Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:32])[NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[S:27]([CH3:30])(=[O:29])=[O:28])=[CH:17][C:16]=1[Cl:31])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.C(Cl)(Cl)Cl>[Cl:31][C:16]1[CH:17]=[C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[S:27]([CH3:30])(=[O:28])=[O:29])[CH:19]=[CH:20][C:15]=1[NH:14][C:13]([CH:9]1[CH2:10][CH2:11][CH2:12][NH:8]1)=[O:32]
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)Nc1ccc(-c2ccccc2S(C)(=O)=O)cc1Cl
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)c1ccccc1-c1ccc(NC(=O)C2CCCN2)c(Cl)c1

Procedure:
2-(3-Chloro-2′-methanesulfonyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (1 g, 2 mmol) was dissolved in 20 mL DCM and 20 mL trifluoroacetic acid and stirred at ambient temperature for 2 hours. Concentrated solution, redissolved in 100 mL CHCl3, repeated CHCl3 co-concentration 4 times to yield title compound as a yellow foam. (quant. yield) APCI (AP+): 379.1, 381.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=[C:8]2[C:4]=1[CH:5](C1C=C(OC)C(OC)=C(OC)C=1)[CH2:6][C:7]2=[O:16].C(=O)([O-])[O-].[K+].[K+].C1OC2C=CC(C=O)=CC=2O1.Cl>O>[CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C:7]2=[O:16]
Reactant: COc1cc(C2CC(=O)c3cc(OC)c(OC)c(OC)c32)cc(OC)c1OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=Cc1ccc2c(c1)OCO2
Solvent: O
Product: COc1cc2c(c(OC)c1OC)CCC2=O
Temperature: 30 °C
Reaction time: 1 h
Yield: 144 %

Procedure:
4,5,6-trimethoxy-3-(3,4,5-trimethoxyphenyl)-indan-1-one (formula 7, 250 mg) was taken in 5% aqueous-methanolic (1:3) potassium carbonate (10 mL). To this stirred solution 3,4-methylenedioxybenzaldehyde (100 mg) was added and further stirred at room temperature at 30° C. for 1 hour. On completion, the reaction mixture was diluted with water, acidified with dil. HCl and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulphate and evaporated to get a residue. The residue was purified through silica gel column to get 2-benzo[1,3]dioxo-5-ylmethylene-4,5,6-trimethoxy-3-(3,4,5-trimethoxyphenyl)-indan-1-one (formula 8, 206 mg)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:19][CH2:20][O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1.O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:19][CH2:20][O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccccc1OCc1ccccc1
Reactant: BrCCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(COc2ccccc2OCCOC2CCCCO2)cc1
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
To a solution of 2-benzyloxyphenol (3.00 g, 15.0 mmol) in N,N-dimethylformamide (15 ml) was added sodium hydride (60% in oil) (719 mg, 18.0 mmol) under ice-cooling, and the mixture was stirred at 30 min. 2-(2-Bromoethoxy)tetrahydropyran (2.72 ml, 18.0 mmol) was added to the reaction mixture and the mixture was stirred at 18 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure to give 2-[2-(2-benzyloxyphenoxy)ethoxy]tetrahydropyran (4.90 g). The obtained compound was used for Step 2 without purification.
Reaction SMILES: CC(C)([O-])C.[K+].C(O)(C)(C)C.[CH3:12][O:13][C:14](=[O:20])[CH2:15][C:16](=[O:19])[CH2:17][CH3:18].Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[Cl:30]>O1CCCC1.O>[CH3:12][O:13][C:14](=[O:20])[CH:15]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[Cl:30])[C:16](=[O:19])[CH2:17][CH3:18]
Reactant: Fc1ccc(CBr)c(Cl)c1
Reactant: CCC(=O)CC(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)(C)O
Product: CCC(=O)C(Cc1ccc(F)cc1Cl)C(=O)OC
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A suspension of potassium tert-butoxide (1.6 g) in anhydrous tetrahydrofuran (25 mL) at 0° C. was treated with a mixture of tert-butanol (1.0 mL) and 3-oxopentanoic acid methyl ester (1.5 g). After stirring at 0° C. for 45 minutes a solution of 1-bromomethyl-2-chloro-4-fluorobenzene (2.6 g) in tetrahydrofuran (5.0 mL) was added and the resulting mixture stirred at room temperature for 3 days. The mixture was diluted with water and the tetrahydrofuran removed under reduced pressure. The mixture was extracted with ethyl acetate and the combined extracts dried over magnesium sulfate and the solvent removed under reduced pressure to afford the title compound, 3.2 g.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]([O:18][CH3:19])=[O:17])=[N:4][CH:5]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:7]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C([O-])(O)=O.[Na+].C([O-])([O-])=O.[K+].[K+].[Na+].[I-].Cl[CH2:47][C:48]([N:50]([CH3:52])[CH3:51])=[O:49]>C(OC(C)=O)(C)C.CO>[CH3:51][N:50]([CH3:52])[C:48](=[O:49])[CH2:47][NH:1][C:2]1[C:3]([C:16]([O:18][CH3:19])=[O:17])=[N:4][CH:5]=[C:6]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=2)[CH:7]=1
Reactant: CN(C)C(=O)CCl
Reactant: COC(=O)c1ncc(Cc2ccc(F)cc2)cc1N
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CO
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CC(=O)OC(C)C
Product: COC(=O)c1ncc(Cc2ccc(F)cc2)cc1NCC(=O)N(C)C
Temperature: 30 °C
Reaction time: 0.25 h

Procedure:
A stirring suspension of methyl 3-amino-5-[(4-fluorophenyl)methyl]-2-pyridinecarboxylate (60 g, 0.23 mol) in i-PrOAc (400 mL) was heated to 30° C. and trifluoroacetic anhydride (35.3 mL, 0.254 mol) was added dropwise. The reaction mixture was stirred 15 min at 30° C.; then cooled to rt and quenched slowly with 0.6 M NaHCO3 solution (512 mL, 0.32 mol). The resulting biphasic mixture was separated and the organic phase was washed twice with water; then diluted with CH3CN (700 mL) and distilled to about half its initial volume. To the remaining solution (ca. 600 mL) was added K2CO3 (34.6 g, 0.255 mol), NaI (5.18 g, 34.6 mol) and 2-chloro-N,N-dimethylacetamide (26.1 mL, 0.254 mol) and the resulting mixture was heated to 80° C. for 3.5 h. The reaction was cooled to 60° C., diluted with MeOH (200 mL), heated at reflux for 2 h and then distilled to approximately half its original volume. The remaining mixture was cooled to 37° C. and water (650 mL) was added over 2 h with gradual cooling to 15° C. A precipitate formed which was collected by filtration and washed with water. Drying of the filter cake in a vacuum oven afforded the product as an off-white solid: 1H NMR (CDCl3) δ 8.56 (1H, br), 7.89 (1H, s), 7.12 (2H, dd, J=8.5, 5.5 Hz), 6.98 (2H, t, J=8.5 Hz), 6.68 (1H, s), 3.96 (3H, s), 3.93 (2H, s), 3.88 (2H, d, J=4.2 Hz), 3.02 (3H, s), 3.01 (3H, s).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:44]([C:48]1[CH:62]=[CH:61][C:51]([CH2:52][NH:53][CH2:54][CH:55]([OH:60])[C:56]([F:59])([F:58])[F:57])=[CH:50][CH:49]=1)([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.O>[C:44]([C:48]1[CH:62]=[CH:61][C:51]([CH2:52][N:53]([CH2:54][CH:55]([OH:60])[C:56]([F:59])([F:57])[F:58])[C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])=[CH:50][CH:49]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: O=C(O)c1cccc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCC(O)C(F)(F)F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(CN(CC(O)C(F)(F)F)C(=O)c2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 21.4 %

Procedure:
To a solution of 30 mg (0.19 mmol) of 1H-indole-7-carboxylic acid and 60 mg of TBTU (0.19 mmol) in 6 ml DMF, were added 0.16 ml (0.93 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 85 mg (0.19 mmol) of [rac]-(4-tert-butyl-benzyl)-(3,3,3-trifluoro-2-hydroxy-propyl)-amine were added. After stirring for 4 h at rt, the reaction mixture was diluted with 60 ml water and extracted with EtOAc (2×). The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (9 g silica gel; EtOAc/heptane 1:4) to give 17 mg white solid (17%). MS (EI) 418.2 (M)+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][S:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)[CH2:4][CH2:3]1.O.O.[Sn](Cl)Cl.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O.C(OCC)(=O)C>[NH2:18][C:15]1[CH:14]=[CH:13][C:12]([S:11][CH2:10][CH2:9][CH2:8][N:5]2[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]2)=[CH:17][CH:16]=1
Reactant: CC1CCN(CCCSc2ccc([N+](=O)[O-])cc2)CC1
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: CC1CCN(CCCSc2ccc(N)cc2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Dissolve 15.5 g (0.0520 mol) of 4-methyl-1-[3-[(4-nitrophenyl)thio]propyl]piperidine in 150 mL of ethanol. Add 59.3 g (0.26 mol) of tin(II) chloride dihydrate and heat mixture to reflux for 5 h. After 5 h, cool the reaction mixture to room temperature. Pour reaction mixture over 100 g of potassium carbonate and dilute with 500 mL of water and 500 mL of ethyl acetate. Filter this suspension through celite and separate the layers. Extract the aqueous layer with 3×300 mL of ethyl acetate. Combine organic layers and dry over anhydrous sodium sulfate. Filter the drying agent and remove the solvent in vacuo to provide the title compound.
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][C:6]1[C:7]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[N:8][N:9]2[CH:14]=[CH:13][CH:12]=[N:11][C:10]=12)C.[OH-].[Na+].C(O)C.C(O)(=O)C>O>[CH3:21][C:18]1[CH:17]=[CH:16][C:15]([C:7]2[C:6]([CH2:5][C:4]([OH:22])=[O:3])=[C:10]3[N:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)=[CH:20][CH:19]=1
Reactant: CCOC(=O)Cc1c(-c2ccc(C)cc2)nn2cccnc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1ccc(-c2nn3cccnc3c2CC(=O)O)cc1
Reaction time: 8 h
Yield: 91.8 %

Procedure:
A stirred mixture of 32.5 g (0.11 mole) of 2-(4-methylphenyl)pyrazolo[1,5-a]pyrimidine-3-acetic acid ethyl ester and 4.5 g (0.11 mole) of sodium hydroxide in 150 mL of 190 ethanol was heated until the material dissolved. After cooling, the reaction mixture was diluted with an equal volume of water, heated until a clear dark brown solution was obtained, then cooled by stirring overnight. The reaction mixture was diluted with an additional 300 mL of water and acidified to pH 6 with glacial acetic acid. The milky solution yielded 27 g (90%) of brown crystalline product, mp 170°-171°. An analytical sample recrystallized from acetonitrile-water yielding pale yellow crystals, mp. 172°-173° C.
Reaction SMILES: I[C:2]1[C:10]2[O:9][CH2:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:12][CH3:13].[C:14]([CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1)#[CH:15]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:13][O:12][C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[O:11])[CH2:8][O:9][C:10]=2[C:2]=1[C:15]#[C:14][CH:16]1[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21]1
Reactant: COc1ccc2c(c1I)OCC2=O
Reactant: C#CC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1C#CC1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
A solution of 7-iodo-6-methoxybenzofuran-3(2H)-one (0.348 g, 1.20 mmol) synthesized in Example B46, Step 2 in triethylamine (10 mL) was added with tert-butyl 4-ethynylpiperidine-1-carboxylate (Journal of Medicinal Chemistry, Vol. 47, p. 3111, 2004, 0.276 g, 1.32 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.0842 g, 0.120 mmol) and copper(I) iodide (0.0229 g, 0.120 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain tert-butyl 4-[(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)ethynyl]piperidine-1-carboxylate (0.245 g, 55%).
Reaction SMILES: CS(O[C@@H:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:9]=1)[CH3:7])(=O)=O.[N-:21]=[N+:22]=[N-:23].[Na+].O>CN(C)C=O>[C:17]([O:16][C:14]([C:10]1[CH:9]=[C:8]([C@@H:6]([N:21]=[N+:22]=[N-:23])[CH3:7])[CH:13]=[CH:12][CH:11]=1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: C[C@@H](OS(C)(=O)=O)c1cccc(C(=O)OC(C)(C)C)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H](N=[N+]=[N-])c1cccc(C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.8 %

Procedure:
(R)-1-(3-tert-butyloxycarbonylphenyl)-ethyl methanesulfonyl ether (3.28 mmol) was dissolved in N,N-dimethylformamide (20 mL) and sodium azide (8.57 mmol) was added. The resultant mixture was heated to 60° C. for 45 min then stirred at room temperature overnight. Worked up by pouring into water and extracting 3× with diethyl ether. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated under reduced pressure to yield 769 mg of an oil which was used without further purification. 1H NMR (500 MHz, CDCl3): δ 7.96 (m, 2H); 7.52 (m, 1H); 7.45 (m, 1H); 4.69 (q, J=6.9 Hz, 1H): 1.63 (s, 9H); 1.57 (d, J=6.8 Hz, 3H).
Reaction SMILES: Br[C:2]1[C:3]([F:14])=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][CH3:13])[CH:8]=[CH:7]2.[N:15]1([CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:14][C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[N:18]1[CH2:19][CH2:20][N:15]([CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[CH2:16][CH2:17]1)=[N:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=2
Reactant: CC(C)(C)OC(=O)NCCN1CCNCC1
Reactant: COc1ccc2ncc(F)c(Br)c2n1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1ccc2ncc(F)c(N3CCN(CCNC(=O)OC(C)(C)C)CC3)c2n1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 41.6 %

Procedure:
In a sealed tube, 8-bromo-7-fluoro-2-(methyloxy)-1,5-naphthyridine (1.1 g, 4.3 mmol), 1,1-dimethylethyl [2-(1-piperazinyl)ethyl]carbamate (1 g, 4.3 mmol), Pd2dba3 (271 mg, 0.262 mmol), rac-Binap (163 mg, 0.262 mmol), Cs2CO3 (2.98 mg, 9.2 mmol) and 18-C-6 (115 mg, 0.436 mmol) in dioxane (22 mL) were combined and flushed with N2. After 15 min, the tube was sealed and heated to 100° C. while stirring rapidly. After 12 h, the solution was filtered, concentrated and the residue purified via column chromatography (silica, 1% MeOH in DCM (1% NH4OH)) yielding the title compound (725 mg, 41%) as an orange oil: LCMS (ES) m/e 406 (M+H)+.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[C:7]([CH2:9]P(=O)(OCC)OCC)#[N:8].[CH3:18][N:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1.O>C1COCC1>[CH3:18][N:19]1[CH2:24][CH2:23][C:22](=[CH:9][C:7]#[N:8])[CH2:21][CH2:20]1
Reactant: CN1CCC(=O)CC1
Reactant: CCOP(=O)(CC#N)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CN1CCC(=CC#N)CC1

Procedure:
9.36 g of K2CO3 and 8.89 ml of diethyl (cyanomethyl)phosphonate are placed in 12 ml of THF in a round-bottomed flask equipped with a magnetic stirrer, and under a stream of nitrogen, and the mixture is left to react for 15 minutes at room temperature and then refluxed for 20 minutes. The resulting mixture is allowed to cool and 6.5 ml of 1-methyl-4-piperidone are added dropwise. This mixture is refluxed for 16 hours. The reaction mixture is then poured into water and extracted with ethyl acetate. The organic phase is dried over Na2SO4, filtered and evaporated under vacuum. 6.8 g of oil are obtained.
Reaction SMILES: [CH:1]([NH:4][S:5]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20](Br)[CH:19]=1)[CH2:12][C:11]2([CH3:26])[CH3:25])(=[O:7])=[O:6])([CH3:3])[CH3:2].Cl.CN(C)CC(O)=O.C(=O)([O-])[O-].[K+].[K+].[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>CS(C)=O.[Cu]I>[CH:1]([NH:4][S:5]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)[CH:19]=1)[CH2:12][C:11]2([CH3:26])[CH3:25])(=[O:7])=[O:6])([CH3:3])[CH3:2]
Reactant: C1COCCN1
Reactant: CC(C)NS(=O)(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(Br)c1)N2
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: CS(C)=O
Product: CC(C)NS(=O)(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(N3CCOCC3)c1)N2
Temperature: 25 °C
Yield: 40.1 %

Procedure:
The mixture solution of 2-(3-bromo-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-sulfonic acid isopropylamide (392.0 mg, 0.9 mmol), CuI (51.0 mg, 0.27 mmol), N,N-dimethylglycine hydrochloride (75.0 mg, 0.54 mmol), potassium carbonate (373.0 mg, 2.7 mmol) and morpholine (0.78 mL, 9.0 mmol) in DMSO (5.0 mL) was stirred at 120° C. for 16 h under a nitrogen atmosphere. Then the reaction mixture was cooled to room temperature and extracted with ethyl acetate (70 mL×2), washed with water (30 mL×3) and saturated aqueous ammonium chloride solution (30 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 4,4-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-sulfonic acid isopropylamide (160.0 mg, 40%) as a light yellow solid: MS (ESI) M+1=444.3.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][C@@H:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13]C(C)(C)C)=O)[CH2:7]1)[CH3:2].O1CCOCC1.C(N(CC)[CH:29]([CH3:31])[CH3:30])(C)C.C1(C(Cl)=O)CC1>Cl.ClCCl.O>[CH:29]1([C:11]([N:8]2[CH2:9][CH2:10][C@@H:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:18])[CH2:7]2)=[O:13])[CH2:31][CH2:30]1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)C[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: O=C(Cl)C1CC1
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C[C@@H]1CCN(C(=O)C2CC2)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 100 %

Procedure:
In a round bottom flask, a solution of 1,1-dimethylethyl (3S)-3-[2-(ethyloxy)-2-oxoethyl]-1-pyrrolidinecarboxylate (64.1 g, 249 mmol) in 4M HCl in dioxane (600 mL, 2400 mmol) was stirred at room temperature for 1 h. Analysis of an aliquot by LCMS confirmed complete removal of the BOC group from the starting material. The reaction was concentrated in vacuo to give a pale orange liquid. A solution of this intermediate as the HCl salt in dichloromethane (500 mL) was treated with N,N-diisopropylethylamine (87 mL, 498 mmol) and stirred for 5 min at room temperature. The yellow solution was cooled to 0° C. and was treated with cyclopropanecarbonyl chloride (24.9 mL, 274 mmol) by syringe. The resultant orange solution was allowed to warm to room temperature and stirred for 1 h. The reaction was diluted with water (400 mL), the layers were separated, and the aqueous layer was extracted with 200 mL dichloromethane. The organic layers were combined, dried over MgSO4, concentrated in vacuo, and pumped under high vacuum to give the title compound as an orange liquid (249 mmol, quantitative). MS(ES)+ m/e 226.2 [M+H]+, 451.1 [2M+H]+.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH3:7])=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][N:15]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[CH3:12][O:13][C:14]1[N:15]=[CH:16][C:17]([C:2]2[O:6][C:5]([CH3:7])=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=2)=[CH:18][CH:19]=1
Reactant: COC(=O)c1cc(Br)oc1C
Reactant: COc1ccc(B(O)O)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1cc(-c2ccc(OC)nc2)oc1C
Yield: 80.5 %

Procedure:
A mixture of methyl 5-bromo-2-methyl-3-furancarboxylate (2.2 g), 2-methoxy-5-pyridineboronic acid (1.8 g), tetrakis(triphenylphosphine)palladium(0) (0.6 g), 2N aqueous sodium carbonate solution (12 mL) and 1,2-dimethoxyethane (20 mL) was stirred under reflux overnight under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 20% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (2.0 g, 81%) as a white solid.
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[F:46][C:47]1[CH:48]=[C:49]([CH:93]=[CH:94][CH:95]=1)[CH2:50][N:51]1[C:55]([CH3:56])=[C:54]([C:57]2[C:65]3[C:60](=[N:61][CH:62]=[C:63]([C:66]4[CH:67]=[C:68]([O:80][CH3:81])[C:69]([NH:72][C:73](=[O:79])[O:74][C:75]([CH3:78])([CH3:77])[CH3:76])=[N:70][CH:71]=4)[CH:64]=3)[N:59](S(C3C=CC(C)=CC=3)(=O)=O)[CH:58]=2)[C:53]([CH3:92])=[N:52]1.[OH-].[Li+]>C1COCC1.CO.O>[F:46][C:47]1[CH:48]=[C:49]([CH:93]=[CH:94][CH:95]=1)[CH2:50][N:51]1[C:55]([CH3:56])=[C:54]([C:57]2[C:65]3[C:60](=[N:61][CH:62]=[C:63]([C:66]4[CH:67]=[C:68]([O:80][CH3:81])[C:69]([NH:72][C:73](=[O:79])[O:74][C:75]([CH3:78])([CH3:77])[CH3:76])=[N:70][CH:71]=4)[CH:64]=3)[NH:59][CH:58]=2)[C:53]([CH3:92])=[N:52]1
Reactant: COc1cc(-c2cnc3c(c2)c(-c2c(C)nn(Cc4cccc(F)c4)c2C)cn3S(=O)(=O)c2ccc(C)cc2)cnc1NC(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1cc(-c2cnc3[nH]cc(-c4c(C)nn(Cc5cccc(F)c5)c4C)c3c2)cnc1NC(=O)OC(C)(C)C
Yield: 64.2 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, tert-butyl (5-(3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-methoxypyridin-2-yl)carbamate (200 mg, 0.287 mmol) was hydrolyzed by lithium hydroxide (121 mg, 2.870 mmol) in THF/methanol/water (5/5/2 ml) to yield 100 mg (64.5% yield) of the titled compound.