Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH:9]([CH2:12]Cl)[CH2:10]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14]([NH2:18])([CH3:17])([CH3:16])[CH3:15]>O>[CH2:1]([O:8][CH:9]1[CH2:12][N:18]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)N
Reactant: ClCC(CCl)OCc1ccccc1
Solvent: O
Product: CC(C)(C)N1CC(OCc2ccccc2)C1
Temperature: 90 °C
Yield: 80 %

Procedure:
21.9 parts of 2-benzyloxy-1,3-dichloro-propane, 71.3 parts of tert.-butylamine and 50 parts of water were added to an autoclave and the mixture was heated at 90° C. for 48 hours with agitation. The reaction mixture was cooled and treated in the same manner as in Example 29, followed by distillation under reduced pressure. As a result 17.5 parts of 3-benzyloxy-1-(tert.-butyl)azetidine boiling at 94° - 96° C. under 2 mm Hg were obtained. The yield was 80%. The results of infra-red spectrum analysis and nuclear magnetic resonance anlaysis are as follows:
Reaction SMILES: [NH2:1][C:2]1[C:11]([S:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH2:14]([C:22]1([C:28](O)=[O:29])[S:27][CH2:26][CH2:25][CH2:24][S:23]1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].S1CCCSC1C(O)=O.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].C(Br)CCCCCCC>>[CH3:13][S:12][C:11]1[C:2]([NH:1][C:28]([C:22]2([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[S:23][CH2:24][CH2:25][CH2:26][S:27]2)=[O:29])=[C:3]2[C:8](=[CH:9][CH:10]=1)[N:7]=[CH:6][CH:5]=[CH:4]2
Reactant: CCCCCCCCC1(C(=O)O)SCCCS1
Reactant: CSc1ccc2ncccc2c1N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C(O)C1SCCCS1
Agent: [Na+]
Solvent: CCCCCCCCBr
Product: CCCCCCCCC1(C(=O)Nc2c(SC)ccc3ncccc23)SCCCS1

Procedure:
5-Amino-6-methylthioquinoline, prepared as described in Example 34, was coupled with 2-octanyl-1,3-dithiane-2-carboxylic acid, prepared by treatment of 1,3-dithiane-2-carboxylic acid with sodiumhexamethyldisilazide and octanyl bromide, according to Example 25 to give the title compound.
Reaction SMILES: [C:1]([C:8]1[NH:9][CH:10]=CN=1)([C:3]1[NH:4][CH:5]=[CH:6]N=1)=S.NC1C=CN=CC=1.[NH:20]([C:22](=[O:43])[C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([C@H:32]2[CH2:37][CH2:36][C@H:35]([CH2:38][C:39]([O:41][CH3:42])=[O:40])[CH2:34][CH2:33]2)=[CH:28][CH:27]=1)=[O:24])[NH2:21].CCN=C=NCCCN(C)C>CC(N(C)C)=O.O>[N:4]1[CH:3]=[CH:1][C:8]([NH:9][C:10]2[O:43][C:22]([C:23]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([C@H:32]4[CH2:37][CH2:36][C@H:35]([CH2:38][C:39]([O:41][CH3:42])=[O:40])[CH2:34][CH2:33]4)=[CH:28][CH:27]=3)=[O:24])=[N:20][N:21]=2)=[CH:6][CH:5]=1
Reactant: S=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)C(=O)NN)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Nc1ccncc1
Solvent: CC(=O)N(C)C
Solvent: O
Product: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)c3nnc(Nc4ccncc4)o3)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Thiocarbonyl diimidazole (190 mg, 1.06 mmol) was added in one portion to a solution of 4-aminopyridine (100 mg, 1.06 mmol) in DMA (8 mL) and the solution was stirred at room temperature for 3 h. Methyl [trans-4-(4-{[hydrazino(oxo)acetyl]amino}phenyl)cyclohexyl]-acetate (Intermediate 43, 284 mg, 0.85 mmol) was added in one portion and the reaction mixture was stirred at room temperature for 30 minutes and then heated at 80° C. for 10 minutes in the microwave. The solution was cooled to room temperature and EDCI (205 mg, 1.06 mmol) was added in one portion and the reaction mixture was heated to 90° C. for 20 minutes in the microwave. The reaction mixture was cooled to room temperature and poured into water (200 mL). The mixture was filtered and the resulting solid was recrystallised (CH3CN) to give the title compound (93 mg, 20%) as a solid; 1H NMR δ 1.15 (2H, t), 1.42-1.51 (2H, m), 1.74-1.82 (5H, m), 2.24-2.26 (2H, d), 3.61 (3H, s), 7.23 (2H, d), 7.54-7.55 (2H, m), 7.69-7.71 (2H, m), 8.43 (2H, s) MS m/e MH+ 436.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]3[NH:22][CH:21]([CH2:23][CH2:24][CH3:25])[CH2:20][O:19][C:11]3=2)[N:6]=1)([CH3:3])[CH3:2].[BH4-].[Na+].[C:28](O)(=O)[CH3:29]>>[CH2:28]([N:22]1[C:10]2[C:11](=[C:12]3[C:7](=[CH:8][CH:9]=2)[N:6]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH:14]=[C:13]3[C:15]([F:18])([F:17])[F:16])[O:19][CH2:20][CH:21]1[CH2:23][CH2:24][CH3:25])[CH3:29]
Reactant: CC(=O)O
Reactant: CCCC1COc2c(ccc3nc(OC(C)C)cc(C(F)(F)F)c23)N1
Agent: [BH4-]
Agent: [Na+]
Product: CCCC1COc2c(ccc3nc(OC(C)C)cc(C(F)(F)F)c23)N1CC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Compound 118 was prepared according to General Method 6 (EXAMPLE 3) from (±)-3,4-dihydro-8-isopropoxy-3-propyl-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline (11 mg, 0.03 mmol) and NaBH4 pellets (>10 equiv) in 1 mL acetic acid (0.03 M) stirred at rt for 12 h to afford 9 mg of (±)-4-ethyl-3,4-dihydro-8-isopropoxy-3-propyl-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline. This material (9 mg, 0.02 mmol) was carried on according to General Method 4 (EXAMPLE 1) by treatment with 4 mL of 1:1 acetic acid:concentrated HCl (5.9 mM) and heated at 90° C. for 6 h to afford 6 mg (75%) of Compound 118 after flash chromatography (3:1 hexanes:EtOAc to 1:1 hexanes:EtOAc, gradient elution). 1H NMR (500 MHz, CDCl3) δ 11.91 (bs, 1H), 7.12 (s, 1H), 7.07 (d, J=8.8, 1H), 6.96 (d, J=8.8, 1H), 4.27 (dd, J=10.3, 2.0, 1H), 3.90 (dd, J=10.3, 2.7, 1H), 3.44 (m, 1H), 3.27 (m, 1H), 3.26 (m, 1H), 1.52 (m, 2H), 1.41 (m, 2H), 1.18 (t, J=7.1, 3H) 0.94 (t, J=7.3, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:14]=[C:15]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH3:27])[CH:16]=[CH:17][C:18]=2C=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:36])C=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:14]=[C:15]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH3:27])[CH:16]=[CH:17][C:18]=2[OH:36])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccccc1-c1ccc(C=O)c(OC2CN(C(=O)OC(C)(C)C)C2)c1
Solvent: ClCCl
Product: Cc1ccccc1-c1ccc(O)c(OC2CN(C(=O)OC(C)(C)C)C2)c1
Reaction time: 15 h
Yield: 81.2 %

Procedure:
To a CH2Cl2 (6 mL) solution of the title compound of Step A (1.40 g, 3.81 mmol) was added m-CPBA (77 wt %, 1.30 g, 5.70 mmol). After 15 h, 10 wt % Na2S2O5 (aq.) was added and the solution allowed to stir until the aqueous was Kl paper negative and extracted with CH2Cl2 (2×). The combined organic layers were washed with saturated NaHCO3 (aq.), concentrated and treated with MeOH (30 mL) and 1N NaOH (15 mL). After 15 h, the reaction was partially concentrated to remove the MeOH and acidified with 1M KHSO4 then extracted with EtOAc (2×). The combined organic layers were dried and concentrated to give the 1.1 g of the title compound that was used in the next step without further purification.
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[C-:2].C1CCN2C(=NCCC2)CC1.[C:20](Cl)(=[O:27])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].O>CN(C=O)C>[CH2:21]([C:20]1[O:27][CH:2]=[N:1][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: CCCCCCC(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: CCCCCCc1ocnc1C(=O)OCC
Temperature: 80 °C
Reaction time: 6 h

Procedure:
Ethyl 2-isocyanoacetate (1.0 g, 8.84 mmol) was dissolved in DMF (5 mL) in a 25 mL 1 neck pear shaped flask that was equipped with a magnetic stirrer and an Ar inlet. DBU (1.999 mL, 13.26 mmol) and heptanoyl chloride (1.770 mL, 11.49 mmol) were added and the reaction mixture was stirred at 80° C. for 6 h. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (3×30 mL). The phases were separated and the organic phase was dried over MgSO4 and concentrated in vacuo to a a dark oil. The desired product was isolated by distillation at 90-95° C. at 0.3 mmHg as a clear oil (0.89 g, 45%). LCMS Anal. Calc'd for C12H19NO3 225.1. found [M+H] 226.1. 1H NMR (500 MHz, CDCl3) δ 7.76 (s, 1H), 4.37 (q, J=7.2 Hz, 2H), 3.03 (t, J=7.6 Hz, 2H), 1.71-1.64 (m, 2H), 1.38 (t, J=7.2 Hz, 3H), 1.35-1.26 (m, 6H), 0.86 (t, J=6.3 Hz, 3H).
Reaction SMILES: [OH:1]CC1C=C(O)C=CC=1.C(=O)([O-])[O-].[K+].[K+].[C:16]([O:19][C:20]1[C:21](=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:22](Cl)=[O:23])(=[O:18])[CH3:17]>CC(C)=O>[C:16]([O:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([OH:1])=[O:23])(=[O:18])[CH3:17]
Reactant: OCc1cccc(O)c1
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)Oc1ccccc1C(=O)O
Yield: 87.5 %

Procedure:
3-hydroxymethylphenol (10 g, 0.08 moles) is dissolved in acetone (50 ml). In the obtained solution potassium carbonate in powder (22.2 g, 0.16 moles) is suspended. To the suspension an acetylsalicylic acid chloride solution (16 g, 0.08 moles) in acetone (50 ml) is added at a temperature of 5°-10° C. under stirring. The mixture is maintained at a temperature in the above mentioned range, under stirring, for 2 hours, then filtered and the solvent evaporated under vacuum. The residue is crystallized from isopropanol. 3-hydroxymethylphenyl ester of the 2-acetoxy-benzoic acid (21.0 g, 0.07 moles, yield 91%) is obtained.
Reaction SMILES: [CH3:1][N:2]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:29]=[C:28]([CH3:36])[CH:27]=2)=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[C:8]([O:10]C(C)(C)C)=[O:9].FC(F)(F)C(O)=O>>[CH3:1][N:2]([S:15]([C:18]1[CH:19]=[CH:20][C:21]([O:24][CH2:25][C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:29]=[C:28]([CH3:36])[CH:27]=2)=[CH:22][CH:23]=1)(=[O:17])=[O:16])[C@H:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[C:8]([OH:10])=[O:9]
Reactant: Cc1cc(COc2ccc(S(=O)(=O)N(C)[C@H]3CCC[C@H]3C(=O)OC(C)(C)C)cc2)c2ccccc2n1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(COc2ccc(S(=O)(=O)N(C)[C@H]3CCC[C@H]3C(=O)O)cc2)c2ccccc2n1

Procedure:
According to the procedure of Example 15, Step 3, the reaction of 215 mg (0.42 mmol) of tert-butyl cis-2-[methyl({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclopentanecarboxylate with trifluoroacetic acid provided cis-2-[methyl({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclopentanecarboxylic acid in quantitative yield. MS: 455.1 (M+H)+
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16]Br)=[CH:11][C:10]=1[F:18])C1C=CC=CC=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[F:18][C:10]1[CH:11]=[C:12]([CH2:15][CH2:16][N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:13]=[CH:14][C:9]=1[OH:8]
Reactant: Fc1cc(CCBr)ccc1OCc1ccccc1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Oc1ccc(CCN2CCOCC2)cc1F
Temperature: 60 °C
Reaction time: 3 h
Yield: 109.6 %

Procedure:
To a solution of 1-benzyloxy-4-(2-bromo-ethyl)-2-fluoro-benzene (1.0 g, 3.2 mmol) and morpholine (278 mg, 3.2 mmol) in DMF (5 mL), was K2CO3 (432 mg, 3.2 mmol) added. The reaction mixture was heated to 60° C. and maintained for 6 hours. The reaction was cooled to room temperature and poured into H2O (50 mL). The organic compound was extracted with ethyl acetate (50 mL) and dried over MgSO4. The ethyl acetate layer was concentrated under vacuum and dissolved in methanol (50 mL). The solution was treated with Pd/C (20 mg) and stirred under H2 (1 atm) for 3 hours. The solid material was filtrated off and the filtrate was concentrated under vacuum to afford the desired compound (790 mg, 93%) as a white oil. The crude compound was used for the next step without further purification. 1H NMR (400 Mz, DMSO-d6) δ 7.33-7.45 (m, 5H), 7.09-7.15 (m, 2H), 6.97-7.01 (m, 1H), 5.13 (s, 2H), 3.56 (m, 4H), 2.64-2.68 (m, 2H), 2.44-2.50 (m, 2H), 2.39 (b, 2H). LCMS 310.5 [MH+].
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:12]([OH:14])=[O:13])[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:18][C:19]1([CH3:23])[CH2:22][O:21][CH2:20]1>CS(C)=O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:10][O:11][CH2:18][C:19]1([CH3:23])[CH2:22][O:21][CH2:20]1)[C:12]([OH:14])=[O:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Reactant: CC1(CBr)COC1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC1(COC[C@H](NC(=O)OC(C)(C)C)C(=O)O)COC1
Reaction time: 1 h
Yield: 63 %

Procedure:
To N-(tert-Butoxycarbonyl)-L-serine (1.2 g, 6.06 mmol) in anhydrous dimethyl sulfoxide (20 mL) at room temperature and under an atmosphere of nitrogen was added sodium hydride (60% in mineral oil, 363 mg, 9.1 mmol) in three portions. The reaction was stirred for 1 h after which was added 3-bromomethyl-3-methyl oxetane (obtained from Fluorochem Ltd., UK), 1 g, 6.06 mmol) and a further amount of sodium hydride (60% in mineral oil, 363 mg, 9.1 mmol). The reaction was stirred for 16 h and quenched by careful addition of water. The solution was washed with diethyl ether (1×) and acidified to pH 2 with 2 M hydrochloric acid. The solution was extracted with ethyl acetate (2×) and the combined organics washed with brine. The organic layer was dried through a hydrophobic frit and concentrated in vacuo to yield the title compound (1.1 g, 63%) as a clear oil. 1H NMR (300 MHz, CDCl3) δ 1.30 (s, 3H), 1.48 (s, 9H), 3.50, 3.53 (ABq, J=9.4 Hz, 2H), 3.77 (dd, J=9.4, 3.8 Hz, 1H), 3.98 (dd, J=9.4, 2.9 Hz, 1H), 4.37 (d, J=5.8 Hz, 2H), 4.47-4.55 (m, 1H), 4.57 (d, J=5.8 Hz, 2H), 5.47 (d, J=8.3 Hz, 1H). LCMS (m/z) 289.3 [M+H], Tr=1.67 min.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([N:12]1[C:16]([C:17]2[C:18]([F:23])=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:15][C:14]([CH2:24][N:25](C)[C:26](=O)OC(C)(C)C)=[CH:13]1)(=[O:11])=[O:10].C(OCC)(=O)C.[ClH:40]>C(O)C>[ClH:40].[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([N:12]1[C:16]([C:17]2[C:18]([F:23])=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:15][C:14]([CH2:24][NH:25][CH3:26])=[CH:13]1)(=[O:11])=[O:10]
Reactant: CN(Cc1cc(-c2cccnc2F)n(S(=O)(=O)c2cccc(F)c2F)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNCc1cc(-c2cccnc2F)n(S(=O)(=O)c2cccc(F)c2F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
To a solution of tert-butyl ({1-[(2,3-difluorophenyl)sulfonyl]-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl}methyl)methylcarbamate (443 mg) in ethanol (4 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (4 mL), and the mixture was stirred at room temperature for 2 hr. The solvent was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound (yield 206 mg, 54%).
Reaction SMILES: [Si]([O:8][CH:9]([C:24]1[O:25][C:26]([I:29])=[CH:27][N:28]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>O1CCCC1>[I:29][C:26]1[O:25][C:24]([CH:9]([OH:8])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)=[N:28][CH:27]=1
Reactant: COc1cccc(CCCCCCC(O[Si](C)(C)C(C)(C)C)c2ncc(I)o2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cccc(CCCCCCC(O)c2ncc(I)o2)c1
Yield: 88 %

Procedure:
2-(1-(tert-Butyl dimethylsilyloxy)-7-(3-methoxyphenyl)heptyl)-5-iodooxazole (0.088 g, 0.166 mmol) was dissolved in tetrahydrofuran (2 mL) under an atmosphere of argon with stirring and 1 M tetrabutylammonium fluoride (in tetrahydrofuran) (0.199 mL, 0.199 mmol) was added. The reaction was allowed to proceed over 90 minutes before dilution with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The solvent was removed in vacuo and the desired product was purified as an oily white solid in 88% yield (0.061 g) using flash column chromatography with silica (0-30% ethyl acetate:hexanes gradient mobile phase): 1H NMR (500 MHz, CDCl3) δ 7.17-7.20 (m, 1H), 7.07 (s, 1H), 6.76 (d, J=7.5 Hz), 6.72 (m, 2H), 4.77 (q, 1H), 3.79 (s, 3H), 3.24 (bs, 1H), 2.57 (t, 2H), 1.80-1.93 (m, 2H), 1.58-1.62 (m, 2H), 1.43-1.48 (m, 1H), 1.30-1.42 (m, 5H); 13C NMR (150 MHz, CDCl3) δ 170.52, 159.48, 144.32, 135.05, 129.11, 120.79, 114.13, 110.80, 110.74, 86.84, 67.48, 55.07, 35.89, 35.21, 31.16, 29.03 (2 C), 24.84; HRMS (ES+) mile calc'd for [M+H]+ C17H23INO3: 416.0717. found 416.0699.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([CH2:22][OH:23])[C@@H:18]([CH2:24][OH:25])[C@@H:17]2[C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:35](Cl)(=[O:37])[CH3:36]>ClCCl>[C:35]([O:23][CH2:22][C@H:19]1[CH2:20][CH2:21][C@H:16]([O:15][C@@H:13]([C:5]2[CH:4]=[C:3]([C:2]([F:1])([F:33])[F:34])[CH:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:6]=2)[CH3:14])[C@@H:17]([C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[C@@H:18]1[CH2:24][OH:25])(=[O:37])[CH3:36]
Reactant: CC(=O)Cl
Reactant: C[C@@H](O[C@H]1CC[C@H](CO)[C@@H](CO)[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClCCl
Product: CC(=O)OC[C@H]1CC[C@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H](c2ccc(F)cc2)[C@@H]1CO
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of [(1S,2R,3R,4S)-4-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-3-(4-fluorophenyl)cyclohexane-1,2-diyl]dimethanol (3.3 g, 6.7 mmol, intermediate step J) in dichloromethane (50 mL) were added acetyl chloride (0.52 mL, 7.4 mmol) and TEA (1.1 mL, 7.9 mmol) at room temperature. The resulting mixture was stirred at r.t. for 6 hr. The solvent was removed under vacuum and the residue was separated by column chromatography on silica gel eluting with 3:1 hexane:ethyl acetate. The less polar mono-alcohol on TLC was collected (0.75 g). MS: (MH)+ 536.2.
Reaction SMILES: [CH:1]1([O:5][C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:51])[C@@H:15]([NH:21][C:22]([C:24]3[CH:28]=[C:27]([O:29][CH2:30][C:31]([N:33]4[CH2:37][CH2:36][CH2:35][C@H:34]4[C:38](=[O:44])[NH:39][CH:40]4[CH2:43][CH2:42][CH2:41]4)=[O:32])[N:26]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[N:25]=3)=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[CH2:10][CH2:9]2)=[O:7])[CH2:4][CH2:3][CH2:2]1.I[CH3:53].[H-].[Na+]>C1COCC1>[CH:1]1([O:5][C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:51])[C@@H:15]([NH:21][C:22]([C:24]3[CH:28]=[C:27]([O:29][CH2:30][C:31]([N:33]4[CH2:37][CH2:36][CH2:35][C@H:34]4[C:38](=[O:44])[N:39]([CH:40]4[CH2:43][CH2:42][CH2:41]4)[CH3:53])=[O:32])[N:26]([C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)[N:25]=3)=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[CH2:10][CH2:9]2)=[O:7])[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(N[C@@H](CCCCO)C(=O)N1CCN(C(=O)OC2CCC2)CC1)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C(=O)[C@@H]1CCCN1C(=O)COc1cc(C(=O)N[C@@H](CCCCO)C(=O)N2CCN(C(=O)OC3CCC3)CC2)nn1-c1ccccc1)C1CCC1
Reaction time: 2 h

Procedure:
To a solution of 65 mg 4-{(S)-2-[(5-{2-[(S)-2-(Cyclobutylcarbamoyl)-pyrrolidin-1-yl]-2-oxo-ethoxy}-1-phenyl-1H-pyrazole-3-carbonyl)-amino]-6-hydroxy-hexanoyl}-piperazine-1-carboxylic acid cyclobutyl ester in 5 ml THF were added at −20° C. 6 l iodomethane and 5 mg sodium hydride (95%). After 2 h and 12 h equivalent amounts of iodomethane and sodium hydride were added before the reaction mixture was quenched with 0.1 M HCl and extracted with dichloromethane. The crude product obtained after evaporation of the solvent was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA) to give the title compound as a mixture with its trifluoroacetyl ester. Repeated lyophilization from MeCN/water yielded the pure title compound. Yield: 17 mg MS (ES+): m/e=722.
Reaction SMILES: C(N=C=NCCCN(C)C)C.[C:12]([O:16][C:17]([NH:19][C@H:20]1[CH2:24][CH2:23][N:22]([C:25](=[O:45])[CH2:26][N:27]([CH2:41][C:42]([OH:44])=O)[C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:30][CH:29]=2)[CH2:21]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].ON1C2N=CC=CC=2N=N1.[Cl:56][C:57]1[CH:58]=[C:59]([CH:62]=[CH:63][CH:64]=1)[CH2:60][NH2:61].CN1CCOCC1>CN(C=O)C.C(OCC)(=O)C>[Cl:56][C:57]1[CH:58]=[C:59]([CH:62]=[CH:63][CH:64]=1)[CH2:60][NH:61][C:42]([CH2:41][N:27]([C:28]1[CH:29]=[CH:30][C:31]([O:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)=[CH:32][CH:33]=1)[CH2:26][C:25]([N:22]1[CH2:23][CH2:24][C@H:20]([NH:19][C:17](=[O:18])[O:16][C:12]([CH3:15])([CH3:13])[CH3:14])[CH2:21]1)=[O:45])=[O:44]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)CN(CC(=O)O)c2ccc(Oc3ccccc3)cc2)C1
Reactant: NCc1cccc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)CN(CC(=O)NCc2cccc(Cl)c2)c2ccc(Oc3ccccc3)cc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.5 %

Procedure:
1-Ethyl-3-(3′-dimethylaminopropyl)carbodiimide (144 mg, 0.75 mmol) was added to a solution of [[2-((S)-3-tert-butoxycarbonylaminopyrrolidin-1-yl)-2-oxo-ethyl]-(4-phenoxyphenyl)amino]acetic acid 20 (176 mg, 0.37 mmol), 1-hydroxy-7-azabenzotriazole (103 mg, 0.76 mmol), 3-chlorobenzylamine (0.092 mL, 0.76 mmol) and N-methylmorpholine (0.11 mL, 1.02 mmol) in DMF (5 mL). The reaction mixture was stirred overnight at room temperature and then diluted with ethyl acetate and washed with 10% hydrochloric acid (×2), brine, saturated aqueous sodium bicarbonate (×2) and then brine, dried (Na2SO4) and evaporated onto silica gel. Flash column chromatography, using ethyl acetate as the eluent, gave the title compound as a hard foam (159 mg, 71%). 1HNMR (300 MHz) (CDCl3) δ 1.45 (6H, s), 1.55 (3H, s), 1.8-2.4 (2H, m), 3.35-3.90 (5H, m), 3.95-4.40 (4H, m), 4.55-4.70 (2H, m), 6.48 (2H, m), 6.75-7.05 (6H, m), 7.12 (3H, m), 7.25 (2H, m) and 9.81 (1H, m).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1B(O)O.I[C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.[Pd].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1
Reactant: Oc1ccc(I)cc1
Reactant: OB(O)c1ccc(F)cc1F
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: Oc1ccc(-c2ccc(F)cc2F)cc1
Yield: 109.6 %

Procedure:
2,4-Difluoro-phenyl-boronic acid (1.29 g, 8.18 mmol) and 4-iodophenol (0.60 g, 2.7 mmol) were suspended in DMF (60 mL) and 6 mL H2O (6 mL). The mixture was degassed with nitrogen. Finely ground potassium carbonate (1.13 g, 8.18 mmol) and bis(tricyclohexylphosphine) palladium(0) (91 mg, 0.13 mmol) were added. The reaction was stirred at reflux overnight under nitrogen and cooled. The mixture was filtered through a plug of silica gel/Celite and evaporated. The residue was diluted with ethyl acetate and washed with saturated sodium bicarbonate (2×20 mL), dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography, eluting with 0-25% ethyl acetate in hexanes to yield 2′,4′-difluoro-biphenyl-4-ol (0.61 g, 100%). LR-MS (ES) calculated for C12H8F2O, 206.19; found m/z 205 [M−H]−.
Reaction SMILES: [NH:1]1[C:10](=[O:11])[C:9]2[NH:8][CH:7]=[N:6][C:5]=2[NH:4][C:2]1=O>C(O)CC.[Ni]>[NH:1]1[C:10](=[O:11])[C:9]2[NH:8][CH:7]=[N:6][C:5]=2[N:4]=[CH:2]1
Reactant: O=c1[nH]c(=O)c2[nH]cnc2[nH]1
Agent: [Ni]
Solvent: CCCO
Product: O=c1[nH]cnc2nc[nH]c12
Yield: 9.8 %

Procedure:
A solution with 22.39 g (43 mM) of the above xanthine (B.) in 580 ml of 1-propanol was treated with 25 g of Raney-nickel (washed with 0.1% aqueous acetic acid) and refluxed for 2 hr. The nickel was filtered off and the solvent evaporated in vacuo. The residue was crystallized from 120 ml of methanol: 12.73 g (60.6%) of hypoxanthine with mp 161-162° C., a second crop gave 1.97 g (9.4%) of hypoxanthine.