Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.[C:18]([N:25]1[CH2:32][CH2:31][CH2:30][C@H:26]1[C:27](O)=[O:28])([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH2:11]([O:10][C:8]([C@H:5]1[CH2:6][CH2:7][C@@H:2]([NH:1][C:27]([CH:26]2[CH2:30][CH2:31][CH2:32][N:25]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:28])[CH2:3][CH2:4]1)=[O:9])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: NC1CCC(C(=O)OCc2ccccc2)CC1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)N[C@H]1CC[C@@H](C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.7 %

Procedure:
To a stirred solution of benzyl 4-aminocyclohexanecarboxylate (900 mg, 3.9 mmol), boc-proline (830 mg, 3.9 mmol), HOBt (521 mg, 3.9 mmol), and triethylamine (1.6 ml, 11.6 mmol) in CH2Cl2 (30.0 ml) was added EDC.HCl (1.1 g, 5.8 mmol) at 0° C. The reaction mixture was stirred at room temperature for 16 hr, and concentrated in vacuo. Water was added to the residue, and extracted with EtOAc. The extract was washed with sat. NaHCO3, 2-M citric acid, and sat. NaHCO3, then dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel with n-hexane-EtOAc (6:1, v/v) as eluent to give benzylcis-4-[(1-tert-butoxycarbonyl-2-pyrrolidinyl)carbonylamino]cyclohexanecarboxylate (600 mg, 36%) as an amorphous solid. 1H-NMR (CDCl3) δ1.44 (s, 9H), 1.50-1.90 (m, 12H), 2.20-2.26 (m, 1H), 3.25-3.50 (m, 2H), 3.80-3.90 (m, 1H), 4.10-4.25 (m, 1H), 5.12 (s, 2H), 7.35-7.36 (m, 5H).
Reaction SMILES: [C:1]1([C:7]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]3[CH2:12][NH:13][CH2:14][CH2:15][N:10]3[C:9](=[O:16])[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[CH2:32](Br)[C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:34].O>O1CCCC1>[O:34]=[C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:32][N:13]1[CH2:14][CH2:15][N:10]2[C:9](=[O:16])[O:8][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:11]2[CH2:12]1
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)C2CNCCN12
Reactant: O=C(CBr)c1ccccc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(CN1CCN2C(=O)OC(c3ccccc3)(c3ccccc3)C2C1)c1ccccc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 65.6 %

Procedure:
To a solution of hexahydro-1,1-diphenyl-3H-oxazolo[3,4-a]pyrazin-3-one (0.10 g, 0.34 mmol) in tetrahydrofuran (2 mL) were sequentially added diisopropylethylamine (0.6 mL) and phenacyl bromide (0.10 g, 0.51 mmol), and the mixture was stirred at room temperature for 17 hours. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=1:1), hexane was added thereto, and powder was formed to obtain the title compound (92 mg, yield 66%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10].[Cl:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1.O>N1C=CC=CC=1>[Cl:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH:1][CH2:2][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[CH3:10])=[O:17])=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: Cc1ccccc1CCN
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccccc1CCNC(=O)c1ccc(Cl)cc1
Yield: 70.2 %

Procedure:
1-Amino-2-(2-methylphenyl)ethane (13.5 g) was dissolved in 80 ml of pyridine. While the solution was cooled with stirring, 18 g of 4-chlorobenzoyl chloride was added dropwise. They were reacted at room temperature for 5 hours. Pouring of the reaction mixture into cold water gave a precipitate of crystals. The crystals were washed in water, dried, and recrystallized from cyclohexane to afford 19.2 g of 1-(4-chlorobenzoylamino)-2-(2-methylphenyl)ethane having a melting point of 95° to 96° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18]([OH:20])=O)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26]>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:20])[NH:26][C:25]3[CH:27]=[CH:28][CH:29]=[C:23]([O:22][CH3:21])[CH:24]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: COc1cccc(N)c1
Reactant: O=C(O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Product: COc1cccc(NC(=O)CC2CCc3cc(Br)cc4[nH]c(=O)c(=O)n2c34)c1
Yield: 96.8 %

Procedure:
A procedure similar to that described in Example 5 was carried out with 9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (150 mg, 0.442 mmol) and m-methoxyaniline (76 mg, 0.62 mmol) to give 190 mg of the title compound (95%): mp 151°~154° C.; 1H NMR (270 MHz, DMSO-d6) δ12.07 (s, 1H), 10.00 (s, 1H), 7.27 (d, 1H, J=2 Hz), 7.24 (bs, 1H), 7.20 (t, 1H, J=8.1 Hz), 7.16 (bs, 1H), 6.64 (dd, 1H, J=8.1, 2 Hz), 6.88 (d, 2H, J =9 Hz), 5.16~5.17 (m, 1H), 3.72 (s, 3H), 3.05 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.82 (dm, 1H, J=16.8 Hz), 2.55~2.65 (m, 2H), 2.09 (dm, 1H, J=13.5 Hz), 1.80~1.96 (m, 1H).
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:17](Cl)[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(OCC)C.C1(C)C=CC=CC=1>[CH2:17]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCOCc1ccccc1
Reactant: C1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: c1ccc(COCc2ccccc2)cc1
Temperature: -78 °C

Procedure:
The carboxylic esters (621A; 3.75 g) were dissolved in anhydrous diethyl ether (50 ml) and cooled to −78° C., under an atmosphere of nitrogen. KHMDS (69 ml of a 0.5M solution in toluene) was added dropwise and the resulting mixture was stirred for a further 15 min., before the addition of BOMCl (1.7 eq.) and the reaction flask was removed from the cooling vessel and allowed to warm slowly to room temperature. Water (approx. 10 ml) was added and the mixture was partitioned between EtOAc and 10% aq. HCl. The organic phase was separated, washed with sat. aq. sodium bicarbonate, water, dried (MgSO4), and the volatiles removed under reduced pressure. The residue was purified by silica gel column chromatography using EtOAc:Hexanes (1:20) as eluent, providing the intermediate benzyl ether (3.01 g), a colorless oil.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:11][N:12]([CH:21]=[O:22])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:23][C@H:24]1[CH2:29][N:28]([CH3:30])[CH2:27][CH2:26][N:25]1[C:31]1[C:36]([F:37])=[C:35]([NH:38][NH2:39])[N:34]=[C:33]([CH3:40])[N:32]=1.CN1CCOCC1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[CH:1]1([CH2:6][C@@H:7]([C:8]([NH:39][NH:38][C:35]2[C:36]([F:37])=[C:31]([N:25]3[CH2:26][CH2:27][N:28]([CH3:30])[CH2:29][C@@H:24]3[CH3:23])[N:32]=[C:33]([CH3:40])[N:34]=2)=[O:10])[CH2:11][N:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1nc(NN)c(F)c(N2CCN(C)C[C@@H]2C)n1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OCc1ccccc1
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OCc2ccccc2)c(F)c(N2CCN(C)C[C@@H]2C)n1
Reaction time: 8 h
Yield: 48.4 %

Procedure:
(2R)-3-Cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoic acid (0.139 g, 0.45 mmol), 4-[(2S)-2,4-dimethyl-1-piperazinyl]-5-fluoro-6-hydrazino-2-methylpyrimidine (0.118 g, 0.46 mmol), NMM (0.15 mL, 1.38 mmol), HOAt (0.063 g, 0.46 mmol), and EDC (0.088 g, 0.46 mmol) were dissolved in DMF (2 mL). The reaction was stirred overnight. Purified by RP-HPLC to provide [(2R)-2-(cyclopentylmethyl)-3-(2-{6-[(2S)-2,4-dimethyl-1-piperazinyl]-5-fluoro-2-methyl-4-pyrimidinyl}hydrazino)-3-oxopropyl][(phenylmethyl)oxy]formamide as a white solid (0.118 g, 47%). LCMS: (M+H)+=542.7.
Reaction SMILES: CO[C:3]([CH:5]1[CH2:7][CH2:6]1)=[O:4].[CH:8]1([C:11](=[O:13])[CH3:12])[CH2:10][CH2:9]1.C[O-].[Na+].Cl>CS(C)=O.C1(C)C=CC=CC=1>[CH:5]1([C:3](=[O:4])[CH2:12][C:11]([CH:8]2[CH2:10][CH2:9]2)=[O:13])[CH2:6][CH2:7]1
Reactant: CC(=O)C1CC1
Reactant: COC(=O)C1CC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: O=C(CC(=O)C1CC1)C1CC1
Temperature: 55 °C
Reaction time: 8 h
Yield: 64.2 %

Procedure:
Methylcyclopropanecarboxylate (20.2 ml, 286.3 mmol) was added to a stirred solution of 1-cyclopropylethanone (9 ml, 152.4 mmol) in dimethylsulfoxide (25 ml). Sodium methoxide powder (10.8 g, 200 mmol) was added, and the reaction was stirred at 55° C. for 8 hours. The mixture was cooled, diluted with toluene, neutralised with 6M hydrochloric acid, and then extracted with toluene. The combined extracts were washed with sodium carbonate, dried over magnesium sulphate and evaporated in vacuo to provide the title compound (14.9 g, 78%) as a mixture 2:1 enol:ketone forms. 1H NMR (CDCl3, 400 MHz): δ=0.79-0.87 (m, 4H), 0.98-1.01 (m, 4H), 1.46-1.51 (m, 2H-enol), 1.93-1.97 (m, 2H-keto), 3.70 (s, 2H-keto), 5.65 (s, 1H-enol); LRMS: APCl+: m/z 153 [MH+]; APCl− m/z 151 [M−H]−.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([NH2:10])[C:8]#[CH:9].F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1[C:21]([F:24])([F:23])[F:22].[K+].[Br-]>CS(C)=O.O.C(N(CC)CC)C>[CH2:7]([NH:10][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1[C:21]([F:22])([F:23])[F:24])[C:8]#[CH:9]
Reactant: C#CCN
Reactant: O=[N+]([O-])c1ccc(F)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: C#CCNc1ccc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 25 °C

Procedure:
To a suspension of potassium carbonate (20.0 g) in DMSO (7 ml) was added triethylamine (3 ml) and 2-propyn-1-amine(7.92 g, 1.44×10-1 mole). The reaction mixture was cooled in an ice bath while 1-fluoro-4-nitro-2-trifluoromethylbenzene (30.13 g, 1.44×10-1 mole) was added gradually with stirring. The mixture was gradually allowed to warm to room temperature and stirred for 24 hours. The reaction mixture was poured into excess water and extracted with ethyl acetate. The ethyl acetate solution was dried over sodium sulfate, filtered and evaporated. The residue was chromatographed on a silica column, eluting with benzene, and recrystallized from benzene to afford yellow crystals; m.p. 71°-72° C. Yield: 24.24 g (69%). I.R. (KBr): 3450 (NH), 3290 (CH), 1588 (Ar-NO2) and 1300 cm-1 (CF3).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[OH-:13].[K+].Cl>C(O)(C)(C)C>[Cl:8][C:7]1[C:2](=[O:13])[NH:3][CH:4]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: [OH-]
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Product: O=c1[nH]cc(C(F)(F)F)cc1Cl
Yield: 75.3 %

Procedure:
4.5 g of 2,3-dichloro-5-trifluoromethylpyridine was added to a solution of 2.7 g of potassium hydroxide dissolved in 40 ml of t-butanol, and the mixture was reacted at the reflux temperature for one hour while stirring. After completion of the reaction, the reaction product was allowed to cool and made acidic with concentrated hydrochloric acid. The contents were concentrated under reduced pressure to obtain a solid which was then purified to obtain 3.1 g of the titled compound having a melting point of 165° to 166° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH2:17][NH2:18])=[CH:14][C:13]=2[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][C:21]1[N:29]=[C:28]([CH2:30][O:31][CH3:32])[CH:27]=[CH:26][C:22]=1[C:23](O)=[O:24].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O.CN(C)C=O>[NH2:20][C:21]1[N:29]=[C:28]([CH2:30][O:31][CH3:32])[CH:27]=[CH:26][C:22]=1[C:23]([NH:18][CH2:17][C:15]1[O:16][C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:19][C:13]=2[CH:14]=1)=[O:24]
Reactant: NCc1cc2cc(OCc3ccccc3)ccc2o1
Reactant: COCc1ccc(C(=O)O)c(N)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COCc1ccc(C(=O)NCc2cc3cc(OCc4ccccc4)ccc3o2)c(N)n1
Temperature: 25 °C
Reaction time: 27 h
Yield: 74.6 %

Procedure:
To a N,N-dimethylformamide (5 mL) solution of C-(5-benzyloxy-benzofuran-2-yl)-methylamine (135 mg, 533 μmol) described in Production Example 7-1-6 were added 2-amino-6-methoxymethyl-nicotinic acid (107 mg, 586 μmol) described in Production Example 4-1-5, triethylamine (223 μL, 1.60 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (306 mg, 693 μmol) at room temperature, which was stirred at room temperature for 27 hours. Water was added to the reaction solution at room temperature followed by extracting with ethyl acetate. The organic layer was washed with water and sat. NaCl followed by drying over anhydrous magnesium sulfate and filtering. The filtrate was concentrated under a reduced pressure and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=1:5) to obtain the title compound (166 mg, 75%) as a white solid.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([NH:8][C:9]2[C:10](=[CH:14][C:15]([Br:18])=[CH:16][CH:17]=2)[C:11](O)=O)=[CH:6][CH:5]=[N:4]1)[CH3:2].O=P(Cl)(Cl)[Cl:21].[NH4+].[OH-]>>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:10]([C:11]([Cl:21])=[C:6]2[CH:5]=[N:4]1)=[CH:14][C:15]([Br:18])=[CH:16][CH:17]=3)[CH3:2]
Reactant: CCn1nccc1Nc1ccc(Br)cc1C(=O)O
Reactant: O=P(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Product: CCn1ncc2c(Cl)c3cc(Br)ccc3nc21
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A mixture of N-(1-ethylpyrazol-5-yl)-5-bromoanthranilic acid (12.6 g) and POCl3 (30 ml) is refluxed overnight. The reaction mixture is poured into ice water (500 ml), stirred for 20 minutes, and then NH4OH is added until a pH of 8-10 is obtained. The mixture is stirred for 0.5 hours, and then the solid that forms is collected by filtration. The solid is dissolved in CH2Cl2, dried over MgSO4 and purified by column chromatography on silica gel eluting with 30% hexane/ethyl acetate to afford 6.5 g of 1-ethyl-4-chloro-6-bromo-1H-pyrazolo[3,4-b]quinoline, m.p. 117°-118° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10](O)[N:9]2[N:13]=[CH:14][N:15]=[C:8]2[N:7]=1)=[O:5])[CH3:2].P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:10]1[N:9]2[N:13]=[CH:14][N:15]=[C:8]2[N:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:11]=1
Reactant: CCOC(=O)c1cc(O)n2ncnc2n1
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cc(Cl)n2ncnc2n1
Temperature: 60 °C

Procedure:
A suspension of 5-ethoxycarbonyl-7-hydroxy-s-triazolo[1,5-a]pyrimidine (6.8 g) in 40 ml of phosphorus oxychloride was heated at 60° C. with stirring, the resultant clear, orange solution was further refluxed for one hour, excess phosphorus oxychloride was distilled off, the brown residue was dissolved in 100 ml of chloroform, and the solution was slowly added to 100 ml of water with stirring. The chloroform solution was separated, dried over anhydrous sodium sulfate, the solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel chromatography, affording 4.6 g of the objective compound as colorless crystals.
Reaction SMILES: CO[C:3]([CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]3([CH3:19])[O:18]CCO3)[CH:12]=2)[N:7]([CH2:20][CH3:21])[C:6]1=[O:22])=[O:4].[NH2:23][C:24]1[CH:25]=[C:26]([CH:38]=[CH:39][CH:40]=1)[C:27]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH3:37])=[CH:32][CH:31]=1)=[O:28]>>[CH2:36]([C:33]1[CH:32]=[CH:31][C:30]([NH:29][C:27]([C:26]2[CH:25]=[C:24]([NH:23][C:3]([CH:5]3[C:13]4[C:8](=[CH:9][CH:10]=[C:11]([C:14](=[O:18])[CH3:19])[CH:12]=4)[N:7]([CH2:20][CH3:21])[C:6]3=[O:22])=[O:4])[CH:40]=[CH:39][CH:38]=2)=[O:28])=[CH:35][CH:34]=1)[CH3:37]
Reactant: CCc1ccc(NC(=O)c2cccc(N)c2)cc1
Reactant: CCN1C(=O)C(C(=O)OC)c2cc(C3(C)OCCO3)ccc21
Product: CCc1ccc(NC(=O)c2cccc(NC(=O)C3C(=O)N(CC)c4ccc(C(C)=O)cc43)c2)cc1

Procedure:
Prepared as in Example 1 from 1-ethyl-5-(2-methyl-[1,3]dioxolan-2-yl)-2-oxo-2,3-dihydro-1H-indole-3-carboxylic acid methyl ester and 3-amino-N-(4-ethyl-phenyl)-benzamide. Purified by chromatography (chloroform/methanol, 10:1). 1H NMR (DMSO-d6) δ 1.15 (m, 6 H), 2.5 (q, 2 H), 3.85 (q, 2 H), 6.85-8.3 (m, 11 H), 10.0 (s, 1 H), 11.1 (s, 1 H).
Reaction SMILES: C(OCC)C.[CH2:6]1[O:9][C@H:7]1[CH3:8].[Si:10]([O:27][C@H:28]([CH3:40])[C@H:29]([NH2:39])[C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[C:32]([F:38])[CH:31]=1)([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl([O-])(=O)(=O)=O.[Li+]>O.C(Cl)Cl>[Si:10]([O:27][C@H:28]([CH3:40])[C@H:29]([NH:39][CH2:6][C@@H:7]([OH:9])[CH3:8])[C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[C:32]([F:38])[CH:31]=1)([C:23]([CH3:24])([CH3:25])[CH3:26])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: C[C@H]1CO1
Reactant: C[C@@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)[C@H](N)c1cc(F)c(F)c(F)c1
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCOCC
Solvent: ClCCl
Solvent: O
Product: C[C@H](O)CN[C@H](c1cc(F)c(F)c(F)c1)[C@@H](C)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A diethylether solution (1 mL) of (S)-(−)-propylene oxide (0.1 mL) and (1R,2R)-2-tert-butyldiphenylsilanyloxy-1-(3,4,5-trifluorophenyl)propylamine (212 mg) was added to a diethylether suspension (1 mL) of lithium perchlorate (750 mg). The resulting reaction solution was stirred in nitrogen atmosphere at room temperature overnight, and then methylene chloride and iced-water were added thereto. The resulting mixture was stirred. The organic layer was separated, and the water layer was re-extracted with methylene chloride. The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (heptane: ethyl acetate=9:1 to 4:1) to give 172 mg of the title compound. The physical property values of this compound were as follows:
Reaction SMILES: C1COCC1.I[C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=1.[C:18]([C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1)#[CH:19]>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.O>[CH:24]([C:23]1[CH:26]=[CH:27][C:20]([C:18]#[C:19][C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=2)=[CH:21][CH:22]=1)=[O:25]
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: C#Cc1ccc(C=O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1ccc(C#Cc2ccc(C=O)cc2)cc1

Procedure:
TEA (46 mL) was added to a THF (0.40 L) suspension of ethyl 4-iodobenzoate (30 g), 4-ethynylbenzaldehyde (14 g) obtained by the synthesis method described in the literature (Tetrahedron Letters, 2007, Vol. 48(33), pp. 5817-5820), PdCl2(PPh3)2 (3.9 g), and CuI (2.1 g), and the mixture was stirred for 4 hours at 45° C. After the reaction mixture was allowed to cool, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The desiccant was filtered out, and the solvent was distilled off under reduced pressure. Hexane/ethyl acetate (1:1 (v/v)) was added to the resulting residue, the mixture was stirred, and then the precipitate was filtered off and dried. The filtrate was concentrated, and then the same procedure was performed. As a result, ethyl 4-[(4-formylphenyl)ethynyl]benzoate (yellow solid) was obtained (27 g, 88%).
Reaction SMILES: [C:1]1([CH2:7][O:8][C@@H:9]2[C@@H:13]([CH2:14][O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:12](OS(C(F)(F)F)(=O)=O)=[CH:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN([CH:34]=[O:35])C.[CH3:36][OH:37].C(N(CC)CC)C>CCCCCC.CCOC(C)=O>[CH3:36][O:37][C:34]([C:12]1[C@H:13]([CH2:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:9]([O:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:10][CH:11]=1)=[O:35]
Reactant: O=S(=O)(OC1=CC[C@H](OCc2ccccc2)[C@H]1COCc1ccccc1)C(F)(F)F
Reactant: CN(C)C=O
Reactant: CO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: COC(=O)C1=CC[C@H](OCc2ccccc2)[C@H]1COCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a round bottomed flask equipped with an argon inlet, magnetic stirrer were mixed crude 81 (3.2 g, 5.5 mmol) DMF (25 mL); MeOH (10 mL) and triethylamine (1.54 mL, 11 mmol). Pd(Ph3)4 (635 mg, 0.55 mmol) was added into the solution and the resulting mixture degassed 3 times with CO gas. The reaction was stirred at 1 atmosphere of CO gas at room temperature for 2 h. TLC showed no the absence of starting material. The reaction was worked up with NaOH (0.5 N, 100 mL) at room temperature and extracted with EtOAc (2×50 mL). The combined EtOAc layer was washed with brine (50 mL); dried (Na2SO4) and concentrated in vacuo to afford a light yellow oil. Flash column chromatography (1:2 hexane/EtOAc) gave 7 (1.36 g, 70% over 4 steps).
Reaction SMILES: C[O:2][C:3](=[O:18])[CH:4]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:9][CH:8]=1)[CH2:5][CH3:6].[OH-].[Na+].Cl>CCO.O>[CH2:14]([O:13][C:10]1[CH:9]=[CH:8][C:7]([CH:4]([CH2:5][CH3:6])[C:3]([OH:18])=[O:2])=[CH:12][CH:11]=1)[CH2:15][CH2:16][CH3:17]
Reactant: CCCCOc1ccc(C(CC)C(=O)OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCOc1ccc(C(CC)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74 %

Procedure:
(Scheme 2, Compound F) To a solution of 2-(4-butoxy-phenyl)-butyric acid methyl ester (2.0 g, 8.0 mmol) in EtOH (30 mL) was added NaOH (10 N, 6 mL, 60 mmol). The resulting mixture was stirred at rt for 3 hours, diluted with H2O (30 mL), acidified to pH˜1.0 using HCl (6N). The precipitates were filtered off by filter paper, washed by H2O and hexanes. This compound was obtained as a white solid. (1.4 g, 5.9 mmol, 74% yield). 1H NMR (DMSO-d6) δ 12.20 (br. s, 1H), 7.16 (d, 2H, J=7.0 Hz), 6.87 (d, 2H, J=8.5 Hz), 3.92 (t, 2H, J=6.5 Hz), 3.31 (t, 2H, J=6.9 Hz), 1.93 (m, 1H), 1.63 (m, 3H), 1.42 (m, 2H), 0.97 (t, 3H, J=7.2 Hz), 0.79 (t, 3H, J=4.0 Hz).
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[CH2:10][CH2:9]1)=[O:7])C.CO.O.O[Li].O>C1COCC1>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[O:14][CH:11]1[CH2:10][CH2:9][N:8]([C:6](=[O:7])[CH2:5][C:4]([OH:22])=[O:3])[CH2:13][CH2:12]1
Reactant: CCOC(=O)CC(=O)N1CCC(Oc2ccccc2Cl)CC1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)CC(=O)N1CCC(Oc2ccccc2Cl)CC1
Reaction time: 0.5 h
Yield: 74.1 %

Procedure:
To a stirred solution of malonic acid monoethyl ester (1.2 g, 0.0089 mole) in DMF (10 mL) was added DIPEA (2.5 g, 0.02 mole), HOBt (1.3 g, 0.0097 mole) and EDCI.HCl (1.9 g, 0.0097 mole). After 2 minutes 4-(2-chloro-phenoxy)-piperidine hydrochloride (2 g, 0.0081 mole) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the product was extracted with ethyl acetate. The organic layers were dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography using silica gel 60-120 mesh (60% ethyl acetate in hexane) to afford 1.1 g (42%) of 3-[4-(2-chloro-phenoxy)-piperidin-1-yl]-3-oxo-propionic acid ethyl ester. LC-MS purity: 326.11 (M+1)+, 90.2%. To a stirred solution of 3-[4-(2-chloro-phenoxy)-piperidin-1-yl]-3-oxo-propionic acid ethyl ester (1.1 g, 0.0034 mole) in a mixture of THF (20 mL), methanol (4 mL) and H2O (4 mL) was added LiOH.H2O (0.286 g, 0.0068 mole) at ambient temperature. The resulting mixture was stirred for 30 minutes. Volatiles were then evaporated and the resulting residue was diluted with water, acidified with 10% aqueous HCl solution. The resulting precipitate was isolated by filtration and dried to afford 0.75 g (75%) of 3-[4-(2-chloro-phenoxy)-piperidin-1-yl]-3-oxo-propionic acid.