Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.OC1C2N=NNC=2C=CC=1.Cl.[CH3:13][O:14][CH2:15][CH2:16][N:17]([CH2:24][C:25]1[CH:26]=[C:27]([CH:43]=[CH:44][CH:45]=1)[CH2:28][CH2:29][NH:30][C:31]1[C:32](=[O:42])[N:33]([CH2:38][C:39](O)=[O:40])[C:34]([CH3:37])=[CH:35][N:36]=1)[C:18](=[O:23])[C:19]([F:22])([F:21])[F:20].CN1CCOCC1.[CH3:53][C:54]1[C:62]2[C:57](=[CH:58][CH:59]=[C:60]([CH2:63][NH2:64])[CH:61]=2)[NH:56][CH:55]=1>CN(C)C=O>[F:21][C:19]([F:20])([F:22])[C:18]([N:17]([CH2:16][CH2:15][O:14][CH3:13])[CH2:24][C:25]1[CH:45]=[CH:44][CH:43]=[C:27]([CH2:28][CH2:29][NH:30][C:31]2[C:32](=[O:42])[N:33]([CH2:38][C:39]([NH:64][CH2:63][C:60]3[CH:61]=[C:62]4[C:57](=[CH:58][CH:59]=3)[NH:56][CH:55]=[C:54]4[CH3:53])=[O:40])[C:34]([CH3:37])=[CH:35][N:36]=2)[CH:26]=1)=[O:23]
Reactant: Cc1c[nH]c2ccc(CN)cc12
Reactant: COCCN(Cc1cccc(CCNc2ncc(C)n(CC(=O)O)c2=O)c1)C(=O)C(F)(F)F
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: COCCN(Cc1cccc(CCNc2ncc(C)n(CC(=O)NCc3ccc4[nH]cc(C)c4c3)c2=O)c1)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Hydroxybenzotriazole hydrate (60 mg, 0.44 mmol) and WSCDl.HCl (93 mg, 0.47 mmol) were added to a solution of 2-[3-[(3-{[(2-methoxyethyl)(2,2,2-trifluoroacetyl)amino]methyl}phenethyl)amino]-6-methyl-2-oxo-1(2H)-pyrazinyl]acetic acid (190 mg, 0.40 mmol) [see preparation 44] in N,N-dimethylformamide (3.0 ml). N-methylmorpholine (123 mg, 1.2 mmol) was added followed by (3-methyl-1H-indol-5-yl)methylamine (72 mg, 0.45 mmol) [see preparation 36]. The reaction mixture was stirred at room temperature for 18 hrs, after which time the mixture was partitioned between ethyl acetate (30 ml) and water (30 ml). The organic layer was washed with water (3×30 ml), brine (30 ml) and dried over MgSO4 and the solvent evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol:0.88 ammonia (99:1:0.1) changing to (98:2:0.2) to afford the title compound as a oil, 113 mg (53%).
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[C:13]2[N:14]([CH3:22])[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:16][C:12]=2[C:11]([CH3:24])([CH3:23])[CH2:10][NH:9][CH:8]=1)=[O:6])([CH3:3])[CH3:2].[F:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][C:34]=1[F:35])[C:29](Cl)=[O:30]>>[CH:1]([O:4][C:5]([C:7]1[C:13]2[N:14]([CH3:22])[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:16][C:12]=2[C:11]([CH3:24])([CH3:23])[CH2:10][N:9]([C:29](=[O:30])[C:28]2[CH:32]=[CH:33][C:34]([F:35])=[C:26]([F:25])[CH:27]=2)[CH:8]=1)=[O:6])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Reactant: CCOC(=O)c1cc2c(n1C)C(C(=O)OC(C)C)=CNCC2(C)C
Product: CCOC(=O)c1cc2c(n1C)C(C(=O)OC(C)C)=CN(C(=O)c1ccc(F)c(F)c1)CC2(C)C

Procedure:
The title compound was prepared in a manner similar to that described in Example 2 by using 1,4,4-trimethyl-1,4,5,6-tetrahydro-pyrrolo[2,3-d]azepine-2,8-dicarboxylic acid 2-ethyl ester 8-isopropyl ester and 3,4-difluoro-benzoyl chloride. 1H-NMR(CDCl3): δ 7.75 (1H, s), 7.43 (1H, m), 7.28 (2H, m), 6.86 (1H, d), 5.06 (1H, m), 4.28 (2H, q), 3.87 (2H, s), 3.66 (3H, s), 1.35 (3H, 3), 1.33 (6H, s), 1.21 (6H, d). MS (ES): 475 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.Cl.[C:26]([NH2:30])([CH3:29])([CH3:28])[CH3:27].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH2:10][C:11](=[O:13])[NH:30][C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: CC(C)(C)N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Product: CC(C)(C)NC(=O)CCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 3-tert-Butoxycarbonylamino-propionic acid (0.5 g, 2.64 mmol) in DCM (5 ml) under an inert atmosphere is treated with 1-hydroxy-7-azabenzatriazole (0.108 g, 0.79 mmol) followed by water soluble carbodiimide (0.491 g, 3.17 mnol) and tert-butylamine (0.305 ml, 2.91 mmol). The reaction mixture is stirred at room temperature for 3 hours and then citric acid (10 ml, 0.5 M) is added to the solution and extracted with DCM (2×10 ml). The combined organic layers are washed with brine (10 ml) and dried over MgSO4. After filtration, the solvent is removed in vacuo to yield the titled compound as an oil.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH3:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:18]Br>C(O)(=O)C>[C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([Br:18])=[CH:12][C:11]=1[O:16][CH3:17])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccccc1OC(=O)c1ccccc1
Reactant: BrBr
Solvent: CC(=O)O
Product: COc1cc(Br)ccc1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of 2-methoxyphenyl benzoate (29.1 g) in glacial acetic acid (150 mL) is treated with a solution of bromine (7.2 mL) in glacial acetic acid (25 mL) during a period of 20 minutes, and the solution is then stirred for a further period of 30 minutes at room temperature. The mixture is concentrated in vacuo, and the resulting residue is dissolved in methyl t-butyl ether (200 mL), washed with water (100 mL) and saturated aqueous sodium bicarbonate solution (3×100 mL), dried over magnesium sulphate and evaporated. The resulting residue is recrystallized from cyclohexane, to give 4-bromo-2-methoxyphenyl benzoate (22.7), m.p. 73°-75° C. [Elemental analysis: C,55.0; H,3.6; Br, 25.5%; calculated: C,54.6; H,3.9; Br, 25.9%].
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH2:12]([N:16]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N+:26]([O-:28])=[O:27])(=[O:19])=[O:18])[CH2:13][CH:14]=[CH2:15]>C(Cl)(Cl)Cl.O.C([O-])(O)=O.[Na+]>[N+:26]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[S:17]([N:16]([CH2:12][CH2:13][CH:14]1[CH2:15][O:9]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=[O:19])=[O:18])([O-:28])=[O:27]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCCN(c1ccccc1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)N(CCC1CO1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
mCPBA (77%, 0.0550 g, 0.246 mmol) was added to N-(but-3-enyl)-2-nitro-N-phenylbenzenesulfonamide (0.0653 g, 0.196 mmol) in 1 mL CHCl3 at 0° C. The mixture was stirred at 0° C. for 30 min, then gradually warmed up to room temperature and continued to stir for 18 hr. After TLC showed the disappearance of starting material, the reaction mixture was diluted with a 1:1 mixture of water and saturated NaHCO3 (2×10 mL) and water (10 mL). The organic layer was dried over anhydrous Na2SO4 and evaporated to afford the crude product, which was subjected to silica gel chromatography using Hexanes/EtOAc to afford 0.0662 g colorless oil as product, yield 96.9%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)(O)[CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)=[C:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)C(O)(c1ccc(F)cc1)c1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)=C(c1ccc(F)cc1)c1ccc(F)cc1
Yield: 41.3 %

Procedure:
A solution of ethyl 3,3-bis(4-fluorophenyl)-3-hydroxy-2-methylpropionate (0.5 g, 1.6 mmol) and p-toluenesulfonic acid (0.18 g) in toluene was heated at reflux for 2.5 hours. The solution was cooled and washed with saturated sodium bicarbonate solution and water. The organic layer was dried with magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica eluting with 0.5% ethyl acetate in hexane to give 0.2 g of the product as a clear oil which was crystallized from petroleum ether to give 0.15 g of the title compound; m.p. =75°-76° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([OH:13])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:20](Cl)(=[O:22])[CH3:21]>ClCCl.C1(C)C=CC=CC=1>[C:1]([C:5]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([C:20](=[O:22])[CH3:21])=[C:7]([OH:13])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(O)cc1C(C)(C)C
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc(C(C)=O)c(O)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 2.4 %

Procedure:
3-Tert-butyl-4-methoxyphenol (1.00 g) was dissolved in dichloromethane (10 ml) to prepare a solution. Pyridine (658 mg) and acetyl chloride (599 mg) were added to the solution, and the mixture was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure, water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous magnesium sulfate, and the solvent was then removed by distillation under the reduced pressure. The residue was dried under the reduced pressure. Scandium trifluoromethane sulfonate (327 mg) was added to the compound thus obtained, the mixture was suspended in toluene (5 ml), and the suspension was heated under reflux overnight. The reaction solution was cooled to room temperature, and the reaction solution was then filtered. The solvent was removed from the filtrate by distillation under the reduced pressure, water was then added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give 1-(4-tert-butyl-2-hydroxy-5-methoxy-phenyl)-ethanone (30 mg, yield 5%).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([NH:21][C@@H:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:24][C@H:23]3[NH2:31])=[N:6][C:7]([CH:18]3[CH2:20][CH2:19]3)=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=3[Cl:17])[N:9]=2)[CH2:3][CH2:2]1.[CH3:32][O:33][CH2:34][CH:35]=O.[BH3-]C#N.[Na+]>CO.C(O)(=O)C.C([O-])(O)=O.[Na+]>[CH:1]1([C:4]2[C:5]([NH:21][C@@H:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:24][C@H:23]3[NH:31][CH2:35][CH2:34][O:33][CH3:32])=[N:6][C:7]([CH:18]3[CH2:19][CH2:20]3)=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=3[Cl:17])[N:9]=2)[CH2:2][CH2:3]1
Reactant: COCC=O
Reactant: N[C@@H]1Cc2ccccc2[C@H]1Nc1nc(C2CC2)c(-c2ccc(Cl)cc2Cl)nc1C1CC1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COCCN[C@@H]1Cc2ccccc2[C@H]1Nc1nc(C2CC2)c(-c2ccc(Cl)cc2Cl)nc1C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.1 %

Procedure:
To a solution of (1R,2R)-N1-[3,6-dicyclopropyl-5-(2,4-dichlorophenyl)pyrazin-2-yl]-2,3-dihydro-1H-indene-1,2-diamine (0.10 g, 0.22 mmol) in MeOH (2 mL) containing acetic acid (2 drops) and methoxyacetaldehye (49 mg, 0.66 mmol) was added NaBH3CN (1 M solution in THF, 0.8 mL, 0.8 mmol). The mixture was stirred at rt overnight. Dilute with sat. aq. NaHCO3 and extract ED with EtOAc (3×30 mL). The combined organic extracts were dried over MgSO4, filtered and concentrated to afford an oil that was purified by biotage MPLC (90 g column, 10% ethyl acetate/hexanes) to afford 0.11 g (20%) of (1R,2R)-N1-[3,6-dicyclopropyl-5-(2,4-dichlorophenyl)pyrazin-2-yl]-N2-(2-methoxyethyl)-2,3-dihydro-1H-indene-1,2-diamine as a solid: 1H NMR (CDCl3) δ 0.60-1.01, 1.45-1.70, 2.83-2.99, 3.22-3.33, 3.47-3.56, 5.19, 5.53, 7.11-7.42; MS (ESI+) for C28H30Cl2N4O m/z 509 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=1)[O:12][CH2:13][CH2:14][CH2:15][NH2:16].[Cl:20][CH2:21][C:22](O)=[O:23].C(Cl)CCl.O>ClCCl>[NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=1)[O:12][CH2:13][CH2:14][CH2:15][NH:16][C:22](=[O:23])[CH2:21][Cl:20]
Reactant: O=C(O)CCl
Reactant: NCCCOc1cccc(CC2CCCCCN2)c1
Solvent: ClCCCl
Solvent: ClCCl
Solvent: O
Product: O=C(CCl)NCCCOc1cccc(CC2CCCCCN2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
0.22 g of 3-{3-(1-perhydroazepinylmethyl)phenoxy}propylamine was dissolved in 10 ml of dichloromethane, and cooled in an ice bath. 0.1 g of monochloroacetic acid and 0.2 g of EDC were added to this solution, and stirred at 0° C. for 30 minutes then at room temperature overnight. 10 ml of water and 10 ml of dichloromethane were added to the reaction solution, and the organic layer was separated, dried over anhydrous magnesium sulfate, and the solvent was evaporated in vacuo to obtain colorless oily N-[3-{3-(1-perhydroazepinylmethyl)phenoxy}propyl]-2-chloroacetamide. Yield: 0.15 g. ##STR159##
Reaction SMILES: C(N)(C)(C)C.[CH3:6][O:7][C:8](=[O:17])[C:9](=[C:14]([CH3:16])[CH3:15])[CH2:10][C:11]([OH:13])=[O:12]>CO>[CH3:6][O:7][C:8](=[O:17])[C@H:9]([CH:14]([CH3:15])[CH3:16])[CH2:10][C:11]([OH:13])=[O:12]
Reactant: COC(=O)C(CC(=O)O)=C(C)C
Solvent: CO
Solvent: CC(C)(C)N
Product: COC(=O)[C@@H](CC(=O)O)C(C)C
Temperature: 0 °C
Reaction time: 22 h

Procedure:
A solution of the tert-butylamine salt of 2-isopropylidenesuccinic acid 1-methyl ester (162 g, 0.66 mol) in methanol (800 mL) was transferred to a 2 L high pressure hydrogenation vessel and degassed by pressurizing and venting four times with 10 bar of hydrogen. The vessel was then cooled to 0° C. and a solution of [Rh(COD)(S,S)-Me-BPE]OTf (0.80 g, 0.0013 mmol) in methanol (10 mL) was added through the solvent port. The reaction was purged again with hydrogen and stirred at 0° C. under a pressure of hydrogen of 10−7 bar. After 22 hours, the temperature was allowed to raise to room temperature, the vessel was vented in a fume hood, the reaction mixture was transferred to a round-bottomed flask and the solvent was evaporated under reduced pressure. A sample (1 g) of the resulting solid residue was partitioned between HCl 2N (5 mL) and ethyl acetate (5 mL). The organic layer was dried over MgSO4 and evaporated to give 2-(S)-isopropylsuccinic acid 1-methyl ester, ee 96% by GC. The bulk residue was suspended in ethyl acetate (600 mL) and stirred at room temperature for 48 hours, then collected and dried under vacuum to give 154 g of the tert-butylamine salt of 2-(S)-isopropylsuccinic acid monomethyl ester (yield: 94%). A sample (1 g) of the salt was worked up and analyzed as above, indicating an enantiomeric excess of 99% for the free acid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[N:9][NH:10][C:4]=2[CH:3]=1.[C:15]1([C@H:21]([NH:23][C:24]([NH2:26])=[O:25])[CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CC(C)([O-])C.[K+]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.C1COCC1>[CH3:14][S:11]([C:8]1[C:5]2[CH:6]=[N:7][C:2]([NH:26][C:24]([NH:23][C@@H:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH3:22])=[O:25])=[CH:3][C:4]=2[NH:10][N:9]=1)(=[O:13])=[O:12]
Reactant: CS(=O)(=O)c1n[nH]c2cc(Cl)ncc12
Reactant: C[C@@H](NC(N)=O)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: C[C@@H](NC(=O)Nc1cc2[nH]nc(S(C)(=O)=O)c2cn1)c1ccccc1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
6-Chloro-3-(methylsulfonyl)-1H-pyrazolo[4,3-c]pyridine (45 mg, 0.194 mmol), (R)-1-(1-phenylethyl)urea (38.3 mg, 0.233 mmol), and BrettPhos pre-catalyst (21.72 mg, 0.027 mmol) were taken up in THF (650 μL) in a 1.5 mL microwave vial. Potassium t-butoxide (1 M in THF, 583 μL, 0.583 mmol) was added and the vial was evacuated and back-filled with N2 (×3). The reaction mixture was stirred at 60° C. for 18 h. The crude reaction mixture was filtered through a Si-Thiol cartridge (6 mL, 500 mg) to remove excess Pd. The filtrate was concentrated in vacuo, dissolved in DMSO/MeOH (with a few drops of TFA), and purified by mass triggered, reverse phase prep-HPLC. The fractions containing pure product were concentrated in vacuo to afford (R)-1-(3-(methylsulfonyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea. MS ESI calc'd. For C16H17N5O3S [M+1]+ 360. found 360. 1H NMR (500 MHz, DMSO-d6) δ 9.21 (s, 1H), 8.92 (s, 1H), 7.87 (s, 1H), 7.50 (br s, 5H), 4.92-4.80 (m, 1H), 3.38 (s, 3H) 1.40 (d, J=7.0 Hz, 3H).
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[O:12][CH3:13])[C:3]#[N:4].[C:14]([Si:18]([CH3:28])([CH3:27])[O:19][C:20]([CH3:26])([CH3:25])[CH2:21][C:22](O)=[O:23])([CH3:17])([CH3:16])[CH3:15].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[Si:18]([O:19][C:20]([CH3:26])([CH3:25])[CH2:21][C:22]([NH:1][CH:2]([C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[O:12][CH3:13])[C:3]#[N:4])=[O:23])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:28])[CH3:27]
Reactant: CC(C)(CC(=O)O)O[Si](C)(C)C(C)(C)C
Reactant: COc1ccc(Cl)cc1C(N)C#N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Cl)cc1C(C#N)NC(=O)CC(C)(C)O[Si](C)(C)C(C)(C)C
Reaction time: 18 h
Yield: 70.9 %

Procedure:
2-amino-2-(5-chloro-2-methoxyphenyl)acetonitrile (500 mg, 2.54 mmol) in DMF (2 mL) was added to a solution of 3-(tert-butyl-dimethyl-silanyloxy)-3-methyl-butyric acid (prepared according to patent EP2025667) (590 mg, 2.54 mmol), diisopropylethylamine (0.87 mL, 5.08 mmol) and HATU (966 mg, 2.54 mmol) in DMF (5 mL) and stirred for 18 hours. Ethyl acetate was added, the organics washed with sodium hydrogen carbonate (sat. aq.) and brine, then evaporated to dryness. The residues were purified by flash chromatography on silica gel (0 to 5% ethyl acetate in dichloromethane) to yield 740 mg (73%) of 3-(tert-butyldimethylsilyloxy)-N-((5-chloro-2-methoxyphenyl)(cyano)methyl)-3-methylbutanamide. LCMS (ESI) m+H=411.4.
Reaction SMILES: C(OC(=O)[NH:10][C@@H:11]([CH3:35])[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]3[O:24][C:23]([CH2:25][NH:26][C:27]([C:29]4[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=4)=[O:28])=[CH:22][C:20]3=2)[CH:15]=[N:14]1)C1C=CC=CC=1>CO.[Pd]>[NH2:10][C@@H:11]([CH3:35])[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]3[O:24][C:23]([CH2:25][NH:26][C:27](=[O:28])[C:29]4[CH:34]=[CH:33][CH:32]=[N:31][CH:30]=4)=[CH:22][C:20]3=2)[CH:15]=[N:14]1
Reactant: C[C@@H](Cn1ncc2ccc3oc(CNC(=O)c4cccnc4)cc3c21)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: C[C@H](N)Cn1ncc2ccc3oc(CNC(=O)c4cccnc4)cc3c21
Temperature: 25 °C
Reaction time: 48 h
Yield: 86.7 %

Procedure:
To a solution of the product from Step C (0.16 g, 0.33 mmol) in methanol (20 mL) was added 10% Palladium on carbon (20 mg) and this mixture was stirred under an atmosphere of hydrogen at room temperature for two days. The reaction mixture was filtered and the filtrate evaporated to give a colorless oil (0.10 g, 87%): LC/MS m/z 350 [M+H]+; 1H NMR (CD3OD) δ 9.052 (s, 1H), 8.70 (m, 1H), 8.31 (m, 1H), 8.08 (s, 1H), 7.62 and 7.36 (ABq, J=9 Hz, 2H), 7.56 (m, 1H), 4.50 (overlapping m and s, 4H), 3.47 (m, 1H), 1.08 (d, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]1[CH:13]=[N:14][N:15]3[C:20]([N:21](COCC[Si](C)(C)C)COCC[Si](C)(C)C)=[CH:19][C:18]([CH:38]([NH:40][CH:41]4[CH2:46][CH2:45][O:44][CH2:43][CH2:42]4)[CH3:39])=[N:17][C:16]=13)=[CH:5]2.Cl.C(O)CO.C([O-])(O)=O.[Na+]>O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]1[CH:13]=[N:14][N:15]3[C:20]([NH2:21])=[CH:19][C:18]([CH:38]([NH:40][CH:41]4[CH2:42][CH2:43][O:44][CH2:45][CH2:46]4)[CH3:39])=[N:17][C:16]=13)=[CH:5]2
Reactant: CC(NC1CCOCC1)c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n2ncc(-c3cnc4ccc(F)cc4c3)c2n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: OCCO
Product: CC(NC1CCOCC1)c1cc(N)n2ncc(-c3cnc4ccc(F)cc4c3)c2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.3 %

Procedure:
A stirred solution of 3-(6-fluoroquinolin-3-yl)-5-[1-(tetrahydro-2H-pyran-4-ylamino)ethyl]-N,N-bis{[2-(trimethylsilyl)ethoxy]methyl}pyrazolo[1,5-a]pyrimidin-7-amine (890 mg, 1.33 mmol) in dioxane (4 mL) was treated with 4 M HCl in dioxane (4 mL) followed by 1,2-ethanediol (4 mL), and the resulting amber mixture was stirred at room temperature for 15 min and then at 50° C. for 5 h at which point the reaction was near completion. The mixture was cooled to room temperature, added carefully in portions to saturated aqueous NaHCO3 (200 mL) with stirring, and extracted with DCM (3×100 mL). The combined organic phase was washed with water (100 mL) and brine (50 mL), dried over Na2SO4 and concentrated under reduced pressure. The solid residue was taken up in 10% MeOH/DCM (˜7-8 mL), diluted with diethyl ether (˜40 mL) and the small amount of precipitate that formed was removed by filtration through a fine frit. The filtrate was concentrated under reduced pressure to give 3-(6-fluoroquinolin-3-yl)-5-(1-(tetrahydro-2H-pyran-4-ylamino)ethyl)pyrazolo[1,5-a]pyrimidin-7-amine (510 mg, 80% yield @ 85% purity) as a tan amorphous solid. MS (ESI+) for C22H23FN6O m/z 407 (MAI); HPLC, 2.43 min (Method B).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:7]23[CH2:11][CH:10]([C:12]([CH3:14])([CH3:13])[C:6]2=[CH:5][CH2:4][CH2:3]1)[CH2:9][CH2:8]3.C(OO)(=[O:18])C>>[CH3:1][C:2]1([CH3:15])[C:7]23[CH2:11][CH:10]([C:12]([CH3:14])([CH3:13])[C:6]42[O:18][CH:5]4[CH2:4][CH2:3]1)[CH2:9][CH2:8]3
Reactant: CC1(C)C2=CCCC(C)(C)C23CCC1C3
Reactant: CC(=O)OO
Product: CC1(C)CCC2OC23C(C)(C)C2CCC13C2

Procedure:
In the first stage, isolongifolene (1) can be reacted in a known manner, for example with peracetic acid, to give isolongifolene oxide (2) (Tetrahedron Lett. 1964, 8, 417; J. Org. Chem. 1970, 35, 1172).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[NH:13][C:14]4[C:19]([C:20]=3[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:18][CH:17]=[CH:16][CH:15]=4)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:26][CH2:27][C:28]#[N:29].CC([O-])(C)C.[K+].[CH:36]1[CH:41]=[CH:40][C:39]([CH2:42]Br)=[CH:38][CH:37]=1>C1COCC1>[CH2:42]([N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[C:12]1[C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([Br:1])=[C:3]([O:26][CH2:27][C:28]#[N:29])[CH:4]=[CH:5]2)[C:39]1[CH:40]=[CH:41][CH:36]=[CH:37][CH:38]=1
Reactant: BrCc1ccccc1
Reactant: CCCCCc1c(-c2ccc3c(Br)c(OCC#N)ccc3c2)[nH]c2ccccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCCc1c(-c2ccc3c(Br)c(OCC#N)ccc3c2)n(Cc2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 76 %

Procedure:
To a stirred solution of {[1-bromo-6-(3-pentyl-1H-indol-2-yl)-2-naphthyl]oxy}acetonitrile (0.135 g, 0.257 mmol) in THF (5 mL) at 0° C. was added KOt-Bu (0.032 g, 0.283 mmol) followed by BnBr (0.019 mL, 0.308 mmol). The reaction was warmed to rt and let stir for 24 h. After this time, the reaction mixture was quenched with 1 N HCl (˜2 mL). The resulting solution was diluted with EtOAc (100 mL). The organic layer was washed with 1 N HCl (10 mL), sat. aq. NaHCO3 (10 mL), and brine (10 mL) and then dried (MgSO4). After concentration, the residue was purified by preparatory plate chromatography (20% EtOAc:petroleum ether) to afford the product (0.105 g, 56%) as a solid; 1H NMR (DMSO-d6) δ 0.73 (t, J=7.4 Hz, 3H), 1.09-1.23 (m, 4H), 1.47-1.63 (m, 2H), 2.70 (t, J=7.7 Hz, 2H), 5.34 (s, 2H), 5.46 (s, 2H), 6.81 (d, J=7.4 Hz, 2H), 7.04-7.23 (m, 5H), 7.41 (d, J=8.1 Hz, 1H), 7.62-7.73 (m, 3H), 8.02 (s, 1H), 8.12 (d, J=9.2 Hz, 1H), 8.20 (d, J=9.2 Hz, 1H); mass spectrum [(+) ESI], m/z 537/539 (M+H)+.