Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([N+:12]([O-])=O)[C:3]=1[N:15]1[C:19]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[N:18][C:17]([C:25]([CH3:28])([CH3:27])[CH3:26])=[N:16]1.O.[OH-].[Na+]>CO.Cl>[NH2:12][C:4]1[CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:15]1[C:19]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[N:18][C:17]([C:25]([CH3:27])([CH3:26])[CH3:28])=[N:16]1
Reactant: CCN(CC)c1nc(C(C)(C)C)nn1-c1c(Cl)cc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCN(CC)c1nc(C(C)(C)C)nn1-c1c(N)cc(C(F)(F)F)cc1Cl
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 46.7 %

Procedure:
1-(2-Chloro-6-nitro-4-trifluoromethylphenyl)-3-tertiary-butyl-5-diethylamino-1,2,4-triazole (0.6g) was dissolved in methanol (20ml) and the solution warmed to 50° C. A solution of stannous chloride dihydrate (2.3g) in concentrated hydrochloric acid (20ml) was added with vigorous stirring. The reaction mixture was allowed to cool, then stirred at room temperature for 30 minutes and poured into water. The solution was basified to pH 8 with 2N sodium hydroxide solution, and then extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulphate and the solvent evaporated under reduced pressure to afford a pale yellow oil which crystallised on standing. Recrystallisation from hexane gave 1-(2-amino-6-chloro-4-trifluoromethylphenyl)-3-tertiary-butyl-5-diethylamino-1,2,4-triazole (260mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH2:5][C:6](=O)[CH:7](Br)[CH2:8][CH3:9])[CH3:2].[F:13][C:14]([F:25])([F:24])[C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH2:21])=[S:20])=[CH:17][CH:16]=1>C(O)C>[CH2:1]([O:3][C:4](=[O:12])[CH2:5][C:6]1[N:21]=[C:19]([C:18]2[CH:17]=[CH:16][C:15]([C:14]([F:24])([F:13])[F:25])=[CH:23][CH:22]=2)[S:20][C:7]=1[CH2:8][CH3:9])[CH3:2]
Reactant: NC(=S)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)CC(=O)C(Br)CC
Solvent: CCO
Product: CCOC(=O)Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CC
Temperature: 25 °C
Yield: 70.6 %

Procedure:
4-Bromo-3-oxo-hexanoic acid ethyl ester (4.68 g, 20.98 mmol) is dissolved into denatured ethanol (100 mL) and para-trifluoromethyl thiobenzamide (4.31 g, 21 mmol) is added in one portion. The reaction is purged of air and flushed with nitrogen then heated to reflux. The reaction is monitored by TLC and HPLC and when complete, the reaction is allowed to cool to room temperature. The solvent is removed and the reaction is diluted with ethyl acetate (200 mL), followed by ishes with saturated sodium bicarbonate solution, water, and brine. The ethyl acetate solution is dried over anhydrous sodium sulfate, then concentrated and further purified using flash column chromatography (10% EtOAc/Hexanes) to yield pure [5-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-acetic acid ethyl ester (5.09 g, 14.82 mmol) or 71% yield.
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)[CH2:6][N:5]([C@H:13]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:14]([O:16]CC2C=CC(OC)=CC=2)=[O:15])[CH2:4]1)=O.[C:32]1([CH2:38][CH2:39][CH2:40][CH:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[C:32]1([CH2:38][CH2:39][CH2:40][CH:41]2[CH2:42][CH2:43][N:44]([CH2:1][C@@H:3]3[C@@H:7]([C:8]4[CH:12]=[CH:11][S:10][CH:9]=4)[CH2:6][N:5]([C@H:13]([CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)[C:14]([OH:16])=[O:15])[CH2:4]3)[CH2:45][CH2:46]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: c1ccc(CCCC2CCNCC2)cc1
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](c3ccsc3)[C@@H](C=O)C2)cc1
Product: O=C(O)[C@@H](C1CCCCC1)N1C[C@H](CN2CCC(CCCc3ccccc3)CC2)[C@@H](c2ccsc2)C1

Procedure:
The title compound was prepared from 2-(R)-(3-(R)-formyl-4-(S)-(3-thienyl)pyrrolidin-1-yl)-2-(cyclohexyl)acetic acid, 4-methoxybenzyl ester (from EXAMPLE 90, Step A) and 4-(3-phenylpropyl)piperidine using procedures analogous to those described in EXAMPLE 1, Step J and EXAMPLE 10, Step F. For the title compound: 1H NMR (500 MHz) δ 0.85-4.20 (35H), 7.11-7.35 (81); ESI-MS 509 (M+H).
Reaction SMILES: [CH:1]1[C:6]([CH:7]=[O:8])=[CH:5][C:4](Br)=[CH:3][C:2]=1[CH:10]=[O:11].C([C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1)=O.[C:23](=O)([O-])[O-:24].[K+].[K+].N#N>COCCOC.O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:4]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:3][C:2]([CH:23]=[O:24])([CH:10]=[O:11])[CH:1]=[C:6]([CH:7]=[O:8])[CH:5]=1
Reactant: O=Cc1cc(Br)cc(C=O)c1
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: O=C([O-])[O-]
Agent: N#N
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: COCCOC
Product: O=CC1=CC(C=O)(C=O)CC(c2ccccc2)=C1
Temperature: 90 °C
Reaction time: 16 h
Yield: 61.2 %

Procedure:
A solution of 5-bromoisophthaldehyde (2.13 g, 10.0 mmol), 3-formylphenylboronic acid (1.49 g, 10.0 mmol) and potassium carbonate (2.76 g, 20.0 mmol) in DME/H2O (5:1 50 mL) was purged with N2 for 5 min. Tetrakispalladium triphenylphosphine (0.12 g, 0.1 mmol) was added and the reaction mixture was heated to 90° C. and stirred for 16 h. The reaction mixture was cooled, filtered through a pad of Celite diatomaceous earth and the solvent evaporated under reduced pressure. Purification by column chromatography (10% EtOAc/hexanes) afforded the desired product (1.47 g, 62%) as a tan solid. 1H NMR (300 MHz, CDCl3) δ ppm 10.20 (s, 2H), 10.10 (s, 1H), 8.42 (s, 3H), 8.21 (s, 1H), 7.98 (t, J=5.4 Hz, 2H), 7.72 (t, J=5.4 Hz, 2H).
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[CH2:23]([O:30][N:31]1[C:37](=[O:38])[N:36]2[CH2:39][C@H:32]1[CH2:33][CH2:34][C@H:35]2[C:40]([NH:42][NH:43][C:44](=O)[CH2:45][NH:46][C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C([O-])(O)=O.[Na+]>C1COCC1>[CH2:23]([O:30][N:31]1[C:37](=[O:38])[N:36]2[CH2:39][C@H:32]1[CH2:33][CH2:34][C@H:35]2[C:40]1[S:10][C:44]([CH2:45][NH:46][C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[N:43][N:42]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)OC(=O)NCC(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1nnc([C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)s1
Temperature: 70 °C
Reaction time: 8 h
Yield: 46.1 %

Procedure:
Lawesson's reagent (0.68 g, 1.68 mol) was added to a solution of tert-butyl 2-(2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)hydrazinyl)-2-oxoethylcarbamate (0.50 g, 1.12 mmol) in THF (30 mL). The reaction mixture was heated at 70° C. for 0.5 h. The solution was cooled down to rt and saturated NaHCO3 was added. The organic layer was separated and the aqueous layer was exacted with EtOAc (2×). The combined organic layer was dried over Na2SO4, and concentrated. The crude sample was dissolved in THF (100 mL), and Hg(OAc)2 (1.68 g) was added. The mixture was stirred at rt overnight, filtered and concentrated. The residue was dissolved in EtOAc (100 mL), stirred for 30 min, filtered and concentrated. The crude material was purified by silica gel column chromatography (20% to 50% EtOAc/petroleum ether) to give tert-butyl ((5-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octan-2-yl)-1,3,4-thiadiazol-2-yl)methyl)carbamate (230 mg, 45%) as a white solid. ESI-MS (EI+, m/z): 446.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[C:26]([N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:27])[C:5]([NH:7][C@H:8]([C:13]1[NH:17][C:16]2[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:15]=2[N:14]=1)[CH2:9][S:10][CH2:11][CH3:12])=[O:6].ClC1C=C(C=CC=1)C(OO)=[O:38].C(O)(=O)C.ClCl>ClCCl.ClCCl.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[C:26]([N:28]1[CH2:29][CH2:30][CH2:31][CH2:32]1)=[O:27])[C:5]([NH:7][C@H:8]([C:13]1[NH:17][C:16]2[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:15]=2[N:14]=1)[CH2:9][S:10]([CH2:11][CH3:12])=[O:38])=[O:6]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCSC[C@H](NC(=O)c1ccc(C(=O)N2CCCC2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Solvent: CC(=O)O
Solvent: CCO
Solvent: ClCCl
Product: CCS(=O)C[C@H](NC(=O)c1ccc(C(=O)N2CCCC2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 97 %

Procedure:
Prepared analogously to Example 85 from 3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-(ethylsulfanyl)ethyl]-4-(pyrrolidin-1-ylcarbonyl)benzamide, 3-chloroperoxybenzoic acid, and glacial acetic acid in dichloromethane. Yield: 97%; Rf value: 0.31 (silica gel; dichloromethane/ethanol=9:1); C23H24C12N4O3S (507.44); mass spectrum: (M+H)+=507/509/511 (chlorine isotope).
Reaction SMILES: [CH3:1][P:2]([O-:8])[O:3][CH2:4][CH:5]([CH3:7])[CH3:6].[C:9](#[N:13])/[CH:10]=[CH:11]/[CH3:12].[H-].[Na+].C(O)(=O)C>C(O)C>[C:9]([CH2:10][CH:11]([P:2]([CH3:1])(=[O:8])[O:3][CH2:4][CH:5]([CH3:7])[CH3:6])[CH3:12])#[N:13]
Reactant: CC(C)COP(C)[O-]
Reactant: C/C=C/C#N
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)COP(C)(=O)C(C)CC#N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 50.0 g of isobutyl P-methylphosphonite and 22.8 g of crotononitrile in 50 ml of dry ethanol is added to a stirred mixture of 0.8 g of sodium hydride (50% dispersion in oil) in 25 ml of ethanol at 0° C., under an atmosphere of nitrogen. The reaction mixture is allowed to warm to room temperature and stirred for 4 hours. 1 ml of glacial acetic acid is added and the mixture is concentrated under reduced pressure. The resulting crude product is dissolved in 50 ml of ethyl acetate, washed twice with 25 ml of water, and the organic extract is dried over magnesium sulphate, and then concentrated under reduced pressure. The crude product is distilled to give isobutyl P-(3-cyanoprop-2-yl)-P-(methyl)-phosphinate, b.p. 110°/0.125 mbar, 31P-NMR spectrum: δ=+55.9 and +55.5 ppm (CDCl3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:20][CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:6]([CH:10]=1)[C:7]([NH:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:30][CH:31]=1)=[O:9]
Reactant: COC(=O)c1ccc(CN)cc1
Reactant: O=C(O)c1cc(Cl)ccc1Oc1ccc(F)cc1
Agent: Cl
Product: COC(=O)c1ccc(CNC(=O)c2cc(Cl)ccc2Oc2ccc(F)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 5-chloro-2-(4-fluorophenoxy)benzoic acid (step 2) and methyl 4-(aminomethyl)benzoate hydrochloride: 1H-NMR (CDCl3) δ 8.24 (1H, d, J=2.8 Hz), 7.97–7.94 (3H, m), 7.36–7.32 (3H, m), 7.11–6.96 (4H, m), 6.74 (1H, d, J=8.8 Hz), 4.71 (2H, d, J=5.9 Hz), 3.90 (3H, s); MS (ESI) m/z 414 (M+H)+, 412 (M−H)−.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][C:9]=2[CH3:16])=[CH:4][CH:3]=1.Br[CH2:18][CH2:19][CH2:20][Cl:21]>>[Cl:21][CH2:20][CH2:19][CH2:18][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][C:9]=2[CH3:16])=[CH:6][CH:7]=1
Reactant: Cc1cc(C#N)ccc1-c1ccc(O)cc1
Reactant: ClCCCBr
Product: Cc1cc(C#N)ccc1-c1ccc(OCCCCl)cc1
Yield: 97 %

Procedure:
The product from Example 165B and 1-bromo-3-chloropropane were processed as described in Example 164C to provide the title compound (97% yield). 1HNMR (300 MHz, CDCl3) δ2.25 (bs, 5H), 3.80 (bs, 2H), 4.20 (bs, 2H), 6.95-7.54 (m, 7H). MS (DCI) m/z 286 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:33]=[CH:32][C:9]2[CH2:10][C@@H:11]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[C:12](=[O:26])[N:13]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:14][C:8]=2[CH:7]=1.Br[C:35]1[N:40]=[CH:39][CH:38]=[CH:37][N:36]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[O:26]=[C:12]1[C@H:11]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH2:10][C:9]2[CH:32]=[CH:33][C:6]([O:5][CH2:4][CH2:3][CH2:2][NH:1][C:35]3[N:40]=[CH:39][CH:38]=[CH:37][N:36]=3)=[CH:7][C:8]=2[CH2:14][N:13]1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1
Reactant: COC(=O)C[C@@H]1Cc2ccc(OCCCN)cc2CN(Cc2ccc(C(F)(F)F)cc2)C1=O
Reactant: Brc1ncccn1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C[C@@H]1Cc2ccc(OCCCNc3ncccn3)cc2CN(Cc2ccc(C(F)(F)F)cc2)C1=O
Temperature: 25 °C
Yield: 40.7 %

Procedure:
A solution of methyl (S)-8-(3-amino-1-propyloxy)-3-oxo-2-[4-(trifluoromethyl)benzyl]-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate (0.09 g, 0.19 mmol), 2-bromopyrimidine (0.09 g, 0.57 mmol) and diisopropylethylamine (0.17 mL, 0.98 mmol) in DMF (2 mL) was heated at 80° C. for 18 h. The reaction was allowed to cool to RT and was concentrated to give a yellow residue. Flash chromatography on silica gel (2% MeOH/EtOAc) gave the title compound (42 mg) as a clear oil. MS (ES) m/e 543.1 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.C([O:12][B:13](OCC)[O:14]CC)C.S(=O)(=O)(O)O.O>C(OCC)C>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([B:13]([OH:14])[OH:12])=[CH:3][CH:4]=1
Reactant: CCOB(OCC)OCC
Reactant: COc1ccc(Br)cc1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: O
Product: COc1ccc(B(O)O)cc1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
100 ml of a solution of 10 g of p-bromoanisole in anhydrous diethyl ether were added dropwise at reflux under an inert gas atmosphere to a suspension of 1.3 g of Mg turnings in 5 ml of anhydrous diethyl ether, and the mixture was refluxed for 2 hours. The mixture was then poured into a solution of 9.02 ml of triethylborate in 60 ml of anhydrous ether cooled to -70° C. After stirring for one hour at -70° C., then for one hour at ambient temperature, the solution was poured into a mixture of 11 ml of sulfuric acid and 50 g of ice and water and stirring was carried out for one hour. The organic phase was extracted with 100 ml of a saturated aqueous solution of sodium bicarbonate and the aqueous phases were combined and reacidified with 6N hydrochloric acid, followed by extraction with ether, drying and evaporating under reduced pressure to obtain 3.9 g of the expected product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([C@@H:8]([NH2:10])[CH3:9])=[N:6][CH:7]=1.Cl[C:12]1[N:17]=[C:16]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)[C:15]([CH3:25])=[CH:14][N:13]=1.CCN(C(C)C)C(C)C>CCCCO>[F:1][C:2]1[CH:3]=[N:4][C:5]([C@@H:8]([NH:10][C:12]2[N:17]=[C:16]([NH:18][C:19]3[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=3)[C:15]([CH3:25])=[CH:14][N:13]=2)[CH3:9])=[N:6][CH:7]=1
Reactant: Cc1cc(Nc2nc(Cl)ncc2C)n[nH]1
Reactant: C[C@H](N)c1ncc(F)cn1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2nc(N[C@@H](C)c3ncc(F)cn3)ncc2C)n[nH]1
Temperature: 180 °C
Yield: 36.3 %

Procedure:
A microwave reaction vessel was charged with (S)-1-(5-fluoropyrimidin-2-yl)ethanamine (Method 7, 111 mg, 0.63 mmol), 2-chloro-5-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Method 22, 0.50 g, 1.77 mmol), and DIPEA (0.225 mL, 1.26 mmol). Anhydrous n-BuOH (2.1 ml) was added, and the tube was sealed and heated in a microwave reactor at 180° C. for 4 hours. The solvent was removed under reduced pressure and the residue was purified by Gilson (5-95% MeCN/H2O, 15 minutes) to give the titled compound as solid (75 mg) 1H NMR (300 MHz, DMSO-d6) δ 10.08 (s, 1H) 8.93 (s, 2H) 8.70 (s, 1H) 7.74 (s, 1H) 5.98 (s, 1H) 4.79-5.44 (m, 1H) 2.23 (s, 3H) 2.10 (s, 3H) 1.57 (d, 3H); m/z 330.
Reaction SMILES: O1[C:10]2[C:5](=[CH:6]C=CC=2)[CH2:4]CC1.COCOC1C(C)=C2C(=C(C)C=1C)OC(CCN1CCNCC1)(C)CC2.[C:37]1(=[O:52])[N:41]([O:42][CH2:43][C:44]([OH:46])=[O:45])[C:40](=[O:47])[C:39]2=[CH:48][CH:49]=[CH:50][CH:51]=[C:38]12.ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.CO.CCOC(C)=O>[C:40]1(=[O:47])[N:41]([O:42][CH2:43][C:44]([O:46][C:5]([CH3:10])([CH3:6])[CH3:4])=[O:45])[C:37](=[O:52])[C:38]2=[CH:51][CH:50]=[CH:49][CH:48]=[C:39]12
Reactant: O=C(O)CON1C(=O)c2ccccc2C1=O
Reactant: c1ccc2c(c1)CCCO2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: COCOc1c(C)c(C)c2c(c1C)CCC(C)(CCN1CCNCC1)O2
Agent: O=C1CCC(=O)N1O
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)CON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Yield: 143.7 %

Procedure:
To a solution of chroman (compound 5) (5.0 g, 13.8 mmole) in dichloromethane (30 ml), compound 7 (3.5 g, 16 mmole) and N-hydroxysuccinimide (1.8 g, 16 mmole) were added, as shown in FIG. 7. The mixture was stirred at room temperature until the formation of a clear solution and then 1,3-dicyclohexylcarbodiimide (16 ml, 1.0 N in dichloromethane, 16.0 mmole) was added. The mixture was stirred at room temperature overnight. The white solid was removed by filtration, and the solvent was evaporated under reduced pressure. The residue was dissolved in chloroform (100 ml), and the solution was washed by saturated NaHCO3 (100 ml) and H2O (100 ml). The organic solvent was evaporated to dryness to give a yellow glass. This yellow glass was passed through a silica column with MeOH/EtOAc (5/95) to give a yellow glass as product 8 (5.5 g, 70% yield). The compound was characterized as NMR and MS as follows: 1) C-NMR (CDCl3): 11.983, 12.861, 13.729, 20.117, 23.550, 30.055, 35.951, 41.494, 45.291, 52.196, 52.087, 57.051, 73.411, 75.309, 99.049, 116.801, 122.420, 123.437, 125.719, 127.671, 128.283, 134.187, 146.465, 147.220, 162.451, 163.470 ppm; 2) H-NMR (CDCl3): 1.244 (s, 3H), 1.790 (m, 4H), 2.052 (s, 3H), 2.119 (s, 3H), 2.157 (s, 3H), 2.9-2.6 (m, 8H), 3.586 (s, 3H), 3.62 (b, 2H), 3.72 (b, 2H), 4.813 (s, 2H), 4.825 (s, 2H), 7.726 (m, 2H), 7.803 (m, 2H) ppm; and 3) MS (ESI): 566.4 [M+H]+, 588.4 [M+Na]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])[CH2:10][C:6]=2[C:5]([F:23])=[C:4](Cl)[N:3]=1.[NH:25]1[CH2:29][CH2:28][C@H:27]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:26]1>C(#N)C>[Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])[CH2:10][C:6]=2[C:5]([F:23])=[C:4]([N:25]2[CH2:29][CH2:28][C@H:27]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])[CH2:26]2)[N:3]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: COc1ccc(CN2Cc3c(F)c(Cl)nc(Cl)c3C2=O)c(OC)c1
Solvent: CC#N
Product: COc1ccc(CN2Cc3c(F)c(N4CC[C@H](NC(=O)OC(C)(C)C)C4)nc(Cl)c3C2=O)c(OC)c1
Temperature: 100 °C
Yield: 55.8 %

Procedure:
A tube containing 4,6-dichloro-2-(2,4-dimethoxybenzyl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one (300 mg, 0.808 mmol) and (S)-tert-butyl pyrrolidin-3-ylcarbamate (301 mg, 1.616 mmol) dissolved in ACN (4 mL) was sealed and heated at 100° C. for 2 d. The reaction mixture was concentrated and dissolved in EtOAc (20 mL) and washed with saturated aq NaHCO3 (10 mL) and brine (10 mL). The organic extracts were dried over Na2SO4 and evaporated to give a crude product, which was purified via preparative HPLC. Pure fractions were collected and evaporated to give the title compound (235 mg, 55.8%). [M+H] calc'd for C25H30ClFN4O5, 521. found, 521.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].[C:38](Cl)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>ClCCl.CO>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:38](=[O:45])[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)NC(=O)c3ccccc3)cc1)n2C)c1ccccn1
Yield: 62 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)amide hydrochloride and benzoyl chloride. Yield: 62% of theory, C33H31N7O4 (589.7); Rf value: 0.50 (silica gel; dichloromethane/methanol=9:1); EKA mass spectrum: (M+H)+=590; (M+Na)+=612.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([N+:8]([O-])=O)[C:5]([O:11][CH2:12][C:13]([O:15]CC)=O)=[CH:4][CH:3]=1>CC(O)=O.CCOC(C)=O.[Fe]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:12][C:13](=[O:15])[NH:8][C:6]=2[N:7]=1
Reactant: CCOC(=O)COc1ccc(Br)nc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C1COc2ccc(Br)nc2N1
Temperature: 90 °C

Procedure:
Ethyl (6-bromo-2-nitro-pyridin-3-yloxy)acetate (38 g, 0.125 mole) was dissolved in glacial AcOH (150 mL), and iron powder (20 g, 0.36 mole) was added. The mixture was mechanically stirred and heated at 90° C. for 5 hr, then was cooled to room temperature and diluted with EtOAc (300 mL). The mixture was filtered through a pad of silica gel and the filtrate was concentrated in vacuo and the residue recrystallized from MeOH (15 g, 52%); MS (ES) m/z229.0 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12](=[O:13])[C:11]([CH3:15])([CH3:14])[O:10][C:9]=2[C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.Cl[CH2:36][C:37]1[N:38]=[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][N:40]2[CH:45]=1>O>[N:38]1[C:37]([CH2:36][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:12](=[O:13])[C:11]([CH3:14])([CH3:15])[O:10][C:9]=3[C:16]3[CH:17]=[CH:18][C:19]([C:20]#[N:21])=[CH:22][CH:23]=3)=[CH:6][CH:7]=2)=[CH:45][N:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=12
Reactant: CC1(C)OC(c2ccc(C#N)cc2)=C(c2ccc(O)cc2)C1=O
Reactant: ClCc1cn2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)OC(c2ccc(C#N)cc2)=C(c2ccc(OCc3cn4ccccc4n3)cc2)C1=O
Temperature: 80 °C
Yield: 60.2 %

Procedure:
4-(3-(4-Hydroxyphenyl)-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile (3.15 g, 10.3 mmol) was added to a mixture of cesium carbonate (13.4 g, 41.3 mmol) and DMF (100 mL) at RT under an atmosphere of nitrogen. The reaction mixture was stirred at RT for 30 min upon which 2-(chloromethyl)imidazo[1,2-a]pyridine (2.0 g, 12.3 mmol) was added. The mixture was heated at 80° C. for 4 h (the reaction was monitored by TLC). The reaction mixture was diluted with water and extracted with EtOAc, the combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 20% ethyl acetate in n-hexane and silica gel (230-400 mesh) to afford 4-(3-(4-(imidazo[1,2-a]pyridin-2-ylmethoxy)phenyl)-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile (2.7 g, 60%,) as an off-white solid. 1H NMR: 500 MHz, DMSO-d6: δ 8.55 (d, 1H), 8.0 (s, 1H), 7.55 (Ar, 3H), 7.3-6.85 (Ar, 8H), 5.15 (s, 2H), 1.25 (s, 6H). MS: [M+H]+: m/z=436.2. HPLC: (97.3%, Condition-A).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[NH:11][CH2:12][CH:13]=[CH2:14])([O-:3])=[O:2].[CH2:15](Br)[CH:16]=[CH2:17].C(=O)([O-])[O-].[K+].[K+].[N+]([C:28]1[CH:29]=C(NCCO)C=C[C:33]=1N(CC=C)CC=C)([O-])=O>C(O)C>[N+:1]([C:4]1[CH:9]=[C:8]([N:10]([CH2:29][CH:28]=[CH2:33])[CH2:15][CH:16]=[CH2:17])[CH:7]=[CH:6][C:5]=1[NH:11][CH2:12][CH:13]=[CH2:14])([O-:3])=[O:2]
Reactant: C=CCBr
Reactant: C=CCN(CC=C)c1ccc(NCCO)cc1[N+](=O)[O-]
Reactant: C=CCNc1ccc(N)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C=CCNc1ccc(N(CC=C)CC=C)cc1[N+](=O)[O-]

Procedure:
A mixture consisting of N-(2-nitro-4-aminophenyl)-allylamine (1.9 g, 0.01 mole), allyl bromide (2.4 g, 0.02 mole) and potassium carbonate (2.8 g, 0.02 mole) was boiled under reflux for 7 hours in 20 ml of ethanol. Working up was carried out in the same way as for compound 4. Yellow crystals, melting point 131°-140° C.