Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([Br:8])=[CH:6][N:5]=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([C:27]#[N:28])=[CH:19][CH:18]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[Br:8][C:7]1[C:2]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([C:27]#[N:28])=[CH:19][CH:18]=2)=[N:3][CH:4]=[N:5][CH:6]=1
Reactant: CC1(C)OB(c2ccc(C#N)c3ccccc23)OC1(C)C
Reactant: Clc1ncncc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2ncncc2Br)c2ccccc12
Temperature: 80 °C
Yield: 69 %

Procedure:
A mixture of 4-chloro-5-bromopyrimidine (193 mg, 1 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphthonitrile (279 mg, 1 mmol) palladium tetrakis triphenylphoshine (0.023 g, 0.02 mmol) and aqueous sodium carbonate solution (2M, 1.5 mL, 3 mmol) in dioxane (3 mL) was heated to 80° C. for 12 hours. The reaction mixture cooled to room temperature, washed with water, extracted with ethyl acetate and purified by chromatography to yield 4-(5-bromopyrimidin-4-yl)-1-naphthonitrile (214 mg, 69%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH2:25]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][C:28]1([CH3:34])[CH3:33])[CH3:26]>>[CH2:25]([N:27]1[CH2:32][CH2:31][N:30]([C:19]([C:18]2[CH:22]=[CH:23][C:15]([N:12]3[C:13]([OH:14])=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=4[CH3:24])[CH:10]=[N:11]3)=[N:16][CH:17]=2)=[O:21])[CH2:29][C:28]1([CH3:34])[CH3:33])[CH3:26]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: CCN1CCNCC1(C)C
Product: CCN1CCN(C(=O)c2ccc(-n3ncc(-c4ccc(C#N)cc4C)c3O)nc2)CC1(C)C

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 1-ethyl,2,2-dimethylpiperazine. 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 0.79-1.20 (m, 9 H) 2.36-2.48 (m, 5 H) 2.59 (d, J=6.06 Hz, 2 H) 3.15 (br. s., 1 H) 3.44 (br. s., 2 H) 3.69 (br. s., 1H) 7.53-7.59 (m, 1 H) 7.60-7.63 (m, 1 H) 7.63-7.66 (m, 1 H) 7.75 (s, 1 H) 8.01 (br. s., 2H) 8.42 (br. s., 1 H); ESI-MS m/z [M+H]+ 445.3.
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.CS(C)=O.[CH:12]1([C:15]2[O:16][C:17]3[C:18](=[C:20]([C:33]#[N:34])[C:21]([CH2:31][F:32])=[C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:23]=3F)[N:19]=2)[CH2:14][CH2:13]1.C(N(CC)CC)C>[Cl-].[Na+].O.C(OCC)(=O)C>[CH:12]1([C:15]2[O:16][C:17]3[C:18](=[C:20]([C:33]#[N:34])[C:21]([CH2:31][F:32])=[C:22]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:23]=3[N:5]3[CH2:6][CH2:7][C@H:3]([NH:2][CH3:1])[CH2:4]3)[N:19]=2)[CH2:13][CH2:14]1
Reactant: N#Cc1c(CF)c(-c2ccccc2)c(F)c2oc(C3CC3)nc12
Reactant: CN[C@H]1CCNC1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CN[C@H]1CCN(c2c(-c3ccccc3)c(CF)c(C#N)c3nc(C4CC4)oc23)C1
Reaction time: 0.5 h
Yield: 23.8 %

Procedure:
Under nitrogen atmosphere at 130° C., (3S)-3-(methylamino)pyrrolidine (85 μl, 801 μmol) was added to a dimethyl sulfoxide (7 ml) solution of 2-cyclopropyl-7-fluoro-5-fluoromethyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-293) (207 mg, 667 μmol) and triethylamine (121 μl, 867 μmol), followed by stirring at the same temperature for 30 minutes. After cooling, saturated brine was added to the reaction liquid, and the mixture liquid was extracted with ethyl acetate. Next, the combined organic layer was washed with saturated brine, then dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by middle-pressure liquid chromatography (eluent, dichloromethane:methanol=5:1, v/v) to obtain a crude product of the entitled compound. The crude product of the entitled compound was dissolved in ethyl acetate, washed with an aqueous saturated sodium hydrogencarbonate solution, then the aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the entitled compound (62 mg, 24%) as an amorphous substance.
Reaction SMILES: C1(P(=[CH:20][C:21]#[N:22])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[Na+].[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33]2[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=2)=[CH:28][C:27]=1[C:41]([F:44])([F:43])[F:42]>C(Cl)Cl.O>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33]2[CH:40]=[CH:39][C:36](/[CH:37]=[CH:20]/[C:21]#[N:22])=[CH:35][CH:34]=2)=[CH:28][C:27]=1[C:41]([F:44])([F:43])[F:42]
Reactant: N#CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: N#C/C=C/c1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.8 %

Procedure:
To the mixture of (triphenylphosphanylidene)acetonitrile (19.8 g, 51.9 mmol) and NaOH (2.59 g, 64.9 mmol) in DCM (30 mL) and water (60 mL) was added 4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}benzaldehyde (13.0 g, 43.2 mmol)) at 0° C. It was stirred at rt for 4 h. Purification via a flash chromatography afforded the title compound as a white solid (12 g).
Reaction SMILES: [CH2:1]([N:8]1[C:12](I)=[C:11]([CH:14]=[O:15])[CH:10]=[C:9]1[C:16]([O:18][CH3:19])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]1([C:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([OH:29])[C:27]#[CH:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(CC)CC>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([N:8]1[C:12]([C:28]#[C:27][C:26]([OH:29])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:11]([CH:14]=[O:15])[CH:10]=[C:9]1[C:16]([O:18][CH3:19])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#CC(O)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1cc(C=O)c(I)n1Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C=O)c(C#CC(O)(c2ccccc2)c2ccccc2)n1Cc1ccccc1
Yield: 83.9 %

Procedure:
A solution of 5 (0.47 g, 1.3 mmol), 1,1-diphenylprop-2-yn-1-ol (0.66 g, 3.2 mmol), CuI (0.05 g, 0.3 mmol), Pd(PPh3)2Cl2 (0.18 g, 0.3 mmol), PPh3 (0.07 g, 0.3 mmol), and Et3N (4 mL) in anhydrous DMF (4 mL) was stirred for 16 hours at 70° C. under N2 atmosphere. The reaction mixture was partitioned between water and EtOAc. The combined organic layer was dried over MgSO4, filtered and concentrated in vacuo. MPLC purification (Hexanes:EtOAc/80:20) of the residue gave 6 as a pale yellow solid (0.49 g, 87%). 1H NMR (400 MHz, CDCl3) δ 9.88 (s, 1H), 7.50-7.52 (m, 4H), 7.36 (s, 1H), 7.24-7.30 (m, 8H), 7.04 (m, 2H), 5.69 (s, 2H), 3.80 (s, 3H), and 3.65 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 185.16, 160.72, 144.07, 136.84, 128.91, 128.72, 128.33, 127.91, 127.79, 127.05, 126.23, 124.96, 116.97, 103.35, 75.37, 75.27, 52.15, and 50.38.
Reaction SMILES: [Cl-].[NH4+].[F:3][C:4]1([F:22])[O:9][C:8]2[CH:10]=[C:11]([F:17])[C:12]([N+:14]([O-])=O)=[CH:13][C:7]=2[N:6]([CH2:18][C:19]#[CH:20])[C:5]1=[O:21]>O.CO.O1CCCC1.[Fe]>[NH2:14][C:12]1[C:11]([F:17])=[CH:10][C:8]2[O:9][C:4]([F:3])([F:22])[C:5](=[O:21])[N:6]([CH2:18][C:19]#[CH:20])[C:7]=2[CH:13]=1
Reactant: C#CCN1C(=O)C(F)(F)Oc2cc(F)c([N+](=O)[O-])cc21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: C#CCN1C(=O)C(F)(F)Oc2cc(F)c(N)cc21
Temperature: 70 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
To ammonium chloride (3.96 g, 74.0 mmol) in water was added iron powder (325 mesh; 4.13 g, 74.0 mmol). To the resulting mixture was added 2,2,7-trifluoro-6-nitro-4-(prop-2-ynyl)-2Hbenzo[b][1,4]oxazin-3(4H)-one (7.06 g, 24.67 mmol) in methanol/tetrahydrofuran. The resulting mixture was stirred vigorously at 70° C. for 2 hours. The reaction was quenched in water/ethyl acetate under stirring. The resulting 2 phase system was filtered and the layers were separated. The water layer was subsequently extracted with ethyl acetate. The combined organic phases were washed with brine, dried with Na2SO4 and concentrated to yield 5.15 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:16]([O:23][C:24]([NH:26][C@@H:27]([CH3:31])[C:28](O)=O)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[CH2:16]([O:23][C:24](=[O:25])[NH:26][C@H:27]([C:28]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=2[N:8]=1)[CH3:31])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1cccc(N)c1Nc1ccccc1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Cc1cccc2nc([C@H](C)NC(=O)OCc3ccccc3)n(-c3ccccc3)c12
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 90.5 %

Procedure:
To a solution of 3-methyl-N2-phenyl-benzene-1,2-diamine (852 mg, 4.3 mmol) in anhydrous DCM (20 mL) were added (S)-2-benzyloxycarbonylaminopropionic acid (1.44 g, 6.45 mmol), HOBt (639 mg, 4.73 mmol), 4-methylmorpholine (1.04 mL, 9.46 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.24 g, 6.45 mmol). The mixture was stirred at RT for 6.5 h and then partitioned between DCM (100 mL) and water. The organic layer was then washed with brine, dried (Na2SO4) and concentrated in vacuo. The resulting residue was dissolved in AcOH (10 mL) and heated to 65° C. for 18 h. After cooling to RT, volatiles were removed under reduced pressure and the residue diluted with EtOAc (100 mL). The organic layer was washed with a saturated solution of NaHCO3, followed by brine, then dried (Na2SO4) and concentrated in vacuo affording [(S)-1-(7-Methyl-1-phenyl-1H-benzoimidazol-2-yl)ethyl]carbamic acid benzyl ester as brown foam (1.5 g, 90%). LCMS: RT 3.07 min [M+H]+ 386.2.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C=O>[C:24]1([CH2:23][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][C:9]3[CH:10]=[CH:11][C:12]([C:13]#[N:14])=[CH:15][CH:16]=3)=[CH:6][CH:7]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: N#Cc1ccc(Cc2ccc(O)cc2)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Cc2ccc(OCc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 26-4 (0.105 g, 0.50 mmol) and cesium carbonate (0.326 g, 1.0 mmol) in dimethylformamide (1 ml) under nitrogen was added benzyl bromide (0.071 ml, 0.60 mmol). The mixture was stirred 18 h at ambient temperature. The resulting mixture was evaporated under reduced pressure. To the residue was added saturated sodium bicarbonate solution (15 ml), and the aqueous mixture was extracted with methylene chloride (2×30 ml). The organic fraction was washed with brine (10 ml), dried (sodium sulfate), and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/hexane (1:6 increasing to 1:5), to give a white solid. The solid was recrystallized from ethyl acetate/hexane to give product 26-5 as white crystals, mp: 110°-111° C.
Reaction SMILES: [CH2:1]([C:13]1[CH:17]=[CH:16][S:15][C:14]=1[CH:18]=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>C1COCC1.Cl[Ti](Cl)(Cl)Cl.[Zn]>[CH2:1]([C:13]1[CH:17]=[CH:16][S:15][C:14]=1/[CH:18]=[CH:18]/[C:14]1[S:15][CH:16]=[CH:17][C:13]=1[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCc1ccsc1C=O
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCc1ccsc1/C=C/c1sccc1CCCCCCCCCCCC
Temperature: 25 °C
Yield: 75 %

Procedure:
To a suspension of low-valent Ti prepared from TiCl4 (0.94 mL, 8.56 mmol) and Zn (1.12 g, 17.11 mmol) in 42 mL of dry THF under N2 at 0° C. was added a dry solution of 11 (2 g, 7.13 mmol) in 14 mL of dry THF. After 2 h of refluxing, the mixture was cooled to room temperature, filtered to remove excess Zn, evaporated, poured into water and extracted with CH2Cl2. The organic phase was washed with water and dried over MgSO4. After solvent removal, the crude solid was purified by column chromatography (silica gel, hexane) to give a pale yellow solid compound 12 in 75% yield. 1H-NMR (CDCl3, 400 MHz) ppm 0.88 (t, 6H, J=6.8 Hz) ppm 1.31 (m, 36H) ppm 1.59 (td, 4H, J=7.4 Hz, J=14.7 Hz) ppm 2.65 (m, 4H) ppm 6.84 (d, 2H, J=5.2 Hz) ppm 6.99 (s, 2H) ppm 7.07 (d, 2H, J=5.2 Hz).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:17]=[N:18][CH:19]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:24][CH:23]=3)[CH:21]=1)[C:10]([CH3:33])([CH3:32])[CH2:9]2)=[O:5])C.Cl>CO.O1CCCC1.[OH-].[Na+].O>[C:28]([C:25]1[CH:24]=[CH:23][C:22]([C:20]2[CH:21]=[C:16]([CH:11]3[C:10]([CH3:33])([CH3:32])[CH2:9][C:8]4[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=4)[NH:12]3)[CH:17]=[N:18][CH:19]=2)=[CH:27][CH:26]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cncc(-c3ccc(C(C)(C)C)cc3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1ccc(-c2cncc(C3Nc4ccc(C(=O)O)cc4CC3(C)C)c2)cc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 97 %

Procedure:
A mixture of 2-[5-(4-tert-butyl-phenyl)-pyridin-3-yl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (880 mg, 1.99 mmol) in methanol (20 mL) and tetrahydrofuran (20 mL), 30% sodium hydroxide in water (10 mL) was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. The residue was re-crystallized from methanol to afford 2-[5-(4-tert-butyl-phenyl)-pyridin-3-yl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (800 mg, 97%) as a yellow solid: LC/MS m/e calcd for C27H30N2O2 (M+H)+: 415.55, observed: 415.1.
Reaction SMILES: [OH:1][C:2]1[C:3]2[N:4]([C:8]([CH2:12][OH:13])=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+].[CH3:22][C:23]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:24]=1[CH2:25]Cl>CC(C)=O>[CH3:22][C:23]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:24]=1[CH2:25][O:1][C:2]1[C:3]2[N:4]([C:8]([CH2:12][OH:13])=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc2c(O)cccn2c1CO
Reactant: Cc1cccc(C)c1CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1cccc(C)c1COc1cccn2c(CO)c(C)nc12
Reaction time: 8 h
Yield: 27.7 %

Procedure:
A mixture of 8-hydroxy-3-hydroxymethyl-2-methylimidazo[1,2-a]pyridine (0.89 g, 5.0 mmol), sodium carbonate (1.5 g), sodium iodide (0.4 g), 2,6-dimethylbenzylchloride (0.7 g, 4.5 mmol) and acetone (60 ml) was stirred overnight. More sodium carbonate (1.0 g) was added. The reaction mixture was refluxed for 2 h. The reaction mixture was filtered and the solvent was removed in vacuo. The residue was suspended in CH2Cl2/MeOH (100:5) and filtered. Vacuum evaporation of solvent gave a residue which was purified by flash chromatography eluting with CH2Cl2—MeOH (100:4), collecting fractions, and recrystallized from CH2Cl2/CH3CN to give 0.37 g of the title compound.
Reaction SMILES: [C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21]([C@@H:23]([CH:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)[CH2:24][C:25]([NH2:27])=O)[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].CN(C)C=O.C(N(CC)CC)C.ClC(Cl)(Cl)C(Cl)=O>[Cl-].[Na+].O.C(OCC)(=O)C>[C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21]([C@@H:23]([CH:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)[CH2:24][C:25]#[N:27])[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:4])([CH3:5])[CH3:3]
Reactant: CC(C)(C)C(=O)OCn1ccc2c(-c3cnn([C@H](CC(N)=O)C4CCCC4)c3)ncnc21
Agent: O=C(Cl)C(Cl)(Cl)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)OCn1ccc2c(-c3cnn([C@H](CC#N)C4CCCC4)c3)ncnc21
Temperature: 2.5 °C
Reaction time: 1.5 h
Yield: 70.2 %

Procedure:
Method A. To a 50 mL round bottom flask equipped with a stir bar and the nitrogen inlet was charged (R)-(4-(1-(3-amino-1-cyclopentyl-3-oxopropyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate ((R)-11, 413 mg, 0.942 mmol), N,N-dimethylformamide (DMF, 10 mL, 129 mmol) and triethylamine (TEA, 0.525 mL, 3.77 mmol, 4.0 equiv) at room temperature. The resulting mixture was then cooled to 0-5° C. in an ice bath before trichloroacetyl chloride (0.315 mL, 2.82 mmol, 3.0 equiv) was added drop wise via a syringe at room temperature. The resulting reaction mixture was stirred at 0-5° C. for 90 min. When TLC and HPLC showed that the reaction was deemed complete, the reaction mixture was treated with ethyl acetate (EtOAc, 25 mL) and 20% aqueous brine (20 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (EtOAc, 2×25 mL). The combined organic extracts were washed with 20% aqueous brine (35 mL), dried over magnesium sulfate (MgSO4), filtered, and concentrated under reduced pressure. The residual brown oily crude product was purified by flash chromatography (SiO2, 0 to 50% ethyl acetate/hexane gradient elution) to afford (R)-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate ((R)-12, 278 mg, 396.1 mg theoretical, 70.2% yield) as the light oil, which was solidified upon standing at room temperature in vacuum. For (R)-12: achiral purity (99.1 area % by HPLC detected at 220 nm); chiral purity (99.6 area % by chiral HPLC; 99.2% ee); 1H NMR (DMSO-d6, 400 MHz) δ ppm 8.84 (s, 1H), 8.78 (s, 1H), 8.39 (s, 1H), 7.74 (d, 1H, J=3.7 Hz,), 7.11 (d, 1H, J=3.8 Hz), 6.23 (s, 2H), 4.53 (ddd, 1H, J=9.9, 9.6, 4.2 Hz), 3.26 (dd, 1H, J=17.4, 9.9 Hz), 3.19 (dd, 1H, J=17.2, 4.3 Hz), 2.41 (m, 1H), 1.87-1.13 (m, 8H), 1.07 (s, 9H); C23H28N6O2 (MW, 420.51), LCMS (EI) m/e 421.4 (M++H).
Reaction SMILES: COC[O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][S:34][CH2:35][CH2:36][CH2:37][C:38]([F:44])([F:43])[C:39]([F:42])([F:41])[F:40])[CH:10]([C:15]3[CH:20]=[CH:19][C:18]([O:21]COC)=[CH:17][CH:16]=3)[CH2:11][O:12]2)=[CH:7][CH:6]=1.Cl.O>CCO>[OH:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][S:34][CH2:35][CH2:36][CH2:37][C:38]([F:44])([F:43])[C:39]([F:40])([F:41])[F:42])[CH:10]([C:15]3[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=3)[CH2:11][O:12]2)=[CH:7][CH:6]=1
Reactant: COCOc1ccc(C2COc3cc(OCOC)ccc3C2CCCCCCCCCSCCCC(F)(F)C(F)(F)F)cc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: Oc1ccc(C2COc3cc(O)ccc3C2CCCCCCCCCSCCCC(F)(F)C(F)(F)F)cc1
Reaction time: 17 h
Yield: 79.5 %

Procedure:
To a solution of (3RS,4RS)-7-methoxymethoxy-3-(4-methoxymethoxyphenyl)-4-[9-(4,4,5,5,5-pentafluoropentylthio)nonyl]chroman (204 mg, 0.314 mmol) in EtOH (2 ml) was added 6N HCl (0.2 ml, 1.2 mmol). The resulting solution was stirred between 40 and 45° C. for 17 hr, and then poured into H2O. The mixture was extracted with AcOEt. The organic layer was washed with saturated aqueous NaCl, dried over Na2SO4, filtered, concentrated, and purified by column chromatography (silica gel, 33% AcOEt/hexane) to afford (3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-4-[9-(4,4,5,5,5-pentafluoropentylthio)nonyl]chroman (140 mg, 80%).
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21](Cl)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:25][NH:26][CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30]>CN(C1C=CN=CC=1)C.CC#N>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21]([N:26]([CH3:25])[CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Reactant: CNCCC(C)C
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CC(C)CCN(C)S(=O)(=O)c1ccc2c(c1)nc(C(C)(C)C)n2CC1CCOCC1

Procedure:
Following the same procedure in Example 1, Step A, using 2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (82 mg, 0.22 mmol), methyl (3-methylbutyl)amine (45 mg, 0.44 mmol) and DMAP (54 mg, 0.44 mmol) in MeCN (4 mL). The crude product was purified by MPLC using Hex/EtOAc (1:1) on silica gel to give 57 mg (60% yield) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 0.89 (d, J=6.64 Hz, 6 H), 1.39 (q, J=6.90 Hz, 2 H), 1.46-1.61 (m, 5 H), 1.64 (s, 9 H), 2.26-2.43 (m, 1 H), 2.70 (s, 3 H), 2.97-3.06 (m, 2 H), 3.29-3.38 (m, 2 H), 3.86-3.97 (m, 2 H), 4.48 (d, J=7.42 Hz, 2 H), 7.81 (dd, J=8.79, 1.76 Hz, 1 H), 7.96 (d, J=8.79 Hz, 1 H), 8.07 (d, J=1.37 Hz, 1 H); MS (ESI) (M+H)+=436.0; Anal. Calcd for C23H37N3O3S+0.70 TFA+0.30 EtOAc+0.5H2O (550.89): C, 55.82; H, 7.52; N, 7.63. Found: C, 55.90; H, 7.46; N, 7.63.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]=[CH:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:21].S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH:13]12[O:21][CH:14]1[CH2:15][N:11]([C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH2:12]2
Reactant: O=C(OCc1ccccc1)N1CC=CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CC2OC2C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 103.5 %

Procedure:
To a solution of 1-benzyloxycarbonyl-3-pyrroline (2.5 g) in dichloromethane (60 mL) was added 3-chloroperoxybenzoic acid (6.08 g, 50-60% purity). The reaction was stirred at room temperature for 72 hours, and then a saturated sodium thiosulfate solution (50 mL) was added. After being stirred for additional 30 minutes, the mixture was extracted with chloroform (50 mL×2). The combined organic layers were washed successively with 2 N aqueous solution of sodium hydroxide (50 mL×2) and brine (50 mL), dried over magnesium sulfate and concentrated in vacuo to afford 2.79 g of the crude benzyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate as an oil. MS obsd. (ESI+) [(M+H)+] 220.
Reaction SMILES: CC([N:5]([CH2:9][C:10]1[C:11](=[O:20])[NH:12][C:13]([CH:17]2[CH2:19][CH2:18]2)=[CH:14][C:15]=1[CH3:16])C(=O)[O-])(C)C.CCOC(C)=O.[ClH:27].O1CCOCC1>CO>[ClH:27].[NH2:5][CH2:9][C:10]1[C:11](=[O:20])[NH:12][C:13]([CH:17]2[CH2:18][CH2:19]2)=[CH:14][C:15]=1[CH3:16]
Reactant: Cc1cc(C2CC2)[nH]c(=O)c1CN(C(=O)[O-])C(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cc(C2CC2)[nH]c(=O)c1CN
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 100 %

Procedure:
1,1-Dimethylethyl[(6-cyclopropyl-4-methyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]carbamate (0.28 g, 1.006 mmol) was added to EtOAc (9 mL) and methanol (1.0 mL). The suspension was stirred at room temperature for 5 min, followed by addition of 4 M HCl in dioxane (5.03 mL, 20.12 mmol), and the contents were stirred at room temperature overnight. The volatiles were then removed in vacuo to afford a solid. The solid was triturated with ether, filtered, and dried in a vacuum oven at 45° C. for 4 h. The title compound was collected (0.22 g, 100% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.78-0.86 (m, 2H), 0.95-1.03 (m, 2H), 1.83 (tt, J=8.46, 5.05 Hz, 1H), 2.16-2.22 (m, 3H), 3.75 (q, J=5.47 Hz, 2H), 5.79 (s, 1H), 8.02 (br. s., 3H), 11.92 (br. s., 1H).