Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([N:26]2[CH2:31][C@@H:30]3[CH2:32][C@H:27]2[CH2:28][NH:29]3)=[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:14][C:13]=3[O:24][CH3:25])[NH:9][C:6]2=[N:7][CH:8]=1.[CH3:33][C@H:34]1[CH2:36][O:35]1.N1C=CC=CC=1.CCN(C(C)C)C(C)C>CO>[Cl:2][C:3]1[C:4]([N:26]2[CH2:31][C@@H:30]3[CH2:32][C@H:27]2[CH2:28][N:29]3[CH2:33][C@@H:34]([OH:35])[CH3:36])=[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:14][C:13]=3[O:24][CH3:25])[NH:9][C:6]2=[N:7][CH:8]=1
Reactant: C[C@H]1CO1
Reactant: COc1cc(N2CCOCC2)ccc1-c1nc2c(N3C[C@@H]4C[C@H]3CN4)c(Cl)cnc2[nH]1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Solvent: CO
Product: COc1cc(N2CCOCC2)ccc1-c1nc2c(N3C[C@@H]4C[C@H]3CN4C[C@H](C)O)c(Cl)cnc2[nH]1
Temperature: 80 °C

Procedure:
6-Chloro-7-(1S,4S)-2,5-diaza-bicyclo[2.2.1]hept-2-yl-2-(2-methoxy-4-morpholin-4-yl-phenyl)-3H-imidazo[4,5-b]pyridine hydrochloride (Compound XXXVII) (50 mg, 0.1 mmol), (S)-2-methyl-oxirane (7.30 mg, 0.126 mmol), pyridine (10.2 μL, 0.126 mmol), and methanol (3.0 mL) were stirred in a sealed tube at room temperature overnight. An additional equivalent each of epoxide and Hunig's base were added and the mixture was heated at 80° C. overnight. The mixture was concentrated and the material was subjected to purification via reverse phase chromatography (Gilson) to afford the title compound as a yellow lyophilate (26 mg, 50%). 1H NMR (d-chloroform): 13.63 (br s, 1H), 8.10 (m, 1H), 7.90 (s, 1H), 7.71 (s, 1H), 7.55 (s, 1H), 6.59 (m, 1H), 6.46 (s, 1H), 4.62 (m, 1H), 4.35 (m, 1H), 4.24 (t, J=7 Hz, 2H), 4.15 (s, 3H), 3.92 (s, 4H), 3.35 (s, 4H), 3.14 (m, 2H), 2.38 (m, 1H), 1.71 (m, 1H), 1.44 (m, 2H), 1.32 (m, 1H), 0.94 (m, 3H). MS: 499.18 (M+H). HPLC retention time: 1.83 minutes (G Method).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:18])([CH3:17])[C:14]([OH:16])=[O:15])=[CH:9][CH:8]=1)=[O:6].[BH4-].[Na+].Cl>CO>[OH:6][CH:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:18])([CH3:17])[C:14]([OH:16])=[O:15])=[CH:9][CH:8]=1)[CH2:4][CH2:3][CH2:2][Cl:1]
Reactant: CC(C)(C(=O)O)c1ccc(C(=O)CCCCl)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C(=O)O)c1ccc(C(O)CCCCl)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 50 mg of 4-(4-chloro-1-oxobutyl)-α,α-dimethylphenylacetic acid, prepared in accordance with Example 4, in 3 mL of methanol is added 50 mg of NaBH4. The mixture is stirred for 30 minutes, acidified with 2N HCl, and the methanol is removed in vacuo. The concentrate is extracted with EtOAc. The organics are dried over Na2SO4, filtered, and concentrated to afford 4-(1-hydroxy-4-chlorobutyl)-α,α-dimethylphenylacetic acid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.[Br:16][CH2:17][CH2:18][OH:19]>C(O)C>[BrH:16].[NH:1]=[C:2]1[N:6]([CH2:17][CH2:18][OH:19])[C:5]2[CH:7]=[CH:8][C:9]([O:11][C:12]([F:15])([F:13])[F:14])=[CH:10][C:4]=2[S:3]1
Reactant: Nc1nc2ccc(OC(F)(F)F)cc2s1
Reactant: OCCBr
Solvent: CCO
Product: Br
Product: N=c1sc2cc(OC(F)(F)F)ccc2n1CCO
Temperature: 20 °C
Yield: 44.4 %

Procedure:
The procedure is as in Example 15, starting with 2-amino-6-trifluoromethoxybenzothiazole (9.4 g) and 2-bromoethanol (10 g) in absolute ethanol (30 cc). The mixture is heated for 95 hours to boiling and then cooled to a temperature in the region of 20° C. The precipitate formed is filtered off and washed with ethyl ether (100 cc). 2-(2-Imino-6-trifluoromethoxy-3-benzothiazolinyl)ethanol hydrobromide (6.4 g), m.p. 219° C., is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29](OCC)=[O:30])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[N:12]=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:14][C:15]=1[CH3:16].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][OH:30])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[N:12]=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:14][C:15]=1[CH3:16]
Reactant: CCOC(=O)CCCCCCc1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(CCCCCCCO)ccc1OCc1nc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of ethyl 7-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]heptanoate (9.6 g) in tetrahydrofuran (THF) (50 ml) was added dropwise, at room temperature, to a suspension of lithium aluminum hydride (0.96 g) in tetrahydrofuran (THF) (50 ml). The mixture was stirred for 30 minutes at room temperature, to which was then added, under ice-cooling, water (6 ml). Insolubles were filtered off, then the filtrate was concentrated. The concentrate was subjected to column chromatography on silica gel. From the fraction eluted with ethyl acetate-hexane (2:3), was obtained 7-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]heptanol, which was recrystallized from chloroform-ether to give colorless needles, m.p.78-79° C.
Reaction SMILES: CO[CH:3]1[CH2:7][CH2:6][CH:5](OC)O1.[NH2:10][CH:11]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[CH2:12][C:13]([OH:15])=[O:14].C([O-])(=O)C.[Na+]>C(O)(=O)C>[OH:22][C:19]1[CH:18]=[CH:17][C:16]([CH:11]([N:10]2[CH:3]=[CH:7][CH:6]=[CH:5]2)[CH2:12][C:13]([OH:15])=[O:14])=[CH:21][CH:20]=1
Reactant: NC(CC(=O)O)c1ccc(O)cc1
Reactant: COC1CCC(OC)O1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(O)CC(c1ccc(O)cc1)n1cccc1
Reaction time: 1 h

Procedure:
At 100° C., 2,5-dimethoxytetrahydrofuran (8.5 mmol) was added to a mixture of 3-amino-3-(4-hydroxyphenyl) propanoic acid (7.7 mmol) and sodium acetate (46 mmol) in acetic acid (34 mL). After stirring for 1 h, acetic acid was removed under reduced pressure. The residue was extracted with ethyl acetate (300 mL). The organic layer was washed with brine and dried over anhydrous Na2SO4 and concentrated. The residue was purified via column chromatography (10% methanol in dichloromethane) to compound 55.1. LC-MS (neg.) m/e: 230.2 (M−H).
Reaction SMILES: [F:1][CH:2]([F:46])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]([CH2:34][CH2:35][CH2:36][N:37]([CH3:39])[CH3:38])[CH:21]3[CH2:26][CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22]3)[N:9]=2)[C:6]2[CH:40]=[CH:41][CH:42]=[C:43]([O:44][CH3:45])[C:5]=2[N:4]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:46][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([N:20]([CH:21]3[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]3)[CH2:34][CH2:35][CH2:36][N:37]([CH3:39])[CH3:38])[N:9]=2)[C:6]2[CH:40]=[CH:41][CH:42]=[C:43]([O:44][CH3:45])[C:5]=2[N:4]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N(CCCN(C)C)C2CCCN(C(=O)OC(C)(C)C)C2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N(CCCN(C)C)C2CCCNC2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
To a solution of tert-butyl 3-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl][3-(dimethylamino)propyl]amino}-1-piperidinecarboxylate (430 mg, 0.67 mmol) in CH2Cl2 (10 mL), was added TFA (5 mL). The resulting mixture was stirred at room temperature for 30 min. The solvent and excess TFA were removed under vacuum. The residue was diluted with water and neutralized with aqueous NH3. The resulting precipitate was filtered, washed with water, and dried to give N-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N3,N3-dimethyl-N1-(3-piperidinyl)-1,3-propanediamine (323 mg, 88%): 1H NMR (DMSO-d6) (rotamers) δ 7.95 and 7.93 (2d, J=9.5, 8.8 Hz, 1H), 7.77 and 7.71 (2t, JHF=53.1 Hz, 1H), 7.42-7.36 (m, 1H), 6.95 (d, J=1 Hz, 1H), 4.55-4.48 and 4.46-4.39 (2m, 1H), 3.98 (s, 3H), 3.81-3.80 (m, 4H), 3.72-3.70 (m, 4H), 3.55-3.45 (m, 2H), 2.99-2.96 (m, 1H), 2.92-2.89 (m, 1H), 2.77-2.66 (m, 1H), 2.45-2.40 (m, 1H), 2.27 (t, J=6.9 Hz, 2H), 2.16 and 2.12 (2s, 6H), 1.80-1.48 (m, 6H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:15]([CH2:16][CH3:17])[CH:14]=[N:13][CH:12]=3)[S:10][C:3]=12.[F:18][C:19]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:20]=1[OH:28].C(=O)([O-])[O-].[K+].[K+].CO.C(Cl)Cl>O(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:16]([N:15]1[C:11]([C:9]2[S:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[O:28][C:20]3[CH:21]=[CH:22][C:23]([N+:25]([O-:27])=[O:26])=[CH:24][C:19]=3[F:18])[CH:8]=2)=[CH:12][N:13]=[CH:14]1)[CH3:17]
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: CCn1cncc1-c1cc2nccc(Cl)c2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CO
Solvent: ClCCl
Product: CCn1cncc1-c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Temperature: 195 °C
Yield: 52.3 %

Procedure:
To a solution of 118 (4 g, 15.16 mmol) in Ph2O (60 ml) was added 2-fluoro-4-nitrophenol (4.76 g, 30.33 mmol) and potassium carbonate (8.38 g, 60.66 mmol). The reaction mixture was heated to 195° C. for 18 hrs the cooled to room temperature. The residue was purified by column chromatography (eluents EtOAc/Hex (9/1 to 5/5) then MeOH/CH2Cl2 (98/2)), to afford title compound 119 (3.05 g, 52% yield) as a yellow solid. MS (m/z): 385.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=2[NH:18][C:19](=[O:44])[C@H:20]([CH2:39][C:40]([O:42][CH3:43])=[O:41])[NH:21]C(OCC2C3C=CC=CC=3C3C2=CC=CC=3)=O)=O)=[CH:4][CH:3]=1.CCN(CC)CC.CC(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:10]3[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=3[NH:18][C:19](=[O:44])[C@H:20]([CH2:39][C:40]([O:42][CH3:43])=[O:41])[N:21]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)Nc1ccc(OC)cc1C(=O)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(OC)ccc2NC1=O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of methyl N1-[2-[(4-chlorophenyl)carbonyl]-4-(methyloxy)phenyl]-N2-{[(9H-fluoren-9-ylmethyl)oxy]carbonyl}-L-α-asparaginate (for a preparation see Reference compound C) (assumed 0.2 mol) in DCM (500 ml) was added Et3N (500 ml, 3.65 mol) and the resulting mixture was refluxed for 24 h before being concentrated. The resulting crude amine was dissolved in 1,2-DCE (1.5 L) and AcOH (104 ml, 1.8 mol) was added carefully. The reaction mixture was then stirred at 60° C. for 2 h before being concentrated in vacuo and dissolved in DCM. The organic layer was washed with 1N HCl and the aqueous layer was extracted with DCM (×3). The combined organic layers were washed twice with water, and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude solid was recrystallised in MeCN leading to the title compound (51 g) as a pale yellow solid. The filtrate could be concentrated and recrystallised in MeCN to give to another 10 g of the desired product Rf=0.34 (DCM/MeOH: 95/5).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][NH:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[H][H].Br[CH:24]([CH2:27][CH3:28])[CH2:25][CH3:26]>CN(C)C=O>[CH2:3]([O:10][N:11]([CH:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[C:12]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:13])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(NOCc1ccccc1)Nc1ccccc1
Reactant: [H][H]
Reactant: CCC(Br)CC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(CC)N(OCc1ccccc1)C(=O)Nc1ccccc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 62.9 %

Procedure:
Under a nitrogen atmosphere, a flask was charged with sodium hydride (1.15 g 60% NaH in mineral oil, 29 mmol). Residual oil was washed from the sodium hydride using several portions of hexanes. N,N-Dimethylformamide (50 mL) was added followed by the dropwise addition of a solution of 1-benzyloxy-3-phenylurea (7.0 g, 29 mmol) in N,N-dimethylformamide (20 mL). Hydrogen evolution occurred immediately. The reaction was stirred for 0.5 hr then 3-bromopentane (4.0 mL, 32 mmol) was added dropwise. The reaction mixture was heated at 60° C. for 15 hours then allowed to cool to room temperature. The reaction was quenched with water then extracted with several portions of diethyl ether. The ether extracts were combined, washed with water and brine, dried over magnesium sulfate and then concentrated to provide 8.7 g of crude product as a pale yellow solid. The crude product was purified by flash chromatography (silica gel; 9:1 hexanes:ethyl acetate)to provide 5.7 g of 1-benzyloxy-1-(1-ethylpropyl)-3-phenylurea as a white solid, m.p. 45.0°-45.6° C.
Reaction SMILES: C([O:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13](F)=[CH:12][CH:11]=1)C1C=CC=CC=1.C(N(C(C)C)CC)(C)C.[NH:27]1[CH2:37][CH2:36][CH:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:29][CH2:28]1.[H][H]>O1CCOCC1.CN(C1C=CN=CC=1)C.CCO.[Pd]>[CH2:34]([O:33][C:31]([CH:30]1[CH2:36][CH2:37][N:27]([C:13]2[CH:12]=[CH:11][C:10]([C:9]([OH:8])=[O:17])=[CH:15][CH:14]=2)[CH2:28][CH2:29]1)=[O:32])[CH3:35]
Reactant: [H][H]
Reactant: O=C(OCc1ccccc1)c1ccc(F)cc1
Reactant: CCOC(=O)C1CCNCC1
Agent: [Pd]
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)C1CCN(c2ccc(C(=O)O)cc2)CC1
Temperature: 120 °C
Yield: 23 %

Procedure:
A solution of 4-fluoro-benzoic acid benzyl ester (720 mg, 3.13 mmol) in dioxane (10 mL) was treated with diisopropyl ethyl amine (1.64 mL, 9.39 mmol), ethyl isonipecotate (1.54 g, 9.39 mmol), a catalytic amount of DMAP and heated in a sealed tube at 120° C. for approximately 18 h. The mixture was then cooled, followed addition of another portion of ethyl isonipecotate (1.54 g, 9.39 mmol) and the mixture was reheated at 120° C. After stirring for one more day the mixture was cooled, another portion of ethyl isonipecotate (1.54 g, 9.39 mmol) was added and the mixture was heated again at 120° C. and stirred for an additional 3 day period. The mixture was then cooled and partitioned between EtOAc and water. The EtOAc layer was collected, dried over Na2SO4, filtered and concentrated and the residue was chromatographed with a silica gel column and 0-50% Et2O in hexanes gradient. The intermediate isolated from this operation was dissolved in EtOH (15 mL). Followed addition of 10% Pd/C (15 mg) and the mixture was hydrogenated under one atmosphere of hydrogen for 3.5 h. Followed filtration, the solids were washed with EtOH and the combined organic layer was evaporated to afford the product (200 mg, Yield 10%). HRMS m/z calcd for C15H19NO4 [M+H]+: 278.1387. Found: 278.1387.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[NH:11][C:10](=[O:14])[O:9]2)=[CH:4][CH:3]=1.[CH2:15]=[O:16].O>CO.C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12](=[O:13])[N:11]([CH2:15][OH:16])[C:10](=[O:14])[O:9]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-n2oc(=O)[nH]c2=O)cc1
Reactant: C=O
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc(-n2oc(=O)n(CO)c2=O)cc1
Reaction time: 2 h

Procedure:
2-(4-Methylphenyl)-1,2,4-oxadiazolidin-3,5-dione (0.05 mole) dissolved in methanol (100 ml) and aqueous formaldehyde (37% conc.; 0.06 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux, with stirring for a period of about 2 hours. After this time the reaction mixture is stripped of methanol and water, leaving a residue. This residue is dissolved in methylene chloride, and the resulting solution is washed with water. The washed solution is dried over anhydrous magnesium sulfate, filtered and stripped of solvent to yield the desired product 2-(4-methylphenyl)-4-hydroxymethyl-1,2,4-oxadiazolidin- 3,5-dione.
Reaction SMILES: [CH:1]1([C:6]([OH:31])([CH2:21][C:22]2[O:23]C(C)(C)O[C:26](=[O:28])[CH:27]=2)[CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([CH3:19])([CH3:18])[C:16]#[N:17])=[C:11]([F:20])[CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C(O)(CC2OC(C)(C)OC(=O)C=2)CCC2C=CC(C3(C#N)CC3)=C(F)C=2)CCCC1>>[CH:1]1([C:6]2([CH2:7][CH2:8][C:9]3[CH:14]=[CH:13][C:12]([C:15]([CH3:19])([CH3:18])[C:16]#[N:17])=[C:11]([F:20])[CH:10]=3)[CH2:21][C:22](=[O:23])[CH2:27][C:26](=[O:28])[O:31]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC1(C)OC(=O)C=C(CC(O)(CCc2ccc(C(C)(C)C#N)c(F)c2)C2CCCC2)O1
Agent: CC1(C)OC(=O)C=C(CC(O)(CCc2ccc(C3(C#N)CC3)c(F)c2)C2CCCC2)O1
Product: CC(C)(C#N)c1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1F

Procedure:
The desired product was prepared analogously to Step 5 of Example A(86), substituting 2-{4-[3-Cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-butyl]-2-fluoro-phenyl}-2-methyl-propionitrile (1.23 g, 2.9 mmol) from Step 3 below in place of 1-{4-[3-Cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-butyl]-2-fluoro-phenyl}-cyclopropanecarbonitrile. Yield: 0.614 g, 56%. 1H NMR (CDCl3) δ: 1.24-1.66 (m, 14H), 1.75-1.80 (m, 2H), 2.10 (p, J=9.35 Hz, 1H), 2.47-2.56 (m, 2H), 2.60 (d, J=5.56 Hz, 2H), 3.26 (d, J=3.28 Hz, 2H), 6.71-6.79 (m, 2H), 7.23 (t, J=8.24 Hz, 1H). MS (ESI): 370 (M−H).
Reaction SMILES: C(OC([N:8]1[CH2:11][C:10]([C:13]2[N:14]([CH3:39])[C:15]3[C:20]([N:21]=2)=[C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:18]=[C:17]([N:28]2[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[N:30]=[C:29]2[CH2:37][CH3:38])[N:16]=3)([F:12])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:37]([C:29]1[N:28]([C:17]2[N:16]=[C:15]3[C:20]([N:21]=[C:13]([C:10]4([F:12])[CH2:11][NH:8][CH2:9]4)[N:14]3[CH3:39])=[C:19]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[N:18]=2)[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[N:30]=1)[CH3:38]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(F)CN(C(=O)OC(C)(C)C)C3)n(C)c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(F)CNC3)n(C)c2n1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 96.3 %

Procedure:
To a solution of 3-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]-3-fluoroazetidine-1-carboxylic acid tert-butyl ester (235 mg, 0.44 mmol) in DCM (10 mL) was added TFA (2 mL) and the resulting mixture was allowed to stir at r.t. for 3.5 h. The reaction mixture was concentrated in vacuo and the resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH. The resulting residue was triturated with Et2O and the resulting solid dried in vacuo affording 834 (185 mg, 97%). LCMS (method I): RT 2.50 min, [M+H]+ 437.3. 1H NMR (DMSO, 400 MHz): δ 8.06-8.05 (1 H, m), 7.64-7.63 (1 H, m), 7.28-7.24 (2 H, m), 4.60-4.10 (4 H, brd s), 4.26 (2 H, dd, J=19.18, 10.17 Hz), 4.01 (2 H, dd, J=22.47, 10.23 Hz), 3.80 (4 H, t, J=4.63 Hz), 3.74-3.73 (3 H, m), 3.28-3.27 (2 H, m), 1.34 (3 H, t, J=7.43 Hz)
Reaction SMILES: [CH2:1]([S:9][C:10]1[CH:11]=[C:12]([C:15]([O:17]C)=[O:16])[NH:13][CH:14]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[K+].Cl>CO.O>[CH2:1]([S:9][C:10]1[CH:11]=[C:12]([C:15]([OH:17])=[O:16])[NH:13][CH:14]=1)[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1cc(SCCc2ccccc2)c[nH]1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc(SCCc2ccccc2)c[nH]1
Temperature: 0 °C
Yield: 36.8 %

Procedure:
A solution of methyl 4-(phenethylthio)-1H-pyrrole-2-carboxylate (233 mg, 0.890 mmol) and KOH (250 mg, 4.46 mmol) in MeOH (1.2 mL) and H2O (0.6 mL) was stirred at 60° C. for 1.5 h, cooled to 0° C., acidified with concentrated HCl and diluted with H2O. The solid precipitate was filtered, washed with H2O and air dried under vacuum to afford the title compound (81.0 mg) as a colorless solid that was used in the next step without purification: 1H NMR (400 MHz, CDCl3) δ 2.84-2.90 (m, 2H), 2.91-2.98 (m, 2H), 7.03-7.07 (m, 1H), 7.07-7.10 (m, 1H), 7.13-7.32 (m, 5H), 9.22 (br. s., 1 H); HPLC a) column: Phenomenex Luna 5μ 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% H3PO4 to 90% MeOH/10% H2O/0.1% H3PO4; 1 min hold, 4 mL/min UV detection at 220 nm, 3.293 min retention time, (95%); HPLC b) column: Phenomenex Luna C18 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA, 1 min hold; 4 mL/min, UV detection at 220 nm, 3.258 min retention time; MS (ES): m/z 248.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[C:10](=O)([O-])[O-].[K+].[K+].Br[C:17]([CH3:28])([CH3:27])[C:18]([C:20]1[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=1)=[O:19].O>CS(C)=O>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][C:17]([CH3:28])([CH3:27])[C:18]([C:20]1[CH:25]=[CH:24][C:23]([CH3:10])=[CH:22][CH:21]=1)=[O:19]
Reactant: Cc1cccc(O)c1C
Reactant: O=C([O-])[O-]
Reactant: CC(C)(Br)C(=O)c1ccc(Br)cc1
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(C(=O)C(C)(C)Oc2cccc(C)c2C)cc1
Temperature: 35 °C
Reaction time: 24 h

Procedure:
To a mixture of 2,3-dimethylphenol (12.2 g, 100 mmol) and potassium carbonate (27.4 g, 200 mmol) in dimethylsulfoxide (138 mL) was added 2-bromo-1-(4-bromophenyl)-2-methylpropane-1-one (42.2 g, 175 mmol) at room temperature, and the mixture was warmed to 35° C. The mixture was stirred at the same temperature for 24 hours, poured into cold water (300 mL), and then extracted with diethyl ether. The organic layer was washed with a 4 N aqueous sodium hydroxide solution and a saturated brine, and then was dried over sodium sulfate. The solvent was concentrated under reduced pressure, and then was purified by silica gel column chromatography (ethyl acetate:hexane=1:9) to obtain 2-(2,3-dimethylphenoxy)-2-methyl-1-(4-methylphenyl)propane-1-one of oily matter. The obtained oily matter was dissolved in methanol (200 mL), sodium borohydride (3.8 g, 100 mmol) was added thereto at 0° C., and the mixture was warmed to room temperature. The oily matter was stirred at the same temperature for 1 hour, cooled to 0° C., and neutralized with 1 N hydrochloric acid, and then the solvent was distilled off under reduced pressure. The residue was extracted with ethyl acetate, and the extract solution was washed with a saturated brine, and then was dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain 17.1 g (yield 60%) of the title compound as an oily matter.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([S:8]([F:13])([F:12])([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[CH3:14]N(C)P(N(C)C)(N(C)C)=O.[C]=O.[OH2:27]>C(#N)C.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>[CH:7]1[C:2]([CH:14]=[O:27])=[CH:3][CH:4]=[C:5]([S:8]([F:13])([F:12])([F:11])([F:10])[F:9])[CH:6]=1
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Reactant: FS(F)(F)(F)(F)c1ccc(I)cc1
Reactant: O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C]=O
Solvent: CC#N
Product: O=Cc1ccc(S(F)(F)(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 20 h
Yield: 86 %

Procedure:
A solution of 4-iodophenylsulfur pentafluoride (250 mg, 0.757 mmol) in acetonitrile (10 mL) was added to a 100 mL pressure bottle containing tetrakis(triphenylphosphine)palladium(0) (43.8 mg, 0.038 mmol), hexamethylphosphoramide (1.25 mL, 7.18 mmol), and poly(methylhydrosiloxane) (1.0 mL, 0.76 mmol). The reaction was pressurized with carbon monoxide (50 psi), and stirred for 20 hr at 80° C. The mixture was cooled to ambient temperature, water (100 mL) was added, and the product was extracted with Et2O (2×100 mL). The organic layer was washed with brine and dried over Na2SO4, filtered, and concentrated in vacuo to a yellow oil. The crude product was chromatographed on silica gel (Analogix® SF10-8G column, 0%-25% EtOAc/hexanes, 10 mL/min) to give 151 mg (86%) of the title compound as a colorless liquid. 1H NMR (300 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.21-8.08 (m, 4H).