Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[C@@H:13]1[CH2:15][O:14]1.[O:16]1[C:20]2([CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[O:19][CH2:18][CH2:17]1.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>ClCCl>[O:16]1[C:20]2([CH2:25][CH2:24][N:23]([CH2:15][C@@H:13]([C:6]3[C:5]4[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)[OH:14])[CH2:22][CH2:21]2)[O:19][CH2:18][CH2:17]1
Reactant: COc1ccc2nccc([C@@H]3CO3)c2c1
Reactant: C1CC2(CCN1)OCCO2
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: ClCCl
Product: COc1ccc2nccc([C@@H](O)CN3CCC4(CC3)OCCO4)c2c1
Reaction time: 6 h

Procedure:
[R]-2-(6-Methoxyquinolin-4-yl)oxirane (1b) (470 mg) and 1,4-dioxa-8-azaspiro-[4,5]-decane (0.33 ml) were dissolved in dry dichloromethane (5 ml) and ytterbium triflate (30 mol %) was added. The mixture was stirred for 6 hours, filtered through celite, evaporated and chromatographed on silica gel (dichloromethane then methanol-dichloromethane) to afford the title compound (690 mg).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([O:18][C:19]([NH:21][C@H:22]([CH2:30][OH:31])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl.CCOCC.C(N(CC)CC)C>[CH2:11]([O:18][C:19]([NH:21][C@H:22]([CH:30]=[O:31])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:20])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(N[C@H](CO)Cc1ccccc1)OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 103.2 %

Procedure:
To a solution of 1.8 ml of dimethyl sulfoxide in 20 ml of dichloromethane cooled to -78° C. was added slowly 1.65 ml of oxalyl chloride. The solution was stirred for 10 min at -78° C. and a solution of 3.6 g (0.012 mol) of N-((benzyloxy)carbonyl)-L-phenylalaninol in 45 ml of dichloromethane was added slowly. The resulting solution was stirred at -78° C. for 15 min, then 1 min at 0° C., recooling to -78° C. and 7.6 ml of triethylamine was added over 10 min. After stirring at -78° C. for 25 min, 20 ml of cold 10% aq. citric acid solution was added. After warming to 0° C., 200 ml of ether and 55 ml of cold 10% citric acid added. The organic layer was separated by separatory funnel and washed repeatedly (5×60 ml) with water and finally with satd. NaCl solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo at RT to give 3.51 g of the desired compound as an off-white solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8]([N:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:18]=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=4)=[CH:13][C:12]3=[O:27])=[CH:9][CH:10]=[C:5]2[C:4]2[CH2:28][N:29](C(OC(C)(C)C)=O)[CH2:30][CH2:31][C:3]1=2>C(Cl)Cl.CO.Cl.CCOCC>[CH3:1][N:2]1[C:6]2=[N:7][C:8]([N:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:18]=[N:19][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:21][CH:22]=4)=[CH:13][C:12]3=[O:27])=[CH:9][CH:10]=[C:5]2[C:4]2[CH2:28][NH:29][CH2:30][CH2:31][C:3]1=2
Reactant: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)nc5)cc4=O)nc31)CN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: CCOCC
Product: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)nc5)cc4=O)nc31)CNCC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.5 %

Procedure:
To a solution of tert-butyl 9-methyl-2-(2-oxo-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-1(2H)-yl)-5,7,8,9-tetrahydro-6H-pyrido[3′,4′:4,5]pyrrolo[2,3-b]pyridine-6-carboxylate (0.81 g, 1.6 mmol) in CH2Cl2 (8.0 mL) was added 1.25 M HCl in MeOH (30 mL), and the resulting suspension was stirred at ambient temperature for 18 h. The suspension was diluted with CH2Cl2 (18 mL), 1.25 M HCl in MeOH (6.0 mL) was added, and the resulting suspension was stirred at ambient temperature for 72 h. The suspension was diluted with Et2O (50 mL), and the resulting solids were collected by filtration, dissolved in CH2Cl2 (30 mL), and washed with saturated NaHCO3 solution (50 mL). The resulting layers were separated, and the organic layer was concentrated under reduced pressure to dryness. Flash chromatography (40 g ISCO column, CH2Cl2/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 1 column volume, increased to 0:100 over 12 column volumes and held for 30 column volumes) provided the title compound (0.50 g, 75%) as a yellow powder: 1H NMR (500 MHz, DMSO-d6) δ 9.20 (d, J=2.0 Hz, 1H), 8.50 (dd, J=8.0, 2.0 Hz, 1H), 8.10-8.02 (m, 2H), 7.94 (d, J=8.0 Hz, 1H), 7.35 (d, J=8.5 Hz, 1H), 7.02 (d, J=2.0 Hz, 1H), 6.83 (dd, J=7.5, 20 Hz, 1H), 3.89 (s, 2H), 3.68 (s, 3H), 3.09 (t, J=5.5 Hz, 2H), 2.76 (t, J=5.5 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1.CO>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:31]([NH:30][C:27]2[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=2)=[O:32])=[CH:18][CH:17]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cc2ncnc(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3)c2cc1OC
Yield: 36 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in chloroform (3 ml), and p-fluorophenyl isocyanate (23 μl) was then added to the solution. The mixture was heated under reflux overnight. Methanol was added to the reaction solution, and the mixture was purified by HPLC by development with chloroform/methanol to give 26 mg (yield 36%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.S(=O)(=O)(O)O.[C:16](=O)(O)[O-].[Na+]>CO>[NH2:1][C:2]1[C:7]([C:8]([O:10][CH3:16])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=C([O-])O
Reactant: Nc1ncccc1C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cccnc1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a solution of 2-aminopyridine-3-carboxylic acid (4.3 g, 31 mmol) in methanol (62 mL) was added dropwise sulfuric acid (31 mL) under ice-cooling, and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was stirred at 70° C. for 15 hr. and neutralized with sodium bicarbonate under ice-cooling. The reaction mixture was extracted twice with ethyl acetate, and the extracts were combined, and washed with brine. The extract was dried over magnesium sulfate, and concentrated under reduced pressure to give the title compound (4.3 g, 90%) as a white solid.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C@@H:16]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([N:35]([CH3:46])[C:36]([NH:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=[O:37])[CH:30]=2)=[CH:25][CH:24]=1)[C:17]([O:19]CC)=[O:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+].Cl>O1CCCC1.CO.O>[C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C@@H:16]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([N:35]([CH3:46])[C:36]([NH:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=[O:37])[CH:30]=2)=[CH:25][CH:24]=1)[C:17]([OH:19])=[O:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(C[C@H](Nc3ccccc3C(=O)c3ccccc3)C(=O)OCC)cc2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(C[C@H](Nc3ccccc3C(=O)c3ccccc3)C(=O)O)cc2)c1
Reaction time: 6 h
Yield: 77.5 %

Procedure:
0.75 g (1.2 mmol) of ethyl (S)-2-(2-benzoylphenylamino)-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propionate (Example 1H) is dissolved in a mixture of 10 ml of tetrahydrofuran, 1 ml of methanol and a few drops of water. 86 mg (2 mmol) of lithium hydroxide are added. The medium is stirred for 6 h and then treated with an aqueous 1N hydrochloric acid solution, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated. The residue obtained is purified by chromatography on a column of silica and eluted with a 1/1 heptane/ethyl acetate mixture. 0.55 g of (S)-2-(2-benzoylphenylamino)-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl)propionic acid is obtained with a 77% yield.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]=1[OH:18])([O-])=O.[Sn](Cl)Cl.[OH-].[Na+]>C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:5]=1[OH:18]
Reactant: O=[N+]([O-])c1cccc(OCc2ccccc2)c1O
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cccc(OCc2ccccc2)c1O
Temperature: 80 °C
Reaction time: 2 h
Yield: 153 %

Procedure:
A mixture of 2-nitro-6-benzyloxyphenol (1.00 g, 4.10 mmol) and tin (II) chloride (2.75 g, 12.2 mmol) in ethanol(150 mL) was heated at 80° C. under argon. After 2 hours, the starting material had disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH7-8), by addition of solid NaOH, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/CH2Cl2) gave the desired product(1.35 g, 88%). 1H NMR (CD3OD): δ7.46 (d, 2H), 7.40-7.35 (m, 5H), 6.55 (d, 1H), 6.40 (d, 1H), 5.10 (s, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C@H:15]([C:20]([O:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:21])[CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:9]1)=O)(C)(C)C.[ClH:28]>ClCCl.O1CCOCC1>[ClH:28].[ClH:28].[NH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C@H:15]([C:20]([O:22][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)=[O:21])[CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:9]1
Reactant: CC(C)C[C@H](NC1CCCN(C(=O)OC(C)(C)C)C1)C(=O)OC1CCCC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)C[C@H](NC1CCCNC1)C(=O)OC1CCCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 24 %

Procedure:
To a solution of 3-((S)-1-cyclopentyloxycarbonyl-3-methyl-butylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.840 g, 2.20 mmol) in dichloromethane (5 mL) was added 4M hydrogen chloride in dioxane (10 mL). The reaction was stirred at room temperature for 90 minutes and then concentrated to give the product (184 mg, 24% yield). LC/MS: m/z 283 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[C:16]([CH3:35])=[C:17]([CH3:34])[C:18]4[O:22][C:21]([CH2:24][N:25]5[CH2:30][CH2:29][C:28](=[O:31])[CH2:27][CH2:26]5)([CH3:23])[CH2:20][C:19]=4[C:32]=3[CH3:33])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.B.[Na]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:10][CH2:11][N:12]([C:15]3[C:16]([CH3:35])=[C:17]([CH3:34])[C:18]4[O:22][C:21]([CH2:24][N:25]5[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27][CH2:26]5)([CH3:23])[CH2:20][C:19]=4[C:32]=3[CH3:33])[CH2:13][CH2:14]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)CC(C)(CN3CCC(=O)CC3)O4)CC2)cc1
Agent: B
Agent: [Na]
Solvent: CCO
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)CC(C)(CN3CCC(O)CC3)O4)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.8 %

Procedure:
To a solution of ethanol (2.0 mL) containing 1-({5-[4-(4-methoxyphenyl)piperazin-1-yl]-2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran-2-yl}methyl)piperidine-4-one (30 mg, 0.0628 mmol) synthesized in Example 132, sodium boron hydride (10 mg, 0.264 mmol) was added, and the mixture was stirred at room temperature for 1 hour. After that, the reaction solution was concentrated under reduced pressure, and the residue was distributed using ethyl acetate and water. The organic layer was washed with water and saturated saline, and then dried using anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel chromatography (hexane-ethyl acetate 65:35-0:100) and crystallized from ethyl acetate-hexane to give 15 mg of the title compound (yield 50%). Melting point was 139 to 143° C.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C:22]1=[O:27])=[O:19])C1C=CC=CC=1>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C:22]1=[O:27])=[O:19]
Reactant: O=C(NN1CCCCC1=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=C(NN1CCCCC1=O)[C@@H]1CC[C@@H]2CN1C(=O)N2O
Reaction time: 2 h
Yield: 88.6 %

Procedure:
To a solution of compound 257 (55 mg, 0.148 mmol) in 10 mL of MeOH was added 100 mg of Pd/C (10%, wet). The mixture was hydrogenated at room temperature for 2 h. The catalyst was removed by filtration through Celite pad. The filtrate was concentrated to afford compound 258 as a colorless gum (37 mg, 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=S.C(N(CC)CC)C.CS(Cl)(=O)=O>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:17])([F:19])[F:18])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:4][C:3]=1[N:22]=[C:23]=[N:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CCOC(=O)CNC(=S)Nc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CN=C=Nc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100.3 %

Procedure:
A solution of N-{{2-chloro-5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-4-fluorophenyl}(thiocarbamoyl)}glycine, ethyl ester (5.0 g, 10.4 mmol) in methylene chloride is treated sequentially with triethylamine (4.3 mL, 31.1 mmol), 4-dimethylaminopyridine (0.05 g) and methanesulfonyl chloride (1.6 mL, 20.7 mmol) stirred at room temperature for 10 minutes, and partially concentrated in vacuo to obtain a heterogeneous mixture. The heterogeneous mixture is placed onto silica gel and eluted with methylene chloride. The resultant solution is concentrated in vacuo to give the title product as an amber syrup (4.68 g) which is identified by 1H and 13C NMR spectral analyses.
Reaction SMILES: I[C:2]1[C:7](=[O:8])[C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[O:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=O)=O)=[CH:15][CH:14]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.FC1C=CC(B(O)O)=CC=1>>[CH3:22][S:19][C:16]1[CH:17]=[CH:18][C:13]([C:3]2[O:4][C:5]3[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=3[C:7](=[O:8])[C:2]=2[C:28]2[CH:29]=[CH:30][C:25]([C:24]([F:35])([F:34])[F:23])=[CH:26][CH:27]=2)=[CH:14][CH:15]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CS(=O)(=O)c1ccc(-c2oc3ccccc3c(=O)c2I)cc1
Agent: OB(O)c1ccc(F)cc1
Product: CSc1ccc(-c2oc3ccccc3c(=O)c2-c2ccc(C(F)(F)F)cc2)cc1

Procedure:
Following the procedure of Example 1, Step 5, but substituting 3-bromo-2-(4-(methylthio)phenyl)-4H-1-benzopyran-4-one(0.1 g, 0.32 mmol) for 3-iodo-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one and 4-trifluoromethylbenzeneboronic acid(0.066 g, 0.35 mmol) for 4-fluorobenzeneboronic acid, the title compound was obtained as a solid(0.05 g, 40%).
Reaction SMILES: IC1C=CC(C2NC([C@@H](N3C(=O)[C@@H](CCC(O)=O)NC3=O)C(C)C)=NC=2)=CC=1.C1(C[C@H]2NC(=O)[N:35]([C@H:39]([C:48]3[NH:49][C:50]([C:54]4[CH:59]=[CH:58][C:57]([I:60])=[CH:56][C:55]=4[F:61])=[C:51]([CH3:53])[N:52]=3)[C@H:40]([C:42]3C=CC=CC=3)[CH3:41])C2=O)CC1.C(O[C:68]([NH:70][C@H:71]([C:75]1[CH:80]=[CH:79][C:78]([O:81][CH2:82][C:83](=[O:87])N(C)C)=[CH:77][CH:76]=1)[C:72]([OH:74])=O)=[O:69])(C)(C)C.ClN1C(=O)CCC1=O>>[F:61][C:55]1[CH:56]=[C:57]([I:60])[CH:58]=[CH:59][C:54]=1[C:50]1[NH:49][C:48]([C@@H:39]([N:35]2[C:72](=[O:74])[C@@H:71]([C:75]3[CH:76]=[CH:77][C:78]([O:81][CH2:82][CH2:83][OH:87])=[CH:79][CH:80]=3)[NH:70][C:68]2=[O:69])[CH:40]([CH3:41])[CH3:42])=[N:52][C:51]=1[CH3:53]
Reactant: Cc1nc([C@H]([C@@H](C)c2ccccc2)N2C(=O)N[C@H](CC3CC3)C2=O)[nH]c1-c1ccc(I)cc1F
Reactant: CN(C)C(=O)COc1ccc([C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Agent: CC(C)[C@@H](c1ncc(-c2ccc(I)cc2)[nH]1)N1C(=O)N[C@H](CCC(=O)O)C1=O
Agent: O=C1CCC(=O)N1Cl
Product: Cc1nc([C@H](C(C)C)N2C(=O)N[C@H](c3ccc(OCCO)cc3)C2=O)[nH]c1-c1ccc(I)cc1F

Procedure:
Prepared by the same method as described in example 1 except that (i) steps A, B and C were omitted; (ii) 1-(2-fluoro-4-iodo-phenyl)-propan-1-one (prepared as described in example 13) was used in place of 1-(2-fluoro-4-iodo-phenyl)-ethanone in step 59-D; (iii) (S)-2-tert-butoxycarbonylamino-3-methylbutyric acid was used in place of (2S,3S)-2-tert-butoxycarbonylamino-3-phenyl-butyric acid in step 59-E and (iv) chlorination of the 5-position of the imidazole ring with N-chlorosuccinimide in step 59-F was omitted. HR-MS: calcd for C25H26FlN4O4 [M+H+] 593.1056. Found 593.1052.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:10](=O)[CH2:9][CH:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[CH2:7][C:6]=2[N:5]=[CH:4][CH:3]=1.[C:19]([NH:22][NH2:23])([NH2:21])=[NH:20].[ClH:24].Cl.O>C(O)C>[ClH:24].[NH:22]([N:23]=[C:10]1[CH2:9][CH:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:7][C:6]2[N:5]=[CH:4][CH:3]=[C:2]([CH3:1])[C:11]1=2)[C:19]([NH2:21])=[NH:20]
Reactant: N=C(N)NN
Reactant: Cc1ccnc2c1C(=O)CC(c1ccccn1)C2
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1ccnc2c1C(=NNC(=N)N)CC(c1ccccn1)C2
Yield: 95.2 %

Procedure:
A mixture of 4-methyl-7-(2-pyridyl)-5,6,7,8-tetrahydroquinolin-5-one (0.28 g), aminoguanidine hydrochloride (0.14 g), concentrated hydrochloric acid (0.41 ml), water (0.41 ml) and ethanol (30 ml) was refluxed for 6 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water. The solution was washed with ethyl acetate and concentrated under reduced pressure, and the residue was recrystallized from water-ethanol to give 5-guanidinoimino-4-methyl-7-(2-pyridyl)-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 75) (0.37 g) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:6](=[O:7])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][C:15]=2[F:22])[O:3]1.ClC1C=C(C=CC=1)C(OO)=[O:29].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:1][C:2]1([CH3:23])[C:6](=[O:7])[C:5]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:21])=[O:29])=[CH:16][C:15]=2[F:22])[O:3]1
Reactant: CSc1ccc(C2=C(c3ccccc3)C(=O)C(C)(C)O2)c(F)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)c1ccc(C2=C(c3ccccc3)C(=O)C(C)(C)O2)c(F)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 74 %

Procedure:
To 241 mg of 2,2-dimethyl-5-{2-fluoro-4-(methylthio)phenyl}-4-phenyl-3(2H)-furanone (Example 314) dissolved in 50 ml dichloromethane, was added 138 mg of 70% m-chloroperoxybenzoic acid. The mixture was stirred at 0° C. for 1.5 hours, which was followed by addition of 30 ml 5% aqueous sodium bicarbonate. Then the mixture was stirred for 10 minutes and the volatile material was removed in vacuo. The resulting residue was extracted with 50 ml water and dichloromethane (30 ml×3). The organic layer was concentrated under reduced pressure, and then was purified by column chromatographic separation (hexane/ethylacetate=1:1) to afford 187 mg of 2,2-dimethyl-5-{2-fluoro-4-(methylsulfinyl)phenyl}-4-phenyl-3(2H)-furanone as a solid. mp: 149-150° C. NMR: δ1.55 (s, 6H), 2.78 (s, 3H), 7.26 (m, 5H), 7.47 (m, 2H), 7.69 (dd, J=8.4, 6.6 Hz, 2H). IR (cm−1): 1700, 1621, 1380, 1223, 1161, 1075.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:22]2[CH:26]=[C:25]([C:27]3[CH:32]=[CH:31][N:30]=[C:29]4[N:33](COCC[Si](C)(C)C)[CH:34]=[CH:35][C:28]=34)[CH:24]=[N:23]2)[CH2:7][N:6]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([NH:16][C@H:17]([CH:19]3[CH2:21][CH2:20]3)[CH3:18])=[O:15])=[N:12][CH:13]=2)[CH2:5]1)#[N:2].C(O)(C(F)(F)F)=O>>[C:1]([CH2:3][C:4]1([N:22]2[CH:26]=[C:25]([C:27]3[CH:32]=[CH:31][N:30]=[C:29]4[NH:33][CH:34]=[CH:35][C:28]=34)[CH:24]=[N:23]2)[CH2:5][N:6]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([NH:16][C@H:17]([CH:19]3[CH2:20][CH2:21]3)[CH3:18])=[O:15])=[N:12][CH:13]=2)[CH2:7]1)#[N:2]
Reactant: C[C@H](NC(=O)c1ccc(N2CC(CC#N)(n3cc(-c4ccnc5c4ccn5COCC[Si](C)(C)C)cn3)C2)cn1)C1CC1
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](NC(=O)c1ccc(N2CC(CC#N)(n3cc(-c4ccnc5[nH]ccc45)cn3)C2)cn1)C1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-{3-(Cyanomethyl)-3-[4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[(1S)-1-cyclopropylethyl]pyridine-2-carboxamide (0.350 g, 0.75 mmol) was dissolved in dichloromethylene (3 mL). To the solution was added TFA (1.5 mL). The mixture was stirred at room temperature for 2 hours. The volatiles were evaporated under reduced pressure. The residue was dissolved in methanol (5 mL), and ethylenediamine (1.0 mL) was added. The mixture was stirred at room temperature overnight, and was purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+: m/z 467.3.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:6]=[CH:7][C:8]3[O:17][CH2:16][CH2:15][C:14]4[N:10]([N:11]=[C:12]([C:18]5[N:19]([CH:23]([CH3:25])[CH3:24])[N:20]=[CH:21][N:22]=5)[CH:13]=4)[C:9]=3[CH:26]=2)[CH2:2]1.[CH:27]([S:29]([CH:32]=C)(=[O:31])=[O:30])=[CH2:28]>>[CH:23]([N:19]1[C:18]([C:12]2[CH:13]=[C:14]3[N:10]([C:9]4[CH:26]=[C:5]([CH:3]5[CH2:2][N:1]([CH2:28][CH2:27][S:29]([CH3:32])(=[O:31])=[O:30])[CH2:4]5)[CH:6]=[CH:7][C:8]=4[O:17][CH2:16][CH2:15]3)[N:11]=2)=[N:22][CH:21]=[N:20]1)([CH3:24])[CH3:25]
Reactant: CC(C)n1ncnc1-c1cc2n(n1)-c1cc(C3CNC3)ccc1OCC2
Reactant: C=CS(=O)(=O)C=C
Product: CC(C)n1ncnc1-c1cc2n(n1)-c1cc(C3CN(CCS(C)(=O)=O)C3)ccc1OCC2

Procedure:
Following the procedure for 152, 9-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene was reacted with vinyl sulfone to give 157 as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.01 (d, J=0.64 Hz, 1 H); 7.84 (d, J=2.19 Hz, 1 H); 7.36 (dd, J=8.32, 2.21 Hz, 1 H); 7.21 (d, J=8.30 Hz, 1H); 6.87 (s, 1 H); 5.60-5.51 (m, 1 H); 4.48 (t, J=6.03 Hz, 2 H); 3.67 (s, 3 H); 3.20-3.10 (m, 6 H); 3.03 (s, 3 H); 2.83 (t, J=6.83 Hz, 2 H); 1.48 (d, J=6.58 Hz, 6 H). LCMS: RT=5.99 min, M+H+=457
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:9][C@H:10]([CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:37]=[N:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=2)=[CH:32][CH:31]=1)[C@H:11]([CH2:15][CH2:16][N:17]1[C:22](=[O:23])[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]=[N:18]1)[C:12]([OH:14])=[O:13])=O.O1CCCC1>CO>[OH:9][C@H:10]([CH2:28][CH2:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]2[CH:37]=[N:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=2)=[CH:34][CH:35]=1)[C@H:11]([CH2:15][CH2:16][N:17]1[C:22](=[O:23])[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]=[N:18]1)[C:12]([OH:14])=[O:13]
Reactant: COc1ccc(-c2ccc(CC[C@@H](OC=O)[C@H](CCn3nnc4ccccc4c3=O)C(=O)O)cc2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(CC[C@@H](O)[C@H](CCn3nnc4ccccc4c3=O)C(=O)O)cc2)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Potassium carbonate (2.3 g) was added to a solution of the compound obtained from step e above (8 g) in methanol (40 mL) and tetrahydrofuran (30 mL) at 0° C. The reaction mixture was stirred at room temperature for 3 hours. The solvents were evaporated, and the residue was taken into water and ethyl acetate. The organic layer was washed with water and brine solution and dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure to obtain a residue which was purified by column chromatography over silica gel using 60% ethyl acetate in hexane as eluant to afford the title compound (3 g).