Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([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)=[O:4]>CO.[Pd]>[NH2:16][C:14]1[C:13]([O:19][CH3:20])=[CH:12][C:9]2[CH2:10][CH2:11][N:5]([C:3](=[O:4])[C:2]([F:1])([F:21])[F:22])[CH2:6][CH2:7][C:8]=2[CH:15]=1
Reactant: COc1cc2c(cc1[N+](=O)[O-])CCN(C(=O)C(F)(F)F)CC2
Agent: [Pd]
Solvent: CO
Product: COc1cc2c(cc1N)CCN(C(=O)C(F)(F)F)CC2
Reaction time: 0.5 h

Procedure:
To a solution of 2,2,2-trifluoro-1-(7-methoxy-8-nitro-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-ethanone in methanol was added palladium 10% wt on Carbon (50% wet). The mixture was shaken in a Parr apparatus under an atmosphere of Hydrogen (50 PSI) for 30 minutes. Filtration through Celite and evaporation of the solvent provided quantitatively 1-(7-amino-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-2,2,2-trifluoro-ethanone, which was used without further purification. 1H-NMR (CDCl3; amide rotamers observed) δ 6.58 (1H), 6.53 (1H), 3.83 (s, 3H), 3.15-4.25 (br s, 2H), 3.60-3.78 (4H), 2.79-2.92 (4H); LC/MS (ESI+): 288.99 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[F:10].[CH3:11][O:12]C(Cl)Cl>[Ti](Cl)(Cl)(Cl)Cl.ClCCl>[Br:1][C:2]1[C:3]([F:10])=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][CH3:9])[CH:11]=[O:12]
Reactant: COc1cccc(F)c1Br
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(C=O)c(F)c1Br
Temperature: 25 °C
Yield: 73.5 %

Procedure:
In a 3-necked 250 mL round-bottomed flask equipped with nitrogen lines and a stir bar was placed 2-bromo-1-fluoro-3-methoxy-benzene (I-29, 2.0 g, 9.75 mmol) and dichloromethane (48 mL). The solution was cooled in an ice water bath for 15 minutes and then titanium tetrachloride (5.02 mL, 45.8 mmol) and dichloromethyl methyl ether (1.32 mL, 14.6 mmol) were added and the reaction mixture was allowed to warm to room temperature and react for 2 hours. The reaction mixture was slowly added to ice water (250 mL) and extracted with dichloromethane (2×100 mL). The organic portions were combined, washed with a saturated sodium bicarbonate solution (75 mL), water (75 mL) and brine (75 mL), dried (MgSO4) and concentrated. The crude material was triturated with hexanes (15 mL) to produce 1.67 g of 3-bromo-2-fluoro-4-methoxy-benzaldehyde (I-30) as an off-white solid in 74% yield. MS (ESI+): 233.2 (M+)
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[N:19]=[C:20]([CH:28]4[CH2:31][CH2:30][CH2:29]4)[N:21]4[CH:26]=[CH:25][N:24]=[C:23]([NH2:27])[C:22]=34)[CH:13]=2)[CH:5]=1.C(OCC)(=O)C>C1COCC1>[NH2:27][C:23]1[C:22]2[N:21]([C:20]([CH:28]3[CH2:31][CH2:30][CH2:29]3)=[N:19][C:18]=2[C:14]2[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=2)[O:11][CH2:10][C:6]2[CH:5]=[C:4]([CH2:3][OH:2])[CH:9]=[CH:8][CH:7]=2)[CH:26]=[CH:25][N:24]=1
Reactant: COC(=O)c1cccc(COc2cccc(-c3nc(C4CCC4)n4ccnc(N)c34)c2)c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1nccn2c(C3CCC3)nc(-c3cccc(OCc4cccc(CO)c4)c3)c12
Temperature: 25 °C

Procedure:
A solution of 3-[3-(8-Amino-3-cyclobutyl-imidazo[1,5-a]pyrazin-1-yl)-phenoxymethyl]-benzoic acid methyl ester (600 mg, 1.40 mmol) in THF was cooled to −78° C. in an acetone/dry ice bath for 5.0 min. The reaction was purged with nitrogen and charged dropwise with 1M lithium aluminum hydride (LAH) (1.40 mL). After all the LAH was added, the solution was removed from the bath and allowed to warm to room temperature (rt). As the solution warmed, a white solid formed on the sides of the flask. The reaction mixture was then charged with ethyl acetate, Na2SO4.10H2O and silica. This solution was then concentrated in vacuo to a solid, and was chromatographed on silica gel [Jones Flashmaster, 50 g cartridge, eluting with 2% NH3 in MeOH:CH2Cl2] to yield the title compound as a white solid; 1H NMR (CDCl3, 400 MHz) δ 1.99-2.07 (m, 1H), 2.11-2.22 (m, 1H), 2.44-2.52 (m, 2H), 2.58-2.68 (m, 2H), 3.76-3.84 (m, 1H), 4.69 (s, 2H), 5.16 (s, 2H), 6.98 (d, J=13.2 Hz, 1H), 7.02-7.05 (m, 1H), 7.08 (d, J=4.8 Hz, 1H), 7.16-7.17 (m, 1H), 7.25-7.28 (m, 1H), 7.35-7.43 (m, 5H); MS (ES+): m/z 401.19 (100) [MH+].
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][C:11](=[O:15])[CH2:12][CH2:13][NH2:14].Br[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>C(Cl)Cl>[CH3:9][O:10][C:11](=[O:15])[CH2:12][CH2:13][NH:14][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]
Reactant: COC(=O)CCN
Reactant: CC(C)(C)OC(=O)CBr
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCNCC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 14 %

Procedure:
Triethylamine (7 mL, 50 mmol) was added to a solution of β-alanine methyl ester hydrochloride (5.25 g, 37.5 mmol) in methylene chloride (100 mL). The solution was cooled to 0° C. and t-butyl bromoacetate (4.88 g, 25 mmol) in methylene chloride (100 mL) was then added. The reaction mixture was warmed to room temperature and stirred overnight. The solvent was removed in vacuo and the residue was taken up in ethyl acetate. The ethyl acetate was washed with saturated NaHCO3, brine, dried over MgSO4, filtered and concentrated in vacuo; 0.80 g (14% yield).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][OH:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[Cl:13][C:14]1[C:15](F)=[CH:16][C:17]([F:27])=[C:18]([CH:26]=1)[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CS(C)=O>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][O:12][C:15]3[C:14]([Cl:13])=[CH:26][C:18]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])=[C:17]([F:27])[CH:16]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(F)cc1F
Reactant: OCC1CCC2(CC1)OCCO2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)c1cc(Cl)c(OCC2CCC3(CC2)OCCO3)cc1F
Temperature: 75 °C
Yield: 43.5 %

Procedure:
To a mixture of 1,4-dioxaspiro[4.5]decan-8-ylmethanol (5.00 g, 29.0 mmol) and tert-butyl 5-chloro-2,4-difluorobenzoate (7.22 g, 29.00 mmol) in anhydrous dimethyl sulfoxide (30 mL) was added cesium carbonate (18.90 g, 58.00 mmol) and the reaction mixture was heated at 70-80° C. for 4 hours. After cooling to ambient temperature, ethyl acetate was added (200 mL) and the mixture was washed with water (4×15 mL), brine (2×15 mL); dried over anhydrous sodium sulfate, and filtered. After concentration of the filtrate in vacuo, the residue was purified by silica gel column chromatography using 0-30% ethyl acetate in hexanes as eluent to afford the title compound as a colorless oil (5.06 g, 44%): 1H NMR (300 MHz, CDCl3) 7.85 (d, J=7.7 Hz, 1H), 6.60 (d, J=12.2 Hz, 1H), 3.95-3.93 (m, 4H), 3.83 (d, J=6.3 Hz, 2H), 1.98-1.87 (m, 4H), 1.84-1.71 (m, 4H), 1.64-1.56 (m, 1H), 1.56 (s, 9H).
Reaction SMILES: [CH3:1][N:2]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:3]([C:5]1[C:10]([N:11]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=2)(=[O:17])=[O:16])COC)=[CH:9][C:8]([Cl:29])=[CH:7][N:6]=1)=[O:4].Cl>O.O1CCOCC1>[CH3:1][N:2]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:3]([C:5]1[C:10]([NH:11][S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=2)(=[O:17])=[O:16])=[CH:9][C:8]([Cl:29])=[CH:7][N:6]=1)=[O:4]
Reactant: COCN(c1cc(Cl)cnc1C(=O)N(C)c1ccccc1)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CN(C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)c1ccccc1

Procedure:
5-Chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylic acid N-methyl-N-phenylamide (132 mg, 0.24 mmol) was magnetically stirred in water (1.0 mL) and 4N HCl in dioxane (2.5 mL) and heated at 85° C. (oil bath) for 7 h. LCMS indicated complete reaction; the reaction was concentrated and the residue was neutralized (pH 7) with aqueous sodium bicarbonate and the aqueous layer was extracted with EtOAc (3×80 mL). The extracts were dried (MgSO4), filtered, and chromatographed on silica gel using ethyl acetate-hexane gradient (0:100 to 50:50) to provide 5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid N-methyl-N-phenylamide. MS m/z: 504.1 (M+H).
Reaction SMILES: [C:1]1([C:13]([OH:15])=O)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C.[C:47]([NH:50][NH2:51])(=[O:49])[CH3:48]>CN(C)C=O>[C:47]([NH:50][NH:51][C:13]([C:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1)=[O:15])(=[O:49])[CH3:48]
Reactant: O=C(O)c1cn2c3c(cccc13)CCC2
Reactant: CC(=O)NN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)NNC(=O)c1cn2c3c(cccc13)CCC2
Temperature: 80 °C

Procedure:
To a solution of 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1-carboxylic acid (20 mg, 100 μmol) in dry N,N-dimethylformamide (700 μL) were added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (42 mg, 110 μmol), triethylamine (21 μL, 150 μmol), and acetohydrazide (10 μmol). The reaction was heated at 80° C. for 24 hours. The solvent was removed under reduced pressure. To the residue were added 1.5 mL of mixture of butanol and 1,2-dichloroethane (1:2.5) and 1.0 mL of sat. NaHCO3. The organic layer was separated and the solvent was removed under reduced pressure to afford N′-acetyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1-carbohydrazide (55). The crude was used for the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[S:4][CH:5]=[CH:6][CH:7]=1.[Br:10][C:11]1[CH:12]=[CH:13][C:14]([Cl:19])=[C:15]([CH:18]=1)[CH:16]=O>>[Br:10][C:11]1[CH:12]=[CH:13][C:14]([Cl:19])=[C:15]([CH2:16][C:5]2[S:4][C:3]([C:2]([F:9])([F:8])[F:1])=[CH:7][CH:6]=2)[CH:18]=1
Reactant: FC(F)(F)c1cccs1
Reactant: O=Cc1cc(Br)ccc1Cl
Product: FC(F)(F)c1ccc(Cc2cc(Br)ccc2Cl)s1

Procedure:
2-Trifluoromethylthiophene (see Japanese Unexamined Patent Publication No. 2000-34239) and 5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16-(1) were treated in a manner similar to Reference Example 7 to give the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][NH:10][C:11](=[O:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:14](OCC)(=O)[CH2:15]C(C)=O.P(Cl)(Cl)Cl>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14]([CH3:15])=[CH:12][C:11]([OH:13])=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(=O)NNc1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)CC(C)=O
Solvent: ClP(Cl)Cl
Product: Cc1cc(O)nn1-c1ccc(Cl)c(Cl)c1
Temperature: 50 °C
Yield: 41.3 %

Procedure:
To a mixture of (V) (5.0 g, 22.8 mmol) and ethyl acetoacetate (2.97 g 22.8 mmol) was slowly added PCl3 (3.13 g, 22.8 mmol). The mixture was warmed to 50° C. for 1.5 h, poured into ice water (150 ml), and the resulting precipitate was collected on a sintered glass funnel and recrystallized from EtOH to yield (VI) (2.29 g, 41%) as white crystals, mp 208-211° C. (lit. 208-209° C.), TLC CHCl3/MeOH 9:1.
Reaction SMILES: [N+:1]([C:4]1[C:9](Cl)=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])([O-:3])=[O:2].[C:17]1([OH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>O>[N+:1]([C:4]1[C:9]([O:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])([O-:3])=[O:2]
Reactant: CCOC(=O)Cc1cccc(Cl)c1[N+](=O)[O-]
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)Cc1cccc(Oc2ccccc2)c1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 4 h
Yield: 28 %

Procedure:
A mixture of ethyl 2-(2-nitro-3-chlorophenyl)acetate (15 g.), phenol (6.4 g.), anhydrous potassium carbonate (13 g.) and cupric oxide (4.5 g.) was stirred for 4 hours at 120° C. To the reaction mixture was added water and the mixture was extracted with diethyl ether. The extract was washed with a diluted aqueous solution of potassium carbonate and water, dried over magnesium sulfate and then evaporated under reduced pressure. The oily residue was distilled under reduced pressure to give ethyl 2-(2-nitro-3-phenoxypheny)acetate (5.2 g.) bp 160°-183° C./0.4 mmHg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]2[N:14]=[C:15]3[CH:21]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([N:28]5[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]5)=[CH:24][CH:23]=4)[NH:19][C:16]3=[N:17][CH:18]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.ClS([N:39]=[C:40]=O)(=O)=O>CN(C)C=O>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([CH2:11][CH2:12][C:13]2[N:14]=[C:15]3[C:21]([C:40]#[N:39])=[C:20]([C:22]4[CH:23]=[CH:24][C:25]([N:28]5[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]5)=[CH:26][CH:27]=4)[NH:19][C:16]3=[N:17][CH:18]=2)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: COc1cc(CCc2cnc3[nH]c(-c4ccc(N5CCN(C)CC5)cc4)cc3n2)cc(OC)c1
Solvent: CN(C)C=O
Product: COc1cc(CCc2cnc3[nH]c(-c4ccc(N5CCN(C)CC5)cc4)c(C#N)c3n2)cc(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.8 %

Procedure:
To a stirred solution of 2-[2-(3,5-dimethoxyphenyl)ethyl]-6-[4-(4-methylpiperazin-1-yl)phenyl]-5H-pyrrolo[2,3-b]pyrazine (from Example 1, Step 5, 50.0 mg, 10.9 μmol) in N,N-dimethylformamide (2 mL), chlorosulfonyl isocyanate (24.0 μL, 27.6 μmol) was added at 0° C. The reaction mixture was then warmed to ambient temperature and kept stirring overnight. The volatiles were removed and the residue was purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.05% TFA, at flow rate of 30 mL/min) to give the desired product (1.2 mg) as its TFA salt. LCMS calculated for C28H31N6O2 (M+H)+: m/z=483.2. Found: 483.2.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[N:19]([CH3:20])[N:18]=[C:17]([O:21][CH2:22][CH2:23][OH:24])[C:16]=2[C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Br:37][C:38]1[CH:39]=[N:40][C:41](Cl)=[N:42][CH:43]=1.[Cl-].[NH4+]>C1COCC1.O>[Br:37][C:38]1[CH:39]=[N:40][C:41]([O:24][CH2:23][CH2:22][O:21][C:17]2[C:16]([C:25]3[CH:26]=[CH:27][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:29][CH:30]=3)=[C:15]([NH:14][S:11]([C:8]3[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][CH:9]=3)(=[O:12])=[O:13])[N:19]([CH3:20])[N:18]=2)=[N:42][CH:43]=1
Reactant: Clc1ncc(Br)cn1
Reactant: Cn1nc(OCCO)c(-c2ccc(C(F)(F)F)cc2)c1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1nc(OCCOc2ncc(Br)cn2)c(-c2ccc(C(F)(F)F)cc2)c1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To 4-(tert-butyl)-N-{3-(2-hydroxyethoxy)-1-methyl-4-[4-(trifluoromethyl)phenyl]-1H-pyrazol-5-yl}benzenesulfonamide (Example 12) (60 mg) in THF (6 ml) at 0° C. was added sodium hydride (12 mg of a 60% dispersion in oil) followed by the 5-bromo-2-chloropyrimidine (39 mg) The reaction was stirred for one hour at 0° C. and then at room temperature overnight. Water (5 ml) was then added to the reaction followed by saturated aqueous ammonium chloride (5 ml) and the mixture was extracted with ethyl acetate (3×10 ml). The combined organics were washed with saturated aqueous ammonium chloride (20 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield the crude material (61 mg). The crude material was purified by HPLC on a 5μ ODS Phenomenex Magellen™ column with a gradient elution of acetonitrile (5% to 95%) and 0.1M NH4OAc (95% to 5%) to yield the desired product as an off white solid (15.5 mg).
Reaction SMILES: [C:1]([S:5][CH2:6][C:7]1[CH:25]=[C:24]([NH:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[CH:23]=[CH:22][C:8]=1[O:9][C:10]1[CH:11]=[C:12]([CH2:18][C:19]([OH:21])=[O:20])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17])([CH3:4])([CH3:3])[CH3:2].[CH2:33]([O:40][C:41]([C@H:43]1[C@H:48]([OH:49])[C@@H:47]([OH:50])[C@H:46]([OH:51])[C@H:45](O)[O:44]1)=[O:42])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CC#N>[CH2:33]([O:40][C:41]([C@H:43]1[C@H:48]([OH:49])[C@@H:47]([OH:50])[C@H:46]([OH:51])[C@H:45]([O:20][C:19](=[O:21])[CH2:18][C:12]2[CH:13]=[CH:14][C:15]([O:16][CH3:17])=[C:10]([O:9][C:8]3[CH:22]=[CH:23][C:24]([NH:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:25][C:7]=3[CH2:6][S:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH:11]=2)[O:44]1)=[O:42])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: COc1ccc(CC(=O)O)cc1Oc1ccc(NC(=O)C(C)(C)C)cc1CSC(C)(C)C
Reactant: O=C(OCc1ccccc1)[C@@H]1O[C@@H](O)[C@@H](O)[C@H](O)[C@H]1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CC#N
Product: COc1ccc(CC(=O)O[C@@H]2O[C@@H](C(=O)OCc3ccccc3)[C@H](O)[C@@H](O)[C@@H]2O)cc1Oc1ccc(NC(=O)C(C)(C)C)cc1CSC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
{3-[2-tert-Butylsulfanylmethyl-4-(2,2-dimethyl-propionylamino)-phenoxy]-4-methoxy-phenyl}-acetic acid (0.200 g, 0.44 mmol), (2R,3R,4R,5S,6R)-3,4,5,6-tetrahydroxy-tetrahydro-pyran-2-carboxylic acid benzyl ester (0.200 g, 0.7 mmol; prepared according to the procedure described in Tetrahedron 2007, 63, 7596), HATU (0.266 g, 0.7 mmol), and N-methylmorpholine (0.1 mL, 0.7 mmol) were combined in MeCN, and the reaction was stirred overnight at room temperature. The mixture was concentrated, and the residue was purified by preparative HPLC to give (2R,3R,4R,5 S,6S)-6-(2-{3-[2-tert-butylsulfanylmethyl-4-(2,2-dimethyl-propionylamino)-phenoxy]-4-methoxy-phenyl}-acetoxy)-3,4,5-trihydroxy-tetrahydro-pyran-2-carboxylic acid benzyl ester, which was subsequently treated with palladium hydroxide on carbon and stirred under an atmosphere of H2 overnight. The crude material was purified by preparative HPLC to give (2R,3R,4R,5 S,6S)-6-(2-{3-[2-tert-Butylsulfanylmethyl-4-(2,2-dimethyl-propionylamino)-phenoxy]-4-methoxy-phenyl}-acetoxy)-3,4,5-trihydroxy-tetrahydro-pyran-2-carboxylic acid.
Reaction SMILES: [CH2:1]([N:8]([C@@H:16]([CH2:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[C:17]([O:19]C)=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[CH2:1]([N:8]([C@@H:16]([CH2:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[C:17]([OH:19])=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H](CC1CCCCC1)N(Cc1ccccc1)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)[C@H](CC1CCCCC1)N(Cc1ccccc1)Cc1ccccc1
Yield: 99.4 %

Procedure:
Methyl 2(S)-(N,N-dibenzylamino)-3-cyclohexylpropionate (200 g) was dissolved in methanol (1 l), and thereto was added an aqueous solution of sodium hydroxide (sodium hydroxide 32.8 g, water 200 ml), followed by refluxing for 6 hours. After the completion of the reaction, the reaction mixture was concentrated, and ethyl acetate (1 l) was added to the residue for dissolution, after which water (400 ml) was added for partition. The organic layer was separated, washed with an aqueous solution of 10% citric acid (400 ml) and saturated brine (400 ml), and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give 191.1 g of 2(S)-(N,N-dibenzylamino)-3-cyclohexylpropionic acid.
Reaction SMILES: [ClH:1].[CH2:2]([N:5]([CH2:15][CH2:16][CH3:17])[C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][N:14]=1)[C:9]([OH:11])=O)[CH2:3][CH3:4].C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:52][C@@H:53]([CH2:67][C:68]1[CH:73]=[C:72]([F:74])[CH:71]=[C:70]([F:75])[CH:69]=1)[C@H:54]([OH:66])[CH2:55][NH:56][CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[C:60]([CH2:64][CH3:65])[CH:59]=1>C(Cl)Cl.C(N(CC)CC)C>[ClH:1].[F:74][C:72]1[CH:73]=[C:68]([CH:69]=[C:70]([F:75])[CH:71]=1)[CH2:67][C@H:53]([NH:52][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][N:14]=[C:6]([N:5]([CH2:2][CH2:3][CH3:4])[CH2:15][CH2:16][CH3:17])[CH:7]=1)[C@H:54]([OH:66])[CH2:55][NH:56][CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[C:60]([CH2:64][CH3:65])[CH:59]=1
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: CCCN(CCC)c1cc(C(=O)O)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCN(CCC)c1cc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNCc2cccc(CC)c2)ccn1
Temperature: 40 °C
Reaction time: 4 h
Yield: 23.6 %

Procedure:
To a mixture of 2-(Dipropylamino)isonicotinic acid hydrochloride (0.2 g) in methylene chloride (15 mL) was added triethylamine (0.195 g), HOBT (0.105 g), and HATU (0.293 g). The mixture was stirred at 39° C. for 10 minutes at which time (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol (0.285 g) was added. The mixture was stirred at 40° C. for 4 h then poured into methylene chloride (50 mL), washed with water then brine, dried over anhydrous magnesium sulfate and concentrated under vacuum. Column chromatography on silica gel (100 mL) using 5% methanol in methylene chloride as eluent and conversion to the hydrochloride salt gave 0.105 g of the title compound: MS (ESI+) for C31H40F2N4O2 m/z 539.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][O:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9]CC1C=CC=CC=1>C(O)(=O)C.[Pd]>[CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][O:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9]
Reactant: CC(C)(C)COCCCCOCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(C)(C)COCCCCO
Reaction time: 3 h
Yield: 27.8 %

Procedure:
To a solution of {[4-(2,2-dimethylpropoxy)butoxy]methyl}benzene (1.50 g) in acetic acid (30 mL) was added 10% palladium-activated carbon (500 mg), followed by stirring under hydrogen atmosphere for 3 hours. The catalyst was removed by filtration, and the solvent was evaporated under reduced pressure to obtain 4-(2,2-dimethylpropoxy)butan-1-ol (267 mg).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[CH:14]=[C:15]4[C@:20]([C:22]([C:24]5[N:25]=[CH:26][S:27][CH:28]=5)=[O:23])([CH2:21][C:12]=3[CH:11]=[N:10]2)[CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]4)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[Cl:45][C:46]1[CH:47]=[C:48]([S:53](Cl)(=[O:55])=[O:54])[CH:49]=[CH:50][C:51]=1[Cl:52]>CCOCC.ClCCl>[Cl:45][C:46]1[CH:47]=[C:48]([S:53]([N:18]2[CH2:17][CH2:16][C:15]3[C@:20]([C:22]([C:24]4[N:25]=[CH:26][S:27][CH:28]=4)=[O:23])([CH2:21][C:12]4[CH:11]=[N:10][N:9]([C:6]5[CH:5]=[CH:4][C:3]([F:2])=[CH:8][CH:7]=5)[C:13]=4[CH:14]=3)[CH2:19]2)(=[O:54])=[O:55])[CH:49]=[CH:50][C:51]=1[Cl:52]
Reactant: CC(C)(C)OC(=O)N1CCC2=Cc3c(cnn3-c3ccc(F)cc3)C[C@]2(C(=O)c2cscn2)C1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1cscn1)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(Cl)c(Cl)c1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
To HCl 2M in ether (2809 μl, 5.62 mmol) was added (R)-tert-butyl 1-(4-fluorophenyl)-4a-(thiazole-4-carbonyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate (135 mg, 0.281 mmol) as a solution in ether (1 mL). The resulting suspension was stirred at room temperature for 1 h. The solvent was removed to give a white solid. This was dissolved in dichloromethane (1.4 mL) and Hunig's base (245 μl, 1.405 mmol), and 3,4-dichlorobenzene-1-sulfonyl chloride (76 mg, 0.309 mmol) was added to the solution. The resulting solution was stirred at room temperature for 18 h. The crude product was purified by chromatography on silica gel (gradient: 5-95% ethyl acetate in isohexane to afford (R)-(6-((3,4-dichlorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone (111 mg) as a pale yellow solid. LCMS (Method F, ES-API): RT 2.76 min, m+H=588.8; 1H NMR (400 MHz, CDCl3): δ 8.85 (1H, d, J=2.2 Hz), 8.22 (1H, d, J=2.2 Hz), 7.77 (1H, t, J=1.2 Hz), 7.52 (2H, d, J=1.2 Hz), 7.45-7.40 (2H, m), 7.28 (1H, s), 7.20-7.13 (2H, m), 6.52 (1H, d, J=2.2 Hz), 5.44 (1H, dd, J=12.6, 2.2 Hz), 4.13 (1H, d, J=16.8 Hz), 3.90-3.87 (1H, m), 2.92-2.81 (2H, m), 2.78 (1H, d, J=12.6 Hz), 2.62-2.50 (2H, m).