Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C@@H:3]([OH:21])[CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([O:19][CH3:20])[C:14]([N+:16]([O-])=O)=[CH:15][C:8]=2[CH2:7][CH2:6]1.C.O>CO.[Pd]>[NH2:16][C:14]1[C:13]([O:19][CH3:20])=[CH:12][C:9]2[CH2:10][CH2:11][N:5]([CH2:4][C@H:3]([OH:21])[C:2]([F:1])([F:22])[F:23])[CH2:6][CH2:7][C:8]=2[CH:15]=1
Reactant: COc1cc2c(cc1[N+](=O)[O-])CCN(C[C@H](O)C(F)(F)F)CC2
Agent: [Pd]
Solvent: O
Solvent: CO
Product: COc1cc2c(cc1N)CCN(C[C@H](O)C(F)(F)F)CC2
Reaction time: 8 h
Yield: 92.7 %

Procedure:
(S)-1,1,1-Trifluoro-3-(7-methoxy-8-nitro-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-propan-2-ol (316 mg, 0.95 mmol) was dissolved in 10 mL methanol, 10% Pd/C, 50% wet (5:45:50, Palladium:carbon black:Water, 0.105 g) was added and the mixture was stirred under an atmosphere of Hydrogen (balloon) overnight. Filtration through Celite with methanol afforded (S)-3-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-1,1,1-trifluoro-propan-2-ol (268 mg, 93%), which was used without further purification. (S)-3-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-1,1,1-trifluoro-propan-2-ol (88 mg, 0.29 mmol), N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (101 mg, 0.298 mmol), and 10-Camphorsulfonic acid (0.10 g, 0.43 mmol) in 2-Methoxyethanol (4 mL) were heated in a microwave vial at 120° C. for a total of 4 h. The light brown solution was diluted with 3 mL satd. bicarbonate solution, resulting in a suspension, which was added to 12 mL satd. bicarbonate solution which was thoroughly mixed and then filtered to afford the product in ˜80% purity by HPLC (93 mg). Trituration from ether gave an oil, so the material wash purified by RP-HPLC (10-30% acetonitrile:water) followed by formation of the free base with Macroporous carbonate resin to afford N-((1R,2R)-2-{5-Chloro-2-[8-methoxy-3-((S)-3,3,3-trifluoro-2-hydroxy-propyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-cyclohexyl)-methanesulfonamide as off white solids (81 mg, 46%). m.p.=122-127° C.; LCMS (m/e) 608 (M+1); 1H-NMR (CD3OD, 400 MHz) δ 7.94 (s, 1H), 7.58 (s, 1H), 7.1-7.3 (m, 3H), 7.04 (s, 1H), 4.70 (m, 1H), 3.94 (m, 1H), 3.89 (s, 3H), 3.4-3.7 (m, 6H), 3.25 (m, 4H), 2.95 (s, 3H), 2.32 (s, 1H), 2.14 (m, 2H), 1.82 (m, 2H), 1.2-1.6 (m, 5H).
Reaction SMILES: [C:1]1([S:7]([CH:10]([F:12])[F:11])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1.[OH-].[Na+].Cl>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].ClCCl>[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]([OH:19])[C:10]([F:12])([F:11])[S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:9])=[O:8])=[CH:16][CH:15]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: O=S(=O)(c1ccccc1)C(F)F
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: Cl
Agent: [Cl-]
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)C(F)(F)C(O)c1ccc(Cl)cc1
Yield: 88.4 %

Procedure:
A reaction mixture generated from 100 mg (0.52 mmol) of difluoromethyl phenyl sulfone, 225 mg (1.6 mmol) of 4-chlorobenzaldehyde, 1.5 mL of dichloromethane, 1 mL of 50% aqueous sodium hydroxide and 20 mg (0.050 mmol) of Aliquat 336 was poured into 20 mL of 1N HCl. Extraction of the aqueous mixture with three 10 mL portions of ethyl acetate followed by combination, drying (MgSO4), and concentration in vacuo of the organic layers gave a residue which was purified by preparative TLC (two 2 mm silica gel plates eluted with 10% ethyl acetate in toluene), affording 153 mg (88% yield) of 1-(4-chlorophenyl)-2,2-difluoro-2-phenylsulfonylethanol as a solid. Crystallization from toluene provided an analytical sample: mp; 100°-102° C.; IR (KBr) 3530, 3060, 2921, 1491, 1446, 1332, 1157, 1120, 1113, 1090, 1016, 1005, 784, 723, 683, 589, 538 cm-1 ; 1H NMR (CDCl3) δ 3.62 (broad s, 1H), 5.56 (dd, 1H, J=20, 3 Hz), 7.26-8.13 (m, 9H); 19F NMR (CDCl3, relative to CFCl3 -104.8 ppm (dd, 1F, JFF =238 Hz, JHF =3 Hz), -119.2 ppm (dd, 1F, JFF =238 Hz, JHF =20 Hz); mass spectrum (70 eV) m/e (relative intensity) 332 (9, M+), 143(44), 141(100, 77(33). Anal. Calcd. for C14H11ClF2O3S: C, 50.53; H, 3.33. Found: C, 50.49; H, 3.41.
Reaction SMILES: C[N:2]1[C:6]([CH3:7])=[CH:5][C:4]([NH:8][C:9]2[C:10](=[O:25])[N:11]([CH3:24])[CH:12]=[C:13](B3OC(C)(C)C(C)(C)O3)[CH:14]=2)=[N:3]1.[C:26]([O:29][CH2:30][C:31]1[C:32]([N:46]2[CH2:57][CH2:56][N:55]3[C:48](=[CH:49][C:50]4[CH2:51][C:52]([CH3:59])([CH3:58])[CH2:53][C:54]=43)[C:47]2=[O:60])=[N:33][CH:34]=[CH:35][C:36]=1B1OC(C)(C)C(C)(C)O1)(=[O:28])[CH3:27].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C(#N)C>[C:26]([O:29][CH2:30][C:31]1[C:32]([N:46]2[CH2:57][CH2:56][N:55]3[C:48](=[CH:49][C:50]4[CH2:51][C:52]([CH3:59])([CH3:58])[CH2:53][C:54]=43)[C:47]2=[O:60])=[N:33][CH:34]=[CH:35][C:36]=1[C:13]1[CH:14]=[C:9]([NH:8][C:4]2[CH:5]=[C:6]([CH3:7])[NH:2][N:3]=2)[C:10](=[O:25])[N:11]([CH3:24])[CH:12]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Reactant: Cc1cc(Nc2cc(B3OC(C)(C)C(C)(C)O3)cn(C)c2=O)nn1C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3cc(C)[nH]n3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 100 °C
Yield: 38 %

Procedure:
A round-bottomed flask equipped with a reflux condenser was charged with 5-bromo-1-methyl-3-(5-methyl-1H-pyrazol-3-ylamino)pyridin-2(1H)-one 218a (201 mg, 0.71 mmol), {3-[(acetyloxy)methyl]-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridin-4-yl}boronic acid 199e (282 mg, 0.71 mmol), Pd(dppf)Cl2 (51 mg, 0.07 mmol), K3PO4 (301 mg, 1.42 mmol), sodium acetate (116 mg, 1.42 mmol), acetonitrile (10 mL), and water (0.2 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 3 h. It was then filtered and the filtrate was evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 1:20 methanol/dichloromethane to afford 260a as a red solid (150 mg, 38%). MS-ESI: [M+H]+ 556.3
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5](=[O:18])[C:6]1[CH:11]=[CH:10][C:9]([O:12]C(=O)C)=[CH:8][C:7]=1[O:16][CH3:17].Cl>C1COCC1.CO.O>[CH3:3][O:4][C:5](=[O:18])[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[O:16][CH3:17]
Reactant: COC(=O)c1ccc(OC(C)=O)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(O)cc1OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 32.5 %

Procedure:
0.1N NaOH (10 mL, 1 mmol) was added to a solution of the product of step 2 (1.10 g, 4.9 mmol) in THF (1 mL) and MeOH (1 mL). Reaction was stirred for three days at room temperature. Reaction solution was concentrated by rotary evaporation and resulting residue was dissolved in water. The solution was neutralized with 1N HCl and a precipitate formed. Collected precipitate and washed with water and hexane. Obtained 0.29 g of 4-Hydroxy-2-methoxy-benzoic acid methyl ester in 33% yield.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4](Cl)=[O:5].[O:13]1[CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]1>>[CH3:1][O:2][CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([CH:15]1[C:16](=[O:19])[CH2:17][CH2:18][O:13][CH2:14]1)=[O:5]
Reactant: O=C1CCOCC1
Reactant: COC(C(=O)Cl)c1ccccc1
Product: COC(C(=O)C1COCCC1=O)c1ccccc1
Yield: 14.5 %

Procedure:
3-(2-Methoxy-2-phenylacetyl)dihydro-2H-pyran-4(3H)-one (54 mg, 14.5%) was synthesised from 2-methoxy-2-phenylacetyl chloride and dihydro-2H-pyran-4(3H)-one according to the general procedure for the preparation of diketones. MS (ES−) m/z 247.1 (M−H)−
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH2:17][C:16]([C:22]3[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[CH:23]=3)([C:18]([F:21])([F:20])[F:19])[O:15][N:14]=2)=[CH:9][C:8]=1[CH3:30])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:52])(=O)=O)=CC=1>O1CCCC1>[C:1]([O:5][C:6](=[O:31])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:17]([F:52])[C:16]([C:22]3[CH:23]=[C:24]([Cl:29])[CH:25]=[C:26]([Cl:28])[CH:27]=3)([C:18]([F:20])([F:19])[F:21])[O:15][N:14]=2)=[CH:9][C:8]=1[CH3:30])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)OC(C)(C)C
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2F)ccc1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 38.5 %

Procedure:
To a solution of 4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid tert-butyl ester (preparation of similar compounds described in, for example, EP 1,731,512) (500 mg) in tetrahydrofuran (6 ml) that was stirred at −78° C. for 15 minutes under argon, was slowly added lithium bis(trimethylsilyl)amide (“LiHMDS”) (1M in hexane) (1.1 ml). The reaction mixture was stirred at −78° C. for 1.5 hours. Then N-fluorobenzenesulfonimide (“NFSI”) (433 mg) was added quickly and the reaction mixture was stirred at −78° C. for 2 hours. The reaction was quenched by addition of aqueous ammonium chloride (saturated) at −78° C. tert-Butyl methyl ether (“TBME”) was added and the phases were separated. The organic layer was washed successively with aqueous ammonium chloride (saturated) and brine, dried over magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/heptane 1:2) to give 4-[5-(3,5-dichloro-phenyl)-4-fluoro-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid tert-butyl ester (200 mg) as a colorless oil.
Reaction SMILES: [Cl-].[Ce+3].[Cl-].[Cl-].[CH3:5][Mg]Br.[C:8]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH3:21])[C:16](=[O:22])[N:15]([CH:23]1[CH2:28][CH2:27][N:26]([C:29]3[C:38]4[C:33](=[CH:34][C:35]([O:41][CH3:42])=[C:36]([O:39][CH3:40])[CH:37]=4)[N:32]=[CH:31][N:30]=3)[CH2:25][CH2:24]1)[C:14]2=[O:43])(=[O:10])[CH3:9].[Cl-].[NH4+]>C1COCC1>[CH3:40][O:39][C:36]1[CH:37]=[C:38]2[C:33](=[CH:34][C:35]=1[O:41][CH3:42])[N:32]=[CH:31][N:30]=[C:29]2[N:26]1[CH2:27][CH2:28][CH:23]([N:15]2[C:14](=[O:43])[C:13]3[C:18](=[CH:19][CH:20]=[C:11]([C:8]([OH:10])([CH3:5])[CH3:9])[CH:12]=3)[N:17]([CH3:21])[C:16]2=[O:22])[CH2:24][CH2:25]1
Reactant: C[Mg]Br
Reactant: COc1cc2ncnc(N3CCC(n4c(=O)c5cc(C(C)=O)ccc5n(C)c4=O)CC3)c2cc1OC
Agent: [Ce+3]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cc2ncnc(N3CCC(n4c(=O)c5cc(C(C)(C)O)ccc5n(C)c4=O)CC3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
In 3 ml of THF was suspended 246.5 mg (1.0 mmol) of thoroughly dried cerium chloride, and 1 ml of a 1M solution of methylmagnesium bromide in THF was added thereto under an argon gas atmosphere, followed by stirring at room temperature for 1 hour. To the reaction mixture was dropwise added a solution of 245.0 mg (0.50 mmol) of Compound 63 obtained in Example 50 in 5 ml of THF, and the mixture was stirred at room temperature for 3 hours. A saturated aqueous solution of ammonium chloride was added thereto in excess to stop the reaction, followed by extraction with chloroform. The organic layer was washed and dried, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=100/1) and recrystallized from ether to give 78.8 mg (yield: 31%) of Compound 61 as white crystals.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[C:11]1[CH:12]=[C:13]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([CH:25]3[CH2:30][O:29][CH2:28][CH2:27][N:26]3[CH3:31])=O)[CH2:19][CH2:18]2)[CH:14]=[CH:15][CH:16]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N:17]2[CH2:18][CH2:19][N:20]([CH2:23][CH:25]3[CH2:30][O:29][CH2:28][CH2:27][N:26]3[CH3:31])[CH2:21][CH2:22]2)[CH:12]=1
Reactant: CN1CCOCC1C(=O)N1CCN(c2cccc(-c3nc4ccccc4n3C)c2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCOCC1CN1CCN(c2cccc(-c3nc4ccccc4n3C)c2)CC1
Temperature: 25 °C
Yield: 46.2 %

Procedure:
To a solution of {4-[3-(1-Methyl-1H-benzoimidazol-2-yl)-phenyl]-piperazin-1-yl}-(4-methyl-morpholin-3-yl)-methanone (0.06 g, 0.16 mmol) in dry THF (2 mL) at room temperature under a nitrogen atmosphere was added lithium aluminium hydride (LiAlH4) (0.02 g, 0.47 mmol). The reaction was heated at reflux for 2 h and other LiAlH4 (0.01 g, 0.24 mmol). After 30 min the solution was cooled to room temperature, quenched with 10% NaOH (3 mL) and then extracted with dichloromethane (3×3 mL) The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was then purified by Preparative HPLC to obtain 0.03 g (41%) of the title compound.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:49][O:50][C:51]1[CH:56]=[CH:55][C:54]([C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([NH2:63])[CH:58]=2)=[CH:53][CH:52]=1>CN(C=O)C>[CH3:49][O:50][C:51]1[CH:52]=[CH:53][C:54]([C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([NH:63][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:58]=2)=[CH:55][CH:56]=1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Reactant: COc1ccc(-c2cccc(N)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(-c2cccc(NC(=O)c3cc4cccc(O)c4oc3=O)c2)cc1
Temperature: 25 °C
Yield: 51.6 %

Procedure:
DIEA (0.0144 mL, 0.083 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.016 g, 0.075 mmol) and HATU (0.032 g, 0.083 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 4′-Methoxy-biphenyl-3-ylamine (0.015 g, 0.075 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.015 g of product in 52% yield: LCMS (ESI) m/z 388 (MH+).
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:35])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][N:18]=2)[N:6]([C@@H:24]([CH2:32][CH3:33])[CH2:25][N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:5]1=[O:34])[CH:2]=C.I([O-])(=O)(=O)=[O:37].[Na+]>C1COCC1.O.[Os](=O)(=O)(=O)=O>[Cl:16][C:12]1[CH:11]=[C:10]([C@@H:8]2[C@@H:7]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][N:18]=3)[N:6]([C@@H:24]([CH2:32][CH3:33])[CH2:25][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[C:5](=[O:34])[C@:4]([CH2:1][CH:2]=[O:37])([CH3:35])[CH2:9]2)[CH:15]=[CH:14][CH:13]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cn2)N([C@@H](CC)CN2CCOCC2)C1=O
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC[C@@H](CN1CCOCC1)N1C(=O)[C@@](C)(CC=O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 0.05 h

Procedure:
To a solution of 42 mg (0.08 mmol) of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methyl-1-((S)-1-morpholinobutan-2-yl)piperidin-2-one (Example 121, Step N) in THF (6 mL) and water (2 mL) added a catalytic amount of osmium tetroxide. After 3 min, 87 mg (0.41 mmol) of sodium periodate was added. The resulting white slurry was stirred at room temperature for 4.25 h, and then filtered through a fritted funnel. The filtrate was partially concentrated under reduced pressure, and then was diluted with a mixture of water and saturated aqueous sodium chloride and extracted with ethyl acetate (2×). The combined organic layers were washed with saturated aqueous sodium thiosulfate and then saturated aqueous sodium chloride. The organic layer was dried over Na2SO4, filtered and the filtrate was concentrated. Purification of the residue by reversed phase prep. HPLC (Sunfire™ Prep C18 OBD 10 μm column (Waters, Milford, Mass.), gradient elution of 35% MeCN in water to 75% MeCN in water over a 35 min period, where both solvents contain 0.1% TFA provided the title compound as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]([C:11]1[CH:20]=[CH:19][C:18]2[CH:17]([NH:21][C:22](=[O:42])[CH2:23][CH:24]3[CH2:28][CH2:27][CH2:26][N:25]3[S:29]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=3)(=[O:31])=[O:30])[CH2:16][CH2:15][CH2:14][C:13]=2[CH:12]=1)=[CH2:10])(C)(C)C>Cl.CCOC(C)=O>[NH2:7][CH2:8][C:9]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH:17]([NH:21][C:22](=[O:42])[CH2:23][CH:24]1[CH2:28][CH2:27][CH2:26][N:25]1[S:29]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:39])[F:40])[CH:33]=1)(=[O:31])=[O:30])[CH2:16][CH2:15][CH2:14]2)=[CH2:10]
Reactant: C=C(CNC(=O)OC(C)(C)C)c1ccc2c(c1)CCCC2NC(=O)CC1CCCN1S(=O)(=O)c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: C=C(CN)c1ccc2c(c1)CCCC2NC(=O)CC1CCCN1S(=O)(=O)c1cccc(C(F)(F)F)c1

Procedure:
A solution of [2-(5-{2-[1-(3-trifluoromethyl-benzenesulfonyl)-pyrrolidin-2-yl]-acetylamino}-5,6,7,8-tetrahydro-naphthalen-2-yl)-allyl]-carbamic acid tert-butyl ester (72 mg, 0.12 mmol) in saturated HCl/EtOAc (3 mL) was stirred at RT for 45 min. The solvent was removed with a rotary evaporator. The crude was diluted with saturated NaHCO3 (60 mL) and extracted with CH2Cl2 (60 mL×3). The extract phase was washed with saturated NaCl, dried over Na2SO4, filtered and concentrated. Reverse phase liquid chromatography [25–100% CH3CN (0.1% TFA)-H2O (0.1% TFA)] afforded the title compound-containing fractional collections. CH3CN was removed from the combined fractional collections with a rotary evaporator. The aqueous phase was neutralized with saturated with NaHCO3 (40 mL), extracted with CH2Cl2 (40 mL×3). The extract phase was washed with saturated with NaCl, dried over Na2SO4, filtered and concentrated. The title compound was obtained as an off-white solid. MS (ESI, pos. ion) m/z: 522 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4](Cl)[N:3]=1.[NH3:13]>>[NH3:3].[Cl:1][C:2]1[N:3]=[C:4]([NH2:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: FC(F)(F)c1cc(Cl)nc(Cl)c1
Agent: N
Product: Nc1cc(C(F)(F)F)cc(Cl)n1
Temperature: 120 °C
Yield: 176.3 %

Procedure:
A mixture of 5.00 g 2,6-dichloro-4-trifluoromethyl-pyridine and 80 g ammonia was heated in an autoclave at 120° C. for 24 h. Ammonia was allowed to evaporate and the residue was purified on silica gel with methylenechloride:methanol:ammonia =9:1:0.1 to yield 4.01 g of the title compound as off white crystals MS (ISP) M+H+=210.9
Reaction SMILES: [CH3:1][CH:2]([CH3:44])[CH2:3][N:4]([C:26]([C:28]1[N:32]([CH2:33][CH2:34][C:35]2[N:39]=[CH:38][O:37][N:36]=2)[C:31]2[CH:40]=[CH:41][CH:42]=[CH:43][C:30]=2[N:29]=1)=[O:27])[C@H:5]1[CH2:10][C@@H:9]([C:11]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[O:12])[CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6]1.C(OCC)(=O)C.[ClH:51]>>[ClH:51].[ClH:51].[CH3:1][CH:2]([CH3:44])[CH2:3][N:4]([C@H:5]1[CH2:10][C@@H:9]([C:11]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[O:12])[CH2:8][NH:7][CH2:6]1)[C:26]([C:28]1[N:32]([CH2:33][CH2:34][C:35]2[N:39]=[CH:38][O:37][N:36]=2)[C:31]2[CH:40]=[CH:41][CH:42]=[CH:43][C:30]=2[N:29]=1)=[O:27]
Reactant: CC(C)CN(C(=O)c1nc2ccccc2n1CCc1ncon1)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)CN(C(=O)c1nc2ccccc2n1CCc1ncon1)[C@@H]1CNC[C@H](C(=O)N2CCOCC2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Hydroxylamine hydrochloride (125 mg) was dissolved in dimethyl sulfoxide (5 ml), sodium hydrogen carbonate (463 mg) was added and the mixture was stirred at 50° C. for 1 hr. A solution of tert-butyl(3S, 5R)-3-[{[1-(2-cyanoethyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (100 mg) in dimethyl sulfoxide (5 ml) was added to the reaction mixture, and the mixture was stirred at 90° C. for 3 hr. The reaction mixture was allowed to cool to room temperature, diluted with water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in trimethyl orthoformate (5 ml) and the mixture was stirred at 100° C. for 5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to basic silica gel chromatography, and a fraction eluted with ethyl acetate was concentrated under reduced pressure to give tert-butyl(3S, 5R)-3-[(2-methylpropyl)({1-[2-(1,2,4-oxadiazol-3-yl)ethyl]-1H-benzimidazol-2-yl}carbonyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate. The obtained tert-butyl(3S, 5R)-3-[(2-methylpropyl)({1-[2-(1,2,4-oxadiazol-3-yl)ethyl]-1H-benzimidazol-2-yl}carbonyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate was dissolved in 4M hydrogen chloride-ethyl acetate (3 ml), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, and the residue was subjected to reversed-phase preparative HPLC and the eluted fraction was concentrated under reduced pressure. The residue was diluted with aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. 4M Hydrogen chloride-ethyl acetate (1 ml) was added and the mixture was stirred for 5 min. The solvent was evaporated under reduced pressure to give the object product (35 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]2[C@:15]34[CH2:17][CH2:18][NH:19][C@@H:9]([C@@H:10]3[CH2:11][CH2:12][C:13](=[O:20])[CH2:14]4)[CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].[CH:27]1([C:31](Cl)=[O:32])[CH2:30][CH2:29][CH2:28]1>CN(C=O)C>[CH:27]1([C:31]([N:19]2[CH2:18][CH2:17][C@@:15]34[C:16]5[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=5[CH2:8][C@@H:9]2[C@@H:10]3[CH2:11][CH2:12][C:13](=[O:20])[CH2:14]4)=[O:32])[CH2:30][CH2:29][CH2:28]1
Reactant: COc1cccc2c1[C@]13CCN[C@H](C2)[C@@H]1CCC(=O)C3
Reactant: O=C(Cl)C1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc2c1[C@]13CCN(C(=O)C4CCC4)[C@H](C2)[C@@H]1CCC(=O)C3
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
To a mixture of 2 g (7.37 mmol) 4-methoxymorphinan-6-one (H2O was removed azeotropic) and 3 g (21.71 mmol) K2CO3 in 20 ml dry DMF was dropped at room temperature during 15 min. a solution of 900 mg (7.59 mmol) cyclobutanecarboxylic acid chloride. This mixture was stirred at room temperature for 1 h, then poured on 200 ml ice water and extracted with ether. The organic layer was extracted with 2 N HCl and brine, dried and evaporated to give an oil, which was crystallized with benzene/u/hexane to yield 2.5 g (96%) N-cyclobutylcarbonyl-4-methoxymorphinan-6-one, m.p. 125°-126°, [α]D26 -204.5° (c 0.76, CHCl3).