Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-])[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH2:20]([N:22](CC)CC)C.C[Si](C#N)(C)C>C(#N)C>[Cl:1][C:2]1[C:3]([C:20]#[N:22])=[N:4][C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: CCN(CC)CC
Reactant: COC(=O)c1cc(Cl)c[n+]([O-])c1-c1cccc(F)c1
Agent: C[Si](C)(C)C#N
Solvent: CC#N
Product: COC(=O)c1cc(Cl)c(C#N)nc1-c1cccc(F)c1
Temperature: 70 °C
Yield: 92.9 %

Procedure:
Methyl 5-chloro-2-(3-fluorophenyl)nicotinate 1-oxide (2.9 g, 10 mmol) was stirred in acetonitrile (30 mL) with triethylamine (2.2 mL, 16 mmol) and trimethylsilyl cyanide (3.4 mL, 26 mmol) was added. The mixture was heated at 70° C. for 1 hour. Evaporation and purification by flash column chromatography using ethyl acetate in hexanes (0-20%) gave the desired compound (2.7 g, 90%). LCMS calculated for C14H9ClFN2O2 (M+H)+: m/z=291.1. found: 290.8.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.C[O:30][C:31]1[CH:36]=[CH:35][C:34]([S:37]([NH:40][C:41]2[CH:49]=[C:48](B3OC(C)(C)C(C)(C)O3)[CH:47]=[C:46]3[C:42]=2[CH:43]=[CH:44][NH:45]3)(=[O:39])=[O:38])=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:48]2[CH:47]=[C:46]3[C:42]([CH:43]=[CH:44][NH:45]3)=[C:41]([NH:40][S:37]([C:34]3[CH:35]=[CH:36][C:31]([OH:30])=[CH:32][CH:33]=3)(=[O:39])=[O:38])[CH:49]=2)=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Reactant: COc1ccc(S(=O)(=O)Nc2cc(B3OC(C)(C)C(C)(C)O3)cc3[nH]ccc23)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3cc(NS(=O)(=O)c4ccc(O)cc4)c4cc[nH]c4c3)n(-c3ccccc3)c(=O)c12
Temperature: 100 °C
Reaction time: 18 h
Yield: 21 %

Procedure:
To a solution of (S)-2-(1-((6-amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (80 mg, 0.18 mmol) were added 4-methoxy-N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-4-yl)benzenesulfonamide (137 mg, 0.27 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(11)dichloride dichloromethane complex (14 mg, 0.02 mmol) and 182 μl of a 2M aqueous solution of cesium carbonate in dioxane (2 ml). The mixture was stirred under argon atmosphere at 100° C. for 18 hours and then diluted with ethyl acetate. The resulting solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude product was purified using SP1® Purification System (50% to 100%, hexane-ethyl acetate) to obtain 27 mg (21% yield, 95% purity) and 98 mg (72% yield, 88% purity) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[C:7]([CH2:8][OH:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=2[F:17])[S:5][N:4]=1)[CH3:2].[F:18][C:19]1[CH:20]=[C:21]([CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:22]=[C:23]([F:26])[C:24]=1O.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1.P(CCCC)(CCCC)CCCC>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[C:7]([CH2:8][O:9][C:24]2[C:23]([F:26])=[CH:22][C:21]([CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:20][C:19]=2[F:18])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=2[F:17])[S:5][N:4]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Reactant: CCc1nsc(-c2ccc(C)cc2F)c1CO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)CCc1cc(F)c(OCc2c(CC)nsc2-c2ccc(C)cc2F)c(F)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Into a 25-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed [3-ethyl-5-(2-fluoro-4-methylphenyl)-1,2-thiazol-4-yl]methanol (50 mg, 0.20 mmol, 1.00 equiv), ethyl 3-(3,5-difluoro-4-hydroxyphenyl)propanoate (69 mg, 0.30 mmol, 1.51 equiv), ADDP (104 mg, 0.42 mmol, 2.09 equiv), Bu3P (60 mg), toluene (10 mL). The resulting solution was stirred overnight at 60° C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5). This resulted in 40 mg (43%) of ethyl 3-(4-[[3-ethyl-5-(2-fluoro-4-methylphenyl)-1,2-thiazol-4-yl]methoxy]-3,5-difluorophenyl)propanoate as colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12]3([CH2:17][CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13]3)[C:11](=[O:25])[N:10]([CH2:26][C:27]3[CH:31]=[C:30]([CH3:32])[O:29][N:28]=3)[CH2:9]2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12]3([CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:11](=[O:25])[N:10]([CH2:26][C:27]3[CH:31]=[C:30]([CH3:32])[O:29][N:28]=3)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: Cc1cc(CN2CC(c3ccc(F)cc3)C3(CCCN(C(=O)OC(C)(C)C)C3)C2=O)no1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(CN2CC(c3ccc(F)cc3)C3(CCCNC3)C2=O)no1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Tert-butyl 4-(4-fluorophenyl)-2-((5-methylisoxazol-3-yl)methyl)-1-oxo-2,7-diazaspiro[4.5]decane-7-carboxylate (243.6 mg; 0.549 mmol) was solubilised in DCM (1 ml). Trifluoroacetic acid (0.86 ml; 11.14 mmol) was added and the mixture stirred at RT for 20 minutes before being concentrated in vacuo. The oil was dissolved with methanol (5 ml) and passed through a 10 g SCX-2 cartridge eluting with 2M NH3 in methanol (50 ml) and concentrated in vacuo to yield the title compound.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7].[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][C:19](O)=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][C:19]([O:1][C@@H:2]2[CH2:6][CH2:5][NH:4][C:3]2=[O:7])=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1NCC[C@@H]1O
Reactant: Oc1ccc(OCc2ccccc2)cc1
Product: O=C1NCC[C@H]1Oc1ccc(OCc2ccccc2)cc1

Procedure:
Typical Procedure 3 was followed. Reaction of (S)-3-hydroxy-pyrrolidin-2-one with 4-benzyloxy-phenol provided the subtitle compound. MS ESI+: m/z=284 [M+H]+.
Reaction SMILES: S([O-])(O)(=O)=O.[CH2:6]([C:11]1[CH:15]=[S+:14][S:13][C:12]=1[C:16]([CH3:19])([CH3:18])[CH3:17])[C:7]([CH3:10])([CH3:9])[CH3:8].N.[CH2:21]([OH:23])[CH3:22]>>[CH2:21]([O:23][C:12]1([C:16]([CH3:19])([CH3:18])[CH3:17])[C:11]([CH2:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[CH:15][S:14][S:13]1)[CH3:22]
Reactant: CCO
Reactant: CC(C)(C)Cc1c[s+]sc1C(C)(C)C
Agent: N
Agent: O=S(=O)([O-])O
Product: CCOC1(C(C)(C)C)SSC=C1CC(C)(C)C
Temperature: 25 °C
Yield: 61 %

Procedure:
Into a mixture of 32 grams of Example 1B, i.e., 4-neopentyl-3-tertiarybutyl 1,2-dithiolium hydrogen sulfate, and 300 cc of ethanol was introduced dry ammonia gas until the mixture was saturated. During the reaction, the mixture was kept at a temperature below 18° C. After the introduction of ammonia gas was completed, the mixture was stirred for an additional hour at room temperature. The solid, which precipitated during the reaction, was filtered off. After removal of the ethanol from the filtrate under diminished pressure, there was isolated 16.5 grams (61% of theory) of 3-ethoxy-3-t-butyl-4-neopentyl 1,2-dithiole.
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[NH2:20].CN1CCCC1=O.C(=O)([O-])O.[Na+]>O>[Cl:16][C:17]1[CH:18]=[C:19]([NH:20][C:2]2[C:3]3[NH:10][C:9]([C:11]4[O:12][CH:13]=[CH:14][CH:15]=4)=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1
Reactant: Clc1ncnc2cc(-c3ccco3)[nH]c12
Reactant: Nc1ccc(OCc2ccccn2)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Clc1cc(Nc2ncnc3cc(-c4ccco4)[nH]c23)ccc1OCc1ccccn1
Temperature: 140 °C
Reaction time: 2 h
Yield: 46.6 %

Procedure:
A mixture of 4-chloro-6-(2-furyl)-5H-pyrrolo[3,2-d]pyrimidine (80 mg), 3-chloro-4-(pyridin-2-ylmethoxy)aniline (94 mg) and 1-methyl-2-pyrrolidinone (2.5 mL) was stirred at 140° C. for 2 hrs, poured into water (10 mL) and adjusted to pH 8 with saturated aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate (30 mL×2). The organic layers were combined and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=1:1→0:1). The object fraction was concentrated under reduced pressure. Chloroform-diisopropyl ether was added to the residue, and the solid was collected by filtration and dried under reduced pressure at 60° C. to give the title compound (71 mg).
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][C:14]([CH3:18])(O)[CH:13]([CH2:19][CH3:20])[CH2:12]1)C1C=CC=CC=1.C(Cl)(=O)C(Cl)=O.CS(C)=O.CCN(CC)CC>C(Cl)Cl>[CH2:19]([C:13]1[CH2:12][CH:11]([CH2:10][CH:9]=[O:8])[CH2:16][CH2:15][C:14]=1[CH3:18])[CH3:20]
Reactant: CCC1CC(CCOCc2ccccc2)CCC1(C)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC1=C(C)CCC(CC=O)C1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
The deprotected alcohol was oxidized by the standard “Swern” procedure (Mancuso, Synthesis 1981 p165, incorporated herein by reference) as follows: The alcohol (5 mmol) was added to a solution of oxalyl chloride (3.5 mL, 7.0 mmol) in CH2Cl2 (30 mL) with DMSO (0.64 mL, 9.0 mmol) at −78° C. After 40 min., NEt3 (2.50 mL) was added and the mixture was warmed to rt. After standard aqueous work-up and purification, (3-ethyl-4-methyl-cyclohex-3-enyl)-acetaldehyde (Intermediate K5) was isolated (90%).
Reaction SMILES: O1CCOCC1.[CH2:7]([Li])[CH2:8][CH2:9][CH3:10].[P:12]([Cl:20])([O:17][CH2:18][CH3:19])([O:14][CH2:15][CH3:16])=[O:13].[CH2:21]1[CH2:25]O[CH2:23][CH2:22]1>>[P:12]([Cl:20])([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:25][CH:19]=1)([O:14][C:15]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:16]=1)=[O:13]
Reactant: [Li]CCCC
Reactant: CCOP(=O)(Cl)OCC
Reactant: C1CCOC1
Solvent: C1COCCO1
Product: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Compound 6 (0.75 g) is first dissolved in refluxing dioxane, evaporated to dryness under reduced pressure, and then dissolved in 600 mL THF. The solution is cooled to -78° C. To this solution is slowly added 4.8 mL (2 eq) butyllithium solution, and the resultant cloudy mixture is stirred at 78° C. for 1 hour. A solution of 2.61 g (2.6 eq) diethyl chlorophosphate in 10 mL THF is then added dropwise. The mixture is maintained at -78° C. for three hours and then quenched by the dropwise addition of 10 mL distilled water, at which point the product precipitated from solution. The mixture is warmed to room temperature and filtered to give a white solid. The product is washed with distilled water, hot THF, toluene, ethanol, and DMF and dried under vacuum. Yield: 0.2 g. IR (cm-1): 3300-3150, 2966, 1601, 1492, 1389, 1280, 1216, 1120, 1030, 934, 844, 767.
Reaction SMILES: Cl[C:2]1[N:6]=[C:5]([CH:7]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH2:10][N:9]([C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])[CH2:8]2)[O:4][N:3]=1.[NH:31]1[CH2:35][CH2:34][C@H:33]([OH:36])[CH2:32]1>C(O)C>[OH:36][C@H:33]1[CH2:34][CH2:35][N:31]([C:2]2[N:6]=[C:5]([CH:7]3[CH2:12][CH:11]([C:13]4[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=4)[CH2:10][N:9]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])[CH2:8]3)[O:4][N:3]=2)[CH2:32]1
Reactant: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(Cl)no2)C1
Reactant: O[C@H]1CCNC1
Solvent: CCO
Product: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(N3CC[C@H](O)C3)no2)C1
Reaction time: 2 h

Procedure:
To a solution of 150 mg (0.337 mmol) of the oxadiazole from Example 23A in 2.25 ml of ethanol were added 588 mg (6.74 mmol) of (3S)-pyrrolidin-3-ol, and then the reaction mixture was stirred in the microwave at 80 for 2 h. The solvent was removed under reduced pressure and the crude product was purified by means of preparative
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=1[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[N:17]([O-])=O.[Na+].[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:23]=1[OH:29].[OH-].[Na+]>>[CH3:21][C:22]1[CH:27]=[C:26]([N:17]=[N:2][C:3]2[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=2[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:6])[CH:25]=[C:24]([CH3:28])[C:23]=1[OH:29]
Reactant: Cc1cccc(C)c1O
Reactant: O=N[O-]
Reactant: Nc1ccccc1C(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(N=Nc2ccccc2C(=O)c2ccccc2)cc(C)c1O
Temperature: 0 °C

Procedure:
A slurry of ice (500 mL), hydrochloric acid (16.8 mL, 202 mmol, conc.), 2-aminobenzophenone (20.00 g, 101 mmol) and NaNO2 (9.0 g, 131 mmol) were added to a stirred solution of 2,6-dimethylphenol (18.40 g, 151 mmol) and sodium hydroxide (16.20 g, 404 mmol) in ice-cold water (100 mL). After 20 minutes the mixture was extracted with diethyl ether. The organic phase was washed with hydrochloric acid (6 M), NaHCO3(aq), dried (MgSO4) and the solvent evaporated. The crude residue was chromatographed on silica (toluene) and pure fractions were pooled and evaporated to give a red oil. The oil was crystallised in hexane/toluene to give 7.73 g (23%).
Reaction SMILES: C([O:5][C:6](=[O:16])[C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([NH2:14])=[CH:9][C:8]=1[F:15])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:14][C:10]1[C:11]([Cl:13])=[CH:12][C:7]([C:6]([OH:16])=[O:5])=[C:8]([F:15])[CH:9]=1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(N)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc(F)c(C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 105.8 %

Procedure:
4-Amino-5-chloro-2-fluorobenzoic acid tert-butyl ester (Intermediate 177; 3.0 g, 12.21 mmol) was dissolved in DCM (75 mL) and trifluoroacetic acid (25 mL) added. The mixture was stirred for 1 hour at room temperature and then concentrated to yield the title compound as a pale yellow solid (2.45 g, 100%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[NH:10][CH2:11][C@H:12]([NH2:18])[C@@H:13]([OH:17])[C:14]#[C:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.[F:27][C:28]([F:43])([F:42])[C:29]1[CH:30]=[C:31]([CH:39]=[CH:40][CH:41]=1)[C:32]([NH:34][CH2:35][C:36](O)=[O:37])=[O:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:19])[NH:10][CH2:11][C@H:12]([NH:18][C:36](=[O:37])[CH2:35][NH:34][C:32](=[O:33])[C:31]1[CH:39]=[CH:40][CH:41]=[C:29]([C:28]([F:27])([F:43])[F:42])[CH:30]=1)[C@@H:13]([OH:17])[C:14]#[C:15][CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CNC(=O)c1cccc(C(F)(F)F)c1
Reactant: CC#C[C@H](O)[C@@H](N)CNC(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC#C[C@H](O)[C@H](CNC(=O)OCc1ccccc1)NC(=O)CNC(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.9 %

Procedure:
(2S,3S)-(2-Amino-3-hydroxy-hex-4-ynyl)-carbamic acid benzyl ester (2.53 g, prepared as in WO PCT 0250019) was dissolved in CH2Cl2 (50 ml) and 4-methylmorpholine (2.53 ml) and cooled to 0° C. prior to the addition of (3-trifluoromethyl-benzoylamino)-acetic acid (1.49 g) and HATU (2.23 g). After the reaction was stirred overnight at room temperature, the CH2Cl2 was removed and EtOAc was added. The organic layer was washed with saturated NH4Cl solution (aq) brine, dried, filtered, and concentrated. Flashed chromatography of the resulting residue gave (2S,3S)-{3-hydroxy-2-[2-(3-trifluoromethyl-benzoylamino)-acetylamino]-hex-4-ynyl}-carbamic acid benzyl ester (1.3 g). MS found: (M+H)+=492.3.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[C:11]([NH:15][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[N:19]=3)=[O:17])[CH:12]=[CH:13][CH:14]=2)=[CH:4][CH:3]=1.[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>N1C=CC=CC=1>[CH3:24][C:20]1[N:19]=[C:18]([C:16]([NH:15][C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][C:5]3[CH:6]=[N:7][C:2]([NH:1][S:31]([C:28]4[CH:29]=[CH:30][C:25]([CH3:35])=[CH:26][CH:27]=4)(=[O:33])=[O:32])=[CH:3][CH:4]=3)[CH:10]=2)=[O:17])[CH:23]=[CH:22][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cccc(C(=O)Nc2cccc(Oc3ccc(N)nc3)c2)n1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2ccc(Oc3cccc(NC(=O)c4cccc(C)n4)c3)cn2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
A mixture of N-{3-[(6-aminopyridin-3-yl)oxy]phenyl}-6-methylpyridine-2-carboxamide (10.41 g, 32.5 mmol), p-toluenesulfonyl chloride (6.83 g, 35.8 mmol) and pyridine (75 mL) was stirred at 80° C. for 2 hr. The reaction solution was concentrated under reduced pressure, and ethyl acetate was added to the residue. The mixture was washed with aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was washed with ethyl acetate-hexane to give the title compound (14.8 g, 96%) as a pale-brown solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:61])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=CC=[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37]5[NH:38][C:39]([C@@H:42]6[CH2:46][CH2:45][CH2:44][N:43]6[C:47](=[O:60])[CH:48]([NH:55][C:56]([O:58][CH3:59])=[O:57])[C:49]6[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=6)=[N:40][CH:41]=5)=[CH:33][CH:32]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].COC(=O)N[CH:66](C(N1CCCC1C1NC(C2C=CC(Br)=CC=2)=CN=1)=O)[CH:67](C)C.C(OC(N1CCCC1C1NC(C2C=CC3C(=CC=C(B4OC(C)(C)C(C)(C)O4)C=3)C=2)=CN=1)=O)(C)(C)C>>[CH3:1][O:2][C:3](=[O:61])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:22]=[CH:23][C:28]([C:27]3[CH:67]=[CH:66][C:32]4[C:31](=[CH:36][CH:35]=[C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH2:45][CH2:44][N:43]6[C:47](=[O:60])[CH:48]([NH:55][C:56]([O:58][CH3:59])=[O:57])[C:49]6[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=6)=[N:40][CH:41]=5)[CH:33]=4)[CH:26]=3)=[CH:29][CH:30]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(Br)cc2)[nH]1)C(C)C
Reactant: COC(=O)NC(C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)ccc4c3)cc2)[nH]1)c1ccccc1
Agent: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc3cc(B4OC(C)(C)C(C)(C)O4)ccc3c2)[nH]1
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)cc4)ccc3c2)[nH]1)c1ccccc1
Yield: 54 %

Procedure:
This compound was prepared following the procedure for [1-(2-{5-[6-(4-{2-[1-(2S)-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester using (1-{2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (1.0 g, 2.2 mmol) and 2-{5-[6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (1.6 g, 3.4 mmol, 1.5 equiv.) to provide [1-(2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (0.03 g, 54%) as a white powder. LCMS-ESI+: calc'd for C47H50N8O6: 822.4 (M+). Found: 823.9 (M+H+). 1H-NMR: 400 MHz, (CDCl3) 8: (Mixture of rotomers) 7.52-7.93 (m, 9H), 7.27-7.42 (m, 6H), 7.16 (s, 2H), 6.08 (m, 1H), 5.48-5.56 (m, 2H), 5.34 (s, 1H), 5.24 (s, 1H), 4.35 (t, 1H), 3.93 (m, 1H), 3.73 (m, 1H), 3.68 (s, 3H), 3.66 (s, 3H), 3.38 (m, 1H), 2.78-2.83 (m, 3H), 2.36 (m, 1H), 2.04-2.23 (m, 6H), 0.86-0.97 (m, 6H).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][CH2:6][C@@H:5]([CH2:9][NH:10][C:11]([C@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[C:18]([C@@H:20]2[CH2:24][C@@H:23]([OH:25])[CH2:22][N:21]2[C:26](=[O:47])[CH2:27][C:28]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:19])=[O:12])[CH2:4]1)[CH3:2].[CH2:48](I)[CH3:49].C(Cl)(Cl)[Cl:52]>>[Cl-:52].[CH2:1]([N+:3]1([CH2:48][CH3:49])[CH2:8][CH2:7][CH2:6][C@@H:5]([CH2:9][NH:10][C:11]([C@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[C:18]([C@@H:20]2[CH2:24][C@@H:23]([OH:25])[CH2:22][N:21]2[C:26](=[O:47])[CH2:27][C:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[O:19])=[O:12])[CH2:4]1)[CH3:2]
Reactant: CCI
Reactant: CCN1CCC[C@@H](CNC(=O)[C@H]2CCCN2C(=O)[C@@H]2C[C@@H](O)CN2C(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Reactant: ClC(Cl)Cl
Product: CC[N+]1(CC)CCC[C@@H](CNC(=O)[C@H]2CCCN2C(=O)[C@@H]2C[C@@H](O)CN2C(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Product: [Cl-]
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To 22 mg of (2R)-N-{((3S)-1-ethyl-3-piperidyl)methyl}-1-{(2S,4R)-4-hydroxy-1-(3,3,3-triphenylpropanoyl)pyrrolidin-2-yl}carbonylpyrrolidine-2-carboxamide, 1 ml of ethyl iodide was added at room temperature, followed by 2 hours' stirring at 70° C. The resultant reaction liquid was diluted with chloroform and the solvent was distilled off under reduced pressure. The resultant residue was dissolved in ultrapure water 0.6 ml/methanol 0.1 ml and the solution was developed on reversed phase medium-pressure liquid chromatograpy [ODS-AQ 120-S50 (YMC)]. Purification and anion exchange were conducted by pouring 20 ml of saturated brine, washing with 150 ml of ultrapure water and eluting the title compound with methanol/water=1/1, to provide 21 mg of the title compound as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])#[N:2].[C:12](Cl)(=O)C(Cl)=O>ClCCl.CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([O:8][CH3:12])=[O:7])#[N:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: N#Cc1cccc(C(=O)O)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1cccc(C#N)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Preparation H11, Step 1: 10 g (0.068 mol) of 3-cyano benzoic acid was taken in 150 ml of dry dichloromethane and cooled to 0° C. Added 50 ml of oxalyl chloride drop wise followed by 5 drops of dry DMF. The reaction mixture was stirred at RT overnight. Dichloromethane was removed and dry methanol (50 ml) was added and stirred at rt for 2 h. Excess methanol was removed and the residue was dissolved in ethyl acetate. The ethyl acetate layer was washed with 10% of sodium bicarbonate, brine and concentrated to give methyl 3-cyanobenzoate (7 g) as a white solid.
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4](=[O:10])[CH2:3][CH2:2]2.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCOCC1>[N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([OH:10])[CH2:3][CH2:2]2
Reactant: O=C1CCN2CCC1CC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1COCCO1
Product: OC1CCN2CCC1CC2
Temperature: 0 °C
Yield: 96.1 %

Procedure:
To 1-azabicyclo[3.2.2]nonan-4-one (0.20 g, 1.4 mmol) in 1,4-dioxane (2.8 mL) at 0° C. was added lithium aluminum hydride[1.0M/THF] (1.7 mL, 1.7 mmol). The reaction mixture was maintained at 0° C. for 15 minutes. The reaction was quenched by the stepwise addition of 46 L of H2O, 46 L of 15% aqueous NaOH, and 138 L of H2O. The mixture was filtered through Celite which was subsequently washed with EtOAc. The solvent was removed in vacuo to afford the product (0.19 g, 96%) which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 3.90-3.86 (m, 1H), 3.09-3.03 (m, 1H), 2.96-2.91 (dd, J=9.2, 6.8 Hz, 1H), 2.86-2.75 (m, 3H), 2.71-2.64 (m, 1H), 2.34-2.27 (bs s, 1H), 1.98-1.86 (m, 3H), 1.71-1.59 (m, 3H), 1.51-1.35 (m, 1H) ppm.