3.0 g, 0.0126 mol) and kept under nitrogen at ambient temperature (25° C.) for 96 hours. The precipitate was collected by filtration, washed with DME and dried to give 2.16 g of the titled product, mp 219°-220° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]2[N:12]([C:16]3[CH:21]=[C:20]([S:22]([N:25]4[C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=5[CH2:29][CH2:28][CH2:27][CH2:26]4)(=[O:24])=[O:23])[C:19]([O:36][CH2:37][CH2:38][O:39][Si](C(C)(C)C)(C)C)=[CH:18][C:17]=3[F:47])[C:13](=[O:15])[NH:14][C:9]2=[C:8]([CH3:48])[CH:7]=1)=[O:5])[CH3:2].[Si](OCCOC1C(S(N2C3C=CC=CC=3CCCC2)(=O)=O)=CC(N)=C(F)C=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]2[N:12]([C:16]3[CH:21]=[C:20]([S:22]([N:25]4[C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=5[CH2:29][CH2:28][CH2:27][CH2:26]4)(=[O:23])=[O:24])[C:19]([O:36][CH2:37][CH2:38][OH:39])=[CH:18][C:17]=3[F:47])[C:13](=[O:15])[NH:14][C:9]2=[C:8]([CH3:48])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(C)c2[nH]c(=O)n(-c3cc(S(=O)(=O)N4CCCCc5ccccc54)c(OCCO[Si](C)(C)C(C)(C)C)cc3F)c2n1
Agent: CC(C)(C)[Si](C)(C)OCCOc1cc(F)c(N)cc1S(=O)(=O)N1CCCCc2ccccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(C)c2[nH]c(=O)n(-c3cc(S(=O)(=O)N4CCCCc5ccccc54)c(OCCO)cc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.6 %

Procedure:
To a solution of 5-ethoxycarbonyl-3-{-4-[2-(tert-butyldimethylsilyloxy)-ethoxy]-2-fluoro-5-(2,3,4,5-tetrahydro-1H-1-benzoazepin-1-ylsulfonyl)phenyl}-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (15 mg), which was prepared in a similar manner to that described in Example 40 using 4-[2-(tert-butyldimethylsilyloxy)-ethoxy]-2-fluoro-5-(2,3,4,5-tetrahydro-1H-1-benzoazepin-1-ylsulfonyl)aniline instead of 2-chloro-4-methoxy-5-(1-methyl-1-phenylethylthio)aniline, in tetrahydrofuran (1.5 mL) was added tetra(n-butyl)ammonium fluoride (1 mol/L tetrahydrofuran solution, 0.031 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 5-ethoxycarbonyl-3-[2-fluoro-4-(2-hydroxyethoxy)-5-(2,3,4,5-tetrahydro-1H-1-benzoazepin-1-ylsulfonyl)phenyl]-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (12 mg). The title compound was prepared in a similar manner to that described in Example 43 using this material instead of 3-[2-chloro-4-methoxy-5-(1-methyl-1-phenylethylsulfonyl)phenyl]-5-ethoxycarbonyl-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one.
Reaction SMILES: [N+:1]([CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:10][CH:9]=1)=[O:7])([O-:3])=[O:2].[BH4-].[Na+].N1C=CC=CC=1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>CO.C(OCC)(=O)C.ClCCl>[C:30]([O:7][CH:6]([C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:12][CH:13]=1)[CH2:5][CH2:4][N+:1]([O-:3])=[O:2])(=[O:32])[CH3:31]
Reactant: CCCCCCCCc1ccc(C(=O)CC[N+](=O)[O-])cc1
Reactant: CC(=O)OC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClCCl
Product: CCCCCCCCc1ccc(C(CC[N+](=O)[O-])OC(C)=O)cc1
Temperature: 0 °C
Reaction time: 4.5 h
Yield: 94 %

Procedure:
To a solution of 3-nitro-1-(4-octylphenyl)propan-1-one (12) (5.00 g) in methanol (25 ml) was added sodium borohydride (0.8 g) at 0° C. and the mixture was left at room temperature for 4.5 hr. The suspension was diluted with ethyl acetate and washed successively with 1 N HCl, sodium bicarbonate solution and brine. The ethyl acetate layer was dried over anhydrous Na2SO4 and concentrated. To the residue was added pyridine (1.5 eq), dichloromethane (10 v) and acetic anhydride (10 eq), and the mixture was left at room temperature overnight. To the reaction mixture was added ice water and the mixture was extracted with ethyl acetate and washed successively with 1 N HCl, sodium bicarbonate solution and brine. The ethyl acetate solution was dried over sodium sulfate and concentrated. The residue was pure enough for transformation to the next step or can be purified by silica gel column chromatography using hexane-ethyl acetate as eluent. Yield=94%, ESIMS 358.2 [M+Na]+
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][C@@H:24]2[OH:27])[C@:20]2([CH3:21])[C@@H:15]([CH2:16][C@@H:17]([O:28][CH2:29][CH2:30][OH:31])[CH2:18][CH2:19]2)[CH2:14][C@H:13]3[OH:32])[CH2:10][CH2:9]1)[CH3:7].[CH3:34][S:35](Cl)(=[O:37])=[O:36].C(N(CC)CC)C.[NH4+].[Cl-]>C1COCC1>[OH:32][C@@H:13]1[CH2:14][CH:15]2[C@:20]([CH3:21])([CH2:19][CH2:18][C@H:17]([O:28][CH2:29][CH2:30][O:31][S:35]([CH3:34])(=[O:37])=[O:36])[CH2:16]2)[C@@H:22]2[C@@H:12]1[C@H:11]1[C@:25]([CH3:26])([C@@H:24]([OH:27])[CH2:23]2)[C@@H:8]([C@H:6]([CH3:7])[CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:33])[CH2:9][CH2:10]1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@@H](OCCO)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)CC4C[C@@H](OCCOS(C)(=O)=O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
The compound of example 1B (1.0 g, 2.1 mmol) was dissolved in THF (21 mL) and cooled to 0° C. To the cooled solution was added methanesulfonyl chloride (0.25 mL, 3.21 mmol) followed by the dropwise addition of triethylamine (0.45 mL, 3.21 mmol). The reaction solution was warmed to room temperature and allowed to stir overnight. Saturated aqueous NH4Cl was added and the solution was extracted twice with ethyl acetate. The organic phase was washed with brine, dried (MgSO4), concentrated and purified via column chromatography (1:1 hexanes:ethyl acetate). The yield of the product was 429 mg (37%).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:31]([OH:33])=O)[CH2:19][C:20]3[CH:29]=[C:28]([CH3:30])[C:23]4[NH:24][C:25](=[O:27])[O:26][C:22]=4[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:34]=[CH:35][CH:36]=[CH:37][C:4]=2[NH:3]1.[NH:38]1[CH2:43][CH2:42][CH:41]([N:44]2[CH2:49][CH2:48][N:47]([C:50](=[O:52])[CH3:51])[CH2:46][CH2:45]2)[CH2:40][CH2:39]1>>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@H:18]([CH2:19][C:20]3[CH:29]=[C:28]([CH3:30])[C:23]4[NH:24][C:25](=[O:27])[O:26][C:22]=4[CH:21]=3)[C:31]([N:38]3[CH2:39][CH2:40][CH:41]([N:44]4[CH2:45][CH2:46][N:47]([C:50](=[O:52])[CH3:51])[CH2:48][CH2:49]4)[CH2:42][CH2:43]3)=[O:33])=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:34]=[CH:35][CH:36]=[CH:37][C:4]=2[NH:3]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc2oc(=O)[nH]c12
Reactant: CC(=O)N1CCN(C2CCNCC2)CC1
Product: CC(=O)N1CCN(C2CCN(C(=O)[C@@H](Cc3cc(C)c4[nH]c(=O)oc4c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1

Procedure:
Prepared analogously to Example 1 h from 600 mg (1.18 mmol) (R)-1-carboxy-2-(4-methyl-2-oxo-2,3-dihydrobenzoxazol-6-yl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 275 mg (1.30 mmol) 1-(4-piperidin-4-yl-piperazin-1-yl)-ethanone.
Reaction SMILES: [C:1]([NH:5][CH:6]1[CH2:9][N:8]([CH:10]2[CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11]2)[CH2:7]1)(=[O:4])[CH:2]=[CH2:3].[ClH:21].CO>>[ClH:21].[NH:12]1[CH2:11][CH:10]([N:8]2[CH2:9][CH:6]([NH:5][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:7]2)[CH2:13]1
Reactant: C=CC(=O)NC1CN(C2CN(C(=O)OC(C)(C)C)C2)C1
Agent: Cl
Solvent: CO
Product: C=CC(=O)NC1CN(C2CNC2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 107.3 %

Procedure:
A mixture of tert-butyl 3-(3-(acrylamido)azetidin-1-yl)azetidine-1-carboxylate (300 mg, 1.07 mmol) in HCl-MeOH (30 mL, 86 mmol) was stirred at room temperature for 1 h. The mixture was concentrated in vacuo to afford the crude product (250 mg) which was used directly in the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[CH:7]=[CH:8][C:9](O)=[O:10])([O-:3])=[O:2].C(OCC)(=O)C.S(Cl)([Cl:23])=O.Cl>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[CH:7]=[CH:8][C:9]([Cl:23])=[O:10])([O-:3])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C=Cc1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Cl)C=Cc1cccc([N+](=O)[O-])c1
Yield: 96.9 %

Procedure:
193.2 g (1 mole) of 3-nitrocinnamic acid and 650 g of ethyl acetate were placed in a reaction vessel. While 200 g of thionyl chloride with some drops of DMF was dropped into the reaction mixtures, the reaction mixtures were refluxed with stirring until the generation of hydrogen chloride gas stopped. The reacted solution was concentrated until a solid could be precipitated and poured into hexane. The precipitate was separated by filtration and dried. 205 g of 3-nitrocinnamoyl chloride was yielded.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)[CH2:3][CH2:2]1.O.C(N(CC)CC)C.Cl[C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:25][C:24]=1[N+:33]([O-:35])=[O:34]>O1CCOCC1>[N+:33]([C:24]1[CH:25]=[C:26]([S:29]([NH2:32])(=[O:30])=[O:31])[CH:27]=[CH:28][C:23]=1[NH:13][CH:10]1[CH2:11][CH2:12][N:7]([CH:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)[CH2:8][CH2:9]1)([O-:35])=[O:34]
Reactant: NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: NC1CCN(C2CCOCC2)CC1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O
Product: NS(=O)(=O)c1ccc(NC2CCN(C3CCOCC3)CC2)c([N+](=O)[O-])c1
Temperature: 90 °C

Procedure:
A mixture of EXAMPLE 173B (22.12 g), water (43 mL), and triethylamine (43.6 mL) in 1,4-dioxane (300 mL) was stirred at room temperature until EXAMPLE 173B completely dissolved. The solution was then treated with 4-chloro-3-nitrobenzenesulfonamide, heated at 90° C. for 16 hours, cooled and concentrated. 10% methanol in dichloromethane was added, and the solution was stirred vigorously at room temperature until a fine suspension existed and the mixture was filtered.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[Br:18]Br>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][Br:18])=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: BrBr
Reactant: Cc1ccc(-c2nc3cc(Br)cnc3[nH]2)cc1
Solvent: CC(=O)O
Product: BrCc1ccc(-c2nc3cc(Br)cnc3[nH]2)cc1

Procedure:
The title compound was prepared by refluxing 6-bromo-2-(4-methylphenyl)-3H-imidazo[4,5-b]pyridine with a large excess of bromine in acetic acid overnight. APCI-MS m/z: 366/368/370 [MH+].
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:10])[CH:3]=1.[CH2:11]([Mg]Cl)[CH2:12][CH3:13]>O1CCCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([OH:7])[CH2:11][CH2:12][CH3:13])=[C:4]([F:10])[CH:3]=1
Reactant: O=Cc1ccc(Br)cc1F
Reactant: CCC[Mg]Cl
Solvent: C1CCOC1
Product: CCCC(O)c1ccc(Br)cc1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 59.4 %

Procedure:
To a −78° C. solution of 4-bromo-2-fluorobenzaldehyde (600 mg, 3 mmol) in tetrahydrofuran (10 mL) was added n-propylmagnesium chloride (2.22 mL, 4.43 mmol) dropwise over 20 minutes. The reaction was warmed to 0° C. and stirred for 2 hours. The reaction was quenched with saturated aqueous ammonium chloride, extracted with ethyl acetate (3×), dried over sodium sulfate, filtered, and concentrated. Purification by preparatory thin layer chromatography gave (+/−)-1-(4-bromo-2-fluorophenyl)butan-1-ol (440 mg, 60%) as a colorless oil. 1H NMR (400 MHz, CDCl3, δ): 7.26-7.30 (m, 1H), 7.21 (d, J=8.0 Hz, 1H), 7.13 (d, J=8.0 Hz, 1H), 4.90 (t, J=5.6 Hz, 1H), 1.53-1.79 (m, 2H), 1.30-1.45 (m, 2H), 0.85 (s, J=5.6 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([O:16]CC2C=CC=CC=2)=[O:15])=[CH:9][CH:8]=1)=[O:4]>CO.[OH-].[OH-].[Pd+2]>[CH3:1][O:2][C:3]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[CH:9][CH:8]=1)=[O:4]
Reactant: COC(=O)COc1ccc(CC(=O)OCc2ccccc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COC(=O)COc1ccc(CC(=O)O)cc1

Procedure:
7.8 g (0.025 Mol) of benzyl 4-methoxycarbonylmethyloxyphenylacetate are exhaustively hydrogenated in 150 ml of methanol in the presence of 8 g of palladium hydroxide on charcoal at ambient temperature and under a hydrogen pressure of 50 psi. After the removal of the catalyst the mother liquor is evaporated to dryness under reduced pressure.