Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1)=[O:5].C(N(CC)CC)C.[CH:27]1[C:37]2[N:36]3[CH:38]=[CH:39][CH:40]=[C:35]3[CH2:34][CH2:33][NH:32][C:31]=2[CH:30]=[CH:29][CH:28]=1>C(Cl)Cl.C(OCC)(=O)C>[CH:27]1[C:37]2[N:36]3[CH:38]=[CH:39][CH:40]=[C:35]3[CH2:34][CH2:33][N:32]([C:11]([C:10]3[CH:14]=[CH:15][C:7]([NH:6][C:4](=[O:5])[C:3]4[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=4[CH3:1])=[CH:8][CH:9]=3)=[O:12])[C:31]=2[CH:30]=[CH:29][CH:28]=1
Reactant: c1ccc2c(c1)NCCc1cccn1-2
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCc3cccn3-c3ccccc32)cc1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
To a mixture of 1.37 g (5 mmol) of 4-[(2-methylbenzoyl)amino]benzoyl chloride in 10 ml of methylene chloride, cooled to 0° C. is added 7 mmol of triethylamine and 5 mmol of 6,7-dihydro-5H-pyrrolo-[1,2-a][1,5]benzodiazepine. The cooling bath is removed and the reaction mixture is allowed to stir at room temperature for 48 hours. The volatiles are removed in vacuo to give a residue. The residue is dissolved in 100 ml of ethyl acetate and washed with water, 2N citric acid, aqueous NaHCO3 and brine. The solution is dried with Na2SO4 and the solvent removed in vacuo to give a solid. The solid is triturated with ether-hexane to give the desired product, mass spectrum (CI):422(M+H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:14][CH:13]2[CH2:15][CH:9]([CH2:10][N:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12]2)[CH:8]=1)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Li+].[O:31]([C:38]1[CH:39]=[C:40](B(O)O)[CH:41]=[N:42][CH:43]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(COC)OC.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>[O:31]([C:38]1[CH:39]=[C:40]([C:7]2[CH2:14][CH:13]3[CH2:15][CH:9]([CH2:10][N:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12]3)[CH:8]=2)[CH:41]=[N:42][CH:43]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: OB(O)c1cncc(Oc2ccccc2)c1
Reactant: CCOC(=O)N1CC2C=C(OS(=O)(=O)C(F)(F)F)CC(C2)C1
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: [Cl-]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)N1CC2C=C(c3cncc(Oc4ccccc4)c3)CC(C2)C1
Temperature: 25 °C
Yield: 86.7 %

Procedure:
To a solution of ethyl 7-(trifluoromethylsulfonyloxy)-3-azabicyclo[3.3.1] non-6-ene-3-carboxylate (0.13 g, 0.38 mmol) in dimethoxyethane (3 mL) was added saturated sodium carbonate solution (1 mL), lithium chloride (0.04 g, 0.9 mmol) and 5-phenoxy-3-pyridinylboronic acid (0.17 g, 0.79 mmol). The flask was alternately evacuated and filled with argon three times. Then, tetrakis(triphenylphosphine)palladium(0) (0.01 g, 0.01 mmol) was added, and the evacuation and argon fill was performed once again. The flask was sealed under argon, and the stirred reaction mixture was heated at 95(C for 2 h. The mixture was cooled to ambient temperature, diluted with water (10 mL), extracted with chloroform (3×5 mL). The extracts were dried over sodium sulfate and filtered. Concentration of the filtrate by rotary evaporation, followed by purification of the residue by silica gel column chromatography, using a gradient of 0-2% methanol in chloroform/as eluent, gave ethyl 7-(5-phenoxy-3-pyridinyl)-3-azabicyclo[3.3.1]non-6-ene-3-carboxylate as a light yellow oil (0.12 g, 87%).
Reaction SMILES: [Cl-].[CH2:2]([P+:6]([CH2:14][CH2:15]CC)([CH2:10][CH2:11]CC)[CH2:7][CH2:8][OH:9])[CH2:3]CC.COC1C=CC(O)=CC=1.[C:27]([Cl:32])(=[O:31])[C:28]([CH3:30])=[CH2:29]>C(#N)C>[Cl-:32].[CH2:14]([P+:6]([CH2:2][CH3:3])([CH2:10][CH3:11])[CH2:7][CH2:8][O:9][C:27](=[O:31])[C:28]([CH3:30])=[CH2:29])[CH3:15]
Reactant: CCCC[P+](CCO)(CCCC)CCCC
Reactant: C=C(C)C(=O)Cl
Agent: COc1ccc(O)cc1
Agent: [Cl-]
Solvent: CC#N
Product: C=C(C)C(=O)OCC[P+](CC)(CC)CC
Reaction time: 2 h

Procedure:
A distillation line was installed instead of the condenser and the obtained tri-n-butyl(2-hydroxyethyl)phosphonium chloride was dissolved in 500 ml of acetonitrile. The solution was heated under a normal pressure while stirring and about 200 ml of acetonitrile was distilled. A condenser having a calcium chloride tube was installed, 1.5 g of hydroquinone monomethyl ether was added as a polymerization inhibitor, and 85.9 g (0.822 mol) of methacryloyl chloride was added thereto dropwise at 50° C. over 2 hours through a dropping funnel, then the solution was maturated for 3 hours at the same temperature.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:7]=[CH:6][N:5]([CH2:8][C:9]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[S:18][CH:19]=[C:20]([C:22]([OH:24])=[O:23])[N:21]=3)[CH2:13][CH2:12]2)=[O:10])[N:4]=1.[CH3:27][C:28]([CH3:33])([CH3:32])[CH2:29][CH2:30]O>>[F:26][C:2]([F:1])([F:25])[C:3]1[CH:7]=[CH:6][N:5]([CH2:8][C:9]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[S:18][CH:19]=[C:20]([C:22]([O:24][CH2:30][CH2:29][C:28]([CH3:33])([CH3:32])[CH3:27])=[O:23])[N:21]=3)[CH2:13][CH2:12]2)=[O:10])[N:4]=1
Reactant: O=C(O)c1csc(C2CCN(C(=O)Cn3ccc(C(F)(F)F)n3)CC2)n1
Reactant: CC(C)(C)CCO
Product: CC(C)(C)CCOC(=O)c1csc(C2CCN(C(=O)Cn3ccc(C(F)(F)F)n3)CC2)n1

Procedure:
A solution of 2-(1-{[3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylic acid (III-2, 200 mg) is reacted analogously to Example I-811 with 3,3-dimethylbutan-1-ol (68.0 mg). This gives, after chromatographic purification, 3,3-dimethylbutyl 2-(1-{[3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (98 mg, 40%).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[N:11]3[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]3=[N:9][C:8]=2[CH3:22])=[C:4]([CH3:23])[CH:3]=1.[Br-].[F:25][C:26]1[CH:27]=[C:28]([Zn+])[CH:29]=[CH:30][C:31]=1[F:32].C1COCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:25][C:26]1[CH:27]=[C:28]([C:2]2[S:6][C:5]([C:7]3[N:11]4[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]4=[N:9][C:8]=3[CH3:22])=[C:4]([CH3:23])[CH:3]=2)[CH:29]=[CH:30][C:31]=1[F:32]
Reactant: Fc1ccc([Zn+])cc1F
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(Br)cc3C)c(C)nc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Br-]
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nn2c(-c3sc(-c4ccc(F)c(F)c4)cc3C)c(C)nc12
Yield: 33 %

Procedure:
Using a procedure similar to Example 32, 3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.50 g, 1.27 mmol) and PdCl2(dppf) (0.047 g, 0.064 mmol) and 0.5 M solution of 3,4-difluorophenylzinc bromide in THF (5.1 mL, 2.55 mmol) are reacted. The residue is purified by ISCO column chromatography (15%-20% EtOAc/hexane gradient) and is chromatographed (50×250 C18 Symmetry column, 30-80% water: 0.1% TPA/ACN: 0.1% TFA gradient) furnish the title compound (0.18 g, 0.42 mmol, 33%). 1H NMR (CDCl3), δ 0.90 (t, J=7.5 Hz, 6H), 1.76-1.94 (m, 4H), 2.16 (s, 3H), 2.50 (s, 3H), 2.54 (s, 3H), 3.31-3.40 (m, 1H), 6.69 (s, 1H), 7.13-7.21 (m, 1H), 7.18 (s, 1H), 7.31-7.36 (m, 1H), 7.39-7.46 (m, 1H). LC/MS (m/z): calcd. for C24H25F2N3S (M+H)+: 426.3; found: 426.2.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:19][O:20][C:21]([CH2:23][C:24]1[CH:50]=[CH:49][C:27]([O:28][CH2:29][C@H:30]([NH:32][CH2:33][C@H:34]([O:41][Si](C(C)(C)C)(C)C)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH3:31])=[CH:26][CH:25]=1)=[O:22]>O1CCCC1.O>[CH3:19][O:20][C:21]([CH2:23][C:24]1[CH:50]=[CH:49][C:27]([O:28][CH2:29][C@H:30]([NH:32][CH2:33][C@@H:34]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[OH:41])[CH3:31])=[CH:26][CH:25]=1)=[O:22]
Reactant: COC(=O)Cc1ccc(OC[C@@H](C)NC[C@H](O[Si](C)(C)C(C)(C)C)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)Cc1ccc(OC[C@@H](C)NC[C@H](O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.1 %

Procedure:
870 mg of tetrabutylammonium fluoride were added to a solution of 510 mg of N-[2-(4-methoxycarbonylmethylphenoxy)-1(R)-methylethyl]-2(R)-t-butyldimethylsilyloxy-2-phenylethanamine (prepared as described in Preparation 29) in 15 ml of tetrahydrofuran, and the resulting mixture was stirred at room temperature for 2 hours. At the end of this time, the reaction mixture was diluted with water, and the aqueous mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and then the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using ethyl acetate as the eluent, to give 0.23 g of the title compound as crystals, melting at 69°-70° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([Cl:11])=[N:9][C:8]([N:12]2[CH2:17][CH2:16][C:15](=[N:18][O:19][CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)[CH2:14][CH2:13]2)=[C:7]([Cl:32])[N:6]=1)=[O:4].C1COCC1.[OH-].[Na+]>Cl>[Cl:11][C:10]1[C:5]([C:3]([OH:4])=[O:2])=[N:6][C:7]([Cl:32])=[C:8]([N:12]2[CH2:13][CH2:14][C:15](=[N:18][O:19][CH:20]3[CH2:21][CH2:22][N:23]([C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27])[CH2:24][CH2:25]3)[CH2:16][CH2:17]2)[N:9]=1
Reactant: COC(=O)c1nc(Cl)c(N2CCC(=NOC3CCN(C(=O)OC(C)C)CC3)CC2)nc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)OC(=O)N1CCC(ON=C2CCN(c3nc(Cl)c(C(=O)O)nc3Cl)CC2)CC1
Temperature: 50 °C

Procedure:
The crude 56b obtained in the previous step was taken up with THF (1 mL) and 1N NaOH (1 mL) and heated to 50° C. for 3 h. The mixture was cooled, diluted with 5 mL of 1N HCl and extracted with EtOAc (3×5 mL). The combined extracts were dried and concentrate to afford 0.13 g of crude 56c. 25 mg of this material was purified by preparative HPLC to afford 56c: LC-MS 474.7 (MH+).
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[S:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[NH2:15])=[N:4][N:3]=[N:2]1.Cl[C:21]([C:23]1[CH:37]=[CH:36][C:26]([O:27][CH2:28][C:29]([O:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:30])=[CH:25][CH:24]=1)=[O:22]>N1C=CC=CC=1.C(Cl)Cl>[NH:4]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[S:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[NH:15][C:21]([C:23]2[CH:37]=[CH:36][C:26]([O:27][CH2:28][C:29]([O:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:30])=[CH:25][CH:24]=2)=[O:22])=[N:1][N:2]=[N:3]1
Reactant: Nc1ccccc1Sc1ccccc1-c1nnn[nH]1
Reactant: CCCCOC(=O)COc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCOC(=O)COc1ccc(C(=O)Nc2ccccc2Sc2ccccc2-c2nnn[nH]2)cc1
Reaction time: 8 h
Yield: 81.7 %

Procedure:
In a mixture of 6 ml of pyridine and 80 ml of methylene chloride was dissolved 5.3 g of 2-[2-(1H-tetrazol-5-yl)phenylthio]aniline followed by dropwise addition of 5.4 g of butyl 4-chloroformylphenoxyacetate, and the mixture was stirred overnight. The solvent was then distilled off and the residue was crystallized from aqueous ethanol and then recrystallized ethyl acetate to give 8.1 g of the title compound as white crystals, m.p. 133-135.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8](I)[C:7]([CH:11]([CH3:13])[CH3:12])=[CH:6][C:5]=1[NH2:14].[CH3:16][N:17]1[C:21]([Sn](CCCC)(CCCC)CCCC)=[CH:20][CH:19]=[N:18]1.O1CCOCC1>CCOC(C)=O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([C:21]2[N:17]([CH3:16])[N:18]=[CH:19][CH:20]=2)[C:7]([CH:11]([CH3:13])[CH3:12])=[CH:6][C:5]=1[NH2:14]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnn1C
Reactant: COC(=O)c1cc(I)c(C(C)C)cc1N
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(-c2ccnn2C)c(C(C)C)cc1N
Temperature: 100 °C
Reaction time: 18 h
Yield: 65.8 %

Procedure:
2-Amino-5-iodo-4-isopropyl-benzoic acid methyl ester (300 mg, 0.94 mmol) and 1-methyl-5-tributylstannanyl-1H-pyrazole (523 mg, 1.5 equiv) were weighed in air and added in a flame-dried flask. [Bistriphenylphosphine]dichloropalladium (67.3 mg, 0.1 equiv) was added and the flask was closed by a septum. Dioxane (1 mL) was added and the mixture was stirred for 18 h (TLC control) at 100° C. The mixture was dissolved with EtOAc, filtered and evaporated to dryness. The crude product was purified by flash chromatography (hexanes to EtOAc/hexanes (4:6)) to yield 2-amino-4-isopropyl-5-(2-methyl-2H-pyrazol-3-yl)-benzoic acid methyl ester (169 mg, 66%) as a yellow solid. (ESI-MS: m/z 274 [M+H]+, rt 5.20 min).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[Cl:9][C:10]1[CH:44]=[CH:43][CH:42]=[CH:41][C:11]=1[CH2:12][N:13]1[C:21]2[C:20](=[O:22])[N:19]([CH3:23])[C:18](=[O:24])[N:17]([CH3:25])[C:16]=2[C:15]([OH:26])=[C:14]1[N:27]1[CH2:32][CH2:31][CH2:30][C@@H:29]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:28]1.S([O-])(O)(=O)=O.[K+]>CN(C)C=O>[Cl:9][C:10]1[CH:44]=[CH:43][CH:42]=[CH:41][C:11]=1[CH2:12][N:13]1[C:21]2[C:20](=[O:22])[N:19]([CH3:23])[C:18](=[O:24])[N:17]([CH3:25])[C:16]=2[C:15]([O:26][CH3:1])=[C:14]1[N:27]1[CH2:32][CH2:31][CH2:30][C@@H:29]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:38])([CH3:39])[CH3:37])[CH2:28]1
Reactant: O=C([O-])[O-]
Reactant: Cn1c(=O)c2c(c(O)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)n2Cc2ccccc2Cl)n(C)c1=O
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1c(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)n(Cc2ccccc2Cl)c2c(=O)n(C)c(=O)n(C)c12
Temperature: 25 °C
Reaction time: 5 h
Yield: 33.1 %

Procedure:
Potassium carbonate (41 mg) and methyl iodide (13 μl) were added to a solution of tert-butyl {(3R)-1-[5-(2-chlorobenzyl)-7-hydroxy-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate (50 mg) in N,N-dimethylformamide (2 ml), and the resulting mixture was stirred at room temperature for 5 hours. A 10% aqueous potassium hydrogensulfate solution was added to the reaction solution, followed by extraction with ethyl acetate (100 ml). The organic layer was washed with a 10% aqueous potassium hydrogensulfate solution and a saturated aqueous sodium chloride solution, dried over sodium sulfate and then filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a preparative thin-layer chromatography (hexane/ethyl acetate=1/1) to obtain the title compound (17 mg).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH:9][C:10]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]3[O:20][C:19]([C:21]4[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=4)=[N:18][C:17]=13)=[O:11])[CH2:2]2.[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+]>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.C1(C)C=CC=CC=1>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH:9][C:10]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]3[O:20][C:19]([C:21]4[CH:26]=[CH:25][C:24]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)=[CH:23][CH:22]=4)=[N:18][C:17]=13)=[O:11])[CH2:2]2
Reactant: OB(O)c1ccccc1
Reactant: O=C(NC1CN2CCC1CC2)c1cccc2oc(-c3ccc(I)cc3)nc12
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: Cc1ccccc1
Product: O=C(NC1CN2CCC1CC2)c1cccc2oc(-c3ccc(-c4ccccc4)cc3)nc12
Temperature: 80 °C
Yield: 78.7 %

Procedure:
To a mixture of N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(4-iodophenyl)benzoxazole-4-carboxamide (30 mg, 0.063 mmol), phenylboronic acid (12 mg, 0.098 mmol), 2 M Na2CO3 (2 mL) and toluene (2 mL) was deoxygenated with nitrogen for 10 min, and then tetrakis(triphenylphosphine)palladium(0) (7.3 mg, 0.0063 mmol) was added. The resulting mixture was heated at 80° C. under nitrogen overnight, and then was cooled to room temperature, quenched with saturated sodium bicarbonate, extracted with methylene chloride. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:10:1 ethyl acetate/methanol/concentrated ammonium hydroxide) to afford N-(1-azabicyclo[2.2.2]oct-3-yl)-2-biphenyl-4-ylbenzoxazole-4-carboxamide (21 mg, 78%) as a light yellow solid: 1H NMR (500 MHz, CDCl3) δ 9.60 (d, J=7.0 Hz, 1H), 8.31 (d, J=8.0 Hz, 2H), 8.21 (d, J=7.5 Hz, 1H), 7.80 (d, J=8.0 Hz, 2H), 7.74 (d, J=7.5 Hz, 1H), 7.69-7.67 (m, 2H), 7.52-7.42 (m, 4H), 4.36-4.30 (m, 1H), 3.53 (ddd, J=14.0, 9.5, 2.0 Hz, 1H), 3.17-2.84 (m, 5H), 2.19-2.10 (m, 2H), 1.80-1.63 (m, 3H); MS (ESI+) m/z 424 (M+H); HPLC 96.3% (AUC), tR=14.01 min.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][C:21]2=[O:26])(=O)=O)=CC=1.C(N(C(C)C)CC)(C)C.[CH3:36][O:37][C:38](=[O:45])[CH2:39][CH:40]1[CH2:44][CH2:43][NH:42][CH2:41]1>CN(C=O)C>[O:26]=[C:21]1[CH2:22][CH2:23][CH2:24][CH2:25][N:20]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][CH2:12][N:42]1[CH2:43][CH2:44][CH:40]([CH2:39][C:38]([O:37][CH3:36])=[O:45])[CH2:41]1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccccc2N2CCCCC2=O)cc1
Reactant: COC(=O)CC1CCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)CC1CCN(CCc2ccccc2N2CCCCC2=O)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
To a solution of 2-[2-(2-oxopiperidin-1-yl)phenyl]ethyl 4-methylbenzenesulfonate a2-3 (2.85 g, 7.65 mmol, 1 eq) in DMF (10 ml) at room temperature are added diisopropylethylamine (2.65 ml, 15.30 mmol, 2 eq) and methylpyrrolidin-3-ylacetate a13-0 (1.08 g, 7.65 mmol, 1 eq). The mixture is stirred at 80° C. overnight. The solvent is removed under vacuum. The residue obtained is purified by chromatography over silicagel (eluent: CH2Cl2/EtOH 95/5) to afford 1.05 g of methyl (1-{2-[2-(2-oxopiperidin-1-yl)phenyl]ethyl}pyrrolidin-3-yl)acetate a13-1 as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH2:10][CH2:11][CH2:12][N:13]=2)[CH:6]=[CH:7][CH:8]=1.C([BH3-])#N.[Na+].C(O)(=O)C>C(O)C.C(OCC)(=O)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:10][CH2:11][CH2:12][NH:13]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C2=NCCC2)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: ClCCl
Product: COc1cccc(C2CCCN2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 38 %

Procedure:
To a solution of 5-(3-methoxy-phenyl)-3,4-dihydro-2H-pyrrole (10.73 g, 61.2 mmol) in ethanol (306 mL) at 0° C. add sodium cyanoborohydride (5.77 g, 91.9 mmol), followed by acetic acid (5.26 mL, 91.9 mmol). After stirring at 0° C. for 30 min, warm to room temperature. After 16 hours the reaction is approximately 50% complete. Add more sodium cyanoborohydride (5.77 g, 91.9 mmol) and acetic acid (5.26 mL, 91.9 mmol) and stir an additional 5 hours. Add saturated aqueous sodium bicarbonate (500 mL), extract with methylene chloride (3×500 mL), dry the combined organic layers over magnesium sulfate, filter, and concentrate under reduced pressure to obtain a crude mixture (11.50 g). Purify the material by flash chromatography [silica gel, 330 g, 0 to 100% gradient of (90:10:1 methylene chloride/methanol/concentrated ammonium hydroxide) in methylene chloride] to obtain 7.06 g. Dissolve this crude material in ethyl acetate (300 mL) and extract with 2 M hydrochloric acid (2×150 mL). Separate the layers, and adjust the aqueous layer to pH 13 with aqueous sodium hydroxide, then extract with ethyl acetate multiple times. Dry the combined organic layers over magnesium sulfate, filter, and concentrate under reduced pressure to obtain 6.03 g. Dissolve in methylene chloride (400 mL) and extract with 2 M hydrochloric acid (3×100 mL). Adjust the combined aqueous layers to pH 13, then extract with methylene chloride (3×150 mL). Separate the layers, and dry the combined organic layers over magnesium sulfate, filter, and concentrate under reduced pressure to obtain the title compound (4.12 g, 38%). MS (ESI+): 178 [C11H15NO+H]+; 1H NMR (300 MHz, CDCl3): δ 7.26-7.20 (m, 1H), 6.95-6.93 (m, 2H), 6.79-6.75 (m, 1H), 3.80 (s, 3H), 4.09 (t, J=7.7 Hz, 1H), 3.24-3.16 (m, 1H), 3.04-2.96 (m, 1H), 2.19 (s, 1H), 2.23-2.12 (m, 1H), 1.98-1.76 (m, 2H), 1.72-1.60 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.[CH3:22][CH:23]1[CH2:28][NH:27][CH2:26][CH2:25][NH:24]1>N1C=CC=CC=1>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:27]2[CH2:26][CH2:25][NH:24][CH:23]([CH3:22])[CH2:28]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1
Reactant: CC1CNCCN1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Solvent: c1ccncc1
Product: CC1CN(c2c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CCN1
Yield: 88.3 %

Procedure:
A mixture of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (1.25 g), 2-methylpiperazine (2.0 g), and pyridine (13 ml) was heated at 105°-110° C. for 1 hour with stirring. The reaction mixture was evaporated to dryness under reduced pressure and water was added to the residue. The mixture was extracted with chloroform and the extract was dried. After evaporation of chloroform, ethanol was added to the residue. The resulting crystals were filtered and recrystallized from chloroform-ethanol to give 5-amino-1-cyclopropyl-6,8-difluoro-7-(3-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (1.4 g), m.p. 251°-253° C.
Reaction SMILES: [O:1]=[C:2]([CH3:14])[CH2:3][C:4](ON1C(=O)CCC1=O)=[O:5].[CH3:15][O:16][C:17]1[CH:30]=[CH:29][C:20]([CH2:21][NH:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:19][CH:18]=1.C(N(CC)CC)C.[Cl-].[Na+]>ClCCl>[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:21][N:22]([CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:4](=[O:5])[CH2:3][C:2](=[O:1])[CH3:14])=[CH:29][CH:30]=1
Reactant: CC(=O)CC(=O)ON1C(=O)CCC1=O
Reactant: COC(=O)CCNCc1ccc(OC)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCN(Cc1ccc(OC)cc1)C(=O)CC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A flask with stirbar was charged with 2,5-dioxopyrrolidin-1-yl 3-oxobutanoate (6.47 g, 32.5 mmol), methyl 3-(4-methoxybenzylamino)propanoate (prepared as described in Bew, S. et al, Chem Commun. 2006 (41), 4338-40, 7.7 g, 34.5 mmol) and triethylamine (5 mL, 35.9 mmol) in dichloromethane (125 mL). The solution was stirred overnight at ambient temperature, then shaken in a separatory funnel with saturated aqueous sodium chloride. The organics were then washed with saturated aqueous sodium chloride containing 0.1M HCl and dried over anhydrous sodium sulfate. Filtration and solvent removal provided the title compound.