Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH:9]2[CH2:11][CH2:10]2)[CH:3]=1.CC1(C)C(C)(C)[O:16][B:15](B2OC(C)(C)C(C)(C)O2)[O:14]1.C(Cl)Cl.CS(C)=O>C(OCC)(=O)C>[CH:9]1([O:8][C:4]2[CH:3]=[C:2]([B:15]([OH:16])[OH:14])[CH:7]=[CH:6][CH:5]=2)[CH2:11][CH2:10]1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: Brc1cccc(OC2CC2)c1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: OB(O)c1cccc(OC2CC2)c1
Yield: 37.2 %

Procedure:
A mixture of 1-bromo-3-cyclopropoxybenzene (1.36 mmol, 0.289 g), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (2.11 mmol, 0.321 mmol), PdCl2dppf.DCM (0.14 mmol, 0.112 g), KAcO (6.11 mmol, 0.600 g) in a DMSO (3 ml) was heated at 130° C. for 45 minutes, under argon atmosphere in a microwave oven. Ethyl acetate was added and filtered through celite. The organic phase was washed with water and evaporated. The crude mixture was purified by reverse phase using a water/AcN/MeOH system gradient affording 0.090 g (yield 23%) of the expected product.
Reaction SMILES: [OH-].[K+].[CH2:3]([C:10]1[NH:14][C:13]2[CH:15]=[CH:16][C:17]([Br:19])=[CH:18][C:12]=2[N:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.I[CH3:21]>CC(C)=O.C(Cl)Cl>[CH2:3]([C:10]1[N:11]([CH3:21])[C:12]2[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:13]=2[N:14]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Brc1ccc2[nH]c(Cc3ccccc3)nc2c1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(C)=O
Product: Cn1c(Cc2ccccc2)nc2ccc(Br)cc21
Reaction time: 1 h

Procedure:
Powdered KOH (5.25 g, 93.50 mmol) was added to a stirred solution of 2-benzyl-5-bromo-1H-benzimidazole (5.37 g, 8.70 mmol) in acetone (100 mL), after 10 min, iodomethane (1.28 mL, 20.57 mmol) was added and the mixture was stirred for 1 h and diluted with DCM. The mixture was washed with water and brine, then dried over Na2SO4 and concentrated. The residue was taken up in DCM and hexanes and the resulting suspension filtered. The filtrate was concentrated and the oily residue taken up in hexanes and stirred for about 1 h. The resulting solid was filtered and the filter cake washed with hexanes and dried (2.0 g, 34%). LC-MS [M+H]+=302.1, RT=2.47 min.
Reaction SMILES: [CH2:1]([Mg]Cl)[CH:2]=[CH2:3].C(Cl)C=C.[CH2:10](Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O1CCCC1.C1(C)C=CC=CC=1>[C:11]1([CH2:10][CH2:3][CH:2]=[CH2:1])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: ClCc1ccccc1
Reactant: C=CC[Mg]Cl
Solvent: C1CCOC1
Solvent: C=CCCl
Solvent: Cc1ccccc1
Product: C=CCCc1ccccc1
Reaction time: 1 h
Yield: 90 %

Procedure:
Example 8 was repeated to form allyl magnesium chloride. The allyl magnesium chloride which flowed out of the flask through the branch was accumulated in a 3 L four-necked flask equipped with a stirrer, a thermometer, a condenser and a dropping funnel placed under a nitrogen atmosphere. A mixed solvent of toluene and tetrahydrofuran dissolving allyl chloride was started to be added dropweise thereto. 2 hours after the start of the addition of the mixed solvent, 300 ml of a mixed solvent of toluene and tetrahydrofuran (a content of terahydrofuran 25% by weight) dissolving 156 g (1.23 mole) of benzyl chloride was added dropwise in the 3 L four-necked flask at a rate of 15 ml per hour at a temperature of 0 to 20° C. After the completion of the dropwise addition, the reaction mixture was stirred for 1 hour at the same temperature. After the completion of the reaction, an aftertreatment was effected in a similar manner to that in Example 1 to obtain 146.9 g (yield 90%, based on benzyl chloride) of 4-phenyl-1-butene which was a colorless liquid. An analysis of the product by gas chromatography indicated the purity of 98.7%.
Reaction SMILES: [H-].[Na+].[C:3]([O:16][CH3:17])(=[O:15])[CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].F[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:20]=1[CH3:28].C(OCC)(=O)C>CN(C)C=O.O>[CH3:17][O:16][C:3](=[O:15])[CH:4]([C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:20]=1[CH3:28])[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6]
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: COC(=O)CC(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(C(=O)OCc1ccccc1)c1ccc([N+](=O)[O-])cc1C

Procedure:
Sodium hydride (1.29 g of 60% dispersion in oil) was added portionwise to a stirred solution of malonic acid, methyl benzyl ester (5.84 ml) in dry N,N-dimethylformamide (40 ml). After 2.5 h 2-fluoro-5-nitro-toluene (5.0 g) was added, and the mixture was warmed to 100° for 18 h. The mixture was cooled then partioned between ethyl acetate and water. The aqueous phase was separated and extracted further with ethyl acetate. The combined organic extracts were dried, concentrated, and purified by chromatography eluting with cyclohexane:ethyl acetate (6:1) to give 2-(2-methyl-4-nitro-phenyl)-malonic acid benzyl ester methyl ester, admixed with the starting malonate ester, as a yellow oil (4.60 g).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:5]2=[CH:4][C:3]=1[C:13](OCC)=[O:14].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[OH:14][CH2:13][C:3]1[CH:4]=[C:5]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:6]2=[N:7][C:2]=1[CH3:1]
Reactant: CCOC(=O)c1cc2c(nc1C)CCCCC2
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc2c(cc1CO)CCCCC2
Reaction time: 2 h
Yield: 72.8 %

Procedure:
In an atmosphere of argon, ethyl 2-methyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-3-carboxylate (586.6 mg, 2.51 mmol) was dissolved in anhydrous THF (5.0 ml), lithium aluminum hydride THF solution (1.0 M, 5.0 ml) was added dropwise to the solution at 0° C., and the mixture was stirred at the same temperature for 2 hours. The reaction solution was mixed with sodium sulfate decahydrate at 0° C. and subjected to celite filtration. The resulting filtrate was mixed with water and extracted with ethyl acetate. The thus obtained organic layer was washed with water and saturated brine in that order and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (ethyl acetate:hexane=2:1) to obtain the title compound (349.5 mg, 72.8%) as white powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][C:6](=[O:10])[CH2:7][CH2:8][CH3:9])[CH3:2].Cl([O-])(=O)(=O)=O.[Mg+2].Cl([O-])(=O)(=O)=O.[Br:23]N1C(=O)CCC1=O>C(OCC)(=O)C.C(OCC)C>[CH2:1]([O:3][C:4](=[O:11])[CH:5]([Br:23])[C:6](=[O:10])[CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCC(=O)CC(=O)OCC
Agent: [Mg+2]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCCC(=O)C(Br)C(=O)OCC
Reaction time: 0.08 h

Procedure:
3-Oxo-hexanoic acid ethyl ester (4.0 mL, 25 mmol) and magnesium perchlorate (1.7 g, 7.6 mmol) were placed in 500 mL of ethyl acetate and allowed to stir for 5 minutes. N-Bromosuccinimide (4.7 g, 26 mmol) was added and the reaction mixture was allowed to stir for 15 minutes, at which time thin-layer chromatography (10% ethyl acetate in hexanes, silica gel, 254 nm irradiation) indicated the reaction was complete. The reaction mixture was diluted with 500 mL of ethyl ether and washed three times with an equal volume of saturated aqueous sodium chloride. The organic layer was then dried over sodium sulfate and evaporated to dryness. This material was used in the next step without further purification.
Reaction SMILES: [H-].[Na+].C1CCCCC1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([C:19](=[O:21])[CH3:20])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18].[C:22](O)(=[O:24])[CH3:23]>C(OCC)(=O)C>[CH3:9][O:10][C:11]1[CH:12]=[C:13]([C:19](=[O:21])[CH2:20][C:22](=[O:24])[CH3:23])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: COc1ccc(C(C)=O)cc1OC
Reactant: CC(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: COc1ccc(C(=O)CC(C)=O)cc1OC

Procedure:
3.9 g of sodium hydride were initially introduced into 150 ml of cyclohexane, and a solution of 15 g of 1-(3,4-dimethoxyphenyl)ethanone in 16.3 ml of ethyl acetate was added. The reaction solution was boiled at 80° C. for 1 h, after which acetic acid was added and the whole was extracted with MTB-ether. The MTB-ether phase was dried over magnesium sulfate and subjected to rotary evaporation. The residue was chromatographed through silica gel (ethyl acetate/heptane 1/6). The following was obtained: 41 C12H14O4 (222.24); MS (ESI) 223 (M+H)
Reaction SMILES: C([O-])(=O)CO.[NH2:6][C:7]1[NH:11][N:10]=[C:9]([CH2:12][OH:13])[N:8]=1.[CH3:14][C:15](=O)[CH2:16][C:17](=O)[CH3:18].C(O)(=O)C>C(Cl)Cl.CCO>[CH3:14][C:15]1[CH:16]=[C:17]([CH3:18])[N:11]2[N:10]=[C:9]([CH2:12][OH:13])[N:8]=[C:7]2[N:6]=1
Reactant: Nc1nc(CO)n[nH]1
Reactant: CC(=O)CC(C)=O
Agent: O=C([O-])CO
Solvent: ClCCl
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cc(C)n2nc(CO)nc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.8 %

Procedure:
To a 2 L, 3-neck flask was charged glycolate salt of (5-amino-1H-1,2,4-triazol-3-yl)methanol (99.93 g, 0.526 mol), 2,4 pentanedione (0.578 mols, 60 mL), acetic acid (6.70 mL), and EtOH (550 mL). The mixture was heated to a slight reflux. One hour after adding the reagents, the resulting solution was cooled to ambient temperature, and CH2Cl2 (500 mL) and Celite (25.03 g) were added. After stirring for 1 h, the mixture was filtered through a 4″ Buchner funnel packed with celite (20 g) and rinsed with EtOH (100 mL). The solution was distilled to 5 vols then cooled to 0° C. for 1-2 hours. The slurry was filtered and the cake was rinsed with cold EtOH (2×100 mL). The solids were dried to provide 76.67 g (81.7%) of the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:8][CH2:7]1.[CH3:18][C:19]12[CH2:26][C:23]([CH3:27])([CH2:24][CH2:25]1)[C:22](=[O:28])[O:21][C:20]2=O>>[N:17]1[CH:16]=[CH:15][CH:14]=[N:13][C:12]=1[N:9]1[CH2:8][CH2:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:1]2[C:22](=[O:28])[C:23]3([CH3:27])[CH2:26][C:19]([CH3:18])([CH2:25][CH2:24]3)[C:20]2=[O:21])[CH2:11][CH2:10]1
Reactant: CC12CCC(C)(C1)C(=O)OC2=O
Reactant: NCCCCN1CCN(c2ncccn2)CC1
Product: CC12CCC(C)(C1)C(=O)N(CCCCN1CCN(c3ncccn3)CC1)C2=O
Yield: 20.4 %

Procedure:
Following substantially the procedure of Example 1, 4.2 g (17.8 mmol) of 1-(4-aminobutyl)-4-(2-pyrimidinyl) piperazine was reacted with 2.99 g (17.8 mmol) of 1,5-dimethyl-3-oxabicyclo[3.2.1]octan-2,4-dione. The product was chromatographed on silica gel, eluting with dichloromethane/methanol (96:4), to give 1.4 g (21% yield) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:17]2[S:21][C:20]([N:22]3[CH2:28][CH2:27][CH2:26][NH:25][C:24](=[O:29])[CH2:23]3)=[N:19][CH:18]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13](SC)[CH:12]=[CH:11][N:10]=2)[CH:7]=1.Cl[C:31]1C=CC=C(C(OO)=O)C=1.[O-:41][S:42]([O-:45])(=S)=O.[Na+].[Na+]>ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]([C:17]2[S:21][C:20]([N:22]3[CH2:28][CH2:27][CH2:26][NH:25][C:24](=[O:29])[CH2:23]3)=[N:19][CH:18]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:10]=[C:11]([S:42]([CH3:31])(=[O:45])=[O:41])[CH:12]=[CH:13][N:14]=2)[CH:7]=1
Reactant: O=S([O-])([O-])=S
Reactant: CSc1ccnc(Nc2cc(C)cc(-c3cnc(N4CCCNC(=O)C4)s3)c2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(Nc2nccc(S(C)(=O)=O)n2)cc(-c2cnc(N3CCCNC(=O)C3)s2)c1
Reaction time: 4 h
Yield: 18.6 %

Procedure:
To 4-[5-(3-methyl-5-{[4-(methylsulfanyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]-1,4-diazepan-2-one (0.94 g, 2.204 mmol) stirring in dichloromethane (11 mL) at room temperature was added 3-chloroperbenzoic acid (1.587 g, 7.08 mmol). Stirred for 4 hr. at room temperature, diluted with 10% Na2S2O3 (aq.), and washed with sat. NaHCO3 (aq.) and brine. The organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo. Purified by CombiFlash (100:0 to 0:20 dichloromethane:methanol) to afford impure 4-[5-(3-methyl-5-{[4-(methylsulfonyl)-2-pyrimidinyl]amino}phenyl)-1,3-thiazol-2-yl]-1,4-diazepan-2-one (0.188 g, 0.411 mmol, 18.6% yield) as an orange solid (contaminated with starting material). MS APCI: [M+H]+ m/z 459.1
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([OH:10])=[O:9])[CH2:3]1.C(=O)([O-])O.[Na+].[CH:16]1[C:28]2[CH:27]([CH2:29][O:30][C:31](ON3C(=O)CCC3=O)=[O:32])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[CH:19]=[CH:18][CH:17]=1.Cl>O.O1CCCC1>[CH:16]1[C:28]2[CH:27]([CH2:29][O:30][C:31]([NH:1][CH:2]3[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([OH:10])=[O:9])[CH2:3]3)=[O:32])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[CH:19]=[CH:18][CH:17]=1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: NC1CCCC(C(=O)O)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(NC1CCCC(C(=O)O)C1)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
3-Aminocyclohexanecarboxylic acid (10 g, 70 mmol) was added to a solution of sodium hydrogen carbonate (7.6 g, 91 mmol) in water (100 mL). A solution of 1-[[(9H-fluoren-9-ylmethoxy)carbonyl]oxy-2,5-pyrrolidinedione (Fmoc-OSu; 28.3 g, 84 mmol) in tetrahydrofuran (200 mL) was added. The solution was stirred at room temperature overnight and then poured into 3 M HCl (200 mL). The mixture was extracted with ethyl acetate (100 mL then 50 mL) and the combined organic layers were washed with saturated brine (3×100 mL), dried (Na2SO4), filtered, and concentrated to approximately 200 mL. Crystallization occurred on concentration. The mixture was allowed to stand overnight, then the solid was filtered off, washed with ethyl acetate and dried in a vacuum oven at 55° C. to give 3-[N-[(9H-fluoren-9-ylmethoxy)carbonyl]amino]cyclohexanecarboxylic acid (14.66, 57%) as a white solid.
Reaction SMILES: [CH:1]([NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[C:21]3[CH:20]=[C:19]([O:22][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[N:18]=[CH:17][C:16]=3[NH:15]/[C:14]/2=[N:31]\[C:32](C2C=CC3C=CSC=3C=2)=[O:33])[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[CH3:43][S:44]([C:47]1[CH:55]=[CH:54][C:50](C(O)=O)=[CH:49][CH:48]=1)(=[O:46])=[O:45]>>[CH:1]([NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[C:21]3[CH:20]=[C:19]([O:22][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[N:18]=[CH:17][C:16]=3[NH:15]/[C:14]/2=[N:31]\[C:32](=[O:33])[C:50]2[CH:54]=[CH:55][C:47]([S:44]([CH3:43])(=[O:46])=[O:45])=[CH:48][CH:49]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:2])[CH3:3]
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc4ccsc4c3)[nH]c3cnc(OCCN4CCCCC4)cc32)CC1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1
Product: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(S(C)(=O)=O)cc3)[nH]c3cnc(OCCN4CCCCC4)cc32)CC1
Yield: 22 %

Procedure:
The title compound was prepared using a method analogous to the preparation of (E)-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzo[b]thiophene-6-carboxamide, using 4-(methylsulfonyl)benzoic acid. The material was purified via preparative HPLC (0.1% NH4OH in ACN/H2O) to provide (E)-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)-4-(methylsulfonyl)benzamide (22.0% yield). MS m/z=611.4 [M+H], calc 610.77 for C31H42N6O5S.
Reaction SMILES: COCC1CCCCN1C1N=CN=C(NC2C=C(CS(N)(=O)=O)C=CC=2)N=1.Cl[C:29]1[N:34]=[CH:33][N:32]=[C:31]([NH:35][C:36]2[CH:37]=[C:38]([CH2:42][S:43]([NH2:46])(=[O:45])=[O:44])[CH:39]=[CH:40][CH:41]=2)[N:30]=1.[C:47]1([CH:53]2[CH2:57][CH2:56][CH2:55][NH:54]2)[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>>[C:47]1([CH:53]2[CH2:57][CH2:56][CH2:55][N:54]2[C:29]2[N:34]=[CH:33][N:32]=[C:31]([NH:35][C:36]3[CH:37]=[C:38]([CH2:42][S:43]([NH2:46])(=[O:45])=[O:44])[CH:39]=[CH:40][CH:41]=3)[N:30]=2)[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Reactant: c1ccc(C2CCCN2)cc1
Agent: COCC1CCCCN1c1ncnc(Nc2cccc(CS(N)(=O)=O)c2)n1
Product: NS(=O)(=O)Cc1cccc(Nc2ncnc(N3CCCC3c3ccccc3)n2)c1

Procedure:
B33 was prepared following the procedure reported for B4 using A1 and rac-2-phenylpyrrolidine, and it was obtained as a white powder; yield: 90 mg (24%). 1H NMR (300 MHz, d6-DMSO, 300K) δ 1.77-2.05 (m, 3H), 2.26-2.48 (m, 1H), 3.61-3.80 (m, 1H), 3.80-3.98 (m, 1H), 4.07 and 4.22 (2 s, 2H), 5.28 and 5.30 (2 s, 1H), 6.75-6.92 (m, 3H), 6.94-7.07 (m, 1H), 7.09-7.42 (m, 6H), 7.70 and 7.90 (2 s, 1H), 8.06 and 8.27 (2 s, 1H), 9.55 and 9.72 (2bs, 1H). MS (ES) C20H22N6O2S requires: 410. found: 411 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:19][CH2:18][C:15]([C:20](ON3C4C=CC=CC=4N=N3)=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:43][C:44]12[CH2:51][CH2:50][C:47]([C:52]([O:54][CH2:55][CH3:56])=[O:53])([CH2:48][CH2:49]1)[CH2:46][CH2:45]2>>[CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:19][CH2:18][C:15]([C:20]([NH:43][C:44]34[CH2:45][CH2:46][C:47]([C:52]([O:54][CH2:55][CH3:56])=[O:53])([CH2:50][CH2:51]3)[CH2:48][CH2:49]4)=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C12CCC(N)(CC1)CC2
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)On3nnc4ccccc43)(CC1)CC2
Product: CCOC(=O)C12CCC(NC(=O)C34CCC(N(CC(=O)N5C[C@@H](F)C[C@H]5C#N)C(=O)OCc5ccccc5)(CC3)CC4)(CC1)CC2
Yield: 73.5 %

Procedure:
In a similar manner to Example 4, (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(benzotriazol-1-yl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and ethyl 4-aminobicyclo[2.2.2]octane-1-carboxylate (22.3 mg) were used to obtain (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-[N-(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (40.7 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=O)[C:3]=1[SH:11].[C:12]([C:14]1[N:19]=[C:18]([CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:17]=[CH:16][CH:15]=1)#[N:13]>N1C=CC=CC=1>[CH3:1][C:2]1[C:3]2[S:11][C:12]([C:14]3[N:19]=[C:18]([CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:17]=[CH:16][CH:15]=3)=[N:13][C:5](=[O:7])[C:4]=2[CH:8]=[CH:9][CH:10]=1
Reactant: Cc1cccc(C(=O)O)c1S
Reactant: CC(C)(C)OC(=O)CCc1cccc(C#N)n1
Solvent: c1ccncc1
Product: Cc1cccc2c(=O)nc(-c3cccc(CCC(=O)OC(C)(C)C)n3)sc12

Procedure:
A mixture of 3-methylthiosalicylic acid (2.52 g, 15 mmol), tert-butyl 3-(6-cyano-2-pyridyl)propanoate (2.32 g, 10 mmol) and pyridine (30 ml) was refluxed under nitrogen atmosphere for 20 hrs and concentrated under reduced pressure. The residue was subjected to a silica gel (100 g) column chromatography. The titled compound (2.79 g, 73%) was given from the fractions eluted with hexane-ethyl acetate (2:1, v/v), which were recrystallized from ethyl acetate-isopropyl ether.
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4](I)[N:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([C:14]2[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=2)[N:3]=1
Reactant: Oc1ccc(I)nc1Br
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Oc1ccc(-c2ccc(Cl)cc2)nc1Br
Temperature: 80 °C
Yield: 51.7 %

Procedure:
A mixture of 2-bromo-6-iodopyridin-3-ol (0.65 g, 2.167 mmol), 4-chlorobenzeneboronic acid (339 mg, 2.167 mmol) and potassium carbonate (749 mg, 5.419 mmol) in dimethoxyethane (15 mL) and water (5 mL) was purged with nitrogen for 20 minutes. Tetrakis(triphenylphosphine)palladium(0) (125.2 mg, 0.108 mmol) was added and the reaction mixture heated to 80° C. in a sealed vial for 15 hours. The cooled reaction mixture was partitioned between ethyl acetate (50 mL) and saturated aqueous ammonium chloride solution (50 mL), the organic phase separated, washed with water (50 mL) and saturated brine (50 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give a yellow syrup. The crude product was purified by chromatography on silica eluting with a solvent gradient of 0 to 40% ethyl acetate in hexanes to give 2-bromo-6-(4-chlorophenyl)pyridin-3-ol (0.319 g, 52% yield) as a yellow crystalline solid.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]3[C:25]([C:26](=[O:29])[NH:27][CH3:28])=[C:24]([C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=4)[O:23][C:7]3=[N:8][C:9]=2[N:10]([CH2:15][CH2:16][CH2:17][C@H:18]([CH3:22])[C:19]([OH:21])=[O:20])[S:11]([CH3:14])(=[O:13])=[O:12])[CH2:3][CH2:2]1.[P:37]([O:55][CH2:56]Cl)([O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38].C(#N)C.O>CN(C=O)C>[CH:1]1([C:4]2[CH:5]=[C:6]3[C:25]([C:26](=[O:29])[NH:27][CH3:28])=[C:24]([C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=4)[O:23][C:7]3=[N:8][C:9]=2[N:10]([CH2:15][CH2:16][CH2:17][C@H:18]([CH3:22])[C:19]([O:21][CH2:56][O:55][P:37]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:38])=[O:20])[S:11]([CH3:14])(=[O:13])=[O:12])[CH2:2][CH2:3]1
Reactant: O=P(OCCl)(OCc1ccccc1)OCc1ccccc1
Reactant: CNC(=O)c1c(-c2ccc(C)cc2)oc2nc(N(CCC[C@H](C)C(=O)O)S(C)(=O)=O)c(C3CC3)cc12
Solvent: O
Solvent: CC#N
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(C)cc2)oc2nc(N(CCC[C@H](C)C(=O)OCOP(=O)(OCc3ccccc3)OCc3ccccc3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(S)-5-(N-(5-cyclopropyl-3-(methylcarbamoyl)-2-p-tolylfuro[2,3-b]pyridin-6-yl)methylsulfonamido)-2-methylpentanoic acid (Example 47, 50 mg, 0.090 mmol) and [dibenzyl chloromethyl phosphate (32.5 mg, 0.1 mmol) were stirred in DMF at RT LCMS-80% done at 1 hr Stirred at RT ON-95% done, trace SM and trace mono-de-benzylated side prod.(+) 714 Added 800 μL ACN and 200 μL water Purified on HPLC C18 20-100% ACN/water 1% NH4OH 40 mL/min over 10 min Conc. on vac at 30° C.—no degradation. To give (S)-((bis(benzyloxy)phosphoryl)oxy)methyl 5-(N-(5-cyclopropyl-3-(methylcarbamoyl)-2-(p-tolyl)furo[2,3-b]pyridin-6-yl)methylsulfonamido)-2-methylpentanoate
Reaction SMILES: C1O[C:4]2([CH2:13][CH2:12][C@H:11]3[C@@H:6]([CH2:7][CH2:8][C:9](=[O:14])[CH2:10]3)[CH2:5]2)[O:3]C1.C(O)=O.O>C1(C)C=CC=CC=1>[CH2:5]1[C@H:6]2[C@@H:11]([CH2:10][C:9](=[O:14])[CH2:8][CH2:7]2)[CH2:12][CH2:13][C:4]1=[O:3]
Reactant: O=C1CC[C@H]2CC3(CC[C@@H]2C1)OCCO3
Solvent: O
Solvent: O=CO
Solvent: Cc1ccccc1
Product: O=C1CC[C@H]2CC(=O)CC[C@@H]2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
21 g of trans-decahydronaphthalen-2,6-dione monoethyleneacetal was dissolved in 110 ml of toluene. 50 ml of formic acid was added to the solution, and the mixture was stirred for 1 hour at room temperature. Water was added to the mixture, and the organic phase was separated, rinsed with water, a saturated aqueous solution of sodium hydrogencarbonate, and a saturated saline solution, in sequence, and dried on anhydrous sodium sulfate. Then, the solvent was evaporated to obtain 16 g of pale yellow solid trans-decahydronaphthalen-2,6-dione.