Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]([N:5]1[CH:9]=[C:8]([CH2:10][CH2:11][CH2:12][OH:13])[N:7]=[CH:6]1)=[O:4].C(N(CC)CC)C.Cl[Si:23]([CH3:26])([CH3:25])[CH3:24]>C(#N)C.CCOCC>[CH3:14][N:2]([CH3:1])[C:3]([N:5]1[CH:9]=[C:8]([CH2:10][CH2:11][CH2:12][O:13][Si:23]([CH3:26])([CH3:25])[CH3:24])[N:7]=[CH:6]1)=[O:4]
Reactant: CN(C)C(=O)n1cnc(CCCO)c1
Reactant: C[Si](C)(C)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CN(C)C(=O)n1cnc(CCCO[Si](C)(C)C)c1
Reaction time: 15 h

Procedure:
1-Dimethylcarbamoyl-4-(3-hydroxypropyl)-imidazole (19.8 g, 0.10 mole) and triethylamine (15 g, 0.15 mole) are dissolved in acetonitrile (100 mL) and the solution is stirred and cooled in an ice bath during the dropwise addition of chlorotrimethylsilane (11.9 g, 0.11 mole). The reaction is stirred at ice-bath temperature for 1 hour and is subsequently allowed to stand at ambient temperature for 15 hours. The mixture is diluted with ether (500 mL), filtered, and the solvent is evaporated to give 1-dimethylcarbamoyl-4-(3-trimethylsilyloxypropyl)-imidazole as an oil; NMR (imidazole protons): 2.2 (s) and 3.05 (s) ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:14]=3[N:15]=2)[C:7](F)=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH2:24]([NH2:27])[CH2:25][CH3:26]>>[N+:1]([C:4]1[CH:5]=[C:6]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:14]=3[N:15]=2)[C:7]([NH:27][CH2:24][CH2:25][CH3:26])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(F)c(-c2nc3cc(C(F)(F)F)ccc3o2)c1
Reactant: CCCN
Product: CCCNc1ccc([N+](=O)[O-])cc1-c1nc2cc(C(F)(F)F)ccc2o1

Procedure:
Prepared by the method of Example 54a), from 2-(3-nitro-6-fluorophenyl)-5-trifluoromethylbenzoxazole (218 mg, 0.8 mmol) and propylamine (328 μL, 4.0 mmol) the subtitle compound was obtained. The product was used directly in the next step without purification.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23](O)=[O:24])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.Cl.[NH2:27][C@@H:28]([CH3:36])[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl>O1CCCC1.C(#N)C>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][C:23]([NH:27][C@@H:28]([CH3:36])[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:24])=[CH:19][CH:20]=2)=[CH:11][CH:10]=1
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Reactant: C[C@@H]1CCCN1CCc1ccc(-c2ccc(CCC(=O)O)cc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CC#N
Product: C[C@H](NC(=O)CCc1ccc(-c2ccc(CCN3CCC[C@H]3C)cc2)cc1)C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-3-(4′-(2-(2-methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl)propanoic acid (40 mg, 0.119 mmol), (S)-tert-butyl 2-aminopropanoate hydrochloride (25.8 mg, 0.142 mmol), and TEA (0.050 mL, 0.356 mmol) in tetrahydrofuran (1 mL) and acetonitrile (1 mL) was added HATU (54.1 mg, 0.142 mmol). The reaction was stirred at 60° C. for 2 h. The mixture was added 1M HCl (1 mL) and purified by HPLC to give the title compound. LCMS m/z=465.5 [M+H]+; 1H NMR (400 MHz, CD3CN) δ ppm 1.27 (d, J=6.7 Hz, 0.4H), 1.28 (d, J=7.2 Hz, 3H), 1.44 (s, 9H), 1.46 (d, J=6.6 Hz, 2.6H), 1.70-1.82 (m, 1H), 2.01-2.12 (m, 2H), 2.23-2.33 (m, 1H), 2.51 (t, J=7.8 Hz, 2H), 2.95 (t, J=7.7 Hz, 2H), 3.05-3.21 (m, 4H), 3.37-3.48 (m, 1H), 3.49-3.62 (m, 1H), 3.73-3.83 (m, 1H), 4.20-4.29 (m, 1H), 6.64 (d, 7.1 Hz, 1H), 7.34 (d, J=8.1 Hz, 2H), 7.39 (d, J=8.1 Hz, 2H), 7.58 (d, J=8.1 Hz, 2H), 7.63 (d, J=8.1 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:36])[O:6][CH:5]([C:7]2[CH:8]=[CH:9][C:10]3[C:16]4=[N:17][O:18][C:19]([C:21]5[O:25][N:24]=[C:23]([C:26]6[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=6)[C:22]=5[C:32]([F:35])([F:34])[F:33])(O)[CH:15]4[CH2:14][O:13][C:11]=3[CH:12]=2)[CH2:4][O:3]1.N1C=CC=CC=1.S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:36])[O:6][CH:5]([C:7]2[CH:8]=[CH:9][C:10]3[C:16]4=[N:17][O:18][C:19]([C:21]5[O:25][N:24]=[C:23]([C:26]6[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=6)[C:22]=5[C:32]([F:35])([F:33])[F:34])=[C:15]4[CH2:14][O:13][C:11]=3[CH:12]=2)[CH2:4][O:3]1
Reactant: CC1(C)OCC(c2ccc3c(c2)OCC2C3=NOC2(O)c2onc(-c3ccccc3)c2C(F)(F)F)O1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: CC1(C)OCC(c2ccc3c(c2)OCc2c-3noc2-c2onc(-c3ccccc3)c2C(F)(F)F)O1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 124.3 %

Procedure:
To a stirred suspension of 7-(2,2-dimethyl-1,3-dioxolan-4-yl)-3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-3a,4-dihydro-3H-chromeno[4,3-c]isoxazol-3-ol (Preparation 61A, 0.035 g, 0.070 mmol) in anhydrous toluene (1.0 mL) at room temperature was added pyridine (0.012 mL, 0.153 mmol) followed by thionyl chloride (8.64 μl, 0.118 mmol). The reaction mixture was stirred at room temperature for 15 min. and then at 80° C. for 15 min. The reaction mixture was cooled to room temperature and concentrated. The solid residue was diluted with dichloromethane, washed with a saturated aqueous solution of sodium bicarbonate, and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded a yellow film. The combined crude products were triturated with methanol with sonication. The solid was collected to provide 7-(2,2-dimethyl-1,3-dioxolan-4-yl)-3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4H-chromeno[4,3-c]isoxazole (0.042 g, 0.087 mmol, 62% yield) as an off-white solid. The product had an HPLC with a ret. time=3.63 min.−Column: Chromolith SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=484.9.
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4][OH:5].C(N(CC)CC)C.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>ClCCl>[F:1][CH2:2][CH2:3][CH2:4][O:5][S:19]([C:16]1[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=1)(=[O:21])=[O:20]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCCF
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCCF)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.1 %

Procedure:
5 g of 3-fluoro-propanol (64.03 mmol) and 18 ml of triethylamine (129.32 mmol) were dissolved in 50 ml of dichloromethane. At 0-5° C., 12.9 g toluene-4-sulfonylchloride (67.66 mmol) were added and the reaction mixture stirred at room temperature for 18 h. Standard work-up yielded 13.7 g of toluene-4-sulfonic acid 3-fluoro-propyl ester.
Reaction SMILES: [NH:1]([C:6]([O:8]C(C)(C)C)=O)[CH2:2][C:3]([OH:5])=[O:4].[NH:13]1[C:17](=[O:18])[CH2:16][CH2:15][C@H:14]1C(O)=O>>[NH:13]1[C:17](=[O:18])[CH2:16][CH2:15][C@H:14]1[C:6]([NH:1][CH2:2][C:3]([OH:5])=[O:4])=[O:8]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: O=C1CC[C@@H](C(=O)O)N1
Product: O=C(O)CNC(=O)[C@@H]1CCC(=O)N1

Procedure:
2 mmoles of Boc-Gly-Rx were used as starting material, and 0.90 g of pGlu were added according to the usual principles for solid peptide synthesis.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([N:30]=[C:31]=[O:32])[CH3:29]>C(Cl)Cl>[CH2:28]([NH:30][C:31]([N:13]1[CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9][C@@H:8]1[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:32])[CH3:29]
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Reactant: CCN=C=O
Solvent: ClCCl
Product: CCNC(=O)N1CCN(c2ccc(OC)c(OC3CCCC3)c2)C[C@@H]1Cc1ccccc1
Reaction time: 1 h
Yield: 68.6 %

Procedure:
A solution of (S)-3-Benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine (Example 2) (73 mg, 0.2 mmol) in CH2Cl2 (0.5 mL) at 0° C. was treated with ethyl isocyanate (19 μL, 0.24 mmol) and stirred for 1 h, then evaporated and the residue purified by silica gel flash chromatography with 50% then 75% EtOAc/hexane as eluant to afford product as a foam (60 mg, 69%) 1H NMR (CDCl3) 1.04 (t, J=7.2, 3H), 1.59-1.64 (m, 2H), 1.79-1.90 (m, 3H), 1.91-1.96 (m, 2H), 2.67-2.75 (m, 2H), 3.00-3.43 (m, 7H), 3.79 (s, 3H), 3.93 (br d, J=12.5, 1H), 4.13-4.27 (m, 2H), 4.70-4.73 (m, 1H), 6.40 (br d, J=7.5, 1H), 6.49 (br s, 1H), 6.78 (d, J=8.8, 1H), 7.22-7.35 (m, 5H). LC/MS 6.86 min, [M+1]+ 438.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8]O)[CH:5]=[C:4]([F:10])[N:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH3:23][C:24]1[CH:25]=[C:26]([CH:39]=[C:40]([CH3:42])[CH:41]=1)[O:27][C:28]1[NH:33][C:32](=[O:34])[NH:31][C:30](=[O:35])[C:29]=1[CH:36]([CH3:38])[CH3:37].C(=O)([O-])[O-].[K+].[K+].[I-].[Li+]>C(Cl)(Cl)Cl.CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([CH2:8][N:33]2[C:28]([O:27][C:26]3[CH:25]=[C:24]([CH3:23])[CH:41]=[C:40]([CH3:42])[CH:39]=3)=[C:29]([CH:36]([CH3:37])[CH3:38])[C:30](=[O:35])[NH:31][C:32]2=[O:34])[CH:5]=[C:4]([F:10])[N:3]=1
Reactant: Cc1cc(C)cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: OCc1cc(F)nc(F)c1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(C)cc(Oc2c(C(C)C)c(=O)[nH]c(=O)n2Cc2cc(F)nc(F)c2)c1
Yield: 49.8 %

Procedure:
(2,6-Difluoro-pyridin-4-yl)-methanol (145 mg, 1 mmol) was dissolved in chloroform (10 ml) and cooled in an ice bath under nitrogen atmosphere. With stirring, triethylamine (210 μl, 1.5 mmol) was added and methanesulfonyl chloride (90 μl, 1.2 mmol) was added dropwise. After stirring for 1.1 hr., the reaction mixture was washed with saturated aqueous sodium bicarbonate, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was further dried in high vacuo for ca. 20 min. and mixed with 6-(3,5-Dimethyl-phenoxy)-5-isopropyl-1H-pyrimidine-2,4-dione (274 mg, 1 mmol), powdered anhydrous potassium carbonate (138 mg, 1 mmol), and lithium iodide (134 mg, 1 mmol). DMF (5 ml) was then added to the mixture at room temperature and stirred for ca. 4 hr. After evaporation of DMF, the residue was dissolved in methanol-chloroform (1:9) and filtered through celite pad. The filtrate was then evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, EA:hexanes (1:2)) to afford 200 mg (50%) of a white solid. 1H-NMR (300 MHz, CDCl3) δ 1.14 (6H, d, J=6.7 Hz), 2.27 (6H, s), 2.78 (1H, m), 4.90 (2H, s), 6.44 (2H, s), 6.61 (2H, s), 6.76 (1H, s), 8.81 (1H, s); m/z (EI) 401 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:10][C:11]([CH3:16])([CH3:15])[CH2:12][CH:13]=[O:14].[OH-].[Na+].[CH2:19]([OH:21])[CH3:20]>O.Cl.O1CCOCC1.[N+]([O-])([O-])=O.[Ag+]>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:10][C:11]([CH3:16])([CH3:15])[CH2:12][C:13]([O:21][CH2:19][CH3:20])=[O:14]
Reactant: COc1ccc(CC(C)(C)CC=O)c(Br)c1
Reactant: CCO
Agent: [Ag+]
Agent: Cl
Agent: O=[N+]([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)CC(C)(C)Cc1ccc(OC)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
Silver nitrate (21 g, 124 mmoles) was dissolved in 35 mL H2O and added to a solution of 4-(2-bromo-4-methoxyphenyl)-3,3-dimethylbutanal (11 g, 38.6 mmoles) in 250 mL ethanol. A solution of NaOH (10 g, 250 mmoles) in 35 mL of H2O was added dropwise, then the reaction was stirred at room temperature for 2 hours. The reaction was passed through a short pad of Celite. Then, the ethanol was evaporated and the residue was partioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate (2×200 mL). The organic layers were discarded. The water layer was acidified with 2 N HCl solution to pH=2, and extracted with ethyl acetate (3×200 mL). The organic extracts were washed with brine, dried (Na2SO4), and concentrated to afford an oil. The oil was dissolved in 60 mL of 4N HCl in dioxane and 120 mL of absolute ethanol overnight at 25° C. The reaction was evaporated to dryness then taken up in ethyl acetate and extracted with a saturated solution of aqueous sodium bicarbonate, brine, dried (Na2SO4), and evaporated to give 9.1 g (71%) of the desired compound. NMR spectrum of the product was consistent for the proposed structure.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[O:5][CH2:6][C:7](=O)[CH3:8].Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br.C(N(C(C)C)C(C)C)C>C(O)C>[Cl:13][C:12]1[C:2]([N:1]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:3][C:4]2[O:5][CH:6]=[C:7]([CH3:8])[C:10]=2[CH:11]=1
Reactant: BrCCCCCBr
Reactant: CC(=O)COc1ccc(Cl)c(N)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1coc2cc(N3CCCCC3)c(Cl)cc12

Procedure:
A mixture of 9.98 g (50 mmole) of 1-(3-amino-4-chlorophenoxy)-2-propanone, 22.9 g (0.10 mole) of 1,5-dibromopentane, 12.9 g (0.10 mole) of N-ethyldiisopropylamine and 60 ml of ethanol is boiled under reflux for 18 hours. The residue obtained after concentration by evaporation in vacuo is taken up in methylene chloride and washed twice with dilute sodium bicarbonate solution. The organic phase is dried, concentrated by evaporation and the crude product is taken up in 250 ml of ethanol, 40 ml of concentrated hydrochloric acid are added and the whole is boiled under reflux for 30 hours. The ethanol is concentrated in a vacuum rotary evaporator and the residue is diluted with ice-water, rendered alkaline with 6N sodium hydroxide solution and extracted with methylene chloride. The organic phases are washed with water, combined, dried over sodium sulphate and concentrated in a vacuum rotary evaporator. Chromatography over silica gel using chloroform as eluant yields 5-chloro-3-methyl-6-(piperidin-1-yl)-benzofuran which, after recrystallisation from petroleum ether, melts at 82°-84°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:28][CH2:27][N:11]2[C:12](=[O:26])[C:13]3[C:18]([CH:10]2[CH2:9]1)=[CH:17][C:16]([O:19]C)=[CH:15][C:14]=3[O:21][C:22]([F:25])([F:24])[F:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].B(Br)(Br)Br.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:28][CH2:27][N:11]2[C:12](=[O:26])[C:13]3[C:18]([CH:10]2[CH2:9]1)=[CH:17][C:16]([OH:19])=[CH:15][C:14]=3[O:21][C:22]([F:24])([F:25])[F:23])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(OC(F)(F)F)c2c(c1)C1CN(C(=O)OC(C)(C)C)CCN1C2=O
Agent: BrB(Br)Br
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN2C(=O)c3c(OC(F)(F)F)cc(O)cc3C2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a stirring solution of N-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-9-methoxy-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-one (201 mg, 0.5 mmol) in dry CH2Cl2 (3 mL) at −78° C. under Ar was added IM boron tribromide in CH2Cl2 (1.75 mL). The reaction was stirred for 1 h and then warmed to room temperature for 18 h. The reaction was refluxed for 24 h and then quenched with water. The reaction was stirred for 30 min and then conc. in vacuo to a brown solid. The solid was treated with 6M HCl. After 1 h, the reaction was conc. in vacuo to a brown solid. The solid was partioned between water and EtOAc, basified with sodium bicarbonate, and treated with di-t-butyl dicarbonate (109 mg, 0.5 mmol). The reaction was stirred for 1 h and extracted with EtOAc (3×10 mL). The organic layers were combined, dried over MgSO4, and conc. in vacuo to a brown solid. The solid was purified by trituration with chloroform to yield 103 mg of the desired product as a white solid. MS (ESI) 389 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][N:10]2[C:18]3[CH:17]=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=3[C:12]3[CH2:20][N:21]([CH3:24])[CH2:22][CH2:23][C:11]2=3)[CH:5]=[N:6][CH:7]=1.C([O-])=O.[NH4+]>CO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][N:10]2[C:18]3[CH:17]=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=3[C:12]3[CH2:20][N:21]([CH3:24])[CH2:22][CH2:23][C:11]2=3)[CH:5]=[N:6][CH:7]=1
Reactant: Cc1ccc2c(c1)c1c(n2C#Cc2cncc(F)c2)CCN(C)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Cc1ccc2c(c1)c1c(n2CCc2cncc(F)c2)CCN(C)C1
Temperature: 75 °C
Reaction time: 1 h

Procedure:
To a degassed solution of 5-(5-fluoro-pyridin-3-ylethynyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (60 mg, 0.188 mmol) in MeOH (3 mL) were added 10% dry Pd—C (35 mg) and ammonium formate (59 mg, 0.940 mmol). The reaction mixture was stirred at 75° C. for 1 h. The reaction mass was filtered through Celite and the filtrate concentrated under reduced pressure to afford crude product, which was purified by reverse phase HPLC to yield 5-[2-(5-fluoro-pyridin-3-yl)-ethyl]-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (CD3OD, TFA salt) δ (ppm): 8.3 (s, 1H), 7.9 (s, 1H), 7.38 (d, 1H), 7.21 (s, 1H), 7.2 (d, 1H), 7.0 (d, 1H), 4.62 (d, 1H), 4.4 (t, 2H), 4.3 (d, 1H), 3.78 (m, 1H), 3.4 (m, 1H), 3.18 (t, 2H), 3.1 (s, 3H), 2.9 (m, 1H), 2.8 (m, 1H), 2.4 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([C:6]2[CH:12]=[CH:11][C:9]([NH2:10])=[C:8]([N+:13]([O-])=O)[CH:7]=2)[CH2:5][CH2:4][CH2:3]1>[Pd].C(O)C>[CH3:1][C:2]1([C:6]2[CH:7]=[C:8]([NH2:13])[C:9]([NH2:10])=[CH:11][CH:12]=2)[CH2:3][CH2:4][CH2:5]1
Reactant: CC1(c2ccc(N)c([N+](=O)[O-])c2)CCC1
Agent: [Pd]
Solvent: CCO
Product: CC1(c2ccc(N)c(N)c2)CCC1
Reaction time: 4 h
Yield: 101.1 %

Procedure:
A solution of 4-(1-methylcyclobutyl)-2-nitroaniline (138 mg. 0.668 mmol) in ethanol (8.5 mL, 140 mmol) was carefully treated with 10% Palladium on Carbon (14.2 mg, 0.0134 mmol) as a slurry in ethanol. The reaction flask was evacuated and filled with hydrogen gas three times and the reaction mixture was stirred under an atmosphere of Hydrogen for 4 h. The reaction mixture was filtered through a pad of Solka floc® and the pad was washed with 20 ml MeOH. The filtrate was concentrated to yield an oil which was placed under high vacuum yielding the desired compound as a solid (119 mg) which was used directly in the next step. 1H NMR (400 MHZ. CDCl3) δH ppm 6.66 (m, 1 H), 6.53 (m, 2 H), 3.34 (br. s., 4 H), 2.33 (m, 2 H), 2.08 (m, 1 H), 1.99 (m. 2 H). 1.80 (m, 1H), 1.42 (s, 3 H).
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][CH3:12].[OH2:13]>COCCOC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:7][C:6]1[C:5]([C:2]2[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=2[O:11][CH3:12])=[C:4]([CH3:3])[O:13][N:8]=1
Reactant: O
Reactant: COc1ccc([N+](=O)[O-])cc1I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: COc1ccc([N+](=O)[O-])cc1-c1c(C)noc1C
Temperature: 80 °C

Procedure:
To a solution of 2-iodo-1-(methoxy)-4-nitrobenzene (2 g, 7.17 mmol, 1 eq.) and (3,5-dimethylisoxazole)boronic acid (3.03 g, 21.5 mmol, 3 eq.) in DME (44 ml) and water (7 ml) were added tetrakis(triphenylphosphine) palladium(0) (0.415 g, 0.05 eq.) and Ba(OH)2.8H2O (4.52 g, 14.33 mmol, 2 eq.). The mixture was heated at 80° C. for 16 h. To complete the reaction (3,5-dimethylisoxazole)boronic acid (1 eq.) was added and the mixture was heated for 4 h. The cooled mixture was filtered and extracted with DCM. The organic phase was washed with saturated aqueous Sodium hydrogen carbonate and water, dried over Na2SO4 and filtered. Evaporation of the solvent in vacuo gave a crude oil which was precipitated with iPr2O to afford the title compound as a rust solid (1.735 g, 97%). GC/MS m/z: 248
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:13][CH:14]([NH:20][C:21]([N:23]2[CH2:28][CH2:27][CH:26]([N:29]3[CH2:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[NH:31][C:30]3=[O:39])[CH2:25][CH2:24]2)=[O:22])[C:15]2[NH:19][N:18]=[N:17][N:16]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][N:9]=[C:8]2[CH3:12])[CH3:2].[C:40](=O)([O-])[O-].[Na+].[Na+].IC>CS(C)=O.O>[CH2:1]([C:3]1[CH:4]=[C:5]([CH2:13][CH:14]([NH:20][C:21]([N:23]2[CH2:24][CH2:25][CH:26]([N:29]3[CH2:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[NH:31][C:30]3=[O:39])[CH2:27][CH2:28]2)=[O:22])[C:15]2[N:16]([CH3:40])[N:17]=[N:18][N:19]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][N:9]=[C:8]2[CH3:12])[CH3:2]
Reactant: CCc1cc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)c2nnn[nH]2)cc2c(C)n[nH]c12
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CI
Solvent: CS(C)=O
Solvent: O
Product: CCc1cc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)c2nnnn2C)cc2c(C)n[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-(7-ethyl-3-methyl-1H-indazol-5-yl)-1-(1H-tetrazol-5-yl)-ethyl]-amide (50 mg, 0.1 mmol, 1.0 equiv), sodium carbonate (40.0 mg, 3.0 equiv), and iodomethane (24 μL, 3.0 equiv) were combined in dimethylsulfoxide and the mixture stirred at room temperature overnight. The mixture was then diluted with water and extracted with ethyl acetate (3×). The combined organic extracts were washed with water (3×), brine (3×), dried over sodium sulfate, and concentrated. Purification by preparative HPLC afforded the title compound. 1H-NMR (CD3OD) δ 1.30 (m, 4H), 1.57 (m, 3H), 2.50 (s, 3H), 2.75-2.95 (m, 5H), 3.40 (m, 2H), 3.68 (m, 3H), 4.05-4.40 (m, 6H), 5.35 (m, 1H), 6.75 (m, 1H), 6.95 (dd, J=7.3, 7.6, 1H), 6.98 (s, 1H), 7.12 (m, 2H), 7.35 (s, 1H). Mass spec.: 543.42 (MH)+.
Reaction SMILES: C([N:8]1[C@@H:13]2[CH2:14][CH2:15][C@@:9]1([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@H:10]([OH:16])[CH2:11][CH2:12]2)C1C=CC=CC=1.C1CC=CCC=1>[Pd].O.C(O)C>[C:17]1([C@:9]23[NH:8][C@H:13]([CH2:14][CH2:15]2)[CH2:12][CH2:11][C@H:10]3[OH:16])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O[C@@H]1CC[C@H]2CC[C@]1(c1ccccc1)N2Cc1ccccc1
Agent: [Pd]
Solvent: O
Solvent: C1=CCC=CC1
Solvent: CCO
Product: O[C@@H]1CC[C@H]2CC[C@]1(c1ccccc1)N2
Temperature: 60 °C
Yield: 60 %

Procedure:
10% Palladium on carbon (4 g) was added as a slurry in water (25 ml) to a solution of (1R*,2R*,5R*)-8-benzyl-1-phenyl-8-azabicyclo[3.2.1]octan-2-ol (Description 9; 29.3 g, 100 mmol) and 1,4-cyclohexadiene (80 g, 1 mol) in ethanol (250 ml). The mixture was heated at 60° C. for 6 hours. On cooling to room temperature the mixture was filtered through Celite™ and the filtrate concentrated in vacuo. The residue was chromatographed on silica gel eluting with 5 and 10% methanol/dichloromethane/1% ammonia to yield the title compound (12.2 g, 60%).
Reaction SMILES: C([O:3][C:4]([C@@:6]1([NH:11][C:12]([CH:14]2[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17][C:16]3=[CH:27][NH:28][N:29]=[C:15]23)=[O:13])[CH2:8][C@H:7]1[CH:9]=[CH2:10])=[O:5])C.[Li+].[OH-]>C1COCC1>[C:23]([O:22][C:20]([N:18]1[CH2:19][CH:14]([C:12]([NH:11][C@:6]2([C:4]([OH:5])=[O:3])[CH2:8][C@H:7]2[CH:9]=[CH2:10])=[O:13])[C:15]2=[N:29][NH:28][CH:27]=[C:16]2[CH2:17]1)=[O:21])([CH3:24])([CH3:25])[CH3:26]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)C1CN(C(=O)OC(C)(C)C)Cc2c[nH]nc21)C(=O)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=C[C@@H]1C[C@]1(NC(=O)C1CN(C(=O)OC(C)(C)C)Cc2c[nH]nc21)C(=O)O
Temperature: 0 °C
Reaction time: 20 h

Procedure:
A solution of ethyl ester 7b (80.0 mg, 0.198 mmol) in THF (1.5 mL) was cooled to 0° C. and 1 M LiOH (1.00 mL, 1.00 mmol) was added. The mixture was stirred for 20 h during which time the temperature reached rt after 1.5 h. The THF was removed in vacuo and the remaining aqueous solution was diluted with deionized H2O to a final volume of 3 mL. The aqueous mixture was extracted with Et2O (3×) and cooled to 0° C. 2 M HCl was added obtain pH=3. The mixture was extracted with EtOAc (3×) and the combined EtOAc portions were washed with brine, dried over MgSO4 and filtered through a Celite plug capped with a layer of MgSO4. The EtOAc solution was concentrated to give the title acid 8b as bronze foam scraped to beige solid; 62 mg, 83%, MS m/z 375.1 (ESI−, M−1).