Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-:1].[Na+:2].[CH3:3][C@@H:4]([CH2:29][CH2:30][CH3:31])[C:5]([O:7][C@@H:8]1[C@H:17]2[C:12]([CH:13]=[CH:14][C@H:15]([CH3:28])[C@@H:16]2[CH2:18][CH2:19][C@H:20]2[O:25][C:24](=[O:26])[CH2:23][C@H:22](O)[CH2:21]2)=[CH:11][CH2:10][CH2:9]1)=[O:6].[OH2:32].Cl>O1CCOCC1>[OH:1][C@H:22]([CH2:21][C@H:20]([OH:25])[CH2:19][CH2:18][C@@H:16]1[C@@H:17]2[C:12](=[CH:11][CH2:10][CH2:9][C@@H:8]2[O:7][C:5](=[O:6])[C@@H:4]([CH3:3])[CH2:29][CH2:30][CH3:31])[CH:13]=[CH:14][C@@H:15]1[CH3:28])[CH2:23][C:24]([O-:26])=[O:32].[Na+:2]
Reactant: O
Reactant: CCC[C@H](C)C(=O)O[C@H]1CCC=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: CCC[C@H](C)C(=O)O[C@H]1CCC=C2C=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(=O)[O-])[C@H]21
Temperature: 60 °C

Procedure:
0.1 ml of a 0.1N aqueous solution of sodium hydroxide was added to a solution of 10 mg of (4R,6R)-6-{2-[(1S,2S,8S,8aR)-1,2,6,7,8,8a-hexahydro-8-[(S)-2-methylvaleryloxy]-2-methyl-1-naphthyl]ethyl}-tetrahydro-4-hydroxy-2H-pyran-2-one [prepared as described in Example 85, above] in 0.2 ml of 1,4-dioxane, and the mixture was heated at 60° C. for 30 minutes. At the end of this time, 10 ml of water were added to the mixture and the pH of the mixture was adjusted to pH 8.5 with the addition of an appropriate amount of a 0.1N solution of aqueous hydrogen chloride. The resulting mixture was then adsorbed onto a column containing 5 ml of Diaion HP-20™. The resin was washed with 20 ml of water and then eluted with a 60% w/v aqueous acetone solution. The resulting eluate was concentrated by evaporation under reduced pressure, using a rotary evaporator, and the concentrate was lyophilized to give 9.8 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:8]([N:10]([O:12][CH3:13])C)=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].C([Al+]CC(C)C)C(C)C>C1COCC1>[Br:1][C:2]1[C:3]([CH:8]=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:8][NH:10][O:12][CH3:13]
Reactant: CON(C)C(=O)c1ncccc1Br
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: CNOC
Product: O=Cc1ncccc1Br
Reaction time: 4 h

Procedure:
To a solution of 3-bromo-N-methoxy-N-methylpyridine-2-carboxamide (3-2; 219 mg, 0.89 mmole) in dry THF (4 mL) was added diisobutylaluminum hydride (0.94 mL, 0.94 mmole, 1M solution in CH2Cl2) slowly at −78° C. After 3 hr the mixture was quenched with 1N HCl and stirred vigorously. After 4 hr the mixture was neutralized with 1M NaOH and extracted with CH2Cl2 (3×). The combined organic layers were dried (MgSO4), filtered, and concentrated to give 3-bromopyridine-2-carboxaldehyde and its animal with N,O-dimethylhydroxylamine as a mixture which was used in the next step without purification.
Reaction SMILES: CO[CH:3](OC)[C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:5]=1[CH:18](O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[C:28]1(=[O:34])[O:33][C:31](=[O:32])[CH:30]=[CH:29]1>C1(C)C=CC=CC=1>[CH2:11]([O:10][C:8]1[CH:9]=[C:4]2[C:5]([C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:30]3[C:31](=[O:32])[O:33][C:28](=[O:34])[C:29]3=[CH:3]2)=[CH:6][CH:7]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C1C=CC(=O)O1
Reactant: COC(OC)c1cc(OCc2ccccc2)ccc1C(O)c1ccccc1
Solvent: Cc1ccccc1
Product: O=C1OC(=O)c2c1cc1cc(OCc3ccccc3)ccc1c2-c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of the alcohol (112 g) from Step 1 in toluene (1.1L) was added maleic anhydride (150 g). The reaction mixture was heated to reflux for 24 hours. After cooling to room temperature, the toluene was evaporated. The residue was triturated in EtOAc at 0° C., filtered and washed with Et2O to afford the title product as a white solid.
Reaction SMILES: Br[CH2:2][C:3]([O:11][CH3:12])=[CH:4][C:5](=[O:10])[C:6]([Cl:9])([Cl:8])[Cl:7].[C:13]([O-:16])(=[O:15])[CH3:14].[K+].C(O)(=O)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C>[C:13]([O:16][CH2:2][C:3]([O:11][CH3:12])=[CH:4][C:5](=[O:10])[C:6]([Cl:9])([Cl:8])[Cl:7])(=[O:15])[CH3:14]
Reactant: CC(=O)[O-]
Reactant: COC(=CC(=O)C(Cl)(Cl)Cl)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: CC#N
Solvent: CC(=O)O
Product: COC(=CC(=O)C(Cl)(Cl)Cl)COC(C)=O

Procedure:
29.6 g (0.1 mol) of 5-bromo-1,1,1-trichloro-4-methoxypent-3-en-2-one, 17 g of potassium acetate, 5 g of tetrabutylammonium bromide and 8 g of acetic acid were stirred at 40° C. in 300 ml of acetonitrile for 16 h. The mixture was concentrated under reduced pressure, and the water was added to the residue. The product was extracted with ethyl acetate, the organic phase was washed with water and the solvent was removed completely under reduced pressure.
Reaction SMILES: [CH2:1]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=2C(O)=O)=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[Na].[OH2:27].[CH2:28]([OH:33])CC(C)C>>[CH2:1]([O:10][C:11]1[CH:12]=[CH:13][C:14]([C@H:17]2[CH2:18][CH2:22][C@H:23]([C:28]([OH:33])=[O:27])[CH2:24][CH2:25]2)=[CH:15][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCCOc1ccc(-c2ccccc2C(=O)O)cc1
Reactant: CC(C)CCO
Reactant: O
Agent: [Na]
Product: CCCCCCCCCOc1ccc([C@H]2CC[C@H](C(=O)O)CC2)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Into a 1000 ml volume three-neck flask charged were 150 ml of iso-amyl alcohol and 2.06 g of 4-nonyloxyphenyl benzoic acid, followed by heating under stirring, to dissolve the latter in the former. Under reflux, a solution of 8 g of metallic sodium in 70 ml of iso-amyl alcohol prepared by heating was added to the flask. The reaction was continued for an additional 20 minutes under reflux, and then additional 8 g of metallic sodium was added to the flask. After the lapse of 30 minutes, a solution prepared by dissolving 12 g of metallic sodium in 60 ml of iso-amyl alcohol was added to the flask, and after the lapse of 40 minutes 25 ml of iso-amyl alcohol was added to the flask. The reaction mixture was further refluxed for an hour, and then cooled to the room temperature. 500 ml of water was added to the cooled reaction mixture, and then the reaction mixture was allowed to stand for one night. The reaction mixture was subjected to extraction using 200 ml of chloroform to obtain 0.9 g of trans-4-(4-nonyloxyphenyl)cyclohexylcarboxylic acid.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][C@@H:4]([NH2:8])[C:5]([OH:7])=[O:6].C(N(CC)CC)C.O.[CH2:17]([O:24][C:25](ON1C(=O)CCC1=O)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCOCC1>[CH2:17]([O:24][C:25]([NH:8][C@H:4]([CH2:3][CH:2]=[CH2:1])[C:5]([OH:7])=[O:6])=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: C=CC[C@@H](N)C(=O)O
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(CC)CC
Product: C=CC[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of D-2-amino-4-pentenoic acid (500 mg) in Dioxane (20 mL) at RT was added triethylamine (1.09 g), water (0.5 mL), and N-(benzyloxycarbonyloxy)succinimide (2.27 g). The reaction mixture was stirred overnight at RT, concentrated in vacuo, diluted with saturated NaHCO3 and extracted with ether (3×). The basic aqueous layer was acidified to pH 2 with 2N HCl and extracted with EtOAc (3×). The combined EtOAc layer was washed with brine, dried (Na2SO4), filtered and concentrated to give a clear viscous oil (1.17 g, quantitative).
Reaction SMILES: S(=O)(=O)(O)O.C(Cl)(Cl)Cl.[Br:10][C:11]1[S:15][C:14]2[C:16](=[O:31])[CH:17]([C:27]([O:29][CH3:30])=[O:28])[CH:18]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=3)[C:13]=2[CH:12]=1.[N-:32]=[N+]=[N-].[Na+]>>[Br:10][C:11]1[S:15][C:14]2[C:16](=[O:31])[NH:32][CH:17]([C:27]([O:29][CH3:30])=[O:28])[CH:18]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=3)[C:13]=2[CH:12]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)C1C(=O)c2sc(Br)cc2C1c1ccc(Cl)c(Cl)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COC(=O)C1NC(=O)c2sc(Br)cc2C1c1ccc(Cl)c(Cl)c1
Temperature: 15 °C
Yield: 48.3 %

Procedure:
To a mixture of sulfuric acid (5.01 mL, 94.0 mmol) and chloroform (49.6 mL, 6.20E2 mmol) was added methyl 2-bromo-4-(3,4-dichlorophenyl)-6-oxo-5,6-dihydro-4H-cyclopenta[b]thiophene-5-carboxylate (5.01 g, 11.9 mmol) followed by sodium azide (3.72 g, 57.2 mmol) in small portions over 3 h with vigorous stirring at 15° C. After addition, the mixture was stirred at rt overnight. The reaction was quenched by ice, basified with sodium bicarbonate, and extracted with DCM. The DCM layer was washed with brine, followed by sodium bicarbonate solution and brine. Dried and evaporated to afford crude product which was purified by silica gel chromatography to afford product as off-white solid (2.50 g, 48.2%). LCMS: (AA) ES+: 435, 437, 1H NMR (400 MHz, CDCl3) δ 7.43-7.38 (m, 1H), 7.28 (d, J=2.2 Hz, 1H), 7.00 (dd, J=8.3, 2.2 Hz, 1H), 6.77 (s, 1H), 5.92 (t, J=9.3 Hz, 1H), 4.67 (d, J=3.3 Hz, 1H), 4.28 (t, J=3.6 Hz, 1H), 3.76 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:12]1([C:18]#[CH:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>[Pd](Cl)Cl.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.C(N(CC)CC)C>[C:12]1([C:18]#[C:19][C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)c1ccnc(Cl)c1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccnc(C#Cc2ccccc2)c1
Temperature: 25 °C

Procedure:
Methyl 2-chloroisonicotinate, 2 (19.08 9, 0.111 mol as 100% pure), phenylacetylene (13.6 g, 0.133 mol), cuprous iodide (1.00 g,5.25 mmol) and triethylamine (30 ml) were mixed together with stirring at room temperature, and to this mixture was added bis(triphenylphosphine) palladium (II) chloride (2.0 g, 2.85 mmol).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH2:14][C@H:13]([NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH2:12]3)O1.Br[C:27]1[CH:28]=[N:29][CH:30]=[C:31](F)[CH:32]=1.[C:34]([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:34][C:27]1[CH:32]=[C:31]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH2:14][C@H:13]([NH:18][S:19]([CH:22]([CH3:23])[CH3:24])(=[O:20])=[O:21])[CH2:12]3)[CH:30]=[N:29][CH:28]=1
Reactant: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2C1
Reactant: O=C([O-])[O-]
Reactant: Fc1cncc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cncc(-c2ccc3c(c2)C[C@@H](NS(=O)(=O)C(C)C)C3)c1
Yield: 79 %

Procedure:
To a solution of N-[(2S)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide (700 mg, 1.92 mmol) in dry 1,4 dioxane (15 ml), polymer supported Pd(PPh3)4 (38 mg, 0.5 mmol/g, 0.019 mmol) was added along with 3-bromo-5-fluoropyridine (675 mg, 3.83 mmol) and 2.7 ml of a 2M Na2CO3 solution in water and the resulting mixture was heated at 90° degrees for 3 hours. Then after cooling the resin was removed by filtration and then the solvent was removed under reduced pressure. The residue was taken up with AcOEt and water. The aqueous phase was separated and acidified with 3N HCl and extracted with AcOEt. Then pH was reverted to basic by addition of NaHCO3 and another extraction with AcOEt was performed. All the organic extracts were collected, dried on Na2SO4, filtered and evaporated. The crude was finally purified on a 40M+ silica cartridge eluting with a cyclohexane/AcOEt 80/20 mixture. 270 mg of title compound were recovered as whitish solid along with 240 mg of slightly less pure fractions (overall yield 79%). Due to the use of chiral Intermediate 7, the final compound is believed to be N-[(2S)-5-(5-methyl-3-pyridinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide.
Reaction SMILES: [Br:1]Br.[OH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C:12](=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[Br:1][C:7]1[C:8]([O:10][CH3:11])=[CH:9][C:4]([OH:3])=[C:5]([C:12](=[O:21])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH:6]=1
Reactant: COc1ccc(C(=O)Cc2ccc(O)cc2)c(O)c1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cc(O)c(C(=O)Cc2ccc(O)cc2)cc1Br
Reaction time: 8 h
Yield: 18.8 %

Procedure:
A solution of bromine (3.6 mL, 75.6 mmol) in acetic acid (50 mL) was added dropwise to a stirring solution of 1-(2-hydroxy-4-methoxy-phenyl)-2-(4-hydroxy-phenyl)-ethanone (20 g, 77.4 mmol) in acetic acid (500 mL), and the reaction mixture was allowed to stir for 8 h. The acetic acid was then removed under reduced pressure, and the resulting solid was recrystallized from methanol/water to provide 8.9 g of crude product. Further purification using reverse-phase preparatory HPLC (30–100% acetonitrile+0.1% TFA in H2O+0.1% TFA, over 18 min, then at 100% acetonitrile for 15 min) provided fractions that were subsequently neutralized with sodium bicarbonate and extracted using ethyl acetate. The organic fractions were combined, dried over magnesium sulfate and filtered, and the solvent was removed under reduced pressure to afford the title compound (4.8 g, 18%). MS (ESI) m/z 337.3 (M+1)+, 339.3 (M+1+2)+.
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]2[C:8](=[C:10]([C:14]([O:16]C)=O)[CH:11]=[CH:12][CH:13]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[NH3:18]>CO>[C:1]([C:5]1[O:6][C:7]2[C:8](=[C:10]([C:14]([NH2:18])=[O:16])[CH:11]=[CH:12][CH:13]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1cccc2oc(C(C)(C)C)nc12
Reactant: N
Solvent: CO
Product: CC(C)(C)c1nc2c(C(N)=O)cccc2o1
Temperature: 40 °C
Reaction time: 6 h

Procedure:
Methyl 2-t-butyl-4-benzoxazole carboxylate (0.1 g; 0.46 mmol) was dissolved in methanol (5 ml), and to this was added aqueous ammonia (5 ml). The mixture was warmed to 40° C. and left to stir for 6 hours at ambient temperature. Once the reaction was complete the solvent was removed under reduced pressure and the product was recrystallised from boiling ethyl acetate and petrol (73%).
Reaction SMILES: [OH2:1].C[O:3][C:4]1C=CC(N([S:12]([O-:15])(=[O:14])=[O:13])N)=C[CH:5]=1.[Na+].ClC1S[CH:20]=[C:21]([C:23](Cl)=[O:24])N=1>O.C(O)(C)(C)C>[C:23]([OH:24])(=[O:1])[CH2:21][CH2:20][C:4]([CH3:5])=[O:3].[S:12](=[O:13])(=[O:24])([OH:14])[OH:15]
Reactant: O=C(Cl)c1csc(Cl)n1
Reactant: COc1ccc(N(N)S(=O)(=O)[O-])cc1
Reactant: O
Agent: [Na+]
Solvent: CC(C)(C)O
Product: CC(=O)CCC(=O)O
Product: O=S(=O)(O)O
Temperature: 70 °C

Procedure:
25.8 g (0.1 mole) of sodium p-methoxyphenylhydrazine sulphonate monohydrate are dissolved in a mixture of 112 ml of water and 48 ml of tert. butanol, and 20 g (0.11 mole) of 2-chlorothiazole-4-carboxylic acid chloride added. The reaction mixture is stirred at room temperature for an hour and at 70°C for another hour. Then, without isolating the product, 43.5 ml of levulinic acid and 5 ml of concentrated sulphuric acid are added, and the mixture is stirred at 80°C for 4 hours. On diluting the reaction mixture with water, the precipitated product is filtered by suction and recrystallized from tert. butanol, affording 23 g of 1-(2-chlorothiazole-4-yl-carboxylic)-2-methyl-5-methoxy-indole-3-yl acetic acid. Yield: 65%, m.p. 158°-160°C.
Reaction SMILES: [CH2:1]([N:4]([CH2:27][CH2:28][CH3:29])[C:5]1[CH:6]=[C:7]([CH2:25][OH:26])[C:8](=[O:24])[N:9]2[C:14]=1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]1[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=1[CH3:23])[CH2:2][CH3:3].C[N+]1([O-])CCOCC1>ClCCl.C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH2:27]([N:4]([CH2:1][CH2:2][CH3:3])[C:5]1[CH:6]=[C:7]([CH:25]=[O:26])[C:8](=[O:24])[N:9]2[C:14]=1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]1[C:16]([CH3:23])=[CH:17][C:18]([CH3:22])=[CH:19][C:20]=1[CH3:21])[CH2:28][CH3:29]
Reactant: CCCN(CCC)c1cc(CO)c(=O)n2c(-c3c(C)cc(C)cc3C)cccc12
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Solvent: CC#N
Product: CCCN(CCC)c1cc(C=O)c(=O)n2c(-c3c(C)cc(C)cc3C)cccc12
Reaction time: 0.5 h
Yield: 73 %

Procedure:
1-(Dipropylamino)-3-(hydroxymethyl)-6-mesityl-4H-quinolizin-4-one (0.60 g, 1.53 mmol) was dissolved in dichloromethane (20 mL) and acetonitrile (4 mL). 0.5 g of crushed sieves (4 angstroms) was added followed by N-methylmorpholine N-oxide (NMO) (0.27 g, 2.3 mmol). Tetrapropylammonium perruthenate (TPAP) (0.081 g, 0.23 mmol) was added last. The reaction stirred for 0.5 h. The solution was filtered and concentrated. Flash chromatography (20% ethyl acetate/hexanes) gave 0.436 g (73% yield) of the title compound as a red solid.
Reaction SMILES: [CH3:1][C:2]([CH3:28])([CH:6]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:7]1[CH:8]=[C:9]2[CH:15]=[N:14][N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:10]2=[N:11][CH:12]=1)[C:3](O)=[O:4].[NH2:29][C:30]1[S:31][CH:32]=[CH:33][N:34]=1.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.FC(F)(F)C(O)=O>CN(C=O)C>[CH3:28][C:2]([CH3:1])([CH:6]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:7]1[CH:8]=[C:9]2[CH:15]=[N:14][N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:10]2=[N:11][CH:12]=1)[C:3]([NH:29][C:30]1[S:31][CH:32]=[CH:33][N:34]=1)=[O:4]
Reactant: CC(C)(C(=O)O)C(c1ccccc1)c1cnc2c(cnn2-c2ccccc2)c1
Reactant: Nc1nccs1
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
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C(=O)Nc1nccs1)C(c1ccccc1)c1cnc2c(cnn2-c2ccccc2)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 40.9 %

Procedure:
To a stirred solution of 2,2-dimethyl-3-phenyl-3-(1-phenyl-1H-pyrazolo[3,4-b]pyridin-5-yl)propanoic acid (8 mg, 0.022 mmol), 2-aminothiazole (9 mg, 0.09 mmol), and diisopropylethylamine (0.015 mL, 0.09 mmol) in anhydrous DMF (0.3 mL) was added HATU (33 mg, 0.09 mmol) under argon. After stirred at rt overnight and 80° C. for 30 min, the mixture was concentrated. HPLC purification gave 2,2-dimethyl-3-phenyl-3-(1-phenyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-N-(thiazol-2-yl)propanamide (Example 162, 5 mg, 0.009 mmol, 41% yield) as a trifluoroacetic acid salt. MS found: (M−H)−=452.11. 1H-NMR (400 MHz, Acetone) δ ppm 8.56 (1 H, d, J=2.54 Hz) 8.39 (1H, d, J=2.03 Hz) 8.24 (2H, d, J=7.63 Hz) 8.18 (1H, s), 7.37-7.47 (4H, m) 7.27 (1H, d, J=3.56 Hz) 7.16-7.23 (3H, m) 7.11 (1H, t, J=7.38 Hz) 6.95 (1H, d, J=3.56 Hz) 4.98 (1H, s) 1.42 (6H, d, J=7.63 Hz).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[Li]C(C)(C)C.[S:16](=[O:18])=[O:17].C1C(=O)N([Cl:26])C(=O)C1>C1COCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[S:16]([Cl:26])(=[O:18])=[O:17]
Reactant: Cn1ccc2ccccc21
Reactant: O=S=O
Reactant: O=C1CCC(=O)N1Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: Cn1c(S(=O)(=O)Cl)cc2ccccc21

Procedure:
1-Methylindole-2-sulfonyl chloride was prepared by the method of Example 34 with 1-methylindole (7.8 mmols, 1.0 ml), t-BuLi (1.7 m, 9.4 mmols, 5.5 ml), sulfur dioxide, NCS (8.6 mmols, 1.2 g) and THF (15 ml). Flash chromatography (2% ethyl acetate/hexanes) provided 0.66 g (3%) of a yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:5]([O:8]C)=[N:6][CH:7]=1.[Li+].[Cl-].S(O)(C1C=CC(C)=CC=1)(=O)=O.O>CN(C=O)C.O>[Br:1][C:2]1[C:3]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1
Reactant: COc1cc(OCC2CC2)c(Br)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: Oc1cc(OCC2CC2)c(Br)cn1
Temperature: 120 °C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
To a solution of the title compound from step 1 (450 mg, 1.74 mmol) in DMF (5 mL) was added LiCl (370 mg, 8.72 mmol) and TsOH H2O (1.52 g, 8.72 mmol) at room temperature. The mixture was heated to 120° C. and stirred for 1 hour. The mixture was diluted with water (100 mL) and extracted with EtOAc (3×100 mL). The combined organic phase was washed with saturated brine (2×200 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the title compound (380 mg, yield: 88.9%) as yellow solid which used directly for the next step without further purification. 1H NMR (CDCl3, 400 MHz) δ 7.49 (s, 1H), 5.91 (s, 1H), 3.87 (d, J=6.8 Hz, 2H), 1.36-1.22 (m, 1H), 0.71-0.67 (m, 2H), 0.46-0.42 (m, 2H). LCMS: 244.0 (M+1)+; 246.0
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[OH-].[K+].[CH:18]([C:20]1[C:21]2[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=2[S:23][CH:24]=1)=[CH2:19]>CN1C(=O)CCC1.O>[S:23]1[CH:24]=[C:20]([CH2:18][CH2:19][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]2=3)[C:21]2[CH:28]=[CH:27][CH:26]=[CH:25][C:22]1=2
Reactant: C=Cc1csc2ccccc12
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CCc2csc3ccccc23)CCN(C)C1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
To a solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (200 mg, 1.0 mmol) in NMP (1 mL) were added powdered KOH (392 mg, 7.0 mmol) and 3-vinyl-benzo[b]thiophene (320 mg, 2.0 mmol). The reaction mixture was stirred at 90° C. for 5 h. The reaction mixture was diluted with water (15 mL) and extracted with EtOAc (3×20 mL). The combined organic layer was washed with water (5×25 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (3% MeOH-DCM) followed by reverse phase HPLC to yield 5-(2-benzo[b]thiophen-3-yl-ethyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (CDCl3, freebase) δ (ppm): 7.82 (d, 1H), 7.6 (d, 1H), 7.38 (m, 2H), 7.2 (m, 2H), 7.0 (d, 1H), 6.93 (s, 1H), 4.3 (t, 2H), 3.62 (s, 2H), 3.5 (s, 3H), 3.21 (t, 2H), 2.63 (t, 2H), 2.41 (m, 5H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[N+:17]([O-])=O)[O:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[H][H]>C(OCC)(=O)C.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([O:5][CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:14]=[CH:15][C:16]=1[NH2:17]
Reactant: O=[N+]([O-])c1ccc(OCCN2CCOCC2)cc1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(OCCN2CCOCC2)cc1F
Yield: 93.5 %

Procedure:
A mixture of 4-[2-(3-fluoro-4-nitro-phenoxy)-ethyl]-morpholine (2.4 g, 8.9 mmol) and 5% Pd—C (0.3 g) in ethyl acetate (70 mL) was shaken under 50 psi of hydrogen for 20 hours. The mixture was filtered through Celite and evaporated, providing 2.0 g of the product, in 94% yield; 1H NMR (DMSO-d6) δ 2.44 (t, J=4.5, 4H), 2.62 (t, J=5.8 Hz, 2H), 3.57 (t, J=4.5, 4H), 3.95 (t, J=5.8 Hz, 2H), 6.50-6.55 (m, 1H), 6.52-6.72 (m, 2H).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH:3]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](C#N)[CH:15]=3)[NH:10][CH:9]=2)[CH2:4]1.[F:20]C1C=CC=C2C=1NC=C2C1CCC(=O)C1>>[F:20][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[NH:10][CH:9]=[C:8]2[CH:5]1[CH2:6][CH2:7][CH:3]([N:2]([CH3:19])[CH3:1])[CH2:4]1
Reactant: CN(C)C1CCC(c2c[nH]c3ccc(C#N)cc23)C1
Reactant: O=C1CCC(c2c[nH]c3c(F)cccc23)C1
Product: CN(C)C1CCC(c2c[nH]c3c(F)cccc23)C1
Yield: 59 %

Procedure:
By the method of Compound 3, using 3-(7-fluoro-1H-indol-3-yl)-cyclopentanone (217 mg, 1.0 mMol) as starting material, 3-(7-fluoro-1H-indol-3-yl)-cyclopentyl-dimethylamine (144 mg, 59%) was obtained. 1H NMR (400 MHz, d4MeOH) δ ppm 1.74 (m, 3 H) 2.17 (m, 3 H) 2.34 (d, J=2.20 Hz, 6 H) 2.84 (m, 1 H) 3.34 (m, 1 H) 6.77 (dd, J=11.13, 8.19 Hz, 1 H) 6.90 (m, J=10.39, 5.07, 4.83, 2.45 Hz, 1 H) 7.05 (d, J=15.16 Hz, 1 H) 7.33 (t, J=7.70 Hz, 1 H). LCMS (XTERRA C18 S5 4.6×50 mm) tR, 1.130 min., MH+ 247.29.