Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[N:14]=[C:13]([O:15][CH2:16][CH:17]3[CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]3)[C:12]([C:28]3[CH:33]=[CH:32][C:31]([N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)=[CH:30][CH:29]=3)=[CH:11][N:10]=2)[CH2:4][CH2:3]1.C(O)(C(F)(F)F)=O>>[NH:19]1[CH2:18][CH:17]([CH2:16][O:15][C:13]2[C:12]([C:28]3[CH:29]=[CH:30][C:31]([N:34]4[CH2:35][CH2:36][O:37][CH2:38][CH2:39]4)=[CH:32][CH:33]=3)=[CH:11][N:10]=[C:9]([NH:8][C@H:5]3[CH2:6][CH2:7][C@@H:2]([CH3:1])[CH2:3][CH2:4]3)[N:14]=2)[CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CC(COc2nc(N[C@H]3CC[C@@H](C)CC3)ncc2-c2ccc(N3CCOCC3)cc2)C1
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1CC[C@@H](Nc2ncc(-c3ccc(N4CCOCC4)cc3)c(OCC3CNC3)n2)CC1

Procedure:
Using the procedure of Example 1 Step 4, tert-butyl 3-((2-(cis-4-methylcyclohexylamino)-5-(4-morpholinophenyl)pyrimidin-4-yloxy)methyl)azetidine-1-carboxylate was deprotected by TFA to provide the title compound at quantitative yield. 1H NMR (CDCl3, 400 MHz) 8.02 (s, 1H), 7.32 (d, 2H), 6.87 (d, 2H), 5.24 (sb, 1H), 4.42 (d, 2H), 4.05 (m, 1H), 3.82-3.80 (m, 4H), 3.65 (m, 2H), 3.50 (m, 2H), 3.14-3.11 (m, 4H), 3.05 (bs 1H), 3.03-2.97 (m, 1H), 1.79-1.48 (m, 6H), 1.23-1.18 (m, 3H), 0.88 (d, 3H); MS (ESI) m/z: Calc: 437.3 (M+). Found. 438.3 (M+1).
Reaction SMILES: [CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[NH:11][C:10](/[CH:15]=[CH:16]/[C:17]3[N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:19]=[N:20][CH:21]=3)=[N:9][C:8]=2[N:7]([CH2:41][CH2:42][CH3:43])[C:5]1=[O:6])[CH2:2][CH3:3].Cl.[CH3:45]O>>[CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[N:11]([CH3:45])[C:10](/[CH:15]=[CH:16]/[C:17]3[N:18]=[CH:19][NH:20][CH:21]=3)=[N:9][C:8]=2[N:7]([CH2:41][CH2:42][CH3:43])[C:5]1=[O:6])[CH2:2][CH3:3]
Reactant: CO
Reactant: CCCn1c(=O)c2[nH]c(/C=C/c3cncn3C(c3ccccc3)(c3ccccc3)c3ccccc3)nc2n(CCC)c1=O
Agent: Cl
Product: CCCn1c(=O)c2c(nc(/C=C/c3c[nH]cn3)n2C)n(CCC)c1=O
Temperature: 50 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
The same procedure as in Example 2 was repeated using 1.96 g (3.44 mmol) of the mixture of Compound l and Compound m to give a crude product. The crude product was dissolved in 50 ml of methanol, and 1.5 ml of 1N hydrochloric acid was added to the solution, followed by stirring at 50° C. for 2 hours. After the solution was concentrated to about a half of its original volume, the concentrate was adjusted to pH 4 and extracted six times with chloroform. The organic layers were combined and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 10% methanol/chloroform) to give 640 mg (overall yield: 55%) of Compound 21 as an amorphous substance. The obtained Compound 21 (2.00 g) was treated with a hydrogen chloride/methanol solution and then recrystallized from isopropanol to give 1.04 g of hydrochloride of Compound 21.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)Br.[F:25][C:26]1[C:31]([CH:32]([CH3:34])[CH3:33])=[CH:30][C:29]([C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][C:36]=2CO)=[C:28]([O:47][CH3:48])[C:27]=1[OH:49]>C(Cl)Cl>[Br:24][CH2:20][C:36]1[CH:37]=[C:38]([C:41]([F:44])([F:42])[F:43])[CH:39]=[CH:40][C:35]=1[C:29]1[CH:30]=[C:31]([CH:32]([CH3:34])[CH3:33])[C:26]([F:25])=[C:27]([OH:49])[C:28]=1[O:47][CH3:48]
Reactant: BrC(Br)(Br)Br
Reactant: COc1c(-c2ccc(C(F)(F)F)cc2CO)cc(C(C)C)c(F)c1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1c(-c2ccc(C(F)(F)F)cc2CBr)cc(C(C)C)c(F)c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of triphenylphosphine (102.8 mg, 0.392 mmol) in dry CH2Cl2 (2 mL) was added by cannula to a stirred solution of carbon tetrabromide (130 mg, 0.392 mmol) and 4-fluoro-2′-(hydroxymethyl)-5-isopropyl-2-methoxy-4′-(trifluoromethyl)biphenyl-3-ol (58.5 mg, 0.163 mmol) in dry CH2Cl2 (2 mL) at 0° C. under N2 and the reaction was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 12×160 mm, 0-40% EtOAc in hexanes gradient) to afford 2′-(bromomethyl)-4-fluoro-5-isopropyl-2-methoxy-4′-(trifluoromethyl)biphenyl-3-ol. Rf=0.55 (20% EtOAc in hexanes). 1H NMR (600 MHz, CDCl3) δ 7.84 (s, 1H), 7.61 (d, J=7.9 Hz, 1H), 7.42 (d, J=8.0 Hz, 1H), 6.69 (d, J=7.8 Hz, 1H), 5.59 (s, 1H), 4.50 (d, J=9.6 Hz, 1H), 4.39 (d, J=9.7 Hz, 1H), 3.47 (s, 3H), 3.29-3.23 (m, 1H), 1.27 (d, J=6.9 Hz, 6H).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[Si:9]([O:26][CH2:27][C@@H:28]([N:31]1[C@H:36]([C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=2)[C@@H:35]([C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([Cl:50])[CH:45]=2)[CH2:34][C@@:33](/[CH:52]=[CH:53]/[C:54]([O:56][CH3:57])=[O:55])([CH3:51])[C:32]1=[O:58])[CH2:29][CH3:30])([C:22]([CH3:25])([CH3:24])[CH3:23])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[S].[I-]>C1COCC1.CS(C)=O>[Si:9]([O:26][CH2:27][C@@H:28]([N:31]1[C@H:36]([C:37]2[CH:38]=[CH:39][C:40]([Cl:43])=[CH:41][CH:42]=2)[C@@H:35]([C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([Cl:50])[CH:45]=2)[CH2:34][C@@:33]([CH:52]2[CH2:4][CH:53]2[C:54]([O:56][CH3:57])=[O:55])([CH3:51])[C:32]1=[O:58])[CH2:29][CH3:30])([C:22]([CH3:25])([CH3:24])[CH3:23])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N1C(=O)[C@@](C)(/C=C/C(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N1C(=O)[C@@](C)(C2CC2C(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of sodium hydride (12 mg, 0.30 mmol, 60% dispersion in oil) in THF (1.0 mL) under an argon atmosphere was added trimethylsulfoxonium iodide (72 mg, 0.33 mmol) portionwise over 1 minute. The reaction was stirred at rt for 1 hour. A solution of (E)-methyl 3-((3R,5R,6S)-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acrylate (120 mg, 0.165 mmol; Example 248, Step D) in DMSO (1.0 mL) was added dropwise over 1 minute. The reaction was stirred at rt overnight. After this time more sulfur ylide was synthesized by suspending trimethylsulfoxonium iodide (140 mg) in DMSO (0.5 mL) under a nitrogen atmosphere and treating the mixture with NaH (24 mg, 60% dispersion in oil) and stirring for 30 minutes. The sulfur ylide was then added to the reaction and the mixture was stirred at rt for 16 hours After this time more sulfur ylide was synthesized by suspending trimesulfoxonium iodide (140 mg) in DMSO (0.5 mL) under a nitrogen atmosphere and treating the mixture with NaH (24 mg, 60% dispersion in oil) and stirring for 30 minutes. The sulfur ylide was then added to the reaction and the mixture was stirred at rt for 16 hours. The reaction was partitioned between ethyl acetate (70 mL) and NH4Cl (30 mL, saturated aqueous solution). The separated organic layer was dried over MgSO4, filtered and evaporated in vacuo. Purification by reverse phase HPLC (Sunfire Prep C18 OBD 10 μm column, gradient elution of 40% MeCN in water to 100% MeCN in water over a 40 min period, where both solvents contain 0.1% TFA) gave the title compound as the first eluting and major diastereomer. Stereochemistry at the cyclopropane is a single but unassigned diastereomer. Mass Spectrum (ESI) m/z=742.2 (M+1).
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][O:6][C@H:7]([CH2:17][CH:18]=[CH2:19])[CH2:8][O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)C.Cl>O1CCCC1>[CH2:10]([O:9][CH2:8][C@H:7]([O:6][CH2:5][CH:4]=[O:3])[CH2:17][CH:18]=[CH2:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C=CC[C@H](COCc1ccccc1)OCC(OCC)OCC
Agent: Cl
Solvent: C1CCOC1
Product: C=CC[C@H](COCc1ccccc1)OCC=O
Temperature: 75 °C

Procedure:
({[(2R)-2-(2,2-Diethoxyethoxy)pent-4-en-1-yl]oxy}methyl)benzene (C2) (10.14 g, 32.88 mmol) was dissolved in tetrahydrofuran (110 mL). Aqueous hydrochloric acid (2 M, 19.5 mL, 39.0 mmol) was added, and the reaction mixture was heated at 75° C. for 1 hour. The reaction was concentrated to approximately half the original volume and then partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The product was obtained as a colorless oil, which was used directly in the following step. Yield: 7.76 g. 1H NMR (400 MHz, CDCl3) δ 2.28-2.42 (m, 2H), 3.54-3.57 (m, 2H), 3.62-3.68 (m, 1H), 4.18-4.28 (m, 2H), 4.53 (br s, 2H), 5.06-5.15 (m, 2H), 5.78-5.89 (m, 1H), 7.27-7.39 (m, 5H), 9.72 (t, J=1.0 Hz, 1H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[OH:9][N:10]=[CH:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1>C(Cl)Cl>[OH:9][N:10]=[C:11]([Br:1])[C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1
Reactant: N#Cc1ccc(C=NO)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: N#Cc1ccc(C(Br)=NO)cc1
Temperature: 25 °C

Procedure:
The compound was prepared according to Tanaka et al. Bull. Chem. Soc. Jpn. 1984, 57, 2184. A 0.05M solution of N-bromosuccinimide (724 mg, 4.07 mmol, 1.20 eq) in CH2Cl2 was added dropwise to a 0° C. solution of 4-(hydroxyiminomethyl)-benzonitrile (496 mg, 3.39 mmol, 1.00 eq) in CH2Cl2 (50 mL). The solution was warmed to room temperature before being volumetrically partitioned between two different reaction vials. Each vial was then concentrated and the crude residues were used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](/[CH:12]=[CH:13]/[C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]4[CH2:22][O:21]4)[CH:15]=3)=[N:9]2)=[CH:4][CH:3]=1.[OH:23][C:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[OH:33])([CH3:26])[CH3:25].C(=O)([O-])[O-].[K+].[K+].C(O)(=O)C>CN(C=O)C.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](/[CH:12]=[CH:13]/[C:14]3[CH:15]=[C:16]([CH:20]([OH:21])[CH2:22][O:33][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[C:24]([OH:23])([CH3:26])[CH3:25])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(O)c1ccccc1O
Reactant: Clc1ccc2ccc(/C=C/c3cccc(C4CO4)c3)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(O)c1ccccc1OCC(O)c1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Temperature: 125 °C
Reaction time: 8 h
Yield: 46.7 %

Procedure:
To a stirred solution of epoxide 30 (10.0 g, 32.57 mmol) in DMF (30 ml) was added alcohol 31 (7.425 g, 48.85 mmol), potassium carbonate (8.99 g, 65.14 mmol). The reaction mixture was stirred overnight at 120-130° C. The resulted mixture was treated with 10% aq. acetic acid, diluted further with water followed by usual workup in ethyl acetate and FC to give diol 32 (7.0 g, 46%).
Reaction SMILES: [CH:1]1([C:4]2[N:14]([CH2:15][C:16]3[S:20][C:19]([C:21]4([C:26]([OH:28])=[O:27])[CH2:25][CH:24]=[CH:23][CH2:22]4)=[CH:18][CH:17]=3)[C:7]3=[N:8][C:9]([CH3:13])=[CH:10][C:11]([CH3:12])=[C:6]3[N:5]=2)[CH2:3][CH2:2]1.[CH3:29][S:30]([NH2:33])(=[O:32])=[O:31]>>[CH3:29][S:30]([NH2:33])(=[O:32])=[O:31].[CH:1]1([C:4]2[N:14]([CH2:15][C:16]3[S:20][C:19]([C:21]4([C:26]([OH:28])=[O:27])[CH2:25][CH:24]=[C:23]=[CH:22]4)=[CH:18][CH:17]=3)[C:7]3=[N:8][C:9]([CH3:13])=[CH:10][C:11]([CH3:12])=[C:6]3[N:5]=2)[CH2:2][CH2:3]1
Reactant: Cc1cc(C)c2nc(C3CC3)n(Cc3ccc(C4(C(=O)O)CC=CC4)s3)c2n1
Agent: CS(N)(=O)=O
Product: Cc1cc(C)c2nc(C3CC3)n(Cc3ccc(C4(C(=O)O)C=C=CC4)s3)c2n1

Procedure:
The title compound was prepared from the product of Example 3, above, by the method of Example 25, except that methanesulfonamide was used in place of benzenesulfonamide.
Reaction SMILES: C(O)C.[C:4]([N:7]1[CH2:12][CH2:11][CH:10]([CH2:13][C:14](=[O:24])[C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=2)[CH2:9][CH2:8]1)(=[O:6])[CH3:5].[BH4-].[Na+]>ClCCl.O>[C:4]([N:7]1[CH2:12][CH2:11][CH:10]([CH2:13][CH:14]([OH:24])[C:15]2[CH:16]=[CH:17][C:18]([N:21]([CH3:22])[CH3:23])=[CH:19][CH:20]=2)[CH2:9][CH2:8]1)(=[O:6])[CH3:5]
Reactant: CC(=O)N1CCC(CC(=O)c2ccc(N(C)C)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: CC(=O)N1CCC(CC(O)c2ccc(N(C)C)cc2)CC1

Procedure:
In a solvent mixture of 60 ml of ethanol and 30 ml of water was dissolved 2.93 g of 1-acetyl-4-(4-dimethylaminobenzoylmethyl)piperidine prepared in Example 39, and at room temperature, 1 g of sodium borohydride was gradually added. The reaction mixture was diluted with dichloromethane and water for distiribution and the dichloromethane layer was dried over anhydrous magnesium sulfate. The solvent was then distilled off and the oily residue was purified by silica gel column chromatography (eluent: ethyl acetate) to give a pale yellow solid melting at 119°-120° C.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][C:6](=O)[CH2:5][CH2:4][C@@H:3]1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[C:14]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:17])[NH:15][NH2:16].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CC(O)=O>[CH2:12]([O:11][C:9]([C@H:3]1[CH2:4][CH2:5][C@@H:6]([NH:16][NH:15][C:14]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:7][C@H:2]1[CH3:1])=[O:10])[CH3:13]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CCOC(=O)[C@H]1CCC(=O)C[C@H]1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)[C@H]1CC[C@@H](NNC(=O)OC(C)(C)C)C[C@H]1C
Reaction time: 0.17 h
Yield: 52.1 %

Procedure:
To a 500-mL 3-neck round-bottomed flask was added (1S,2R)-ethyl 2-methyl-4-oxocyclohexanecarboxylate (10.00 g, 54.3 mmol) in chloroform (201 ml). Then AcOH, glacial (3.13 ml, 54.3 mmol), and tert-butyl carbazate (7.89 g, 59.7 mmol) was added into the reaction mixture. The flask was placed into a pre-heated bath (30° C.) and allowed to stir 10 min. Then NaBH(OAc)3 (34.5 g, 163 mmol) was slowly added into the reaction mixture in small portions. The bath was removed after the addition and the overall mixture was allowed to stir under inert atmosphere 16 h. The progress of the reaction was monitored by LC/MS and TLC (30% EtOAc/DCM; Ninhydrin stain) which suggested reaction completion. The mixture was neutralized with the slow addition of sat. aq. NaHCO3 into the reaction mixture. After the material was neutralized, the layers were separated and the aqueous layer was extracted with DCM (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in-vacuo. The crude sample was analyzed by TLC (30% EtOAc/hexane; ninhydrin stain; Peak 1: Rf=0.46 & Peak 2: Rf=0.38) The crude material was divided into two portions and purified by chromatography through an Interchim (25 micron) silica-gel column (300 g)*(Two 300 Gram Columns were used), eluting with a gradient of 0-30% EtOAc in hexane, to provide tert-butyl 2-((1R,3R,4S)-4-(ethoxycarbonyl)-3-methylcyclohexyl)hydrazinecarboxylate (8.512 g, 28.3 mmol, 52.2% yield) (Peak 1; Cis)1H NMR (400 MHz, CDCl3) δ 6.03-6.28 (m, 1H), 4.07-4.16 (m, 2H), 3.59-3.90 (m, 1H), 2.76-2.97 (m, 1H), 2.55 (d, J=2.74 Hz, 1H), 2.01 (dd, J=3.03, 13.40 Hz, 1H), 1.59-1.77 (m, 3H), 1.49-1.56 (m, 2H), 1.46 (s, 10H), 1.19-1.31 (m, 3H), 1.02 (d, J=7.04 Hz, 3H); LCMS (ESI) m/z 301.1 (M+H)+ and tert-butyl 2-((1S,3R,4S)-4-(ethoxycarbonyl)-3-methylcyclohexyl)hydrazinecarboxylate (5.089 g, 16.94 mmol, 31.2% yield) (Peak 2; trans)1H NMR (400 MHz, DMSO-d6) δ 7.89-8.27 (m, 1H), 5.75 (s, 1H), 4.08-4.19 (m, 1H), 2.74-2.93 (m, 1H), 2.21-2.46 (m, 2H), 1.99 (s, 1H), 1.66 (d, J=3.91 Hz, 3H), 1.38 (s, 9H), 1.14-1.26 (m, 5H), 0.79 (d, J=7.04 Hz, 3H); LCMS (ESI) m/z 301.1 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[NH2:32][CH2:33][CH:34]([OH:37])[CH2:35][OH:36].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:37][CH:34]([CH2:35][OH:36])[CH2:33][NH:32][C:3](=[O:5])[CH:2]([OH:1])[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:18]=3[C:28]([F:30])([F:29])[F:31])[O:14][N:13]=2)=[CH:8][CH:7]=1
Reactant: NCC(O)CO
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(NCC(O)CO)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 31.4 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 30 mg, 0.070 mmol), (R/S)-3-aminopropane-1,2-diol (9.51 mg, 0.104 mmol), 4-methylmorpholine (28.1 mg, 0.278 mmol), and HATU (34.4 mg, 0.090 mmol) were dissolved in DMF (1 mL). The mixture was stirred for 1 h and then purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×250 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 30 min, 25 mL/min, 220 nM, product retention=28.9 min) to provide (R/S)-N-(2,3-dihydroxypropyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (15 mg, 0.022 mmol, 32.1% yield): LCMS=505.1 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.17 (2 H, d, J=8.35 Hz), 7.50-7.81 (7 H, m), 5.15 (1 H, s), 3.65-3.79 (1 H, m), 3.41-3.52 (2 H, m), 3.23-3.39 (2 H, m); HPLC peak RT=7.9 min (Method A).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]=[O:8])=[CH:5][N:4]=[C:3]1[CH3:9].C(=O)([O-])[O-].[K+].[K+].[F:16][C:17]([Si](C)(C)C)([F:19])[F:18]>CN(C)C=O>[CH3:1][N:2]1[C:6]([CH:7]([OH:8])[C:17]([F:19])([F:18])[F:16])=[CH:5][N:4]=[C:3]1[CH3:9]
Reactant: Cc1ncc(C=O)n1C
Reactant: C[Si](C)(C)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ncc(C(O)C(F)(F)F)n1C
Yield: 58.6 %

Procedure:
According to Reference Example 8-2, by use of 1,2-dimethyl-1H-imidazole-5-carbaldehyde (125 mg, 1.01 mmol) dissolved in N,N-dimethylformamide (2.5 mL), potassium carbonate (28 mg, 0.20 mmol) and (trifluoromethyl)trimethylsilane (0.358 mL, 2.42 mmol), the mixture was stirred and reacted at a temperature of room temperature to 50° C. for 2.8 hours. Then, purification by preparative thin-layer chromatography (chloroform/methanol=15/1) was performed to give 1-(1,2-dimethyl-1H-imidazol-5-yl)-2,2,2-trifluoroethanol (Compound DZ) (115 mg, yield: 59%).
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:8][NH:7][CH2:6][C@@H:5]([CH2:9][N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])[CH2:4]1.[CH3:21][O:22][C:23]1[CH:24]=[CH:25][C:26]2[N:31]=[CH:30][C:29](=[O:32])[N:28]([CH2:33][CH:34]=O)[C:27]=2[N:36]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO.C(Cl)(Cl)Cl>[CH3:1][O:2][CH:3]1[CH2:8][N:7]([CH2:34][CH2:33][N:28]2[C:29](=[O:32])[CH:30]=[N:31][C:26]3[CH:25]=[CH:24][C:23]([O:22][CH3:21])=[N:36][C:27]2=3)[CH2:6][CH:5]([CH2:9][N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])[CH2:4]1
Reactant: CO[C@H]1CNC[C@@H](CN2C(=O)c3ccccc3C2=O)C1
Reactant: COc1ccc2ncc(=O)n(CC=O)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccc2ncc(=O)n(CCN3CC(CN4C(=O)c5ccccc5C4=O)CC(OC)C3)c2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 55 %

Procedure:
To cis-2-{[(3RS,5SR)-5-(methyloxy)-3-piperidinyl]methyl}-1H-isoindole-1,3(2H)-dione (125 mg, 0.43 mmol) in MeOH (1 ml) and CHCl3 (5 ml) was added [6-(methyloxy)-3-oxopyrido[2,3-b]pyrazin-4(3H)-yl]acetaldehyde (for a preparation see Example 126(e)) (100 mg; 0.50 mmol) and the reaction was allowed to stir at room temperature under N2 for 4 hours. Na(OAc)3BH (210 mg; 1.0 mmol) was added and the reaction was allowed to stir at room temperature under nitrogen for an additional 14 hours. The reaction was partitioned between saturated aqueous NaHCO3 (5 mL) and CH2Cl2 (20 mL), the aqueous layer was further extracted with CH2Cl2 (20 mL), and the combined organic layers were dried over Na2SO4. The solvents were removed and the crude residue was purified by chromatography on silica gel using a 0-10% MeOH/DCM gradient to provide the desired compound (10 mg; 55%) as a colorless oil.
Reaction SMILES: [NH:1]=[C:2]1[NH:6][C:5]([C:11]([F:14])([F:13])[F:12])([C:7]([F:10])([F:9])[F:8])[C:4](=[C:15]([F:20])[C:16]([F:19])([F:18])[F:17])[S:3]1.C(N(CC)CC)C.[F:28][C:29]([F:40])([F:39])[C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1>C1(C)C=CC=CC=1>[F:28][C:29]([F:39])([F:40])[C:30]1[CH:38]=[CH:37][C:33]([C:34]([NH:1][C:2]2[S:3][C:4](=[C:15]([F:20])[C:16]([F:17])([F:18])[F:19])[C:5]([C:7]([F:10])([F:9])[F:8])([C:11]([F:12])([F:13])[F:14])[N:6]=2)=[O:35])=[CH:32][CH:31]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: N=C1NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(NC1=NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1)c1ccc(C(F)(F)F)cc1
Temperature: 103 °C
Reaction time: 3 h

Procedure:
In toluene (40 ml) were dissolved 2-imino-4,4-bis(trifluoromethyl)-5-(tetrafluoroethylidene)-1,3-thiazolidine (2.0 g) and triethylamine (1.0 ml), and a solution of 4-trifluoromethylbenzoyl chloride (1.5 g) dissolved in toluene (10 ml) was gradually added thereto under cooling and the mixture was stirred at 103° C. for 3 hours.
Reaction SMILES: [CH3:1][C@@H:2]1[O:6][C:5](=[O:7])[C@H:4]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C@H:3]1[O:16][Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19].CC(C[AlH]CC(C)C)C>C(Cl)Cl>[CH2:8]([C@H:4]([C@@H:3]([O:16][Si:17]([CH:21]([CH3:23])[CH3:22])([CH:24]([CH3:26])[CH3:25])[CH:18]([CH3:19])[CH3:20])[C@@H:2]([OH:6])[CH3:1])[CH2:5][OH:7])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)[Si](O[C@H]1[C@H](C)OC(=O)[C@@H]1CCc1ccccc1)(C(C)C)C(C)C
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: CC(C)[Si](O[C@H]([C@H](CO)CCc1ccccc1)[C@H](C)O)(C(C)C)C(C)C
Temperature: -78 °C
Reaction time: 8 h
Yield: 69.2 %

Procedure:
To an oven-dried flask were added (3R,4R,5S)-5-methyl-3-phenethyl-4-((triisopropyl-silyl)oxy)dihydrofuran-2(3H)-one (670 mg, 1.601 mmol) and CH2Cl2 (8 mL)) and the mixture was cooled to −78° C. and treated with DIBAL-H (1.0 M in CH2Cl2, 4.00 mL, 4.00 mmol) dropwise over 10 min. The dry ice/acetone bath was removed and the mixture allowed to warm to room temperature while stirring overnight. The reaction was cooled to 0° C. and quenched by addition of saturated potassium sodium tartrate solution (50 mL). The mixture was diluted with CH2Cl2 (25 mL) and stirred until two clean-splitting phases were formed. The phases were separated, and the aqueous extracted further with CH2Cl2. The combined organic extracts were dried and concentrated to a colorless oil which was purified by flash chromatography (SiO2, 030% EtOAc/hexanes) to give (2S,3R,4S)-2-phenethyl-3-((triisopropylsilyl)oxy)pentane-1,4-diol (422 mg, 69%): 1H NMR (400 MHz, CDCl3) δ 7.30-7.23 (m, 2H), 7.21-7.14 (m, 3H), 4.02-3.92 (m, 2H), 3.77 (dd, J=4.3, 3.1 Hz, 1H), 3.72-3.61 (m, 1H), 3.18 (s, 1H), 2.92-2.76 (m, 2H), 2.62-2.51 (m, 1H), 2.10-1.96 (m, 1H), 1.80-1.62 (m, 2H), 1.27 (d, J=6.7 Hz, 3H), 1.07-0.93 (m, 21H); 13C NMR (101 MHz, CDCl3) δ 141.94, 128.48, 128.36, 125.86, 78.18, 71.24, 59.48, 45.39, 34.24, 29.69, 18.64, 18.14, 18.10, 12.54; ESIMS m/z 403 ([M+Na]+).