Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.C([N:10]1[CH2:15][CH2:14][C@@H:13]([CH3:16])[C@@H:12]([N:17]([CH3:27])[C:18]2[CH:23]=[CH:22][N:21]=[C:20]3[NH:24][CH:25]=[N:26][C:19]=23)[CH2:11]1)C1C=CC=CC=1.C1CC=CCC=1>C(O)C.[OH-].[OH-].[Pd+2]>[ClH:1].[ClH:1].[CH3:27][N:17]([C@@H:12]1[C@H:13]([CH3:16])[CH2:14][CH2:15][NH:10][CH2:11]1)[C:18]1[CH:23]=[CH:22][N:21]=[C:20]2[NH:24][CH:25]=[N:26][C:19]=12
Reactant: C[C@@H]1CCN(Cc2ccccc2)C[C@@H]1N(C)c1ccnc2[nH]cnc12
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: C1=CCC=CC1
Solvent: CCO
Product: C[C@@H]1CCNC[C@@H]1N(C)c1ccnc2[nH]cnc12
Temperature: 25 °C
Yield: 94.8 %

Procedure:
In a microwave reaction vessel, to a solution of rel-N-[(3R,4R)-1-benzyl-4-methyl-3-piperidinyl]-N-methyl-3H-imidazo[4,5-b]pyridin-7-amine dihydrochloride (130 mg) in ethanol (1.3 mL) were added 1,4-cyclohexadiene (1.5 mL) and palladium hydroxide on carbon (130 mg). The vessel was sealed and reacted in the microwave reactor at 110° C. for 0.5 hour. The reaction mixture was cooled to ambient temperature and filtrated through a pad of Celite. The filtrate was concentrated under reduced pressure and the residue was washed with diisopropyl ether to give N-methyl-N-[(3R,4R)-4-methyl-3-piperidinyl]-3H-imidazo[4,5-b]pyridin-7-aminedihydrochloride (48 mg) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[F:27])[CH:12]([CH3:19])[CH2:13][CH2:14][CH2:15][S:16]([CH3:18])=[O:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:36])C=1.C(OCC)C.C(Cl)Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[F:27])[CH:12]([CH3:19])[CH2:13][CH2:14][CH2:15][S:16]([CH3:18])(=[O:36])=[O:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(CCCS(C)=O)C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(CCCS(C)(=O)=O)C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.2 %

Procedure:
The 2-[1-[(4-chlorophenyl)sulfonyl]-2-methyl-5-(methylsulfinyl)pentyl]-1,4-difluorobenzene (76 mg, 0.18 mmol) obtained in Example 44 was dissolved in methylene chloride (5 ml). Under ice cooling, 3-chloroperbenzoic acid (36 mg, 0.21 mmol) was added. The resulting mixture was stirred at room temperature for 2 hours. The residue obtained by concentrating the reaction mixture was purified by silica gel chromatography (methylene chloride:methanol=100:1) to yield a pale yellowish brown oil. The resulting pale yellowish brown oil was solidified with diethyl ether/methylene chloride, whereby the title compound (61 mg, 77%) was obtained as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:6][N:7]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:8][CH2:9][C:10]=1[NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:4].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C.C(O)(=O)C>[CH3:1][O:2][C:3]([C@H:5]1[C@@H:10]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9][CH2:8][N:7]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:6]1)=[O:4]
Reactant: COC(=O)C1=C(NCc2ccccc2)CCN(C(=O)OC(C)(C)C)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: COC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NCc1ccccc1
Reaction time: 1.75 h

Procedure:
A solution of crude 4-benzylamino-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (3.86 g, approximately 10 mmol) in acetonitrile (30 mL) and acetic acid (20 mL) was stirred on an ice bath and treated with sodium triacetoxyborohydride (4.83 g, 22.5 mmol). After 1.75 hours, additional sodium triacetoxyborohydride (4.82 g, 22.5 mmol) was added. After 2.25 hours, the mixture was concentrated under vacuum, and the residue was diluted with 1.0 N aqueous sodium hydroxide (50 mL), and the mixture was stirred on ice and the pH was adjusted to 10 with 50% aqueous sodium hydroxide. The mixture was extracted with dichloromethane, and the organic phase was dried over sodium sulfate and concentrated to provide an orange gum. Purification by flash chromatography with 40% ethyl acetate in hexane provided a colorless viscous oil (2.86 g, 82% for two steps). 1H NMR (300 MHz, CDCl3) δ7.4-7.3 (m, 5H), 4.03 (m, 1H), 3.88 (ab pattern, 2H), 3.73 (m, 1H), 3.71 (s, 3H), 3.38 (m, 1H), 3.20 (m, 1H), 3.12 (m, 1H), 2.90 (m, 1H), 1.91 (m, 1H), 1.78 (m, 1H), 1.46 (s, 9H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]3[CH:16]=[N:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[C:25]([NH:29][S:30]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)(=[O:32])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([NH:29][S:30]([C:33]1[CH:34]=[CH:35][CH:36]=[C:37]([C:2]2[CH:7]=[C:6]([C:8]3[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]4[CH:16]=[N:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=4)[N:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:38]=1)(=[O:32])=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)nc2)nc(-c2ccnc(Cl)c2)n1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Product: Cc1cc(-c2ccc(C(F)(F)F)nc2)nc(-c2ccnc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c2)n1

Procedure:
3-{4-[4-Methyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonic acid tert-butylamide was prepared from 2-(2-chloro-pyridin-4-yl)-4-methyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine (example B.10) (0.175 g, 0.5 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.15 g, 0.6 mmol) according to the general procedure III. Obtained as off-white solid (0.08 g), which was subsequently deprotected.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:42][O:43][C:44]1[C:45]2[N:58]=[C:57]([NH2:59])[S:56][C:46]=2[C:47]([N:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)=[N:48][CH:49]=1>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:59][C:57]2[S:56][C:46]3[C:47]([N:50]4[CH2:55][CH2:54][O:53][CH2:52][CH2:51]4)=[N:48][CH:49]=[C:44]([O:43][CH3:42])[C:45]=3[N:58]=2)=[O:8])=[CH:9][CH:10]=1
Reactant: COc1cnc(N2CCOCC2)c2sc(N)nc12
Reactant: O=C(O)c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COc1cnc(N2CCOCC2)c2sc(NC(=O)c3ccc(F)cc3)nc12
Reaction time: 8 h
Yield: 57 %

Procedure:
To a stirred solution of 79 mg (0.56 mmol) 4-fluoro-benzoic acid in 4 ml THF were added 225 mg (0.59 mmol) HATU and 0.12 ml (1.13 mmol) N-methylmorpholine and stirring continued at 30° C. for 8 h. 75 mg (0.28 mmol) 7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-ylamine was then added and stirring continued at 35° C. for 48 h. The reaction mixture was then partitioned between tetrahydrofuran and saturated brine. The organic phases was dried over sodium sulfate and concentrated in vacuo. Flash chromatography (ethyl acetate/heptane) followed by trituration in ether afforded 62 mg (56%) 4-fluoro-N-(7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-yl)-benzamide as a white crystalline solid. ES-MS m/e (%): 389 (M+H+, 100).
Reaction SMILES: [OH:1][C@H:2]([C:10]1[CH:19]=[CH:18][C:13]2[C:14](=[O:17])[O:15][CH2:16][C:12]=2[C:11]=1[CH3:20])[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[O:21]1[CH2:23][CH:22]1[C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=1>>[OH:21][CH:22]([C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=1)[CH2:23][N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH:2]([OH:1])[C:10]2[C:11]([CH3:20])=[C:12]3[C:13](=[CH:18][CH:19]=2)[C:14](=[O:17])[O:15][CH2:16]3)[CH2:5][CH2:6]1
Reactant: N#Cc1ccc(C2CO2)cc1
Reactant: Cc1c([C@@H](O)CN2CCNCC2)ccc2c1COC2=O
Product: Cc1c(C(O)CN2CCN(CC(O)c3ccc(C#N)cc3)CC2)ccc2c1COC2=O

Procedure:
4-[1-Hydroxy-2-[4-[2-hydroxy-2-(4-methyl-1-oxo-3H-isobenzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]benzonitrile was prepared in a similar fashion to that described for the synthesis of EXAMPLES 2C and 28-29 starting from 5-[(1R)-1-hydroxy-2-(piperazin-1-yl)ethyl]-4-methyl-2-benzofuran-1(3H)-one and 4-(oxiran-2-yl)benzonitrile.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][N:9]([C:14]3[CH:19]=[CH:18][C:17]([S:20]([N:23]4[CH2:28][CH2:27][CH:26]([CH2:29][NH:30][CH2:31][C@H:32]([OH:45])[C:33]5[CH:38]=[CH:37][C:36]([OH:39])=[C:35](S(C)(=O)=O)[C:34]=5N)[CH2:25][CH2:24]4)(=[O:22])=[O:21])=[CH:16][CH:15]=3)[C:10]=2[CH:11]=[CH:12][CH:13]=1)=[O:4].[OH-:46].[Na+].Cl>CO>[OH:45][C@H:32]([C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[C:35]([NH:23][S:20]([CH3:17])(=[O:21])=[O:46])[CH:34]=1)[CH2:31][NH:30][CH2:29][CH:26]1[CH2:25][CH2:24][N:23]([S:20]([C:17]2[CH:16]=[CH:15][C:14]([N:9]3[C:10]4[CH:11]=[CH:12][CH:13]=[C:5]([C:3]([OH:2])=[O:4])[C:6]=4[CH:7]=[CH:8]3)=[CH:19][CH:18]=2)(=[O:21])=[O:22])[CH2:28][CH2:27]1
Reactant: [OH-]
Reactant: COC(=O)c1cccc2c1ccn2-c1ccc(S(=O)(=O)N2CCC(CNC[C@H](O)c3ccc(O)c(S(C)(=O)=O)c3N)CC2)cc1
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNCC2CCN(S(=O)(=O)c3ccc(-n4ccc5c(C(=O)O)cccc54)cc3)CC2)ccc1O

Procedure:
A solution of 1-[4-(4-{[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonyl-amino-phenyl)-ethylamino]-methyl}-piperidine-1-sulfonyl)-phenyl]-1H-indole-4-carboxylic acid methyl ester (0.118 g, 0.18 mmol) and 0.8 mL of 1N NaOH in 10 mL methanol was heated at reflux overnight. On cooling the reaction was neutralized with 0.8 mL of 1N HCl. The reaction mixture was concentrated in vacuo and triturated with H2O. The solids were filtered and dried (high vac) to give 0.095 g of the title compound as an off white solid.
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[CH:10]=2)=[CH:4][CH:3]=1.O.[NH2:22][NH2:23]>CC(O)C>[NH:22]([C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[CH:10]=2)=[CH:4][CH:3]=1)[NH2:23]
Reactant: Cn1cc(-c2cc(Oc3ccc(F)nc3)ccn2)cn1
Reactant: NN
Solvent: CC(C)O
Solvent: O
Product: Cn1cc(-c2cc(Oc3ccc(NN)nc3)ccn2)cn1
Temperature: 80 °C
Reaction time: 12 h
Yield: 87.1 %

Procedure:
4-((6-Fluoropyridin-3-yl)oxy)-2-(1-methyl-1H-pyrazol-4-yl)pyridine (0.99 g, 3.66 mmol) was dissolved in 2-propanol (7.3 mL) in a screw-cap reaction vessel. Hydrazine hydrate (64%) (0.9 mL, 18.3 mmol) was added, the vessel was sealed, and the reaction mixture was stirred at 80° C. for 12 h. The mixture was partitioned between sat. aqueous NaHCO3 (aq) (30 mL) and EtOAc (30 mL). The organic phase was collected and the aqueous phase was extracted with EtOAc (4×30 mL). The combined organics were dried (Na2SO4) and concentrated in vacuo to afford 4-((6-hydrazinylpyridin-3-yl)oxy)-2-(1-methyl-1H-pyrazol-4-yl)pyridine (0.9 g, 87%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.29 (s, 1H), 8.33 (d, J=5.7 Hz, 1H), 8.23 (s, 1H), 8.00 (d, J=2.9 Hz, 1H), 7.93 (s, 1H), 7.48 (dd, J=9.0, 2.9 Hz, 1H), 7.16 (d, J=2.4 Hz, 1H), 7.12 (d, J=9.0 Hz, 1H), 6.62 (dd, J=5.7, 2.4 Hz, 1H), 4.10 (d, J=4.5 Hz, 2H), 3.84 (s, 3H); MS (ESI) m/z: 283.1 (M+H+).
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5]N(C=O)C.[Br:10][C:11]1[CH:20]=[C:19]([Br:21])[CH:18]=[C:17]2[C:12]=1[CH:13]=[CH:14][CH:15]=[C:16]2[C:22](Cl)=[O:23].Cl.COCN>C(N(CC)CC)C>[C:22]([C:16]1[C:17]2[C:12](=[C:11]([Br:10])[CH:20]=[C:19]([Br:21])[CH:18]=2)[CH:13]=[CH:14][CH:15]=1)(=[O:23])[CH3:5]
Reactant: CN(C)C=O
Reactant: O=C(Cl)c1cccc2c(Br)cc(Br)cc12
Agent: COCN
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)c1cccc2c(Br)cc(Br)cc12

Procedure:
The 1-acetyl-5,7-dibromonaphthalene used in the foregoing procedure was prepared by dibromination of benz[cd]-indol-2(1H)-one with bromine in glacial acetic acid to give 41 g of 6,8-dibromobenz[cdindol-2(1H)-one, m.p. 259° C.-260° C. The latter (12.8 g) was heated under reflux for one hour in two liters of 5% potassium hydroxide, the reaction mixture was cooled, filtered and then treated with 2.8 g of a solution of sodium nitrite in 50 ml of water. The resulting solution, cooled to 0° C., was added dropwise to 800 ml of a 40% solution of sulfuric acid while maintaining the temperature at -5° C. The reaction mixture was stirred for one hour, then poured slowly into a solution of 140 g of sodium hypophosphite in 800 ml of water at 0° C. with stirring. The solid which separated was collected by filtration and dissolved in 3 liters of 2% sodium carbonate solution, and the resulting solution was filtered, acidified with concentrated hydrochloric acid and the mixture extracted with ethyl acetate. The combined organic extracts were dried and taken to dryness to give 8 g of 5,7-dibromo-1-naphthalenecarboxylic acid which was heated with thionyl chloride in the presence of a small amount of DMF. The resulting crude 5,7-dibromo1-naphthalenecarboxylic acid chloride, together with 6.0 g of methoxymethylamine hydrochloride in 750 ml of MDC, was treated dropwise at 0° C. with 60 ml of triethylamine in 250 ml of MDC. The reaction mixture was filtered, the filtrate was taken to dryness, and the resulting residue (12.0 g) was dissolved in THF and treated at 0° C. with stirring with a solution of 29.5 ml of 3M methyl magnesium bromide. The reaction mixture was stirred for ten minutes, quenched with water, taken to dryness and the residue partitioned between ethyl acetate and water. The mixture was filtered, the organic extracts were separated, dried and taken to dryness to give 9.9 g of 1-acetyl-5,7-dibromonaphthalene.
Reaction SMILES: [O:1]1CCOCC1.[Cl:7][C:8]1[CH:9]=[C:10]2[C:18](=[CH:19][C:20]=1[Cl:21])[NH:17][C:16]1[C:15]([CH3:23])([CH3:22])[C:14]3[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:13]=3[CH2:12][C:11]2=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>O>[Cl:7][C:8]1[CH:9]=[C:10]2[C:18](=[CH:19][C:20]=1[Cl:21])[NH:17][C:16]1[C:15]([CH3:22])([CH3:23])[C:14]3[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:13]=3[C:12](=[O:1])[C:11]2=1
Reactant: C1COCCO1
Reactant: COc1ccc2c(c1)C(C)(C)c1[nH]c3cc(Cl)c(Cl)cc3c1C2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Product: COc1ccc2c(c1)C(C)(C)c1[nH]c3cc(Cl)c(Cl)cc3c1C2=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 26 %

Procedure:
Under nitrogen atmosphere, to the 1,4-dioxane (1.7 mL)-water (0.1 mL) solution of 2,3-dichloro-8-methoxy-6,6-dimethyl-6,11-dihydro-5H-benzo[b]carbazole (Compound Y2, 61.0 mg, 0.176 mmol), DDQ (120 mg, 0.529 mmol) was added and the mixture was stirred at room temperature for 16 hr and 15 min. The reaction mixture was purified by flash column chromatography {Merck Kieselgel60, solution for elution:hexane/ethyl acetate (2:1)} to obtain the title compound (pale orange solid, 16.7 mg, 26%).
Reaction SMILES: Br[CH2:2]/[CH:3]=[C:4](\[CH3:12])/[CH:5]([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH2:7]([O:6][CH:5]([O:9][CH2:10][CH3:11])/[C:4](/[CH3:12])=[CH:3]/[CH2:2][O:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([O:14][CH3:13])[CH:16]=1)[CH3:8]
Reactant: COc1cccc(O)c1
Reactant: CCOC(OCC)/C(C)=C/CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(OCC)/C(C)=C/COc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 43 h

Procedure:
A mixture of 12.65 g of crude (E)-4-bromo-1,1-diethoxy-2-methyl-2-butene, 6.4 ml of m-methoxyphenol, and 8.1 anhydrous potassium carbonate in 100 ml sieve dried dimethylformamide is stirred at room temperature under nitrogen for about 43 hours and the reaction mixture diluted to 500 ml with water and extracted with a 300 ml and two 100 ml portions of hexane. The combined hexane extracts are washed with two portions of brine and dried with sodium sulfate. Concentration of the hexane extracts yields 6.45 g (E)-1,1-diethoxy-(4-m-methoxyphenoxy)-2-methyl-2-butene.
Reaction SMILES: C(OC(=O)C(NC(=O)C1C=CC(NC(OC(C)(C)C)=O)=CC=1)CC1C=CC(C2N=C(C3C=CC(NC(OC(C)(C)C)=O)=CC=3)ON=2)=CC=1F)C.CCN=C=NCCCN(C)C.[C:62]([O:66][C:67]([NH:69][C:70]1[CH:78]=[CH:77][C:73]([C:74](O)=[O:75])=[CH:72][CH:71]=1)=[O:68])([CH3:65])([CH3:64])[CH3:63].C([O:81][C:82](=[O:113])[CH:83]([NH:96][C:97](=[O:112])[C:98]1[CH:103]=[CH:102][C:101]([NH:104][C:105]([O:107][C:108]([CH3:111])([CH3:110])[CH3:109])=[O:106])=[CH:100][CH:99]=1)[CH2:84][C:85]1[CH:90]=[CH:89][C:88]([C:91](=[NH:94])[NH:92]O)=[C:87]([F:95])[CH:86]=1)C>C(Cl)Cl>[C:108]([O:107][C:105]([NH:104][C:101]1[CH:102]=[CH:103][C:98]([C:97]([NH:96][CH:83]([CH2:84][C:85]2[CH:90]=[CH:89][C:88]([C:91]3[N:94]=[C:74]([C:73]4[CH:77]=[CH:78][C:70]([NH:69][C:67]([O:66][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:68])=[CH:71][CH:72]=4)[O:75][N:92]=3)=[C:87]([F:95])[CH:86]=2)[C:82]([OH:113])=[O:81])=[O:112])=[CH:99][CH:100]=1)=[O:106])([CH3:111])([CH3:109])[CH3:110]
Reactant: CCOC(=O)C(Cc1ccc(C(=N)NO)c(F)c1)NC(=O)c1ccc(NC(=O)OC(C)(C)C)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CCOC(=O)C(Cc1ccc(-c2noc(-c3ccc(NC(=O)OC(C)(C)C)cc3)n2)cc1F)NC(=O)c1ccc(NC(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccc(C(=O)NC(Cc2ccc(-c3noc(-c4ccc(NC(=O)OC(C)(C)C)cc4)n3)c(F)c2)C(=O)O)cc1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 9.1 %

Procedure:
2-(4-tert-Butoxycarbonylamino-benzoylamino)-3-{4-[5-(4-tert-butoxycarbonylamino-phenyl)-[1,2,4]oxadiazol-3-yl]-2-fluoro-phenyl}-propionic acid ethyl ester. EDCI (10 mg, 0.05 mmol) was added to a solution of 4-tert-butoxycarbonylamino-benzoic acid (12 mg, 0.05 mmol) in dry CH2Cl2 (5 mL). After the mixture was stirred for 0.5 hrs, 2-(4-tert-butoxycarbonylamino-benzoylamino)-3-[3-fluoro-4-(N-hydroxycarbamimidoyl)-phenyl]-propionic acid ethyl ester (25 mg) was added and the mixture was heated for another 1 hr at 120° C. in a sealed tube. The mixture was partitioned between EtOAc and water. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by silica gel chromatography to give the title compound (3 mg) as a white solid.
Reaction SMILES: [C:1]([N:8]1[CH2:15][CH:14]([OH:16])[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CC([O-])(C)C.[K+].Cl[C:24]1[C:33]2[C:28](=[CH:29][C:30]([O:34][CH3:35])=[CH:31][CH:32]=2)[N:27]=[C:26]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=2)[CH:25]=1>CS(C)=O.O>[C:4]([O:3][C:1]([N:8]1[CH2:15][CH:14]([O:16][C:24]2[C:33]3[C:28](=[CH:29][C:30]([O:34][CH3:35])=[CH:31][CH:32]=3)[N:27]=[C:26]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=3)[CH:25]=2)[CH2:13][CH:9]1[C:10]([OH:12])=[O:11])=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CC(O)C[C@H]1C(=O)O
Reactant: COc1ccc2c(Cl)cc(-c3ccccn3)nc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc2c(OC3CC(C(=O)O)N(C(=O)OC(C)(C)C)C3)cc(-c3ccccn3)nc2c1
Reaction time: 1.5 h
Yield: 51.3 %

Procedure:
To a solution of N—Boc-4-hydroxyproline (1.6 g, 6.7 mmol) in DMSO (20 mL) was added t-BuOK (1.9 g, 16.8 mmol). The generated mixture was stirred for 1.5 h and 4-Chloro-7-methoxy-2-pyridin-2-yl-quinoline (2.0 g, 7.4 mmol) and DMSO (10 mL) were added. The reaction mixture was stirred for 38 h, diluted with cold water and extracted with EtOAc/ether (1/4, 2×). the aqueous layer was acidified to pH 4 and extracted with EtOAc/THF (5×). the combined extract was dried (Na2SO4/MgSO4), removed the solvent in vacuo and the residue was purified by preparative HPLC (0-80% solvent B) to provide the product (1.6 g, 50%): LC-MS (retention time: 1.23, Method I), MS m/z 466 (M++1).
Reaction SMILES: [O:1]=[S:2]1(=[O:27])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]2[CH:11]=[C:12]([NH:15][C:16]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]([OH:26])=O)[CH2:20][CH2:19]3)=[O:17])[CH:13]=[CH:14][C:3]1=2.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.CCN=C=NCCCN(C)C.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[O:1]=[S:2]1(=[O:27])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]2[CH:11]=[C:12]([NH:15][C:16]([N:18]3[CH2:19][CH2:20][CH:21]([C:24]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[O:26])[CH2:22][CH2:23]3)=[O:17])[CH:13]=[CH:14][C:3]1=2
Reactant: C1COCCN1
Reactant: O=C(O)C1CCN(C(=O)Nc2ccc3c(c2)-c2ccccc2S3(=O)=O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc2c(c1)-c1ccccc1S2(=O)=O)N1CCC(C(=O)N2CCOCC2)CC1

Procedure:
5,5-Dioxo-2-(4-carboxypiperidinocarbonylamino)dibenzothiophene (Example 84; 75 mg, 0.19 mmol), DMF (2.5 ml), morpholine (16.5 mg, 0.19 mmol), EDAC (44 mg, 0.23 mmol), 1-hydroxybenzotriazole hydrate (25.65 mg, 0.19 mmol) were stirred together for 18 hours. The solvent was removed under vacuum and the residue partitioned between H2O/EtOAc. The organic layers were washed with water, saturated aqueous NaHCO3 then brine, and then dried, filtered and evaporated to an amorphous solid. NMR: 9.08 (s, 1H)) 8.21 (d, 1H), 7.93 (m, 2H), 7.79 (m, 2H), 7.65 (m, 2H), 4.14 (m, 2H), 3.52 (m, 6H), 3.45 (m, 2H), 2.92 (m, 3H), 1.68 (m, 2H), 1.53 (m, 2H); m/z 456.73.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N)cc2)CC1

Procedure:
2.74 g (8.5 mmol) of 1-t-butoxycarbonyl-4-(4-nitrophenoxy)piperidine was dissolved in 20 ml of ethanol. 20 mg of 10% palladium/carbon was added to the solution, and they were stirred at room temperature in 1 atm. hydrogen atmosphere for 3 hours. Palladium/carbon was removed by the suction filtration. The filtrate was once concentrated and then treated with dichloromethane as extractant in an ordinary manner to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[O:13][CH3:14].C([N:17](CC)CC)C.ClC(OCC)=O.N>C(OCC)(=O)C.C1COCC1>[Br:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]([C:6]([NH2:17])=[O:7])=[CH:4][C:3]=1[O:13][CH3:14]
Reactant: CCN(CC)CC
Reactant: COc1cc(C(=O)O)cc(OC)c1Br
Agent: CCOC(=O)Cl
Agent: N
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(C(N)=O)cc(OC)c1Br
Yield: 78.8 %

Procedure:
To a mixture of 4-bromo-3,5-dimethoxybenzoic acid (15 g, 57.6 mmol) and THF (200 mL) were added triethylamine (9.63 mL, 69.0 mmol) and ethyl chloroformate (5.79 mL, 60.6 mmol) while stirring on ice, and the resulting mixture was stirred for 20 minutes while cooling on ice. After adding 28% aqueous ammonia to the mixture and stirring at room temperature for 2 hours, ethyl acetate was further added. After then thoroughly shaking the mixture, the organic layer was separated and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The mixture was filtered, and the solvent in the filtrate was distilled off under reduced pressure. The obtained residue (solid) was washed with diethyl ether and collected by filtration to obtain the title compound (11.8 g, 45.4 mmol).