Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:17][O:18][CH2:19]Cl.O>C(#N)C>[OH:1][C:2]1[CH:9]=[C:8]([O:10][CH2:17][O:18][CH3:19])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1ccc(O)cc1O
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: COCOc1ccc(C=O)c(O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 2,4-dihydroxybenzaldehyde (0.83 g) and cesium carbonate (1.7 g) in acetonitrile (30 mL) was added chloromethyl methyl ether (0.55 mL), and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gal (eluent: hexane/ethyl acetate=4/1) to give 2-hydroxy-4-(methoxymethyloxy)benzaldehyde (0.84 g).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C@H:17]([OH:19])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:37])[C@@H:15]2[CH2:20][CH2:21][C@H:22]2[O:27][C:26](=[O:28])[CH2:25][C@H:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:23]2)=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N([CH2:43][CH3:44])CC)C.Cl>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1>[Si:1]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:17](=[O:19])[C@:16]([CH2:43][CH3:44])([CH3:11])[CH2:15][CH2:14][CH3:13])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:37])[C@@H:15]2[CH2:20][CH2:21][C@H:22]2[O:27][C:26](=[O:28])[CH2:25][C@H:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:31])[CH3:32])[CH2:23]2)=[CH:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CCN(CC)CC
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: Cc1ccccc1
Product: CCC[C@](C)(CC)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Temperature: 25 °C
Yield: 31 %

Procedure:
121 μl (1.66 mmol) of thionyl chloride were added to 60 mg (0.42 mmol) of (-)-(2S)-2-ethyl-2-methylpentanoic acid [prepared as described in Preparation 16], and the resulting mixture was heated at 100° C. for one hour. At the end of this time, the mixture was concentrated by evaporation under reduced pressure. The whole of the (-)-(2S)-2-ethyl-2-methylvaleryl chloride obtained in this manner was added, directly and without purification, to a solution of 458 mg (0.83 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], 203 mg (1.66 mmol) of 4-(N,N-dimethylamino)pyridine, a catalytic amount (20 mg) of 4-dimethylaminopyridine and 232 μl of triethylamine in 2.5 ml of toluene, and the resulting mixture was heated under reflux for 24 hours. At the end of this time, the reaction mixture was cooled to room temperature and then mixed with 10 ml of a 10% w/v aqueous solution of hydrogen chloride. The aqueous mixture was extracted three times, each time with 20 ml of ethyl acetate. The combined extracts were then washed with a saturated aqueous solution of sodium chloride, after which the washed solution was dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting pale-yellow oily residue was purified by flash column chromatography through silica gel, using a 5:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 88 mg (31% yield) of the title compound as a foam-like substance.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][C:12]1=[O:17])[C:5]([OH:7])=O.[Cl:18][C:19]1[CH:33]=[CH:32][C:22]2[NH:23][C:24]([C@@H:26]([NH2:31])[CH2:27][CH2:28][O:29][CH3:30])=[N:25][C:21]=2[CH:20]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[Cl:18][C:19]1[CH:33]=[CH:32][C:22]2[NH:23][C:24]([C@@H:26]([NH:31][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][C:12]4=[O:17])=[C:2]([CH3:1])[CH:3]=3)[CH2:27][CH2:28][O:29][CH3:30])=[N:25][C:21]=2[CH:20]=1
Reactant: Cc1cc(C(=O)O)ccc1N1CCOCC1=O
Reactant: COCC[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COCC[C@H](NC(=O)c1ccc(N2CCOCC2=O)c(C)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1f from 3-methyl-4-(morpholin-3-on-4-yl)-benzoic acid, (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methoxy-propylamine, TBTU and DIPEA in THF with subsequent purification by chromatography on silica gel.
Reaction SMILES: [N+:1]([C:4]1[C:5]2[C:9]([CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH:20]4[CH2:25][CH2:24][CH2:23][CH2:22][O:21]4)[CH:14]=3)[CH:12]=1)=[N:8][N:7]([CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][O:27]1)[CH:6]=2)([O-])=O>C(OCC)(=O)C.[Pd]>[O:27]1[CH2:28][CH2:29][CH2:30][CH2:31][CH:26]1[N:7]1[CH:6]=[C:5]2[C:9]([CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH:20]4[CH2:25][CH2:24][CH2:23][CH2:22][O:21]4)[CH:14]=3)[CH:12]=[C:4]2[NH2:1])=[N:8]1
Reactant: O=[N+]([O-])c1cc(-c2cccc(OC3CCCCO3)c2)cc2nn(C3CCCCO3)cc12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1cc(-c2cccc(OC3CCCCO3)c2)cc2nn(C3CCCCO3)cc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-Nitro-2-(tetrahydro-2H-pyran-2-yl)-6-[3-(tetrahydro-2H-pyran-2-yloxy)phenyl]-2H-indazole (1.06 g, 2.5 mmol) was dissolved in ethyl acetate (100 ml) and 10% Pd/C (53 mg) was added. The reaction was stirred under an atmosphere of hydrogen gas (1 atm) at RT for 16 h. The reaction mixture was filtered through celite and the solvent was removed in vacuo to yield the title compound, 828 mg, used without further purification.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.[N+:12]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1)([O-:14])=[O:13]>CS(C)=O>[N+:12]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19][N:3]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[CH:4]2)=[CH:17][CH:16]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Reactant: c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(Cn2ccc3ccccc32)cc1
Temperature: 65 °C
Reaction time: 14 h

Procedure:
A mixture of 5.28 g of sodium hydride (0.22 mol, mineral oil suspension) in 200 ml of dimethyl sulfoxide is treated with a solution of 23.4 g (0.2 mol) of indole in 100 ml of dimethyl sulfoxide. It is heated at 65° C. for 1 hour, then allowed to cool and 37.7 g (0.22 mol) of 4-nitrobenzyl chloride are then added dropwise. The solution is heated to 60° C., kept at room temperature for 14 hours and then poured into 700 ml of ater with stirring. The mixture is extracted in portions with a total of 300 ml of methylene chloride, the organic phase is dried using anhydrous sodium sulfate, filtered and the filtrate is concentrated in vacuo. The residue is purified on a silica gel column (silica gel 60, Merck AG, Darmstadt; eluent methylene chloride/ethanol 9:1, v/v).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:14]([O:16]C)=[O:15])[CH:3]=1.[CH3:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][NH2:22].C1(O)C=CC=CC=1>C(OCC)(=O)C>[CH3:13][O:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([C:14]([OH:16])=[O:15])[CH:3]=[C:2]2[NH:22][CH2:21][C:20]1[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=1[CH3:18]
Reactant: Cc1ccccc1CN
Reactant: COC(=O)c1cc(Cl)c2cccc(OC)c2n1
Solvent: Oc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cccc2c(NCc3ccccc3C)cc(C(=O)O)nc12
Temperature: 140 °C
Reaction time: 1 h
Yield: 27.2 %

Procedure:
A mixture of 54 g (=215 mmol) of methyl 4-chloro-8-methoxyquinoline-2-carboxylate, 33.7 g (=278 mmol) of 2-methylbenzylamine and 243 g (=2.58 mmol) of phenol was heated at 140° C. in an autoclave for 4 hours. The cooled reaction mixture was added dropwise to 4 1 of ethyl acetate, and the resulting precipitate was filtered off with suction. The solid was dissolved in 1 1 of THF and the pH was adjusted to 10 with 10% NaOH. The mixture was stirred at 50° C. for 1 hour, maintaining the pH constant, cooled to 10° C. and adjusted to pH 5-6 with dilute HCl. This resulted in the product crystallizing. 18.85 g of 8-methoxy-4-(2-methylbenzylamino)quinoline-2-carboxylic acid of melting point 276-277° C. were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[F:9].C([Mg]Cl)(C)C.[O:15]=[C:16]1[CH2:19][CH:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17]1>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:16]2([OH:15])[CH2:17][CH:18]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:19]2)=[CH:4][C:3]=1[F:9]
Reactant: CC(C)(C)OC(=O)C1CC(=O)C1
Reactant: Fc1cc(I)ccc1Br
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1CC(O)(c2ccc(Br)c(F)c2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.5 %

Procedure:
Into a 2000-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of 1-bromo-2-fluoro-4-iodobenzene (58 g, 192.76 mmol, 1.00 equiv) in tetrahydrofuran (600 mL), followed by the addition of i-PrMgCl (96.3 mL, 1.00 equiv) dropwise with stirring at 0° C. over 30 min. The mixture was stirred at 0° C. for 3 h. To this was added tert-butyl 3-oxocyclobutane-1-carboxylate (32.7 g, 192.12 mmol, 1.00 equiv) dropwise with stirring at −78° C. over 10 min. The mixture was stirred at −78 degree C. for 1 h and overnight at room temperature. The reaction was then quenched by the addition of 200 mL of saturated aqueous NH4Cl at 0° C. and extracted with 3×500 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum to afford 62 g (crude) of tert-butyl 3-(4-bromo-3-fluorophenyl)-3-hydroxycyclobutane-1-carboxylate as a yellow oil.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([NH:10][C:11]([C@@H:13]2[CH2:17][CH2:16][CH2:15][NH:14]2)=[O:12])[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[O:19]1[CH2:24][CH2:23][CH:22]([CH:25]=O)[CH2:21][CH2:20]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([C:5]1[N:6]=[C:7]([NH:10][C:11]([C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[CH2:25][CH:22]2[CH2:23][CH2:24][O:19][CH2:20][CH2:21]2)=[O:12])[S:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1csc(NC(=O)[C@@H]2CCCN2)n1
Reactant: O=CC1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)c1csc(NC(=O)[C@@H]2CCCN2CC2CCOCC2)n1
Reaction time: 0.62 h

Procedure:
To a solution of (S)-pyrrolidine-2-carboxylic acid (4-tert-butyl-thiazol-2-yl)-amide; hydrochloride (0.310 g; 1.070 mmol) in 1,2-dichloroethane (2 mL) was added tetrahydro-pyran-4-carbaldehyde (0.244 g; 2.140 mmol), acetic acid (0.2 mL; 3.497 mmol), and sodium sulfate(5-10 equivalents). The mixture is stirred for 30-45 minutes before adding sodium triacetoxyborohydride (0.454 g; 2.140 mmol) and stirring overnight at room temperature. After this time, the mixture is filtered through a plug of silica/Celite® and concentrated in vacuo. Crude material is purified by preparative HPLC. Product fractions are pooled and concentrated in vacuo to afford title compound as an oil. ESI m/z 352 [M+H]+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[F:16][C:17]([F:28])([F:27])[C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:22](=[O:23])[C:21]3[CH:25]=[CH:26][C:18]([C:17]([F:16])([F:27])[F:28])=[CH:19][CH:20]=3)[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Product: O=C(NC1CCCc2c1[nH]c1ccc(Br)cc21)c1ccc(C(F)(F)F)cc1

Procedure:
N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-4-(trifluoromethyl)benzamide was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine and 4-trifluoromethyl benzoyl chloride in a similar manner as described above to give a tan solid (63% yield). 1H-NMR (CDCl3): δ 8.83 (s, 1H), 7.89 (d, 2H), 7.70 (d, 2H), 7.61 (m, 1H), 7.23 (d, 1H), 7.18 (d, 1H), 6.42 (d, 1H), 5.33 (m, 1H), 2.72 (m, 2H), 2.31 (m, 1H), 1.97 (m, 3H); MS m/z 437 (M−1).
Reaction SMILES: O[CH2:2][NH:3][C:4](=[O:17])[CH2:5][CH2:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:38]>>[Cl:38][CH2:2][NH:3][C:4](=[O:17])[CH2:5][CH2:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8]
Reactant: O=C(CCC(=O)OCc1ccccc1)NCO
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C(CCC(=O)OCc1ccccc1)NCCl

Procedure:
A solution of 24.2 g. (0.10 mole) of benzyl N-hydroxymethylsuccinamate and 28.9 g. (0.11 mole) of triphenylphosphine in 500 ml. carbon tetrachloride is stirred at reflux for 12 hours. After filtering and washing the precipitate with benzene, the organic solvents are removed at 15 - 20 mm. and 30° - 40°C. to give benzyl N-chloromethylsuccinamate of sufficient purity for use in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[OH:11].[H-].[Na+].I[CH3:15].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[O:11][CH3:15]
Reactant: CI
Reactant: O=[N+]([O-])c1cccc(Br)c1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(Br)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Bromo-6-nitrophenol (5.1 g, 23.4 mmol) was dissolved in DMF (60 mL), then 95% NaH (900 mg, 35.6 mmol) was added in a few portions, followed by the addition of iodomethane (3.0 mL, 6.8 g, 48.5 mmol). The reaction was stirred at room temperature overnight, then heated at 50° C. for 3 hours. The reaction was cooled, poured into water, and the solids filtered off and dried. The product (5.5 g, 100%) was recovered as tan solids. 1H NMR (300 MHz, DMSO-d6) δ 8.02 (dd, J=8.1, 1.7 Hz, 1H), 7.96 (dd, J=8.1, 1.7 Hz, 1H), 7.83 (dd, 8.1, 8.1 Hz, 1H), 3.92 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[N:15]=[C:14]4[CH2:17][CH2:18][CH2:19][C:20](=[O:22])[CH2:21][C:13]4=[CH:12][C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH:39]=O.C(O)(=O)C>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[N:15]=[C:14]4[CH2:17][CH2:18][CH2:19][C:20](=[O:22])/[C:21](=[CH:39]/[C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][N:33]=5)/[C:13]4=[CH:12][C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccccn1
Reactant: O=C1CCCc2nc3c(cnn3-c3ccc(F)cc3)cc2C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C1CCCc2nc3c(cnn3-c3ccc(F)cc3)cc2/C1=C\c1ccccn1
Temperature: -70 °C
Reaction time: 0.08 h

Procedure:
1-(4-Fluorophenyl)-5,7,8,9-tetrahydrocyclohepta[b]pyrazolo[4,3-e]pyridin-6 (1H)-one (114, R1=4-Fluorophenyl) (15.0 g, 50.8 mmol) and THF (430 mL) were stirred until a solution formed. The mixture was cooled to about −70° C. then LiHMDS (1M in THF, 53 mL, 53.0 mmol) was added keeping the internal temperature between about −65 and −70° C. After about 45 min picolinaldehyde (16.32 g, 152 mmol) was added. After about 5 min the mixture was allowed to warm to about −10° C. over about 90 min. Acetic acid (5.8 mL, 102 mmol) was added to the mixture then the slurry was concentrated under reduced pressure. The material was partitioned between water (500 mL), sat. aq. NaHCO3 (˜75 mL) and DCM (200 mL). The aqueous layer was extracted with DCM (60 mL) then the combined organics were dried over MgSO4, filtered and concentrated on the rotovap to yield (E)-1-(4-fluorophenyl)-5-(pyridin-2-ylmethylene)-5,7,8,9-tetrahydrocyclohepta[b]pyrazolo[4,3-e]pyridin-6(1H)-one which was used directly in the next step without further manipulation; LC/MS, method 3, Rt=2.46 min, MS m/z 385 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([C@H:9]2[CH2:13][O:12][C:11](=[O:14])[NH:10]2)[CH:6]=[CH:7][CH:8]=1.Br[C:18]1[CH:19]=[CH:20][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[N:22][CH:23]=1>>[Cl:31][C:28]1[CH:27]=[CH:26][C:25]([O:24][C:21]2[N:22]=[CH:23][C:18]([N:10]3[C@@H:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:15])[F:16])[CH:4]=4)[CH2:13][O:12][C:11]3=[O:14])=[CH:19][CH:20]=2)=[CH:30][CH:29]=1
Reactant: O=C1N[C@@H](c2cccc(C(F)(F)F)c2)CO1
Reactant: Clc1ccc(Oc2ccc(Br)cn2)cc1
Product: O=C1OC[C@H](c2cccc(C(F)(F)F)c2)N1c1ccc(Oc2ccc(Cl)cc2)nc1

Procedure:
(S)-3-[6-(4-Chloro-phenoxy)-pyridin-3-yl]-4-(3-trifluoromethyl-phenyl)-oxazolidin-2-one is prepared from (S)-4-(3-trifluoromethyl-phenyl)-oxazolidin-2-one and 5-bromo-2-(4-chloro-phenoxy)-pyridine using the same conditions as example 4. 1H NMR (CDCl3, 400 MHz) δ 8.03 (dd, 1H), 7.88 (d, 1H), 7.62 (d, 1H), 7.45˜7.55 (m, 3H), 7.3 (d, 2H), 7.01 (d, 2H), 5.40 (dd, 1H), 4.85 (t, 1H), 4.24 (dd, 1H); HPLC-MS calculated for C21H15ClF3N3O2 (M+H+) 435.1, found 435.1.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([CH3:10])[N:7]=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:42])[C:25](=[O:41])[C:26]4[N:34]5[C:29]([CH2:30][CH2:31][CH2:32][CH2:33]5)=[CH:28][C:27]=4[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)[CH:5]=1.[CH3:43]I>C1COCC1.C(Cl)Cl>[CH3:3][C:4]1[CH:9]=[C:8]([CH3:10])[N:7]=[C:6]([N:11]2[CH2:12][CH2:13][N:14]([C:17]3[CH:18]=[CH:19][C:20]([N:23]([CH3:43])[C:24](=[O:42])[C:25](=[O:41])[C:26]4[N:34]5[C:29]([CH2:30][CH2:31][CH2:32][CH2:33]5)=[CH:28][C:27]=4[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:21][CH:22]=3)[CH2:15][CH2:16]2)[CH:5]=1
Reactant: CI
Reactant: Cc1cc(C)nc(N2CCN(c3ccc(NC(=O)C(=O)c4c(-c5ccccc5)cc5n4CCCC5)cc3)CC2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cc(C)nc(N2CCN(c3ccc(N(C)C(=O)C(=O)c4c(-c5ccccc5)cc5n4CCCC5)cc3)CC2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 59.2 %

Procedure:
Sodium hydride (55% dispersion in oil, 24 mg, 0.56 mmol) was added to an ice-cold solution of N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-2-(2-phenyl-5,6,7,8-tetrahydro-indolizin-3-yl)-acetamide (prepared as described in Example 3, 200 mg, 0.37 mmol) in THF, and stirred for 10 minutes at 0° C. Methyl iodide (0.036 mL, 0.56 mmol) was added, the mixture warmed to room temperature and stirred for 30 min. The solvent was evaporated and the residue partitioned between ice-water and DCM. The organic layer was separated and washed successively with water, sodium bicarbonate solution and brine, dried over sodium sulfate and concentrated to give a residue. This was dissolved in the minimum amount of DCM and re-precipitated by addition of petroleum ether to afford N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-N-methyl-2-oxo-2-(2-phenyl-5,6,7,8-tetrahydro-indolizin-3-yl)-acetamide (120 mg, 58%) as light yellow powder.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:7][C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:5][CH:4]=1.[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][N:24]([C:27]2[S:28][C:29]([C:33](O)=[O:34])=[C:30]([CH3:32])[N:31]=2)[C:23](=[O:36])[CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][N:24]([C:27]2[S:28][C:29]([C:33]([NH:1][CH2:2][C:3]3[O:7][C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:5][CH:4]=3)=[O:34])=[C:30]([CH3:32])[N:31]=2)[C:23](=[O:36])[CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1ccc(CN)o1
Reactant: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)O
Product: CCOC(=O)c1ccc(CNC(=O)c2sc(-n3ccc(OCc4ccccc4)cc3=O)nc2C)o1
Yield: 67 %

Procedure:
Following the procedure as described in Example 22, making variation only as required to use ethyl 5-(aminomethyl)furan-2-carboxylate in place of benzo[b]thiophen-2-ylmethanamine to react with 2-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 67% yield: 1H NMR (300 MHz, DMSO-d6) δ 8.85 (t, J=5.6 Hz, 1H), 8.61 (d, J=8.1 Hz, 1H), 7.45-7.33 (m, 5H), 7.20 (d, J=3.5 Hz, 1H), 6.45 (d, J=3.5 Hz, 1H), 6.39 (dd, J=8.1, 2.7 Hz, 1H), 6.23 (d, J=2.7 Hz, 1H), 5.16 (s, 2H), 4.45 (d, J=5.5 Hz, 2H), 4.23 (q, J=7.1 Hz, 2H), 2.54 (s, 3H), 1.24 (t, J=7.1 Hz, 3H); MS (ES+) m/z 494.2 (M+1).
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][C@@H:3]([CH2:7][NH:8][C:9]([C:11]1[C:20]3[O:19][CH2:18][CH2:17][O:16][C:15]=3[CH:14]=[CH:13][CH:12]=1)=[O:10])[NH:2]2.[Cl:21][C:22]1[CH:23]=[C:24]([C:28]2[C:29]([C:34](O)=[O:35])=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:25]=[CH:26][CH:27]=1>>[Cl:21][C:22]1[CH:23]=[C:24]([C:28]2[C:29]([C:34]([N:2]3[C@H:3]([CH2:7][NH:8][C:9]([C:11]4[C:20]5[O:19][CH2:18][CH2:17][O:16][C:15]=5[CH:14]=[CH:13][CH:12]=4)=[O:10])[CH2:4][C@H:5]4[C@@H:1]3[CH2:6]4)=[O:35])=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: O=C(O)c1ccccc1-c1cccc(Cl)c1
Reactant: O=C(NC[C@@H]1C[C@@H]2C[C@@H]2N1)c1cccc2c1OCCO2
Product: O=C(NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1ccccc1-c1cccc(Cl)c1)c1cccc2c1OCCO2

Procedure:
prepared by reaction of 2,3-dihydro-benzo[1,4]dioxine-5-carboxylic acid [(1S,3S,5S)-2-aza-bicyclo[3.1.0]hex-3-ylmethyl]-amide with 3′-chloro-biphenyl-2-carboxylic acid. LC-MS (basic): tR=1.43 min; [M+H]+=489.0.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[CH2:26]([O:28][C:29]1[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=1[C:31](Cl)=[O:32])[CH3:27]>C(Cl)Cl>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH2:3][C@H:2]([NH:1][C:31](=[O:32])[C:30]2[CH:34]=[CH:35][CH:36]=[CH:37][C:29]=2[O:28][CH2:26][CH3:27])[CH2:11][CH2:10]3)[CH2:13][CH2:14]1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Reactant: CCOc1ccccc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1ccccc1C(=O)N[C@@H]1CCc2cccc(N3CCN(C)CC3)c2C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65 %

Procedure:
To an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (110 mg, 0.43 mmol) and triethylamine (90 μL, 0.65 mmol) in methylene chloride (15 mL) was added dropwise 2-ethoxybenzoyl chloride (84 mg, 0.45 mmol) in methylene chloride (5 mL). After the addition, the reaction was allowed to stir at ambient temperature for 15 min and was then washed with water. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:3) as the eluent. Yield: 110 mg (64%) of the title compound as white solid: [α]21D −36° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 393 (15, M+). The hydrochloride salt was precipitated out of diethyl ether and 110 mg (59% yield) of white crystals were isolated; mp sinters at 176° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Br)[N:3]=1.[Na].[NH:10]1[CH:14]=[N:13][CH:12]=[N:11]1>CS(C)=O.O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)[N:3]=1
Reactant: c1nc[nH]n1
Reactant: Brc1cccc(Br)n1
Agent: [Na]
Solvent: CS(C)=O
Solvent: O
Product: Brc1cccc(-n2cncn2)n1
Temperature: 25 °C
Yield: 45 %

Procedure:
A stirred solution of 2,6-dibromopyridine (2.0 g, 8.3 mmol) and 1,2,4-triazole sodium salt (1.0 g, 9.9 mmol) in dimethylsulfoxide (10 ml) was heated at 60° C. for 5 h. After cooling to ambient temperature the reaction was diluted with water and extracted into dichloromethane. Combined organic extracts were washed with water and saturated brine then dried over magnesium sulfate, filtered and evaporated in vacuo to give a solid. Purification by chromatography on silica gel eluting with dichloromethane, then dichloromethane containing 5% methanol, gave 2-bromo-6-(1H-[1,2,4]triazol-1-yl)pyridine (0.84 g) as a white solid: δH (400 MHz, CDCl3) 7.49 (1H, d, J 8), 7.74 (1H, dd, J 8 and 8), 7.87 (1H, d, J 8), 8.09 (1H, s), 9.15 (1H, s); m/z (ES+) 224/226 (M++H).