Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[NH:12][C:13](=O)[C:14]([CH3:17])([CH3:16])[CH3:15].Cl.[CH:20]([O:23][NH2:24])([CH3:22])[CH3:21]>C(O)(C)C>[C:14]([C:13]1[N:24]([O:23][CH:20]([CH3:22])[CH3:21])[C:2]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N:5]=[CH:4][C:3]=2[N:12]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)C(=O)Nc1cnc2ccccc2c1Cl
Reactant: CC(C)ON
Agent: Cl
Solvent: CC(C)O
Product: CC(C)On1c(C(C)(C)C)nc2cnc3ccccc3c21
Temperature: 80 °C
Yield: 43.3 %

Procedure:
Under a nitrogen atmosphere, a mixture of N-(4-chloroquinolin-3-yl)trimethylacetamide (6.00 g, 1 eq), O-isopropylhydroxylamine hydrochloride (7.6 g, 3 eq), and anhydrous isopropanol (80 mL) was heated at 80° C. for 19 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane, washed sequentially with saturated aqueous potassium carbonate, water, and brine, dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified by column chromatography (150 g of silica gel eluted with a gradient of 20-55% ethyl acetate in dichloromethane) to provide 2.8 g of 2-tert-butyl-1-isopropoxy-1H-imidazo[4,5-c]quinoline as a brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.[Br:10]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.CCCCCC.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([Br:8])[CH:7]=1)[CH2:9][Br:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(Br)cc(Br)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCCCCC
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cc(Br)cc(Br)c1
Temperature: 25 °C
Yield: 43.5 %

Procedure:
3,5-dibromotoluene (78.92 g, 0.316 mole) was dissolved in 1.27 L of carbon tetrachloride; to this solution was added N-bromosuccinimide (61.65 g, 0.346 mole) at room temperature. A portion of dibenzoyl peroxide (0.6 g, 0.008 equivalents) was added and the solution heated to reflux temperature for 2.5 hours. The reaction mixture was cooled to room temperature, filtered and the solvent removed in vacuo to yield a solid. The solid was dissolved in 200 mL of warm hexane, filtered and cooled to room temperature. Crystallizations ensued; the crystals were filtered off and washed with cold hexane and air dried to give 45.15 g (44%) of 3,5-dibromobenzyl bromide. 1H-NMR(CDCl3); δ7.6 (1H), 7.47 (2H), 4.36 (2H).
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].[F:5][C:6]([F:17])([F:16])[C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10](Cl)=[O:11]>C(Cl)Cl>[CH2:1]([NH:4][C:10](=[O:11])[C:9]1[CH:13]=[CH:14][CH:15]=[C:7]([C:6]([F:5])([F:16])[F:17])[CH:8]=1)[C:2]#[CH:3]
Reactant: C#CCN
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Product: C#CCNC(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.3 %

Procedure:
To a solution of 2-propyn-1-amine (2.0 g, 35.7 mmol) and Hunnig's base (12.5 mL, 71.4 mmol) in CH2Cl2 (20 mL) was added 3-(trifluoromethyl)benzoyl chloride (5.4 mL, 35.7 mmol) at 0° C. The mixture was stirred at rt overnight. CH2Cl2 was added and the organic solution was washed with water twice, brine once, and dried over MgSO4. Concentration and purification by radial chromatography (0-40% EtOAc-hexanes gradient) afforded the title compound (7.0 g, 96% yield): MS (ES) m/z 228 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:29])=[N:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3([C:22]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[O:23])[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.Br[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:32]=1.C(=O)([O-])[O-].[K+].[K+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:29][C:3]1[C:2]([NH:1][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:32]=2)=[C:6]([C:7]2[CH:8]=[CH:9][C:10]([C:13]3[CH:14]=[CH:15][C:16]([C:19]4([C:22]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[O:23])[CH2:21][CH2:20]4)=[CH:17][CH:18]=3)=[CH:11][CH:12]=2)[O:5][N:4]=1
Reactant: Brc1cccc(-c2ccccc2)n1
Reactant: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)NS(C)(=O)=O)CC4)cc3)cc2)c1N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)NS(C)(=O)=O)CC4)cc3)cc2)c1Nc1cccc(-c2ccccc2)n1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
N-{1-[4′-(4-Amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarbonyl}-methanesulfonamide (0.103 g, 0.25 mmol), 2-bromo-6-phenylpyridine (0.059 g, 0.25 mmol), potassium carbonate (0.243 g, 0.75 mmol), and BINAP (15 mg, 0.025 mmol) were combined in THF (10 mL) and the solution was degassed with N2 for 10 minutes. Palladium(II)acetate (0.003 g, 0.0125 mmol) was added and degassing was continued for 10 minutes. The reaction mixture was sealed and heated at 65° C. overnight then poured into EtOAc/water. The organic layer was concentrated and purified by silica gel chromatography to give the title compound.
Reaction SMILES: [OH:1][C:2]([CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)([C:10]([OH:12])=[O:11])CC(=NO)C(O)=O>O>[NH:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]([CH2:13][C:2](=[O:1])[C:10]([OH:12])=[O:11])=[CH:15]1
Reactant: O=C(O)C(CC(O)(Cc1c[nH]c2ccccc12)C(=O)O)=NO
Solvent: O
Product: O=C(O)C(=O)Cc1c[nH]c2ccccc12

Procedure:
To a solution of aldol reaction containing 4-hydroxy-4-(3-indolylmethyl)-2-ketoglutaric acid is added an excess amount (about 4 equimolar amount for the used amount of indole-3-pyruvic acid) of hydroxyamine, and the mixture was adjusted to pH 7.0 to 10.0 by addition of 2N sodium hydroxide aqueous solution or 1N hydrochloric acid. 2) The mixture was stirred at room temperature overnight to form 4-hydroxy-4-(3-indolylmethyl)-2-hydroxyiminoglutaric acid. 3) A portion of the resulting reaction mixture was weighed and diluted with pure water in a mess-flask so that the concentration of 4-hydroxy-4-(3-indolylmethyl)-2-hydroxyiminoglutaric acid became 100 to 150 ppm; thus a sample for analysis was prepared. Method of Determination of the Yield 4) The sample for analysis prepared in the above item 3) was applied to the following high performance liquid chromatography, and the yield was calculated by comparison in the percentage of the area of sample to that of a standard solution of 4-hydroxy-4-(3-indolylmethyl)-2-hydroxyiminoglutaric acid; thus, the yield (%) from indole-3-pyruvic acid used was calculated. Analytical condition for high performance liquid chromatography (gradient) Column: CAPCELL PAK C18 (MGII) 5 μm 4.6 mm×250 mm Column temperature: 25° C. Wavelength for detection: 210 nm Flow rate: 1.0 ml/min Mobile phase composition: Solution A: KH2PO4 (20 mM)+K2HPO4 (20 mM) aqueous solution/acetonitrile=100/5 Solution B: KH2PO4 (20 mM)+K2HPO4 (20 mM) aqueous solution/acetonitrile=1/1 Injected amount of sample: 10 μL Retention time: 11 minutes (4-hydroxy-4-(3-indolylmethyl)-2-hydroxyiminoglutaric acid) Method of Determination of Enantiomeric Excess 5) The sample for analysis mentioned in the above item 3) was applied to the following high performance liquid chromatography, and on the basis of the peak integral value derived from the enantiomer at the 4 position of 4-hydroxy-4-(3-indolylmethyl)-2-hydroxyiminoglutaric acid, the selectivity and enantiomeric excess (% ee) of the enantiomer at the 4 position were calculated by the following procedure from the following equation: Enantiomeric excess of the enantiomer at 4 =(Peak area of 4S-isomer−Peak area of 4R isomer)/(Peak area of 4S-isomer+Peak area of 4R isomer)×100 (Regarded as % ee4S when the Sign is +, and % ee4R when the Sign is −) Analytical condition for high performance liquid chromatography (gradient) Column: SUMICHIRAL OA7100 4.6 mm×250 mm Column temperature: 10° C. Wavelength for detection: 210 nm Flow rate: 0.5 ml/min Mobile phase composition: Solution A: KH2PO4 (20 mM)+K2HPO4 (20 mM) aqueous solution/acetonitrile=100/5 Solution B: KH2PO4 (20 mM)+K2HPO4 (20 mM) aqueous solution/acetonitrile=1/1 Injected amount of sample: 10 μL Retention time: 19 min for 4R isomer; 21 min for 4S isomer
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH3:9])=[CH:4][C:3]=1[S:10](Cl)(=[O:12])=[O:11].[OH-].[NH4+:15].O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH3:9])=[CH:4][C:3]=1[S:10]([NH2:15])(=[O:12])=[O:11]
Reactant: [NH4+]
Reactant: CCc1ccc(Cl)c(S(=O)(=O)Cl)c1
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCc1ccc(Cl)c(S(N)(=O)=O)c1
Reaction time: 0.25 h

Procedure:
To a solution of 2-chloro-5-ethylbenzenesulfonyl chloride (0.41 g, 1.7 mmol, the product of Step A) in tetrahydrofuran (30 mL) was added 30% ammonium hydroxide (0.41 mL, 3.5 mmol) dropwise. The reaction mixture was stirred for 15 minutes, during which time a suspension formed. To this mixture water (10 mL) was added, and the tetrahydrofuran was evaporated under reduced pressure to precipitate a solid. The solid was dissolved in diethyl ether, dried over magnesium sulfate, and concentrated under reduced pressure. Diethyl ether and hexane were added to precipitate a solid. The solid was isolated by filtration to afford 190 mg of the title compound. 1H NMR (CDCl3) δ 7.95 (s, 1H), 7.43 (d, 1H), 7.35 (d, 1H), 5.08 (br s, 2H), 2.71 (q, 2H), 1.25 (t, 3H).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].CC(N(C)C)=O.[Br:23][C:24]1[C:25]([CH3:38])=[C:26]([CH3:37])[C:27]2[O:31][C:30]([CH2:33]I)([CH3:32])[CH2:29][C:28]=2[C:35]=1[CH3:36]>C(OCC)(=O)C.O>[Br:23][C:24]1[C:25]([CH3:38])=[C:26]([CH3:37])[C:27]2[O:31][C:30]([CH2:32][N:8]3[CH2:9][CH2:10][C:5]4([O:4][CH2:3][CH2:2][O:1]4)[CH2:6][CH2:7]3)([CH3:33])[CH2:29][C:28]=2[C:35]=1[CH3:36]
Reactant: Cc1c(C)c2c(c(C)c1Br)CC(C)(CI)O2
Reactant: C1CC2(CCN1)OCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1c(C)c2c(c(C)c1Br)CC(C)(CN1CCC3(CC1)OCCO3)O2
Temperature: 200 °C
Reaction time: 0.17 h
Yield: 74.8 %

Procedure:
1,4-dioxa-8-azaspiro[4.5]decane (725 mg, 5.06 mmol) and potassium carbonate (699 mg, 5.06 mmol) were added to a solution of DMA (3 mL) containing 5-bromo-2-(iodomethyl)-2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran (400 mg, 1.01 mmol) synthesized in Reference Example 133, and the mixture was stirred under microwave irradiation at 200° C. for 10 minutes. The reaction solution was cooled to room temperature, and water and ethyl acetate were added thereto to separate an organic layer. The organic layer was washed with water and saturated saline, and dried using anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was purified by silica gel chromatography (hexane-ethyl acetate 95:5-80:20) to give 310 mg of the title compound (yield: 75%).
Reaction SMILES: C(O[C@@H]1[C@H](OC(=O)C)[C@@H](COC(=O)C)O[C@H]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22]([Cl:36])=[N:23][C:24]=2[N:28]1[CH:32]=[CH:31][N:30]=[C:29]1[CH2:33][CH2:34][CH3:35])(=O)C.C(Cl)(C)=O>CC(O)=O>[Cl:36][C:22]1[N:21]=[C:20]2[C:25]([NH:26][CH:27]=[N:19]2)=[C:24]([N:28]2[CH:32]=[CH:31][N:30]=[C:29]2[CH2:33][CH2:34][CH3:35])[N:23]=1
Reactant: CCCc1nccn1-c1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Solvent: CC(=O)Cl
Solvent: CC(=O)O
Product: CCCc1nccn1-c1nc(Cl)nc2nc[nH]c12
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 87.2 %

Procedure:
9-(2,3,5-Tri-O-acetyl-β-D-ribofuranosyl)-2-chloro-6-(2-propylimidazol-1-yl)purine (4.99 g, 9.6 mmol) was dissolved in HOAc (400 mL). To the solution was added AcCl (4.0 mL, 4.42 g, 56.3 mmol), and the mixture was stirred at 65° C. for 1.5 h in a sealed flask (reaction almost complete, TLC). Volatiles were evaporated in vacuo, and the residue was washed (CH2Cl2), and dissolved in 0.1 N NaOH/H2O. Precipitation with CO2 gave 2-chloro-6-(2-propylimidazol-1-yl)purine (2.20 g, 88%). Recrystallization (MeOH) gave the pure material (1.93 g, 77%).
Reaction SMILES: Cl[CH2:2][O:3][C:4](=[O:18])[C@H:5]([C@H:14]([CH2:16][CH3:17])[CH3:15])[NH:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[I-:19].[Na+]>C(#N)C>[I:19][CH2:2][O:3][C:4](=[O:18])[C@H:5]([C@H:14]([CH2:16][CH3:17])[CH3:15])[NH:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: [I-]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCCl
Agent: [Na+]
Solvent: CC#N
Product: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCI
Temperature: 60 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
To a solution of N-BOC-L-isoleucine chloromethyl ester (19.6 g, 70 mmol) in acetonitrile (300 mL), was added sodium iodide (31.5 g, 210 mmol). The solution was stirred for 4 h at 60° C. The resulting suspension was filtered and the filtrate was evaporated. The residue was dissolved in CH2Cl2 and washed with aqueous sodium thiosulfate (0.1 M). The organic phase was dried (Na2SO4) and concentrated under reduced pressure. The crude product was column chromatographed (silica gel, 2% MeOH in CH2Cl2), to give 22.6 g of N-BOC-L-isoleucine iodomethyl ester.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCCC1.[CH3:14][S:15][C:16]1[N:21]=[CH:20][C:19]2=[CH:22][CH:23]=[C:24]([CH:25]=[O:26])[N:18]2[N:17]=1>C(OCC)(=O)C>[CH3:14][S:15][C:16]1[N:21]=[CH:20][C:19]2=[CH:22][CH:23]=[C:24]([CH:25]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[OH:26])[N:18]2[N:17]=1
Reactant: CSc1ncc2ccc(C=O)n2n1
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CSc1ncc2ccc(C(O)c3ccccc3)n2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.00 M of Phenylmagnesium bromide in Tetrahydrofuran (1.552 mL, 1.552 mmol) was added to a solution of 2-Methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine-7-carbaldehyde (250.0 mg, 1.294 mmol) in Tetrahydrofuran (8.0 mL, 99 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature with stirring for 3 hours. The mixture was then diluted with ethyl acetate and quenched with saturated ammonium chloride. The resulting mixture was washed with water and the organic layer was extracted, dried over sodium sulfate and reduced. The resulting oil was then purified via Isco flash column chromatography (hexanes/ethyl acetate) to afford 340 mg of (2-Methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl-methanol. 1H NMR (400 MHz, DMSO, d6) δ 8.90 (s, 1H), 7.43 (m, 2H), 7.32 (m, 2H), 6.93 (m, 1H), 6.88 (m, 1H), 6.24 (m, 1H), 6.14 (m, 1H), 3.29 (s, 4H).
Reaction SMILES: [N+]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:10])([O-])=O.[C:11]1(=[O:17])CCCC[CH2:12]1>>[C:11]([O:10][C:5]1[CH2:6][CH2:7][CH2:8][CH2:9][CH:4]=1)(=[O:17])[CH3:12]
Reactant: O=C1CCCCC1[N+](=O)[O-]
Reactant: O=C1CCCCC1
Product: CC(=O)OC1=CCCCC1

Procedure:
nitrocyclohexanone process in which cyclohexanone is acetylated to obtain cyclohexenyl acetate, the obtained cyclohexenyl acetate is nitrated to obtain 2-nitrocyclohexanone, the obtained 2-nitrocyclohexanone is subjected to hydrolysis, thereby causing ring cleavage of the 2-nitrocyclohexanone to obtain nitrocapronic acid, the obtained nitrocapronic acid is hydrogenated to obtain ε-aminocapronic acid, and the obtained ε-aminocapronic acid is converted into ε-caprolactam.
Reaction SMILES: [ClH:1].O1CCOCC1.[CH3:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11]([CH2:41][C:42]1[CH:47]=[CH:46][C:45](/[CH:48]=[CH:49]/[CH2:50][CH2:51][N:52]3[CH2:57][C:56]4([CH2:62][CH2:61][N:60](C(OC(C)(C)C)=O)[CH2:59][CH2:58]4)[CH2:55][CH2:54][CH2:53]3)=[CH:44][CH:43]=1)=[CH:12][N:13]2[C@H:18]1[C@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@@H:22]([O:28][C:29](=[O:31])[CH3:30])[C@H:21]([O:32][C:33](=[O:35])[CH3:34])[C@@H:20]([CH2:36][O:37][C:38](=[O:40])[CH3:39])[O:19]1>ClCCl>[ClH:1].[ClH:1].[C:38]([O:37][CH2:36][C@@H:20]1[C@@H:21]([O:32][C:33](=[O:35])[CH3:34])[C@H:22]([O:28][C:29](=[O:31])[CH3:30])[C@@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@H:18]([N:13]2[C:14]3[C:10](=[C:9]([CH3:8])[CH:17]=[CH:16][CH:15]=3)[C:11]([CH2:41][C:42]3[CH:47]=[CH:46][C:45](/[CH:48]=[CH:49]/[CH2:50][CH2:51][N:52]4[CH2:57][C:56]5([CH2:58][CH2:59][NH:60][CH2:61][CH2:62]5)[CH2:55][CH2:54][CH2:53]4)=[CH:44][CH:43]=3)=[CH:12]2)[O:19]1)(=[O:40])[CH3:39]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(Cc3ccc(/C=C/CCN4CCCC5(CCN(C(=O)OC(C)(C)C)CC5)C4)cc3)c3c(C)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(Cc3ccc(/C=C/CCN4CCCC5(CCNCC5)C4)cc3)c3c(C)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 3 h

Procedure:
Add 4N HCl in 1,4-dioxane (112 5 mmol) to a solution of tert-butyl 4-[(E)-4-[4-[[4-methyl-1-[(2R,3R,4S,5R,6R)-3,4,5-triacetoxy-6-(acetoxymethyl)tetrahydropyran-2-yl]indol-3-yl]methyl]phenyl]but-3-enyl]-4,9-diazaspiro[5.5]undecane-9-carboxylate (22.5 mmol) in dichloromethane (200 mL) at room temperature. Stir for 3 hours, then concentrate under reduced pressure to yield crude [(2R,3R,4S,5R,6R)-3,4,5-triacetoxy-6-[3-[[4-[(E)-4-(4,9-diazaspiro[5.5]undecan-4-yl)but-1-enyl]phenyl]methyl]-4-methyl-indol-1-yl]tetrahydropyran-2-yl]methyl acetate dihydrochloride (22.5 mmol): MS (m/z): 758.0 (M+H). Add triethylamine (112 5 mmol) to a solution of [(2R,3R,4S,5R,6R)-3,4,5-triacetoxy-6-[3-[[4-[(E)-4-(4,9-diazaspiro[5.5]undecan-4-yl)but-1-enyl]phenyl]methyl]-4-methyl-indol-1-yl]tetrahydropyran-2-yl]methyl acetate dihydrochloride (22 5 mmol) in dichloromethane (200 mL). In a separate flask, add CDI (28.1 mmol) portion wise to a solution of 2-(tert-butoxycarbonylamino)acetic acid (27 mmol) in dichloromethane (50 mL). After stirring for 45 minutes at room temperature, add the solution to the previously prepared amine solution and stir at room temperature for 1 hour. Wash with a concentrated sodium bicarbonate solution (200 mL) and brine (200 ml). Dry the organics over sodium sulfate, filter, and concentrate under reduced pressure to yield crude title compound (21.6 g, 22.5 mmol): MS (m/z): 915.2 (M+H).
Reaction SMILES: CS(O[CH2:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[C@H:16]2[C@H:20]([OH:21])[C@H:19]([OH:22])[C@@H:18]([CH2:23][O:24][CH3:25])[O:17]2)=[C:9]([NH:26][CH2:27][CH:28]([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)[N:8]=1)(=O)=O.C(N(CC)CC)C.[C:48]1([SH:54])[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>O1CCCC1>[C:35]1([CH:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:27][NH:26][C:9]2[N:8]=[C:7]([CH2:6][S:54][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[C@H:16]2[C@H:20]([OH:21])[C@H:19]([OH:22])[C@@H:18]([CH2:23][O:24][CH3:25])[O:17]2)[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: Sc1ccccc1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(COS(C)(=O)=O)nc32)[C@H](O)[C@@H]1O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CSc4ccccc4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 36.7 %

Procedure:
{9-[(2R,3R,4S,5R)-3,4-Dihydroxy-5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9H-purin-2-yl}methyl methanesulfonate (400 mg, 0.7 mmol) (Preparation 25), triethylamine (0.2 ml, 1.4 mmol) and thiophenol (100 mg, 0.9 mmol) were dissolved in tetrahydrofuran (3 ml) and the reaction mixture stirred for 24 hr at room temperature. The solvent was then removed under reduced pressure and the residue purified by column chromatography on silica gel eluting with a solvent gradient of dichloromethane:methanol (99:1) increasing in polarity to (95:5). This gave the title compound (150 mg) as a foam. MS: 584 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=1)[C:5]([O:7]C)=[O:6].[N:20]1([C:24]([C:26]2[CH:31]=[CH:30][C:29](Br)=[CH:28][N:27]=2)=[O:25])[CH2:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O>[N:20]1([C:24]([C:26]2[N:27]=[CH:28][C:29]([O:1][C:2]3[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH2:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:11]=3)[C:5]([OH:7])=[O:6])=[CH:30][CH:31]=2)=[O:25])[CH2:23][CH2:22][CH2:21]1
Reactant: COC(=O)c1cc(O)cc(OCc2ccccc2)c1
Reactant: O=C(c1ccc(Br)cn1)N1CCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: O=C(O)c1cc(OCc2ccccc2)cc(Oc2ccc(C(=O)N3CCC3)nc2)c1
Yield: 76 %

Procedure:
A mixture of methyl 3-hydroxy-5-phenylmethoxy-benzoate (CAS no. 54915-31-0) (5.16 g, 20 mmol), azetidin-1-yl-(5-bromopyridin-2-yl)methanone (CAS no. 845306-16-3, Intermediate 34) (5.3 g, 22 mmol), caesium carbonate (19.6 g, 60 mmol) and tris(triphenylphosphine)copper bromide (CAS no. 15709-74-7) (3.73 g, 4 mmol) in DMA (100 mL) was stirred at 160° C. for 6 hours. The DMA was evaporated under reduced pressure and the residue was dissolved in water (200 mL), washed with ethyl acetate (3×50 mL), acidified with 2N hydrochloric acid and extracted with ethyl acetate (3×100 mL). The organic layer washed with water (2×20 mL) and brine (20 mL), dried (MgSO4) and the solvent removed under reduced pressure to afford the product (6.18 g, 76%). 1H NMR δ (400 MHz, CDCl3) 2.29 (s, 2H), 4.20 (s, 2H), 4.64 (s, 2H), 5.04 (s, 2H), 6.83 (s, 1H), 7.22-7.44 (m, 7H), 7.49 (s, 1H), 7.79-8.63 (m, 2H); m/z 405 (M+H)+.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1[C:27]1[CH:32]=[C:31]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([N:40]3[CH2:45][CH2:44][N:43]([CH3:46])[CH:42]([CH2:47][F:48])[CH2:41]3)=[CH:36][N:35]=2)[C:30](=[O:49])[N:29]([CH3:50])[CH:28]=1)(=O)C.O[Li].O>CC(O)C.C1COCC1.O>[F:26][C:9]1[CH:8]=[C:7]([C:27]2[CH:32]=[C:31]([NH:33][C:34]3[CH:39]=[CH:38][C:37]([N:40]4[CH2:45][CH2:44][N:43]([CH3:46])[CH:42]([CH2:47][F:48])[CH2:41]4)=[CH:36][N:35]=3)[C:30](=[O:49])[N:29]([CH3:50])[CH:28]=2)[C:6]([CH2:5][OH:4])=[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])[CH:10]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C)C(CF)C4)cn3)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CN1CCN(c2ccc(Nc3cc(-c4cc(F)cc(N5CCn6c(cc7c6CCCC7)C5=O)c4CO)cn(C)c3=O)nc2)CC1CF
Temperature: 30 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
A mixture of 111h (750 mg, 1.09 mmol) and LiOH hydrate (2.3 g, 55 mmol) in iPrOH (10 mL), THF (10 mL) and H2O (10 mL) was stirred at 30° C. for 1 h. The mixture was evaporated in vacuo, and the residue was extracted with DCM (3×30 mL). The combined extracts were concentrated under reduced pressure. And the residue was purified on silica gel column (DCM: MeOH=50:1) to give 111 as a yellow solid (700 mg, 93%). MS: [M+H]+ 644. 1H NMR (500 MHz, MeOD) δ 8.54 (d, J=2.0 Hz, 1H), 7.93 (d, J=1.5 Hz, 1H), 7.41 (m, 1H), 7.33 (d, J=2.0 Hz, 1H), 7.21 (d, J=9.0 Hz, 2H), 7.02 (d, J=9.0 Hz, 1H), 6.72 (s, 1H), 4.67-4.46 (m, 4H), 4.19 (s, 3H), 4.02 (m, 1H), 3.70 (s, 3H), 3.51 (d, J=11.5 Hz, 1H), 3.42 (d, J=11. Hz, 1H), 3.36 (s, 1H), 2.96 (d, J=11.5 Hz, 1H), 2.85 (m, 1H), 2.73-2.50 (m, 7H), 2.48 (s, 3H), 1.88 (m, 2H), 1.78 (m, 2H)
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][C:4]=1[C:18]([F:21])([F:20])[F:19].[C:22]([Si](C)(C)C)#[N:23].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C(#N)C>[O:10]1[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=[C:9]1[C:6]1[CH:7]=[CH:8][C:3]([CH2:2][C:22]#[N:23])=[C:4]([C:18]([F:21])([F:20])[F:19])[CH:5]=1
Reactant: FC(F)(F)c1cc(-c2nc3ccccc3o2)ccc1CBr
Reactant: C[Si](C)(C)C#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC#N
Product: N#CCc1ccc(-c2nc3ccccc3o2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 2-[4-(bromomethyl)-3-(trifluoromethyl)phenyl]-1,3-benzoxazole (528 mg, 1.5 mmol) and cyanotrimethylsilane (0.30 mL, 2.2 mmol) in acetonitrile (19 mL) was added TBAF (1.0M in THF, 2.2 mL, 2.2 mmol) and the mixture was stirred at rt for 2 h. The solvent was removed in vacuo and the crude was purified by flash chromatography eluting with EtOAc:hexanes (1:9) to afford the desired [4-(1,3-benzoxazol-2-yl)-2-(trifluoromethyl)phenyl]acetonitrile as a colorless solid. 1H NMR (CDCl3, 300 MHz) δ 8.60 (s, 1H), 8.48 (d, 1H), 7.88 (d, 1H), 7.82 (m, 1H), 7.63 (m, 1H), 7.43 (m, 2H), 4.05 (s, 2H). MS (ESI) 303 (M+H)+.