Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([CH3:27])([CH3:26])[C:24]#[N:25])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:28])[CH3:9])=[CH:4][CH:3]=1.Br[C:30]1[CH:35]=[CH:34][N:33]([CH3:36])[C:32](=[O:37])[CH:31]=1>>[CH3:26][C:23]([CH3:27])([CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:28])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:30]3[CH:35]=[CH:34][N:33]([CH3:36])[C:32](=[O:37])[CH:31]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1)[C:24]#[N:25]
Reactant: Cn1ccc(Br)cc1=O
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccn(C)c(=O)c2)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)-2,2-dimethylpropanenitrile following procedures analogous to those described in Example 313 Steps 3 and 4 using 4-bromo-1-methylpyridin-2(1H)-one in Step 4. LC-MS Method 2 tR=1.103, m/z=470.4; 1H NMR (CDCl3) 1.26 (s, 3H), 1.41 (s, 3H), 1.49 (d, 3H), 2.09 (s, 2H), 2.24 (m, 1H), 2.53 (m, 2H), 2.88 (m, 1H), 3.56 (s, 3H), 5.59 (m, 1H), 6.38 (d, 1H), 6.78 (s, 1H), 6.84 (d, 2H), 7.19 (m, 2H), 7.31 (m, 6H).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.C(OP([CH2:21][C:22]([OH:24])=[O:23])(OCC)=O)C.[NH2:25][C:26]1[C:27]2[C:34]([C:35]3[CH:40]=[CH:39][C:38]([O:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)=[CH:37][CH:36]=3)=[CH:33][N:32]([CH:48]3[CH2:53][CH2:52][C:51](=O)[CH2:50][CH2:49]3)[C:28]=2[N:29]=[CH:30][N:31]=1>O1CCCC1>[NH2:25][C:26]1[C:27]2[C:34]([C:35]3[CH:36]=[CH:37][C:38]([O:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)=[CH:39][CH:40]=3)=[CH:33][N:32]([CH:48]3[CH2:53][CH2:52][C:51](=[CH:21][C:22]([OH:24])=[O:23])[CH2:50][CH2:49]3)[C:28]=2[N:29]=[CH:30][N:31]=1
Reactant: CCOP(=O)(CC(=O)O)OCC
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C1CCC(=CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 70.7 %

Procedure:
A solution of diisopropylamine (1.40 g, 13.82 mmol) in tetrahydrofuran (60 mL) was added into a solution of 2.2 M n-BuLi (6.29 mL, 13.82 mmol) in tetrahydrofuran (20 mL) at −78° C. A solution of diethylphosphonoacetic acid (1.29 g, 6.59 mmol) in tetrahydrofuran (60 mL) was added at −78° C. under the atmosphere of nitrogen. The mixture was kept at −78° C. for 20 minutes and allowed to warm up to ambient temperature. The mixture was then transferred into a suspension of 4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexanone (2.50 g, 6.28 mmol) in tetrahydrofuran (150 mL) at −78° C. quickly. The resulting mixture was allowed to warm up to ambient temperature overnight and the solvent was removed under reduced pressure. The residue was taken in water and adjusted PH to be 3-4 with 1M aqueous acetic acid followed by extraction with ethyl acetate three times. The combined organic extracts were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and evaporated under reduced pressure to give 2-{4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexyliden}acetic acid (1.96 g, 4.44 mmol) as a white solid: 1H NMR (DMSO-d6, 400 MHz) δ 11.98(br, 1H), 7.45(d, 2H), 7.41(s, 1H), 7.40(d, 2H), 7.16(t, 1H), 7.08(m, 4H), 6.10(br, 2H), 5.70(s, 1H), 4.80(m, 1H), 2.50-1.90(m, 8H); RP-HPLC (Hypersil C18, 5 μm, 100 A, 250×4.6 mm; 25%-100% acetonitrile-0.05M ammonium acetate over 10 min, 1 mL/min) Rt 9.70 min. MS: MH+ 441.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[C@H:29]1[CH2:34][CH2:33][C@H:32]([O:35][CH2:36][C:37](=[O:39])[CH3:38])[CH2:31][CH2:30]1.C[Si](C)(C)[C:42]([F:45])([F:44])[F:43].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>O1CCCC1>[O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[C@H:29]1[CH2:30][CH2:31][C@H:32]([O:35][CH2:36][C:37]([OH:39])([CH3:38])[C:42]([F:45])([F:44])[F:43])[CH2:33][CH2:34]1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)=O)CC2)c2ncnn12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)(O)C(F)(F)F)CC2)c2ncnn12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4′-({5-Oxo-4-[trans-4-(2-oxopropoxy)cyclohexyl]-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.30 g) and trimethyl(trifluoromethyl)silane (0.20 g) were dissolved in tetrahydrofuran (3 mL), tetrabutylammonium fluoride (0.22 mL, 1.0 M tetrahydrofuran solution) was added dropwise at 0° C., and the mixture was stirred at 0° C. for 1 hr. Trimethyl(trifluoromethyl)silane (0.20 g) and tetrabutylammonium fluoride (0.22 mL, 1.0 M tetrahydrofuran solution) were added, and the mixture was stirred at 0° C. for 1 hr and then at room temperature for 16 hr. The reaction mixture was added to 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.092 g, 27%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:17][C:18]([O:20]CC)=[O:19])[N:5]([CH3:16])[C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)=[O:8].Cl>[OH-].[Na+]>[Br:1][C:2]1[CH:3]=[C:4]([CH2:17][C:18]([OH:20])=[O:19])[N:5]([CH3:16])[C:6]=1[C:7]([C:9]1[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=1)=[O:8]
Reactant: CCOC(=O)Cc1cc(Br)c(C(=O)c2ccc(C)cc2)n1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(C(=O)c2c(Br)cc(CC(=O)O)n2C)cc1

Procedure:
A suspension of 2.6 g. (0.0715 mole) of ethyl 4-bromo-1-methyl-5-(p-toluoyl)pyrrole-2-acetate in 14.4 ml of 0.5N sodium hydroxide solution is heated under reflux for 30 minutes. It is then poured into dilute hydrochloride acid and the precipitated solid is filtered and air dried. Recrystallization of this precipitate from ether by addition of cyclohexane and evaporation of the ether until crystallization occurs yields as a white solid 4-bromo-1-methyl-5-(p-toluoyl)pyrrole-2-acetic acid; m.p. 155°-157° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.C1(S([N:18]2[C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[C:20]([C:27]3[CH:32]=[CH:31][N:30]=[C:29](Cl)[N:28]=3)=[CH:19]2)(=O)=O)C=CC=CC=1>>[NH:18]1[C:22]2=[N:23][CH:24]=[CH:25][CH:26]=[C:21]2[C:20]([C:27]2[CH:32]=[CH:31][N:30]=[C:29]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=3)[N:28]=2)=[CH:19]1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Reactant: Cc1ccc(N)cc1
Product: Cc1ccc(Nc2nccc(-c3c[nH]c4ncccc34)n2)cc1
Yield: 43.1 %

Procedure:
Using the procedure of example 1, p-toluidine (87 mg) was reacted with compound 1f (100 mg) to provide compound 10 (35 mg, 43%). 1H NMR (400 MHz, CD3OD) δ 8.82 (d, J=8.0 Hz, 1H), 8.28 (m, 2H), 8.13 (s, 1H), 7.62 (s, 1H), 7.56 (d, J=8.0 Hz, 2H), 7.21 (m, 2H), 7.12 (d, J=5.2 Hz, 1H), 2.38 (s, 3H). MS (ESI) m/z: 302 (M+H)+.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.C1COCC1.CCCCCCC.C(C1C=CC=CC=1)C.[N:29]1([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:34][CH2:33][CH2:32][CH:31]([C:35]([O:37]CC)=O)[CH2:30]1.[CH:47](=[N:54][Si](C)(C)C)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>C1COCC1>[O:37]=[C:35]1[C:31]2([CH2:32][CH2:33][CH2:34][N:29]([C:40]([O:42][C:43]([CH3:44])([CH3:45])[CH3:46])=[O:41])[CH2:30]2)[CH:47]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[NH:54]1
Reactant: C[Si](C)(C)N=Cc1ccccc1
Reactant: CCOC(=O)C1CCCN(C(=O)OC(C)(C)C)C1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCc1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: CC(C)(C)OC(=O)N1CCCC2(C1)C(=O)NC2c1ccccc1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
A solution of 2M LDA in THF/n-heptane/ethylbenzene (10.7 ml, 21.37 mmol) was cooled to −78° C. and a solution of 1-tert-butyl 3-ethyl piperidine-1,3-dicarboxylate (5 g, 19.43 mmol) in THF (5 mL) was added dropwise. The mixture was stirred for 40 minutes and allowed to warm to 0° C. for 10 minutes and cooled again to −78° C. N-benzylidene-1,1,1-trimethylsilanamine (2.63 ml, 21.37 mmol) was added and the mixture was left to stir for 3 h at 0° C. The reaction was quenched with water (5 ml) and the resulting solution was extracted using ethyl acetate. The organic portion was separated, dried (MgSO4) and concentrated in vacuo to yield a yellow oil. Purification by flash chromatography on silica (220 g column) eluting with 20-70% EtOAc in iso-hexane afforded the title compound;
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=O)[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[NH2:14][C@H:15]([C:24]([OH:26])=[O:25])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.[BH4-].[Na+].Cl>CO>[CH:2]([O:25][C:24](=[O:26])[CH:15]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=1)[NH:14][CH:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1)[C:10]([O:12][CH:5]([CH3:6])[CH3:4])=[O:11])([CH3:7])[CH3:3]
Reactant: O=C(O)C(=O)Cc1ccc(O)cc1
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)OC(=O)C(Cc1ccc(O)cc1)NC(Cc1ccc(O)cc1)C(=O)OC(C)C
Temperature: 60 °C
Reaction time: 6 h

Procedure:
9.01 g (50.0 mmol) of 4-hydroxyphenylpyruvic acid and 9.06 g (50.0 mmol) of tyrosine are dissolved in 60 ml of methanol and stirred for six hours at 60° C. Then, it is allowed to cool to room temperature and 0.76 g (20 mmol) of sodium borohydride is added. It is allowed to stir overnight and then the reaction mixture is mixed carefully with diluted hydrochloric acid until no more gas generation can be observed. The reaction mixture is concentrated by evaporation and dried in an oil pump vacuum for several hours at 100° C. The residue is taken up in isopropanol. Hydrogen chloride gas is introduced until saturation is achieved, stirred for two hours at room temperature and then for eight hours at 85° C. Then, it is concentrated by evaporation, the residue is dispersed between ethyl acetate and sodium bicarbonate solution, the organic phase is dried on sodium sulfate, filtered and concentrated by evaporation. The residue is chromatographed on silica gel with use of hexane/ethyl acetate as mobile solvent. The fractions that contain the pure product are combined and concentrated by evaporation.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl[CH2:23][CH2:24][N:25]([CH3:27])[CH3:26]>C(#N)C.CCOCC>[CH3:26][N:25]([CH3:27])[CH2:24][CH2:23][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1.[CH3:26][N:25]([CH3:27])[CH2:24][CH2:23][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1
Reactant: CN(C)CCCl
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOCC
Product: CN(C)CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 25 °C
Yield: 190.9 %

Procedure:
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2 g, 10.31 mmol), cesium carbonate (6.72 g, 20.61 mmol) and 2-chloro-N,N-dimethylethanamine hydrochloride (2.227 g, 15.46 mmol) were suspended in acetonitrile (30 mL) and the mixture was heated at reflux for 5 h, then cooled to room temperature, diluted with Et2O and filtered. The filtrate was concentrated in vacuo to give N,N-dimethyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]ethanamine dimethyl{2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]ethyl}amine (2.61 g, 9.84 mmol, 95% yield) as an amber oil which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:14]([O-])=O)=[C:6]([CH:13]=1)[O:7][C@@H:8]1[CH2:12][CH2:11][O:10][CH2:9]1>CO.[Ni]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:14])=[C:6]([O:7][C@@H:8]2[CH2:12][CH2:11][O:10][CH2:9]2)[CH:13]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1O[C@@H]1CCOC1
Agent: [Ni]
Solvent: CO
Product: Nc1ccc(F)cc1O[C@@H]1CCOC1

Procedure:
To a solution of (R)-3-(5-fluoro-2-nitrophenoxy)tetrahydrofuran (1.8 g) in MeOH (60.0 ml) was added Ra/Ni (200.0 mg), the mixture hydrogenated at room temperature. The catalyst was filtered off and the filtrate was concentrated.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([C:25]([O:27]CC)=[O:26])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([NH:35][C:36]([C:38]([CH3:41])([CH3:40])[CH3:39])=[O:37])[CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>C(O)C>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][CH:18]([C:25]([OH:27])=[O:26])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([NH:35][C:36]([C:38]([CH3:39])([CH3:41])[CH3:40])=[O:37])[CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(C)cc(NC(=O)C(C)(C)C)cc2n1Cc1ccc(OC(C(=O)OCC)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCc1nc2c(C)cc(NC(=O)C(C)(C)C)cc2n1Cc1ccc(OC(C(=O)O)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 1b from 2-n-butyl-4-methyl-1-[4-[(α-ethoxycarbonyl)benzyloxy]benzyl]-6-tert.butylcarbonylamino-benzimidazole and 2N sodium hydroxide solution in ethanol.
Reaction SMILES: [CH2:1]([C@H:8]([NH:30][C:31](=[O:38])[O:32][CH:33]1[CH2:37][CH2:36][O:35][CH2:34]1)[C@@H:9]([OH:29])[CH:10]([NH:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[O:11][CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N[C@@H](CC1C=CC=CC=1)[C@H](O)CN(OC1CCCC1)S(C1C=CC(OC)=CC=1)(=O)=O.C(N(CC)C(C)C)(C)C>>[CH2:1]([C@H:8]([NH:30][C:31](=[O:38])[O:32][C@H:33]1[CH2:37][CH2:36][O:35][CH2:34]1)[C@@H:9]([OH:29])[CH:10]([NH:17][S:18]([C:21]1[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)(=[O:20])=[O:19])[O:11][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(S(=O)(=O)NC(OC2CCCC2)[C@H](O)[C@H](Cc2ccccc2)NC(=O)OC2CCOC2)cc1
Agent: COc1ccc(S(=O)(=O)N(C[C@@H](O)[C@@H](N)Cc2ccccc2)OC2CCCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(S(=O)(=O)NC(OC2CCCC2)[C@H](O)[C@H](Cc2ccccc2)NC(=O)O[C@H]2CCOC2)cc1
Reaction time: 18 h
Yield: 87 %

Procedure:
tetrahydro-3-furanyl N-((1S,2R)-1-benzyl-3-(cyclopentyloxy)[(4-methoxyphenyl)sulfonyl]amino-2-hydroxypropyl)carbamate. A mixture of 2,5-dioxo-1-pyrrolidinyl [(3S)tetrahydro-3-furanyl]carbonate (13.8 mg, 0.0602 mmol, W094/05639), N1-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N1-(cyclopentyloxy)-4-methoxy-1-benzenesulfonamide x trifluoracetic acid (Step 1, Example 48), (30 mg, 0.0547 mmol), and N,N-diisopropylethylamine (23.8 AL, 0.137 mmol) were combined at ambient temperature under an Argon atmosphere. After stirring for 18 hours, the reaction mixture was evaporated in vacuo to a residue and purified on a preparative silica gel TLC plate (20x20 cm, 500 WM) eluting with 96:4 chloroform : methanol. The product band was removed, eluted with 3:1 methylene chloride methanol, filtered, evaporated in vacuo and dried under high vacuum to provide (3S)tetrahydro-3-furanyl N-((1S,2R) -1-benzyl-3-(cyclopentyloxy)[(4-methoxyphenyl)sulfonyl]amino-2-hydroxypropyl)carbamate (26 mg, 87%) as a foam. H1-NMR (chloroform-D3): 1.73 (m, 9H), 2.14 (m, 1H), 2.92 (m, 5H), 3.77 (m, 6H), 3.87 (s, 3H), 4.79 (bm, 2H), 5.10 (bs, 1H), 6.97 (d, 2H), 7.23 (m, 5H), 7.70 (d, 2H). MS(ESI): 571 (M+Na).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[C:11]4[CH:12]=[CH:13][CH:14]=[C:15]([C:18]([OH:20])=[O:19])[C:16]=4[CH2:17][C:5]=3[C:4]=2[CH:3]=1.S(=O)(=O)(O)O.[CH2:26](O)[CH3:27]>>[CH2:26]([O:19][C:18]([C:15]1[C:16]2[CH2:17][C:5]3[C:4]4[CH:3]=[C:2]([Cl:1])[CH:10]=[CH:9][C:8]=4[NH:7][C:6]=3[C:11]=2[CH:12]=[CH:13][CH:14]=1)=[O:20])[CH3:27]
Reactant: CCO
Reactant: O=C(O)c1cccc2c1Cc1c-2[nH]c2ccc(Cl)cc12
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cccc2c1Cc1c-2[nH]c2ccc(Cl)cc12

Procedure:
The product of Example 20 was converted to its ethyl ester by treatment with sulfuric acid in ethanol to give the title compound as an off-white solid: mp 202-204° C.; 1H NMR (DMSO-d6,): δ 1.39 (t, 3H), 4.00 (s, 2H), 4.38 (q, 2H), 7.11 (d, 1H), 7.48 (d, 1H), 7.52 (t, 1H), 7.67 (s, 1H), 7.79-7.84 (m, 2H), 11.86 (s, 1H); MS [EI, m/z]: 311 [M]+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4](/[CH:11]=[CH:12]\[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15](O)[CH:14]=2)[CH:5]=[C:6]([I:10])[C:7]=1[O:8][CH3:9].[C:22](OC(=O)C)(=[O:24])[CH3:23]>N1C=CC=CC=1>[I:1][C:2]1[CH:3]=[C:4](/[CH:11]=[CH:12]\[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([C:22](=[O:24])[CH3:23])[CH:14]=2)[CH:5]=[C:6]([I:10])[C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(/C=C\c2cc(I)c(OC)c(I)c2)cc1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1ccc(/C=C\c2cc(I)c(OC)c(I)c2)cc1C(C)=O
Reaction time: 2 h
Yield: 41 %

Procedure:
An appropriate phenol 22a (0.45 g) was dissolved in pyridine (3 mL)-acetic anhydride (170 μL) and stirred for 2 hrs. The mixture was concentrated under reduced pressure from toluene (3×10 mL). The residue was diluted with EtOAc (30 mL), washed successively with water (10 mL), NaHCO3 (10% aq. sol., 10 mL), dried, and the solution filtered and concentrated. The acetate was further purified by flash chromatography on silica using 1:24 hexane-EtOAc:hexane as eluent to afford acetate 22c (0.20 g, 41%) as a colorless solid:recrystallized from hexane mp 121–122° C.; 1H-NMR (300 MHz, CDCl3) δ 2.29 (s, 3 H), 3.83 (s, 3 H), 3.85 (s, 3 H), 6.29 (d, 1 H, J=12 Hz), 6.48 (d, 1 H, J=12 Hz), 6.85 (d, 1 H, J=8.7 Hz), 6.93 (d, 1 H, J=2.43), 7.06 (d, 1 H, J=1.5), 7.09 (d, 1 H, J=2.4 Hz) and 7.67 (s, 2 H); 13C-NMR (125 MHz, CDCl3) δ 20.66, 55.94, 60.72, 90.11, 112.16, 123.25, 125.41, 127.47, 128.85, 130.64, 137.10, 139.54, 139.89, 150.69, 157.67 and 168.79; HRMS calcd for C19H20I2O5582.9479 [M+CH3OH]+, found 582.9482; Anal. calcd for C18H16I2O4 C, 39.30; H, 2.93. Found C, 39.30; H, 3.13%.
Reaction SMILES: C([N:8]1[C@@H:13]2[CH2:14][CH2:15][C@@:9]1([C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)[C@H:10]([O:16][CH2:17][C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=1)[CH2:11][CH2:12]2)C1C=CC=CC=1.C(O)(=O)C>C(OCC)(=O)C.[OH-].[Pd+2].[OH-]>[F:31][C:28]([F:29])([F:30])[C:20]1[CH:19]=[C:18]([CH2:17][O:16][C@@H:10]2[CH2:11][CH2:12][C@@H:13]3[NH:8][C@@:9]2([C:32]2[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=2)[CH2:15][CH2:14]3)[CH:23]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:21]=1
Reactant: Fc1ccc([C@]23CC[C@H](CC[C@H]2OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)N3Cc2ccccc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Fc1ccc([C@]23CC[C@H](CC[C@H]2OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)N3)cc1
Yield: 40.2 %

Procedure:
(1R*,2R*,5R*)-8-Benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-1-(4-fluorophenyl)-8-azabicyclo[3.2.1]octane (Example 17; 1.51 g, 2.81 mmol) was dissolved in ethyl acetate (20 ml) and glacial acetic acid (2 ml) and 10% palladium hydroxide (200 mg) added and hydrogenated at 45 psi overnight. The reaction mixture was filtered then concentrated in vacuo. The oil was basified (4N sodium hydroxide) and the solution extracted with ethyl acetate (×3). The organics were dried (MgSO4) and concentrated in vacuo. The mixture was purified by flash column chromatography [7.5% methanol in dichloromethane] to give a yellow oil which solidified on standing to give the title compound (506 mg, 40%). The hydrochloride salt was made by adding 1 equivalent of 1N hydrogen chloride in diethyl ether to the title compound (31 mg, 0.06 mmol). A white solid formed which was triturated in diethyl ether and filtered then dried at 60° C. in vacuo (29.8 mg, 89%).
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][CH:3]=1.[F:9][C:10]1[CH:17]=[C:16](B2OC(C)(C)C(C)(C)O2)[CH:15]=[CH:14][C:11]=1[C:12]#[N:13].C(=O)([O-])[O-].[K+].[K+].ClCCl.[OH-].[Na+]>O1CCOCC1.O>[NH2:8][C:5]1[N:6]=[N:7][C:2]([C:16]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([F:9])[CH:17]=2)=[CH:3][N:4]=1
Reactant: Nc1ncc(Br)nn1
Reactant: CC1(C)OB(c2ccc(C#N)c(F)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2cnc(N)nn2)cc1F
Temperature: 86 °C
Reaction time: 2 h
Yield: 82.3 %

Procedure:
A mixture of 6-bromo-1,2,4-triazin-3-amine (17, 100.0 g, 571.47 mmol) and 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (19, 145.43 g, 588.61 mmol, 1.03 equiv) in 1,4-dioxane (1200 mL) was stirred at room temperature for 10 min before potassium carbonate (K2CO3, 355.4 g, 2572 mmol) in water (600 mL) was added to give a deep red solution. The mixture was degassed by bubbling with nitrogen for 10 min before 1,1′-bis(diphenyl phosphino)ferrocene dichloropalladium(II) complex with dichloromethane (1:1) (Pd(dppf)2Cl2, 14.14 g, 17.14 mmol, 0.03 equiv) was added at room temperature. The resulting reaction mixture was degassed by bubbling with nitrogen for 10 min and then heated at 86° C. under nitrogen. After 2 h, HPLC showed that the reaction was deemed complete, and the reaction mixture was cooled to room temperature and then to 0-5° C. with an ice-water bath. 1,4-Dioxane (400 mL) was added to the cooled reaction mixture before a solution of 3.3 M aqueous hydrochloric acid solution (HCl, 1900 mL) was added dropwise with stirring to adjust pH to 0.40-0.93. The mixture was stirred at room temperature for 30 min and filtered. The solid collected was stirred with 1,4-dioxane (260 mL) and then added 1N HCl (400 mL). The mixture was stirred at room temperature for 10 min and filtered. The filtrate was combined with the filtrate obtained earlier and washed with ethyl acetate (EtOAc, 2×2 L). The combined ethyl acetate extracts was extracted with 1 N aqueous hydrochloric acid solution (HCl, 3×200 mL). The combined aqueous solution was then treated with activated charcoal (20 g) and stirred at room temperature for 30 min. The mixture was filtered through a celite bed and the filtrate was cooled to 0-5° C. with an ice-water bath. A solution of 50% of sodium hydroxide in water (NaOH, 240 mL, 4500 mmol) was added dropwise at 5-12° C. to adjust pH to 10.6-11.6. The mixture was stirred at 0-5° C. for 30 min and then filtered. The solids collected were washed with aqueous ammonium hydroxide (1 to 3 of 28% concentrated NH4OH to water, 1900 mL) and dried under vacuum at 40-45° C. to constant weight to afford 4-(3-amino-1,2,4-triazin-6-yl)-2-fluorobenzonitrile (20, 101.2 g, 122.9 g theoretical, 82.3% yield) as a off-white powder. For 20: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.94 (s, 1H), 8.12 (d, 1H, J=11.41 Hz), 8.08-8.00 (m, 2H), 7.71 (br s, 2H); C10H6FN5 (MW 215.19), LCMS (EI) m/e 215.9 (M++H).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12][CH2:13][CH2:14]OS(C)(=O)=O)=[CH:8][C:7]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([F:28])[CH:21]=3)=[N:6]2)[CH2:3][CH2:2]1.[NH:29]([CH2:33][CH2:34][OH:35])[CH2:30][CH2:31][OH:32]>>[OH:32][CH2:31][CH2:30][N:29]([CH2:14][CH2:13][CH2:12][C:9]1[C:10](=[O:11])[N:5]([CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:6]=[C:7]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([F:28])[CH:21]=2)[CH:8]=1)[CH2:33][CH2:34][OH:35]
Reactant: OCCNCCO
Reactant: COc1ccc(-c2cc(CCCOS(C)(=O)=O)c(=O)n(CC3CC3)n2)cc1F
Product: COc1ccc(-c2cc(CCCN(CCO)CCO)c(=O)n(CC3CC3)n2)cc1F
Yield: 13.1 %

Procedure:
Following the procedure of Example 1(10), 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(3-methanesulfonyloxypropyl)-2H-pyridazin-3-one and diethanolamine were reacted to yield the title compound as a yellow oil (yield: 13.1%).