Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:17]([C:19]1[N:20]([CH2:33][C:34]#[CH:35])[C:21]2[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[N:24]=[C:23]([NH2:31])[C:22]=2[N:32]=1)[CH3:18]>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].[Cu]I>[IH:1].[NH2:31][C:23]1[C:22]2[N:32]=[C:19]([CH2:17][CH3:18])[N:20]([CH2:33][C:34]#[C:35][C:2]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=3)[C:21]=2[C:30]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[N:24]=1
Reactant: C#CCn1c(CC)nc2c(N)nc3ccccc3c21
Reactant: N#Cc1ccc(I)cc1
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCc1nc2c(N)nc3ccccc3c2n1CC#Cc1ccc(C#N)cc1
Product: I
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 6.3 %

Procedure:
Tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (62.1 mg, 0.03 eq.), 4-iodobenzonitrile (0.50 g, 0.11 eq.), triethylamine (0.61 g, 3 eq.), and copper (I) iodide (23 mg, 0.06 eq.) were added sequentially to a solution of 2-ethyl-1-(2-propynyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.5 g, 2.0 mmol, 1.0 eq) in DMF. The reaction mixture was stirred at ambient temperature for 3.5 hours. The reaction mixture was concentrated under reduced pressure to provide crude product which was purified by column chromatography (silica gel eluting with 5/95 methanol/dichloromethane). The residue was purified by recrystallization from 1,2-dichloroethane to provide 60 mg of 4-[3-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1-propynyl]benzonitrile hydroiodide as a brown powder, mp 180-241° C. (dec). 1H NMR (300 MHz, DMSO-d6) δ 13.23 (br s, 1H), 8.47 (d, J=8.1 Hz, 1H), 8.44 (br, 2H), 7.82 (m, 3H), 7.69 (t, J=7.2 Hz, 1H), 7.60 (t, J=7.1 Hz, 1H), 7.54 (d, J=8.7 Hz, 2H), 5.84 (s, 2H), 3.13 (q, J=7.4 Hz, 2H), 1.42 (t, J=7.4 Hz, 3H); MS m/z 352 (M+H)+; Anal. calcd for C22H17N5.HI.0.09 1,2-dichloroethane: C, 54.50; H, 3.79; N, 14.33. Found: C, 54.54; H, 3.59; N, 14.26.
Reaction SMILES: C=O.[C:3]([O:7][C:8]([N:10]([CH3:26])[C@@H:11](C)[C:12](N[C@@H](C1CCCCC1)C(O)=O)=O)=[O:9])([CH3:6])([CH3:5])[CH3:4].O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>C1COCC1.CCOC(C)=O>[C:3]([O:7][C:8](=[O:9])[N:10]([CH2:11][CH3:12])[CH3:26])([CH3:6])([CH3:5])[CH3:4]
Reactant: C[C@@H](C(=O)N[C@H](C(=O)O)C1CCCCC1)N(C)C(=O)OC(C)(C)C
Agent: C=O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCN(C)C(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 2 h
Yield: 299.1 %

Procedure:
To a solution of 4-fluoro-phenyl)-(S)-5-pyrrolidin-2-yl-pyridin-3-yl) -methanone (2.57 g, 9.5 mmole) and (S)-[(S)-2-(tert-butoxycarbonyl-methyl-amino)-propionylamino]-cyclohexyl-acetic acid (5) (3.58 g, 10.5 mmole) in 75 mL of THF at 0° C., is added 4-(4,6-dimethoxy-[1,3,5]triazin-2-yl)-4-methyl-morpholinium chloride hydrate (2.97 g, 10.7 mmole) in one portion. After stirring at 20° C. for 2 hours, the reaction mixture is diluted with 100 mL of EtOAc, and washed with 3×20 mL of water. After concentration, the crude product is purified by flash column chromatography (CH2Cl2 95%, MeOH 5%) to give (S) -1-(S)-1-cyclohexyl-2-{(S)-2-[5-(4-fluoro-benzoyl)-pyridin-3-yl]-pyrrolidin-1-yl}-2-oxo-ethylcarbamoyl)-ethylmethyl-carbamic acid tert-butyl ester (6) (5.0 g, yield 88%) as pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([F:11])[F:10])=[CH:6][C:5]([NH:12][NH2:13])=[C:4]([F:14])[CH:3]=1.C1(C)C=CC=CC=1.C([O:24][C:25]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][C:28]1=O)=O)C.O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:7]([O:8][CH:9]([F:11])[F:10])=[CH:6][C:5]([N:12]2[C:25](=[O:24])[C:27]3[CH2:32][CH2:31][CH2:30][CH2:29][C:28]=3[NH:13]2)=[C:4]([F:14])[CH:3]=1
Reactant: NNc1cc(OC(F)F)c(Cl)cc1F
Reactant: CCOC(=O)C1CCCCC1=O
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Solvent: O
Product: O=c1c2c([nH]n1-c1cc(OC(F)F)c(Cl)cc1F)CCCC2
Yield: 32.3 %

Procedure:
To 12.7 g of 4-chloro-5-difluoromethoxy-2-fluorophenylhydrazine were added 127 ml of toluene and 9.5 g of 2-ethoxycarbonylcyclohexanone V-1, and the resultant mixture was refluxed for 24 hours. After cooling, the reaction mixture was mixed with water and shaken with chloroform. The chloroform layer was dried and concentrated. The residue was chromatographed on a column of silica gel, eluting with n-hexane-ethyl acetate (1:1 v/v). The elutate was concentrated to give 6,0 g of the titled compound VIII-1 (containing a certain amount of its tautomer 2,3a,4,5,6,7-hexahydro compound).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH2:7][CH2:8][Li])[CH2:4][CH3:5])[CH3:2].[Cl-].[CH3:11][Ga+:12][CH3:13]>CCCCC>[CH2:1]([N:3]([CH2:6][CH2:7][CH2:8][Ga:12]([CH3:13])[CH3:11])[CH2:4][CH3:5])[CH3:2]
Reactant: [Li]CCCN(CC)CC
Reactant: C[Ga+]C
Agent: [Cl-]
Solvent: CCCCC
Product: CCN(CC)CCC[Ga](C)C
Reaction time: 24 h

Procedure:
3.6 g (30 mmol) of diethylaminopropyllithium dissolved in 100 ml of pentane are added to a solution of 4 g (30 mmol) of dimethylgallium chloride in 50 ml of pentane at -78°. The solution is allowed to come to room temperature and is stirred for a further 24 hours. The working up is carried out analogously to Example 1. Instead of the distillation, a sublimitation is carried out. Diethylaminopropyl(dimethyl)gallium with an M.p. of 43°-45° is obtained.
Reaction SMILES: [Br:1][C:2]1[N:22]([S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])[C:5]2=[N:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[CH:13]=3)[N:9]=[C:4]2[CH:3]=1.[B-](F)(F)(F)[F:33].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.O>C(#N)C>[Br:1][C:2]1[N:22]([S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])[C:5]2=[N:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]3[CH:13]=[C:14]([O:20][CH3:21])[CH:15]=[C:16]([O:18][CH3:19])[C:17]=3[F:33])[N:9]=[C:4]2[CH:3]=1
Reactant: F[B-](F)(F)F
Reactant: COc1cc(CCc2cnc3c(cc(Br)n3S(=O)(=O)c3ccccc3)n2)cc(OC)c1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Solvent: O
Product: COc1cc(CCc2cnc3c(cc(Br)n3S(=O)(=O)c3ccccc3)n2)c(F)c(OC)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of 6-bromo-2-[2-(3,5-dimethoxyphenyl)ethyl]-5-(phenylsulfonyl)-5H-pyrrolo[2,3-b]pyrazine (25.0 mg, 0.0498 mmol) and 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane ditetrafluoroborate (17.6 mg, 0.0498 mmol) in acetonitrile (0.3 mL)/water (0.06 mL) was stirred at 50° C. overnight. The solvent was removed and the residue was used in the next step w/o purification. LCMS calculated for C22H20BrFN3O4S (M+H)+: m/z=520.0. Found 520.0.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.O1[CH:20]=[CH:19][C:18](=[O:21])[CH:17]=[CH:16]1.Cl.N>O>[O:21]=[C:18]1[CH:19]=[CH:20][N:1]([C:2]2[CH:3]=[CH:4][C:5]([C:8]3[S:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=3)=[CH:6][CH:7]=2)[CH:16]=[CH:17]1
Reactant: Nc1ccc(C2=NNC(=O)CS2)cc1
Reactant: O=c1ccocc1
Agent: Cl
Agent: N
Solvent: O
Product: O=C1CSC(c2ccc(-n3ccc(=O)cc3)cc2)=NN1

Procedure:
A stirred mixture of 2-(4-aminophenyl)-4H,6H-1,3,4-thiadiazin-5-one (1.0 g), 4H-pyran-4-one (0.51 g), water (20 ml) and concentrated hydrochloric acid (0.42 ml), was heated under reflux for 3 hours. The warm solution was neutralised with concentrated aqueous ammonia and cooled to give a solid, 1.33 g. Recrystallisation from methanol gave the title compound, 0.89 g, m.p. 289°-291° C.
Reaction SMILES: [CH2:1]([O:13][C@H:14]([CH2:44][O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[CH2:15][S:16][CH2:17][C@@H:18]([C:37]([O:39]C(C)(C)C)=[O:38])[NH:19][C:20](=[O:36])[O:21][CH2:22][CH:23]1[C:35]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>C(O)(C(F)(F)F)=O.C(Cl)Cl.CC(OC)(C)C>[CH:34]1[C:35]2[CH:23]([CH2:22][O:21][C:20]([NH:19][C@@H:18]([CH2:17][S:16][CH2:15][C@H:14]([O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:44][O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[C:37]([OH:39])=[O:38])=[O:36])[C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:30]=2[CH:31]=[CH:32][CH:33]=1
Reactant: CCCCCCCCCCCCOC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C)OCCCCCCCCCCCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COC(C)(C)C
Product: CCCCCCCCCCCCOC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)OCCCCCCCCCCCC

Procedure:
A solution of (5R,9R)-tert-butyl 9-(dodecyloxy)-1-(9H-fluoren-9-yl)-3-oxo-2,11-dioxa-7-thia-4-azatricosane-5-carboxylate in 50% TFA in DCM (0.3 M) was stirred at room temperature until complete deprotection of tert-butyl group (30 minutes). The reaction mixture was diluted in MTBE, washed three times with 1M citric acid (adjusted to pH3), and once with 1:2 1N HCl/brine. The organic layer was dried over anhydrous Na2SO4 and concentrated en vaccuo. The resulting waxy solid was used for the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:15])[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[OH:8].[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1>[C:22]([O:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:15])[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[O:8][C:14](=[O:15])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(C=Cc1cc(O)c(O)c([N+](=O)[O-])c1)c1ccccc1
Solvent: C1CCOC1
Product: O=C(C=Cc1cc(OC(=O)c2ccccc2)c(OC(=O)c2ccccc2)c([N+](=O)[O-])c1)c1ccccc1

Procedure:
1.0 g of the product obtained in Example 8 and 2.0 ml of benzoylchloride were dissolved in 5 ml of tetrahydrofuran. Tetrahydrofuran was distilled off to a great extent and the residue was refluxed for 2 h. After cooling ether was added to the mixture and the product was filtered and trituratedwith ethylmethylketone. Yield 0.50 g (29%), m.p. 206°-210° C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[C:16]1([C:22]([C:25]2[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=2)([CH3:24])[CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.N1C=CC=CC=1>CC#N>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:28]1[CH:29]=[CH:30][C:25]([C:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:24])[CH3:23])=[CH:26][CH:27]=1)(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CC(C)(c1ccccc1)c1ccc(O)cc1
Solvent: c1ccncc1
Solvent: CC#N
Product: CC(C)(c1ccccc1)c1ccc(OS(=O)(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Trifluoromethanesulfonic anhydride (1.99 mL) was added dropwise to a solution of 4-(2-phenylpropan-2-yl)phenol (1.68 g) and pyridine (1.277 ml) in MeCN (10 ml) at 0° C. The mixture was stirred at room temperature for 2 days. The mixture was quenched with 0.1 N HCl aq. at 0° C. and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate, filtered through silica-Celite pad (eluted with EtOAc) and concentrated in vacuo to give 4-(2-phenylpropan-2-yl)phenyl trifluoromethanesulfonate (2.65 g) as a yellow oil.
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4](=[O:26])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[C:7]([Cl:25])[CH:6]=1.[OH-].[Na+]>CO.O1CCCC1.O>[Cl:25][C:7]1[CH:6]=[C:5]([C:4](=[O:26])[C:3]([OH:27])=[O:2])[CH:10]=[CH:9][C:8]=1[O:11][CH2:12][CH2:13][O:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1
Reactant: COC(=O)C(=O)c1ccc(OCCOc2ccc3ccccc3c2)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C(=O)c1ccc(OCCOc2ccc3ccccc3c2)c(Cl)c1
Yield: 93.4 %

Procedure:
A solution of 3-chloro-4-[2-(2-naphthalenyloxy)ethoxy]-alpha-oxobenzeneacetic acid methyl ester (0.7 g) in warm methanol (10 mL) and tetrahydrofuran (10 mL) was treated with 1N sodium hydroxide (2.5 mL) and after 10 minutes the mixture was diluted with water and concentrated to remove the organic solvents. The residue was acidified with excess hydrochloric acid and extracted with dichloromethane containing a little tetrahydrofuran. The organic layer was washed with water, dried (Na2SO4), filtered and evaporated to give crude product. Crystallization from acetone-hexane provided 0.63 g of purified 3-chloro-4-[2-(2-naphthalenyloxy)ethoxy]-alpha-oxobenzeneacetic acid as a colorless solid, mp 167°-168° C.
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:6][OH:7])[CH2:5][CH2:4]1.C[O:9][C:10]([C:12]1[C:17](C)=[CH:16][C:15]([Br:19])=[C:14](Cl)[N:13]=1)=[O:11]>>[Br:19][C:15]1[CH:16]=[CH:17][C:12]([C:10]([OH:11])=[O:9])=[N:13][C:14]=1[O:7][CH2:6][CH:3]1[CH2:5][CH2:4]1
Reactant: COC(=O)c1nc(Cl)c(Br)cc1C
Reactant: OCC1CC1
Agent: [H-]
Agent: [Na+]
Product: O=C(O)c1ccc(Br)c(OCC2CC2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.1 %

Procedure:
Sodium hydride (4.83 g, 0.12 mol) was added into cyclopropanemethanol (CAN 2516-33-8, 30 g) at 0° C. and the mixture was stirred at 0° C. for 1 h. Then to the mixture was added methyl 5-bromo-6-chloro-pyridine-2-carboxylic acid methyl ester (3 g, 12.75 mmol). The obtained solution was heated to 90° C. for 2 h. Then the mixture was evaporated to dryness, the residue was dissolved in 40 mL of water, and adjusted to pH=4 with hydrochloric acid (3 N), and extracted with ethyl acetate (3×30 mL). The combined organic layer was washed with water (2×30 mL) and brine (2×50 mL) then evaporated to dryness to obtain the product as a white solid (2.5 g, 76.7%); MS (EI): m/e=272.0 [M+H]+.
Reaction SMILES: [H-].[Na+].[OH:3][C@@H:4]([CH2:20][N:21]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)[CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:5][O:6][C:7]1[C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]=2[CH:10]=[CH:9][CH:8]=1.Br[C:34]([CH3:39])([CH3:38])[C:35]([NH2:37])=[O:36]>O1CCOCC1>[OH:3][C@@H:4]([CH2:20][N:21]([C:26]1[CH:31]=[CH:30][C:29]([O:32][C:34]([CH3:39])([C:35](=[O:36])[NH2:37])[CH3:38])=[CH:28][CH:27]=1)[CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:5][O:6][C:7]1[C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)CN(C[C@H](O)COc1cccc2[nH]c3ccccc3c12)c1ccc(O)cc1
Reactant: CC(C)(Br)C(N)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)CN(C[C@H](O)COc1cccc2[nH]c3ccccc3c12)c1ccc(OC(C)(C)C(N)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
Sodium hydride (10.8 mg of a 60% dispersion in oil, 0.27 mmol) was added to a solution of the phenol prepared in example 91 (100 mg, 0.25 mmol) in dry dioxane (1 ml) and the mixture stirred for 1 h at room temperature. 2-Bromo-2-methylpropanamide (Coutts, I. G. C., Southcott, M. R. J. Chem. Soc. Perkin Trans. 1, 1990, 767) was then added and the mixture heated at 100° C. for 8 h. The reaction mixture was filtered, concentrated in vacuo, and purified by flash chromatography (1:1 ethyl acetate: hexanes) to afford a light yellow solid (94.4 mg, 94%). MS (FD+) 489.6, Mp 84-86° C.
Reaction SMILES: [NH:1]1[CH:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:4][CH:3]2[CH2:11][O:12][CH2:13][CH:2]12.[CH2:14]([O:21][C:22]([NH:24][C@H:25]([C:27]([OH:29])=[O:28])[CH3:26])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(OCC)(=O)C>[CH2:14]([O:21][C:22]([NH:24][C@H:25]([C:27]([N:1]1[C@@H:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:4][CH:3]2[CH2:11][O:12][CH2:13][CH:2]12)=[O:28])[CH3:26])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH2:14]([O:21][C:22]([NH:24][C@H:25]([C:27]([N:1]1[C@H:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:4][CH:3]2[CH2:11][O:12][CH2:13][CH:2]12)=[O:29])[CH3:26])=[O:23])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCOC(=O)C1CC2COCC2N1
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H]1CC2COCC2N1C(=O)[C@H](C)NC(=O)OCc1ccccc1
Product: CCOC(=O)[C@H]1CC2COCC2N1C(=O)[C@H](C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of ethyl hexahydrofuro[3,4-b]pyrrole-2-carboxylate in ethyl acetate add N-benzyloxycarbonyl-(S)-alanine, N-hydroxysuccinimide ester. Stir the reaction mixture at room temperature for 20 hours and concentrate it in vacuo. Place the residue on a column of silica gel (3000 g, 60-200 mesh) and elute with chloroform: ethyl acetate 10:1 to give 1-[N-benzyloxycarbonyl-(S)-alanyl]hexahydrofuro[3,4-b]pyrrole-2(R)-carboxylic acid, ethyl ester, and 1-[N-benzyloxycarbonyl(S)-alanyl]hexahydrofuro[3,4-b]pyrrole-2(S)-carboxylic acid, ethyl ester.
Reaction SMILES: C[O:2][C:3](=[O:72])[C@H:4]([CH2:60][CH2:61][CH2:62][CH:63]([C:65]([O:67][C:68]([CH3:71])([CH3:70])[CH3:69])=[O:66])[NH2:64])[NH:5][NH:6][C:7]([C:9]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[N:12]=[C:11]([NH:23][C:24]([C:26]2[N:30]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=3)[N:29]=[C:28]([NH:40][C:41]([C:43]3[N:47]([CH2:48][C:49]4[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=4)[N:46]=[C:45]([N+:57]([O-:59])=[O:58])[CH:44]=3)=[O:42])[CH:27]=2)=[O:25])[CH:10]=1)=[O:8].[OH-].[Li+]>CO.C1COCC1.O>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:13]2[C:9]([C:7]([NH:6][NH:5][C@H:4]([C:3]([OH:72])=[O:2])[CH2:60][CH2:61][CH2:62][CH:63]([C:65]([O:67][C:68]([CH3:71])([CH3:70])[CH3:69])=[O:66])[NH2:64])=[O:8])=[CH:10][C:11]([NH:23][C:24]([C:26]3[N:30]([CH2:31][C:32]4[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=4)[N:29]=[C:28]([NH:40][C:41]([C:43]4[N:47]([CH2:48][C:49]5[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=5)[N:46]=[C:45]([N+:57]([O-:59])=[O:58])[CH:44]=4)=[O:42])[CH:27]=3)=[O:25])=[N:12]2)=[CH:16][CH:17]=1
Reactant: COC(=O)[C@H](CCCC(N)C(=O)OC(C)(C)C)NNC(=O)c1cc(NC(=O)c2cc(NC(=O)c3cc([N+](=O)[O-])nn3Cc3ccc(OC)cc3)nn2Cc2ccc(OC)cc2)nn1Cc1ccc(OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1ccc(Cn2nc(NC(=O)c3cc(NC(=O)c4cc([N+](=O)[O-])nn4Cc4ccc(OC)cc4)nn3Cc3ccc(OC)cc3)cc2C(=O)NN[C@@H](CCCC(N)C(=O)OC(C)(C)C)C(=O)O)cc1

Procedure:
A 143 mg (146 μmol, 1.00 equiv) amount of 2-(1-(4-methoxybenzyl)-3-(1-(4-methoxybenzyl)-3-(1-(4-methoxybenzyl)-3-nitro-1H-pyrazole-5-carboxamido)-1H-pyrazole-5-carboxamido)-1H-pyrazole-5-carboxamido-6-(tert-butoxycarbonyl)-lysine methyl ester and 9 mg lithium hydroxide (376 μmol, 2.57 equiv) were stirred in a mixture of methanol/THF/water (5:5:1) for 16 h at 65° C. Workup and purification were conducted according to general procedure A to yield the free carboxylic acid as a colorless solid. Yield: 111 mg (115 μmol, 79%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C.[CH3:27][S:28]([O:31][C@H:32]1[CH2:36][N:35]([C:37]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][C:44]([N+:47]([O-:49])=[O:48])=[CH:43][CH:42]=2)=[O:38])[C@H:34]([C:50](O)=[O:51])[CH2:33]1)(=[O:30])=[O:29]>C(#N)C>[OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:50]([C@@H:34]2[CH2:33][C@@H:32]([O:31][S:28]([CH3:27])(=[O:30])=[O:29])[CH2:36][N:35]2[C:37]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][C:44]([N+:47]([O-:49])=[O:48])=[CH:43][CH:42]=2)=[O:38])=[O:51])[CH2:6][CH2:5]1
Reactant: OCCN1CCNCC1
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)N2CCN(CCO)CC2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.2 %

Procedure:
1.11 g of 1-(2-hydroxyethyl)piperazine, 1.29 ml of diethyl cyanophosphonate and 1.18 ml of triethylamine were added, in that order, whilst ice-cooling, to a solution of 3.00 g of trans-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)-L-proline [prepared as described in step 54(a)(i) above] in 35 ml of dry acetonitrile, and the resulting mixture was stirred at room temperature for 30 minutes. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the residue was purified by column chromatography through silica gel, using a 5:1 by volume mixture of ethyl acetate and methanol as the eluent, to give 2.60 g of the title compound, as a powder.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[OH-:18].[Na+].[CH2:20]([OH:22])[CH3:21]>>[O:18]1[CH2:11][CH2:1][CH2:6][CH2:5][CH:4]1[S:7][CH2:21][CH2:20][OH:22]
Reactant: [OH-]
Reactant: CCO
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Agent: c1cc[nH+]cc1
Product: OCCSC1CCCCO1
Temperature: 55 °C
Reaction time: 4 h

Procedure:
To a solution of the compound of Reference Example 16 (78.8 g) in ethanol (1.5 ) was added pyridinium p-toluenesulfonate (8.04 g) and the mixture was stirred at 55° C. for 4 hours. To this reaction mixture was added 1N-NaOH (ca. 30 ml) and the solvent was distilled off under reduced pressure. To the residue was added ether (300 ml) and the suspension was dried over anhydrous sodium sulfate. The insolubles were filtered off and the filtrate was concentrated under reduced pressure. The residue was subjected to vacuum distillation to give 42.4 g of 2-[(tetrahydropyran-2-yl)thio]ethanol. bp 93°-94° C. /0.2 mmHg
Reaction SMILES: C(Cl)(Cl)Cl.[Cl:5][C:6]1[CH:27]=[CH:26][CH:25]=[CH:24][C:7]=1[C:8]([C:10]1[C:15](OS(C(F)(F)F)(=O)=O)=[CH:14][CH:13]=[CH:12][N:11]=1)=[O:9].[F:28][C:29]([F:66])([F:65])[C:30]1[CH:31]=[C:32]([CH:58]=[C:59]([C:61]([F:64])([F:63])[F:62])[CH:60]=1)[CH2:33][N:34]1[C:38]([C:39]2[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=2)=[C:37]([Sn](CCCC)(CCCC)CCCC)[N:36]=[N:35]1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].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>[F:64][C:61]([F:62])([F:63])[C:59]1[CH:58]=[C:32]([CH:31]=[C:30]([C:29]([F:28])([F:65])[F:66])[CH:60]=1)[CH2:33][N:34]1[C:38]([C:39]2[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=2)=[C:37]([C:15]2[C:10]([C:8]([C:7]3[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=3[Cl:5])=[O:9])=[N:11][CH:12]=[CH:13][CH:14]=2)[N:36]=[N:35]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1ccncc1
Reactant: O=C(c1ccccc1Cl)c1ncccc1OS(=O)(=O)C(F)(F)F
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C(c1ccccc1Cl)c1ncccc1-c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1ccncc1
Temperature: 120 °C
Yield: 10.8 %

Procedure:
Add Pd2(dba)3.CHCl3 (42 mg, 0.04 mmol) to a degassed solution of trifluoro-methanesulfonic acid 2-(2-chloro-benzoyl)-pyridin-3-yl ester (149 mg, 0.41 mmol) and 4-[3-(3,5-bis-trifluoromethyl-benzyl)-5-tributylstannanyl-3H-[1,2,3]triazol-4-yl]-pyridine (296 mg, 0.45 mmol) in toluene (2 mL). Seal the mixture under N2 and heat at 120° C. for 2 hours. Add Pd(PPh3)4 (94 mg, 0.08 mmol), seal and heat at 120° C. for another 48 hours. Concentrate, dissolve in ACN, wash with hexanes (×3), dry over MgSO4 and concentrate. Purify the residue by flash chromatography on silica gel eluting with 0-10% ACN/Et2O to afford the title compound (26 mg, 11%) as tan solid. MS(IS) 588 (M+1). TLC: Rf=0.33 (10% ACN/Et2O).