Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:17]([C@:27]([C:44]([OH:46])=[O:45])([OH:43])[C@:28]([C:33](=[O:42])[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)([OH:32])[C:29]([OH:31])=[O:30])(=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1>CC(=O)CC>[C:33]([C@:28]([C:29]([OH:31])=[O:30])([OH:32])[C@:27]([C:17](=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)([OH:43])[C:44]([OH:46])=[O:45])(=[O:42])[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1.[Cl:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OCCC1(c2ccc(Cl)c(Cl)c2)CCNC1
Agent: COc1ccc(C(=O)[C@@](O)(C(=O)O)[C@](O)(C(=O)O)C(=O)c2ccc(OC)cc2)cc1
Solvent: CCC(C)=O
Product: OCC[C@]1(c2ccc(Cl)c(Cl)c2)CCNC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Combine 3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine (1.0 g, 38.5 mmol) and butanone. Add a solution of (R,R)-di-p-anisoyltartaric acid (1.6 g, 38.0 mmol) in butanone (80 mL). Heat to reflux. After 15 minutes, cool to ambient temperature and then cool further in an salt-ice bath. Filter the solid that forms and rinse with butanone. Recrystallize the solid from water/methanol to give (S)-(-)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt: mp; 201°-204° C. (dec). [α]2D0 =-18.9°(c=0.60, dimethylsulfoxide). X-ray diffraction analysis of a single crystal confirms the (S)-configuration. Analysis on HPLC, on an analytical sample of the free amine obtained by extraction, using a CHIRALPAK AD 25 cm×0.46 cm column eluting with pentane/methanol/triethylamine (80/10/0.1) with a flow rate of 1.0 mL/minute indicates an enantiomeric excess of 96%, (96% ee), retention time of the (S)-isomer 11.2 minutes, retention time of the (R)-isomer 14.5 minutes.
Reaction SMILES: [OH:1][CH:2]([CH:9]([CH3:13])[CH2:10][CH2:11][CH3:12])[CH:3]([CH3:8])[C:4]([O:6][CH3:7])=[O:5].[O:14]1[CH:19]=[CH:18][CH2:17][CH2:16][CH2:15]1.C(Cl)Cl>O1CCCC1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[CH3:8][CH:3]([CH:2]([O:1][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][O:14]1)[CH:9]([CH3:13])[CH2:10][CH2:11][CH3:12])[C:4]([O:6][CH3:7])=[O:5]
Reactant: C1=COCCC1
Reactant: CCCC(C)C(O)C(C)C(=O)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCC(C)C(OC1CCCCO1)C(C)C(=O)OC
Reaction time: 8 h
Yield: 121.2 %

Procedure:
200 mg (1.06 mmol) of methyl (+)-3-hydroxy-2,4-dimethylheptanoate (+)-(4) was dissolved in 4 ml of tetrahydrofuran, and 134 mg (1.59 mmol) of dihydropyran and 1 mg of pyridinium p-toluenesulfonate were added, and the mixture was reacted overnight at room temperature. Since TLC (Thin Layer Chromatography) showed that the starting materials still remained, 5 mg of pyridinium p-toluenesulfonate and 3 ml of methylene chloride were added, and the reaction was further carried out overnight at room temperature. The reaction mixture was extracted with ether. The ethereal layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and then with an aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, filtered, and concentrated to give 350 mg of crude methyl (+)-2,4-dimethyl-3-tetrahydropyranyloxy-1-heptanoate.
Reaction SMILES: [BH4-].[Na+].CS(O)(=O)=O.[O:8]=[C:9]([N:23]1[CH2:28][CH2:27][N:26]2[C:29]([C:32]([F:35])([F:34])[F:33])=[N:30][N:31]=[C:25]2[CH2:24]1)[CH:10]=[C:11]([NH2:22])[CH2:12][C:13]1[CH:18]=[C:17]([F:19])[C:16]([F:20])=[CH:15][C:14]=1[F:21].N>O.CC(O)C.C1COCC1>[O:8]=[C:9]([N:23]1[CH2:28][CH2:27][N:26]2[C:29]([C:32]([F:35])([F:34])[F:33])=[N:30][N:31]=[C:25]2[CH2:24]1)[CH2:10][CH:11]([NH2:22])[CH2:12][C:13]1[CH:18]=[C:17]([F:19])[C:16]([F:20])=[CH:15][C:14]=1[F:21]
Reactant: NC(=CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Agent: CS(=O)(=O)O
Agent: N
Agent: [BH4-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: NC(CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Temperature: -12.5 °C
Reaction time: 0.75 h

Procedure:
In a 250 mL round bottom flask THF (75 mL) was taken. It was cooled to −15 to −10° C. and NaBH4 (1.87 g) was added. After that methanesulfonic acid (11.8 g) was added dropwise at −15 to −10° C. over a period of 30-45 min. 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)but-2-en-2-amine (10.0 g) is mixed in a solvent mixture of THF and IPA and added into the reaction mixture, keeping the temperature −10 to −5° C. It was stirred for 30-60 min. at −10 to −5° C. Reaction mixture was poured into cold water. It was basified by adding aq. ammonia solution. Product was extracted in ethyl acetate. The organic layer was collected. It was washed with water and dried over anhydrous sodium sulfate. Solvent was evaporated at reduced pressure to obtain the product. (Wt.-9.15 g; % Y-91%; % Purity by HPLC-88.6%).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][CH:12]=[C:11]3[C:17](=O)[CH2:18][C@@H:19]2[CH2:23][CH2:22][CH2:21][N:20]2[C:24](OCC2C=CC=CC=2)=O)[C:4]([CH3:7])=[CH:5][CH:6]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].N>C1COCC1.CO.C(Cl)Cl>[CH3:1][C:2]1[N:3]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][CH:12]=[C:11]3[CH2:17][CH2:18][C@@H:19]2[CH2:23][CH2:22][CH2:21][N:20]2[CH3:24])[C:4]([CH3:7])=[CH:5][CH:6]=1
Reactant: Cc1ccc(C)n1-c1ccc2[nH]cc(C(=O)C[C@@H]3CCCN3C(=O)OCc3ccccc3)c2c1
Agent: N
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc(C)n1-c1ccc2[nH]cc(CC[C@@H]3CCCN3C)c2c1
Temperature: 75 °C

Procedure:
To an argon purged round bottom flask fitted with a magnetic stirbar and containing a solution 144 (210 mg, 0.461 mmol) in anhydrous THF (5 mL) was added lithium aluminum hydride (79 mg, 2.08 mmol). The flask was fitted with a condenser and placed in an oil bath. The reaction was heated to 75° C. and stirred at reflux with an argon flow for 4.5 hrs. The reaction was revealed to be complete by TLC (10% 2M NH3 in MeOH, 90% CH2Cl2) and was cooled gradually to room temperature. The reaction was quenched by the addition of water (0.2 mL), 3N sodium hydroxide (0.3 mL) and water (0.6 mL). The react was filtered through celite and partitioned with ethyl acetate (10 mL). The aqueous layer was extracted twice more with ethyl acetate (2×10 mL). The combined organics were washed with brine, dried over sodium sulfate and concentrated after decanting to afford a brown oil. The product was purified by silica gel column chromatography (1:1 Ethyl acetate/Hexanes to 5% 2M NH3 in MeOH, 95% CH2Cl2) to afford the desired product as a yellow oil, compound 145. Yield: 105 mg (71%). 1H NMR (CDCl3) δ 8.09 (bs, 1H), 7.44-7.43 (d, 1H, J=1.5 Hz), 7.41-7.38 (d, 1H, 8.7 Hz), 7.08 (d, 1H, J=2.1 Hz), 7.03-7.00 (dd, 1H, J=1.8, 8.1 Hz), 5.91 (bs, 2H), 3.49 (s, 1H), 3.15-3.10 (m, 2H), 2.86-2.65 (m, 3H), 2.34 (s, 4H), 2.03 (bs, 6H), 1.90-1.52 (m, 4H). MS-ESI (m/z, %) 322 (M+, 100)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1.[CH3:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][NH2:22].C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([NH:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[CH3:18])[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1
Reactant: Cc1ccccc1CN
Reactant: CS(=O)c1nc(N)nc(-n2cccn2)c1C#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: Cc1ccccc1CNc1nc(N)nc(-n2cccn2)c1C#N

Procedure:
From 2-amino-4-methanesulfinyl-6-pyrazol-1-yl-pyrimidine-5-carbonitrile, 2-methyl-benzylamine and DBU in DME. ES-MS m/e (%): 328 (M+Na+, 35), 306 (M+H+, 100).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][C:8](O)=[O:9].O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH2:8][OH:9]
Reactant: O=C(O)CCc1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: OCCCc1cccs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 103.5 %

Procedure:
To a solution of 3-(2-thienyl)propionic acid (5.0 g, 32.0 mmol) in tetrahydrofuran (20 ml) at 0° C. was added 1 M borane tetrahydrofuran complex (33.5 ml, 33.5 mmol) dropwise over 30 minutes. The reaction mixture was then stirred for 18 h whilst warming to room temperature. The temperature was then reduced to 0° C. and water (20 ml) was added to quench the reaction. The solution was then basified with potassium carbonate, the layers separated and the aqueous layer washed with diethyl ether. The combined organic layers were washed with brine, dried and concentrated to yield the title compound (4.71 g) as an oil. DCI MS m/z 142 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]([C:18]([O:20]C)=[O:19])=[N:10]2)=[CH:5][CH:4]=1.S(=O)(=O)(O)O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]([C:18]([OH:20])=[O:19])=[N:10]2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1cc(C(=O)OC)n(-c2ccc(OC)cc2)n1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cc(C(=O)O)nn1-c1ccc(OC)cc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 63.2 %

Procedure:
To a solution of dimethyl 1-[(4-methoxy)phenyl]pyrazole-3,5-dicarboxylate (32.7 g, 110 mmol) in 50 mL of dioxane and 100 mL of water was added concentrated sulfuric acid (1.50 mL, 28.2 mmol). The resulting solution was stirred at 100° C. for 18 h and then cooled to room temperature. The reaction was made basic with potassium carbonate and then extracted with ether to remove unreacted diester. The aqueous layer was acidified with HCl and was extracted twice with ethyl acetate. The combined organics were washed with brine, dried (MgSO4) and concentrated to afford 19.2 g (63%) of the title compound along with 5.0 g (15%) of unreacted starting material. The title compound was used without further purification. LRMS (ES−): 274.9 (M−H)−.
Reaction SMILES: C(O)=O.[CH2:4]([C:6]1[CH:11]=[C:10]([C:12]2[N:16]=[C:15]([C:17]3[S:18][C:19]([CH2:23][N:24]([CH:26]([CH3:28])[CH3:27])[CH3:25])=[C:20]([CH3:22])[CH:21]=3)[O:14][N:13]=2)[CH:9]=[C:8]([CH3:29])[C:7]=1[CH2:30][CH2:31][C:32](O)=[O:33])[CH3:5].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.[CH2:67]([O:69][C:70](=[O:73])[CH2:71][NH2:72])[CH3:68]>CN(C=O)C>[CH2:67]([O:69][C:70](=[O:73])[CH2:71][NH:72][C:32](=[O:33])[CH2:31][CH2:30][C:7]1[C:8]([CH3:29])=[CH:9][C:10]([C:12]2[N:16]=[C:15]([C:17]3[S:18][C:19]([CH2:23][N:24]([CH:26]([CH3:28])[CH3:27])[CH3:25])=[C:20]([CH3:22])[CH:21]=3)[O:14][N:13]=2)=[CH:11][C:6]=1[CH2:4][CH3:5])[CH3:68]
Reactant: CCc1cc(-c2noc(-c3cc(C)c(CN(C)C(C)C)s3)n2)cc(C)c1CCC(=O)O
Reactant: CCOC(=O)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=CO
Product: CCOC(=O)CNC(=O)CCc1c(C)cc(-c2noc(-c3cc(C)c(CN(C)C(C)C)s3)n2)cc1CC
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
To a solution of 3-[2-ethyl-4-(5-{5-[(isopropyl-methyl-amino)-methyl]-4-methyl-thiophen-2-yl}-[1,2,4]oxadiazol-3-yl)-6-methyl-phenyl]-propionic acid formate salt (9 mg, 18 μmol) in DMF (1 mL), DIPEA (14.3 mg, 0.111 mmol) and TBTU (7 mg, 20 μmol) is added. The mixture is stirred for 5 min before glycine ethyl ester hydrochloride (3.9 mg, 28 μmol) is added. The mixture is stirred at rt for 1 h before it is separated by prep. HPLC to give the title compound (8 mg) as a pale yellow resin; LC-MS: tR=0.61 min; [M−1]−=527.19.
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](O)=[O:4].Cl.Cl.[NH2:34][CH2:35][C:36]1[C:37]([NH2:43])=[N:38][C:39]([CH3:42])=[N:40][CH:41]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CO.CN(C=O)C>[NH2:43][C:37]1[C:36]([CH2:35][NH:34][C:3](=[O:4])[CH:2]([OH:1])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]=[C:15]([C:17]4[O:21][N:20]=[C:19]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[C:18]=4[C:28]([F:29])([F:30])[F:31])[O:14][N:13]=3)=[CH:8][CH:7]=2)=[CH:41][N:40]=[C:39]([CH3:42])[N:38]=1
Reactant: Cc1ncc(CN)c(N)n1
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: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: CO
Product: Cc1ncc(CNC(=O)C(O)c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2)c(N)n1
Reaction time: 1 h
Yield: 67.2 %

Procedure:
2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-Va, 50 mg, 0.116 mmol), 5-(aminomethyl)-2-methylpyrimidin-4-amine-2 HCl (36.7 mg, 0.174 mmol), 4-methylmorpholine (46.9 mg, 0.464 mmol), and HATU (57.3 mg, 0.151 mmol) were added to DMF (2 mL). The mixture was stirred for 1 h. Methanol was added and the mixture was filtered for prep HPLC. It was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention=11.2 min) to provide single enantiomer N-((4-amino-2-methylpyrimidin-5-yl)methyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (45 mg, 0.078 mmol, 67.6% yield): LCMS=552.3 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.13-8.25 (2 H, m), 7.91 (1 H, s), 7.53-7.75 (7 H, m), 5.21 (1 H, s), 4.20-4.39 (2 H, m), 2.51 (3 H, s); HPLC peak RT=8.3 min (Method A).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][NH:8][C:9](=O)[CH3:10].N1C(C)=CC=CC=1C.[C:20]([NH:28][NH2:29])(=O)[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1>C(Cl)Cl>[CH3:7][N:8]1[C:9]([CH3:10])=[N:29][N:28]=[C:20]1[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1
Reactant: NNC(=O)c1ccncc1
Reactant: CNC(C)=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: Cc1nnc(-c2ccncc2)n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.9 %

Procedure:
860 μl (10 mmol) oxalyl chloride was slowly added to a solution of 731 mg (10 mmol) N-methyl-acetamide and 2.33 ml (20 mmol) 2,6-lutidine in 20 ml CH2Cl2 at 0° C. After 15 min 1.37 g (10 mmol) isonicotinic acid hydrazide was added in one portion. The resulting mixture was stirred at room temperature for 1 h and the neutralized with NaHCO3(sat). The phases were separated and the water phase was extracted with CH2Cl2. The combined organic phases were dried and concentrated. The residue was dissolve in 20 ml acetic acid and heated at 120° C. for 2 h. After cooling the solvent was removed. Flashchromatography (CH2Cl2/MeOH 10:1) afforded 765 mg (44%) of a grey/white solid. 1H NMR (CDCl3), d (ppm): 2.52 (s, 3 H) 3.66 (s, 3 H) 7.58 (d, 2 H) 8.76 (d, 2 H).
Reaction SMILES: C(N(CC)CC)C.O.ON1C2C=CC=CC=2N=N1.[C:19]([O:23][P:24]([O:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][C:41]([CH2:44][CH2:45][C@@:46]([CH3:54])([S:50]([CH3:53])(=[O:52])=[O:51])[C:47](O)=[O:48])=[CH:40][CH:39]=2)=[CH:34][CH:33]=1)([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])([CH3:22])([CH3:21])[CH3:20].[O:55]1[CH2:60][CH2:59][CH2:58][CH2:57][CH:56]1[O:61][NH2:62].Cl.CN(C)CCCN=C=NCC>ClCCl.O>[P:24]([O:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:39]=[CH:40][C:41]([CH2:44][CH2:45][C@@:46]([CH3:54])([S:50]([CH3:53])(=[O:52])=[O:51])[C:47](=[O:48])[NH:62][O:61][CH:56]3[CH2:57][CH2:58][CH2:59][CH2:60][O:55]3)=[CH:42][CH:43]=2)=[CH:34][CH:33]=1)([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])([O:23][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:25]
Reactant: CC(C)(C)OP(=O)(Oc1ccc(-c2ccc(CC[C@](C)(C(=O)O)S(C)(=O)=O)cc2)cc1)OC(C)(C)C
Reactant: NOC1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OP(=O)(Oc1ccc(-c2ccc(CC[C@](C)(C(=O)NOC3CCCCO3)S(C)(=O)=O)cc2)cc1)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 62.7 %

Procedure:
A solution of triethylamine (2.0 mL, 15 mmol, 1.8 equiv), 1-hydroxyl benzotriazole monohydrate (2.3 g, 15 mmol, 1.8 equiv), (2R)-4-{4′-[(di-tert-butoxyphosphoryl)oxy]biphenyl-4-yl}-2-methyl-2-(methylsulfonyl)butanoic acid (4.4 g, 8.2 mmol, 1.0 equiv), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (1.4 g, 12 mmol, 1.4 equiv), and N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI) (2.2 g, 11 mmol, 1.4 equiv) in dichloromethane (205 mL) was allowed to stir at room temperature for 1 day. The reaction was diluted with water (600 mL) and dichloromethane (600 mL), the aqueous phase was separated and extracted with dichloromethane (2×300 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (60% ethyl acetate in heptane) to provide the title compound (3.29 g, 63%). MS (LCMS) m/z 638.8 (M−1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:18][C:19]([F:23])([F:22])[CH2:20][NH2:21].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.C(Cl)CCl>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[C:15](=[O:17])[NH:21][CH2:20][C:19]([F:23])([F:22])[F:18])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1C(=O)O
Reactant: NCC(F)(F)F
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1C(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
To a mixture of cis-2-tertbutoxycarbonylamino-cyclohexanecarboxylic acid (Acros, 2 g, 8.22 mmol), 2,2,2-trifluoroethylamine (0.969 mL, 12.33 mmol), HOBT (1.888 g, 12.33 mmol) and DIPEA (4.31 mL, 24.66 mmol) in DMF (10 mL) was added EDC (2.364 g, 12.33 mmol) and the mixture allowed to stir at RT for 1 hr. The reaction was quenched into 10% aq. KHSO4 (100 mL) and product extracted with ethyl acetate (100 mL). Organic washed with aq. NaHCO3 (50 mL) and then brine (50 mL). Aqueous extracts backwashed with ethyl acetate (50 mL) and organic extracts combined, dried over sodium sulfate, filtered and concentrated to give 2.55 gm of a white solid, I-5a. 1H NMR (600 MHz, CDCl3) δ 6.18 (m, 1H), 5.07 (m, 1H), 3.75-4.0 (m 3H), 2.62 (m, 1H), 1.3-2.0 (br m, 8H), 1.40 (s, 9H).
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH2:8][CH:7]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[C:6]=2[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:3]=1[CH3:29].C(OC([N:37]1[CH:41]=[CH:40][CH:39]=[C:38]1B(O)O)=O)(C)(C)C>>[NH:37]1[CH:41]=[CH:40][CH:39]=[C:38]1[C:2]1[C:10]2[O:9][CH2:8][CH:7]([C:11]3[CH:12]=[CH:13][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:15][CH:16]=3)[C:6]=2[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:25])[CH3:26])[C:3]=1[CH3:29]
Reactant: Cc1c(Br)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Product: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1-c1ccc[nH]1)OCC2c1ccc(C(C)C)cc1
Yield: 19 %

Procedure:
Using N-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 35 and (1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl)boronic acid, the title compound was obtained in the same manner as in Example 107. Yield: 19%. Melting point: 188-190° C. (ethyl acetate).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[CH:5]([C:16]1[C:25]([CH3:26])=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2[O:27][CH3:28])[C:17]=1[C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[O:6]CC1C=CC(OC)=CC=1)[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:3][C:4](=[O:36])[CH:5]([C:16]1[C:25]([CH3:26])=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2[O:27][CH3:28])[C:17]=1[C:29]1[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=1)[OH:6])[CH3:2]
Reactant: CCOC(=O)C(OCc1ccc(OC)cc1)c1c(C)cc2c(OC)cccc2c1-c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C(O)c1c(C)cc2c(OC)cccc2c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of [1-(4-chloro-phenyl)-5-methoxy-3-methyl-naphthalen-2-yl]-(4-methoxy-benzyloxy)-acetic acid ethyl ester (58 mg, 0.115 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (58 μL). The reaction mixture was stirred for 2 h at room temperature and then quenched carefully with sat. NaHCO3. The aqueous layer was extracted with dichloromethane twice, and then the combined organic layers were washed with water, dried (Na2SO4), concentrated and purified by flash column chromatography to give desired (23 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][CH:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])[CH:5]=[CH:6][C:7]=1I.[C:25]([N:29]1[C:33](=[O:34])[CH:32]=[CH:31][S:30]1(=[O:36])=[O:35])([CH3:28])([CH3:27])[CH3:26].C(N(CC)CC)C>CCCC[N+](CCCC)(CCCC)CCCC.[Cl-].CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][CH:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:11](=[O:12])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:6][C:7]=1[C:31]1[S:30](=[O:35])(=[O:36])[N:29]([C:25]([CH3:27])([CH3:26])[CH3:28])[C:33](=[O:34])[CH:32]=1
Reactant: O=C(c1ccccc1)C(Cc1ccc(I)c(Br)c1)c1ccccc1
Reactant: CC(C)(C)N1C(=O)C=CS1(=O)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)N1C(=O)C=C(c2ccc(CC(C(=O)c3ccccc3)c3ccccc3)cc2Br)S1(=O)=O
Temperature: 70 °C
Yield: 42.6 %

Procedure:
A solution of 1.36-A (25.0 mg, 51 μmol), 2-tert-butylisothiazol-3(2H)-one 1,1-dioxide (19.3 mg, 0.102 mmol), tetra-N-butylammonium chloride (21.2 mg, 76 μmol) and palladium acetate (1.71 mg, 7.6 μmol) in N,N-dimethylformamide (0.48 mL) was treated with triethylamine (0.0213 mL, 0.153 mmol). The reaction mixture was degassed by bubbling with a nitrogen balloon for 10 minutes and heated at 70° C. for 1 h. The reaction mixture was diluted with ethyl acetate (5 mL) and washed with water (5 mL) and 1 N HCl (5 mL). The organic extract was dried with magnesium sulfate, filtered, and concentrated to a crude residue which was purified by flash column chromatography to yield the desired product (12 mg, 43%). LCMS found for C28H27BrNO4S (M+H)+: m/z=552, 554.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[Cl:19][C:20]1[C:21]([C:27](O)=[O:28])=[N:22][CH:23]=[C:24]([Cl:26])[N:25]=1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:27]([C:21]3[C:20]([Cl:19])=[N:25][C:24]([Cl:26])=[CH:23][N:22]=3)=[O:28])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: O=C(O)c1ncc(Cl)nc1Cl
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Product: C[C@]1(c2cc(NC(=O)c3ncc(Cl)nc3Cl)ccc2F)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 3,5-dichloro-pyrazine-2-carboxylic acid following procedure I yielded the title compound as a white solid. MS (ISP): m/z=434.1 [M+H]+, 436.1 [M+2+H]+.