Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]#[C:13][Si](CC)(CC)CC)[C:5]([O:7][CH3:8])=[O:6].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(OCC)(=O)C.O>[C:12]([C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[CH3:1])#[CH:13]
Reactant: CC[Si](C#Cc1ccc(C(=O)OC)cc1C)(CC)CC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1ccc(C(=O)OC)cc1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-methyl-4-((triethylsilyl)ethynyl)benzoate (from the previous step) (1.0 eq.) in THF (0.2 M), was added TBAF (0.2 eq.) slowly at 0° C. Then the reaction mixture was stirred at 0° C. for 1 hour. After warmed to ambient temperature, the reaction mixture was diluted with ethyl acetate and water. The two phases were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vaccuo. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-80% ethyl acetate in hexane to give methyl 4-ethynyl-3-methylbenzoate as a white solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=2[O:9][CH2:10][C:11]([O:13]CC)=O)[CH2:3][CH2:2]1.[NH2:20][CH2:21][CH:22]([OH:34])[CH2:23][N:24]1[CH2:33][CH2:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25]1>CCO>[CH2:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:32][CH2:33][N:24]1[CH2:23][CH:22]([OH:34])[CH2:21][NH:20][C:11](=[O:13])[CH2:10][O:9][C:8]1[CH:16]=[CH:17][CH:18]=[CH:19][C:7]=1[N:4]1[CH2:3][CH2:2][O:1][CH2:6][CH2:5]1
Reactant: NCC(O)CN1CCc2ccccc2C1
Reactant: CCOC(=O)COc1ccccc1N1CCOCC1
Solvent: CCO
Product: O=C(COc1ccccc1N1CCOCC1)NCC(O)CN1CCc2ccccc2C1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 9.4 %

Procedure:
A mixture of ethyl 2-(2-morpholinophenoxy)acetate (53 mg, 0.2 mmol) and 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (41 mg, 0.2 mmol) in EtOH (1 mL) was stirred at 120° C. over microwave for 30 min. The solvent was removed by concentration and the crude product was purified by prep-HPLC separation to afford product the desired title compound (8.0 mg, Yield 10%). 1H NMR (400 MHz, MeOD): 7.09-6.98 (m, 8H), 4.64 (s, 2H), 3.95 (br.s, 1H), 3.89-3.87 (m, 4H), 3.63-3.46 (m, 2H), 3.33-3.30 (m, 1H), 3.07-3.03 (m, 4H), 2.88 (dd, J=6.0 Hz, 2H), 2.77 (dd, J=6.0 Hz, 2H), 2.49 (d, J=6.0 Hz, 2H). LCMS (m/z): 426.2 (M+1).
Reaction SMILES: C(C1OC1)Cl.B(F)(F)F.[CH3:10][CH2:11][O:12][CH2:13][CH3:14].[F:15][B-:16]([F:19])([F:18])[F:17].[CH2:20]([O+:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH3:21].[CH3:27][N:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=CC1=O>CCOCC.C(Cl)Cl>[F:15][B-:16]([F:19])([F:18])[F:17].[CH2:20]([O+:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH3:21].[F:15][B-:16]([F:19])([F:18])[F:17].[CH2:11]([O:12][C:13]1[CH:14]=[CH:31][C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[N+:28]=1[CH3:27])[CH3:10]
Reactant: CCOCC
Reactant: Cn1c(=O)ccc2ccccc21
Agent: CC[O+](CC)CC
Agent: FB(F)F
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: ClCC1CO1
Product: CCOc1ccc2ccccc2[n+]1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.5 %

Procedure:
Triethyloxonium fluoroborate is prepared from 3.70 g (0.040 mole) of epichlorohydrin in 14 ml of ether and 7.58 g (0.054 mole) of boron trifluoride etherate in 6 ml of ether. The resulting solid triethyloxonium fluoroborate is dissolved in 20 ml of dry methylene chloride and treated under nitrogen with 6.47 g (0.040 mole) of N-methyl-2-quinolone in 15 ml of methylene chloride. The reaction mixture is stirred under nitrogen at room temperature overnight. The solid is filtered to give 9.2 g (83.5%) of 2-ethoxy-1-methylquinolinium fluoroborate.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:12][CH3:13])([O:10][CH3:11])[CH3:9])=[CH:4][CH:3]=1.[Mg].[CH:15]1[N:16]=[CH:17][N:18]2[CH2:23][CH2:22][CH2:21][C:20](=[O:24])[C:19]=12>O1CCCC1>[CH3:11][O:10][C:8]([C:5]1[CH:6]=[CH:7][C:2]([C:20]2([OH:24])[CH2:21][CH2:22][CH2:23][N:18]3[CH:17]=[N:16][CH:15]=[C:19]23)=[CH:3][CH:4]=1)([O:12][CH3:13])[CH3:9]
Reactant: COC(C)(OC)c1ccc(Br)cc1
Reactant: O=C1CCCn2cncc21
Agent: [Mg]
Solvent: C1CCOC1
Product: COC(C)(OC)c1ccc(C2(O)CCCn3cncc32)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The Grignard reagent, prepared from 3.68 mmol of 1-bromo-4-(1,1-dimethoxyethyl)benzene [53578-00-0] and 14.72 mmol of magnesium in 5.5 ml of tetrahydrofuran is added slowly dropwise to a solution of 1.84 mmol of 6,7-dihydro-5H-imidazo[1,5-a]pyridin-8-one [426219-51-4] in 10 ml of tetrahydrofuran under argon. The reaction mixture is stirred at room temperature for 12 hours and then quenched with 0.5N HCl. It is extracted with dichloromethane and the phases are separated. The aqueous phase is rendered basic with sodium hydrogen carbonate and the precipitated solid is isolated by filtration and dried at 40° C. The title compound is obtained as a greyish solid. Rt=3.42 (Gradient I). By the process described in Example 3 the following compounds are prepared analogously:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:3]=1[Cl:13].[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]=[C:22]=[O:23].CCN(CC)CC>C1COCC1>[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][C:22](=[O:23])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:3]=1[Cl:13]
Reactant: COC(=O)Cc1ccc(N)c(Cl)c1
Reactant: O=C=Nc1ccccc1Br
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(NC(=O)Nc2ccccc2Br)c(Cl)c1
Reaction time: 24 h
Yield: 67.3 %

Procedure:
To a mixture of methyl 4-amino-3-chlorophenylacetate (1.00 g, 5.01 mmol) and 2-bromophenyl isocyanate (0.62 ml, 5.01 mmol) in THF (20 ml) was added Et3N (0.14 ml, 1.00 mmol) at room temperature. After 1 day stirring, 2-bromophenyl isocyanate (0.60 ml, 5.01 mmol) was added to the reaction mixture and stirred 24 h. The reaction mixture was concentrated in vacuo. The residue was triturated by the addition of n-hexane to give methyl 4-[N′-(2bromophenyl)ureido]-3-chlorophenylacetate (1.34 g, 67%) as a colorless powder. 1H-NMR (CDCl3) δ3.58 (s, 3H), 3.70 (s, 2H), 6.98 (m, 3H), 7.19 (dd, J=8.3, 1.9 Hz, 1H), 7.32 (m, 1H), 7.51 (m, 2H),k 8.05 (m, 1H); MS (ESI) m/z 398 (M++1), 400 (M++3), 402 (M++5).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([CH3:18])[CH:17]=1)[C:11]([O:13]C)=[O:12])[CH3:6].O.[OH-].[Li+]>CO.O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([CH3:18])[CH:17]=1)[C:11]([OH:13])=[O:12])[CH3:6]
Reactant: COCCN(C)Cc1cc(C)cc(C(=O)OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COCCN(C)Cc1cc(C)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of methyl 3-{[(2-methoxyethyl)(methyl)amino]methyl}-5-methylbenzoate (180 mg, 0.72 mmol) in methanol (2 mL), tetrahydrofuran (1 mL), and water (1 mL) is added lithium hydroxide (302 mg, 7.2 mmol) and the reaction mixture stirred at room temperature for 2 h. The reaction mixture is concentrated under reduced pressure, dissolved in methylene chloride, filtered, and the filtrate concentrated under reduced pressure to provide the title compound. ESI MS m/z 238 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[N:35]=[C:34]([CH2:36][O:37][CH3:38])[CH:33]=[CH:32][C:10]=1[C:11]([NH:13][CH2:14][C:15]1[O:16][C:17]2[CH:23]=[C:22]([O:24]CC3C=CC=CC=3)[CH:21]=[CH:20][C:18]=2[CH:19]=1)=[O:12].C1(SC)C=CC=CC=1.C(=O)(O)[O-].[Na+]>O>[NH2:8][C:9]1[N:35]=[C:34]([CH2:36][O:37][CH3:38])[CH:33]=[CH:32][C:10]=1[C:11]([NH:13][CH2:14][C:15]1[O:16][C:17]2[CH:23]=[C:22]([OH:24])[CH:21]=[CH:20][C:18]=2[CH:19]=1)=[O:12]
Reactant: COCc1ccc(C(=O)NCc2cc3ccc(OCc4ccccc4)cc3o2)c(N)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Solvent: O
Product: COCc1ccc(C(=O)NCc2cc3ccc(O)cc3o2)c(N)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
To a trifluoroacetic acid (11 mL) solution of 2-amino-N-(6-benzyloxy-benzofuran-2-ylmethyl)-6-methoxymethyl-nicotinamide (557 mg, 1.33 mmol) described in Example 4 was added thioanisole (626 μL, 5.35 mmol) at 0° C., which was stirred at 0° C. for 3 hours. To the reaction solution were added sodium bicarbonate and water at 0° C. followed by extraction with ethyl acetate and tetrahydrofuran. The organic layer was washed with 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 NH silica gel column chromatography (ethyl acetate:methanol=10:1) to obtain the title compound (331 mg, 76%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:38])[CH2:9][N:10]([CH2:23][CH2:24][CH2:25][O:26][C:27]2[CH2:28][C:29](=[CH:33][C:34]([O:36]C)=[O:35])[CH:30]=[CH:31][CH:32]=2)[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[C:13]=2[Cl:22])=[CH:4][CH:3]=1.ClC1C=CC=CC=1C(C)CN(CCCOC1CC(=CC(O)=O)C=CC=1)CC1C=CC=C(C(F)(F)F)C=1Cl>>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:38])[CH2:9][N:10]([CH2:23][CH2:24][CH2:25][O:26][C:27]2[CH2:28][C:29](=[CH:33][C:34]([OH:36])=[O:35])[CH:30]=[CH:31][CH:32]=2)[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:19])[F:21])[C:13]=2[Cl:22])=[CH:4][CH:3]=1
Reactant: COC(=O)C=C1C=CC=C(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(C)c2ccc(Cl)cc2)C1
Agent: CC(CN(CCCOC1=CC=CC(=CC(=O)O)C1)Cc1cccc(C(F)(F)F)c1Cl)c1ccccc1Cl
Product: CC(CN(CCCOC1=CC=CC(=CC(=O)O)C1)Cc1cccc(C(F)(F)F)c1Cl)c1ccc(Cl)cc1
Product: Cl
Yield: 55 %

Procedure:
The titled compound was prepared from N-(2-[4-Chlorophenyl]-propyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carbomethoxymethylenephenoxy)propylamine in 55% yield in the same manner as the preparation of N-(2-(2-Chlorophenyl]-propyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylamine in Example 184g. MS (ESI) 554 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].S(O[CH2:28][CH2:29][CH:30]1[O:35][C:34]2[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=2[O:32][CH2:31]1)(C)(=O)=O>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:28][CH2:29][CH:30]4[O:35][C:34]5[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=5[O:32][CH2:31]4)[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)OCCC1COc2ccccc2O1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1ccc2c(C3CCN(CCC4COc5ccccc5O4)CC3)noc2c1

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (4.7 g, 21 mmoles), K2CO3 (3.5 g, 25.4 mmoles) and 2-mesyloxyethyl-1,4-benzodioxan (5.5 g, 21.3 mmoles) in acetonitrile (250 ml) was heated at reflux for 3.5 hours. At the end of the reaction, insolubles were filtered. The solid was washed with dichloromethane (200 ml). The solutions were combined and evaporated to an oil. This crude oil was purified by flash chromatography on a silica gel column. The material thus obtained was crystallized from ethanol. The 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-1,4-benzodioxan crystals were collected and weighed 3.8 g, 48%, m.p.=112°-113° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[NH:13][C:12]2=[O:20])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[I-].[CH3:23][N:24]1[C:32]2[C:27](=[C:28]([CH3:33])[CH:29]=[CH:30][CH:31]=2)[C:26]([CH2:34][N+](C)(C)C)=[CH:25]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]([CH2:34][CH:26]3[C:27]4[C:32](=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])[N:24]([CH3:23])[CH2:25]3)[C:12]2=[O:20])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: COC(=O)CC1(n2c(=O)[nH]c3ccccc32)CCCCC1
Reactant: Cc1cccc2c1c(C[N+](C)(C)C)cn2C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)CC1(n2c(=O)n(CC3CN(C)c4cccc(C)c43)c3ccccc32)CCCCC1
Temperature: 100 °C
Reaction time: 4 h
Yield: 73.2 %

Procedure:
To a mixture of [1-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-cyclohexyl]-acetic acid methyl ester (115 mg, 0.40 mmol) and (1,4-dimethyl-1H-indol-3-ylmethyl)-trimethylammonium iodide (200 mg, 0.58 mmol) in DMF (2.5 mL) was added K2CO3 (110 mg, 0.80 mmol). The mixture was stirred at 100° C. for 4 hours. The reaction mixture was diluted with EtOAc (50 mL) and washed with H2O (50 mL×3). The organic layer was dried over sodium sulfate and concentrated. The resulting residue was purified by CombiFlash with 30% EtOAc in Hexane as the eluent to afford the desired {1-[3-(1,4-dimethyl-3H-indol-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-cyclohexyl}-acetic acid methyl ester (131 mg, 74%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1(O)[C:14]2[C:9](=[CH:10][C:11]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.CCOC(C)=O>C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:25])[CH:4]=[C:5]1[C:14]2[C:9](=[CH:10][C:11]([S:15]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)(=[O:16])=[O:17])=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1
Reactant: COC(=O)CC1(O)CCCc2cc(S(=O)(=O)c3ccccc3)ccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: COC(=O)C=C1CCCc2cc(S(=O)(=O)c3ccccc3)ccc21
Yield: 81.3 %

Procedure:
A solution of (6-benzenesulfonyl-1-hydroxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-acetic acid methyl ester (1.28 g, 3.42 mmol) and para-toluenesulfonic acid (0.50 g) in 250 mL of benzene was refluxed for 2 hours using a Dean-Stark trap. The reaction mixture was cooled and poured into 500 mL of EtOAc, and this organic phase was washed with water, saturated NaHCO3, and dried (MgSO4). Evaporation under reduced pressure gave a dark oil that was purified by elution on silica gel (hexanes:EtOAc 7:3) to yield 0.991 g (2.78 mmol, 81.2% of a white crystalline solid. MS: 357 (M+H)+.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[C:9](O)(=O)[CH2:10][CH2:11][C:12](O)=O>Cl>[CH2:11]([C:12]1[NH:8][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[N:7]=1)[CH2:10][C:9]1[NH:8][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[N:7]=1
Reactant: Nc1ccccc1N
Reactant: O=C(O)CCC(=O)O
Agent: Cl
Product: c1ccc2[nH]c(CCc3nc4ccccc4[nH]3)nc2c1

Procedure:
To a flask were added 3 g of 1,2-phenylene diamine, 1.6 g of succinic acid, and 30 ml of 4M hydrochloric acid. The mixture was heated to reflux under nitrogen for 22 hours, and then cooled to 22 C. The solid was filtered, washed with a little water and dissolved in a warm mixture of 30 ml of acetone and 40 ml of water. Enough ammonium hydroxide was added to basify the mixture, and after cooling to 22 C, the product was filtered and washed with 20 ml of 50% acetone and dried, resulting in a light pink solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[C:13]2[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[N:18]=2)[N:5]=[C:4]([CH3:24])[N:3]=1.Cl[CH2:26][CH:27]=O>CN(C=O)C>[F:23][C:19]1[N:18]=[C:17]([C:13]2[N:12]([CH2:11][C:6]3[N:5]=[C:4]([CH3:24])[N:3]4[CH:26]=[CH:27][N:1]=[C:2]4[C:7]=3[CH2:8][CH2:9][CH3:10])[CH:16]=[CH:15][N:14]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: O=CCCl
Reactant: CCCc1c(N)nc(C)nc1Cn1ccnc1-c1cccc(F)n1
Solvent: CN(C)C=O
Product: CCCc1c(Cn2ccnc2-c2cccc(F)n2)nc(C)n2ccnc12

Procedure:
A solution of 126 (1.2 mmol) and chloroacetaldehyde (1 mL) in DMF (10 ml) is heated at 70° C. in a sealed tube overnight. The solvent is removed in vacuo and water (15 ml) and EtOAc (15 ml) are added to the residue. The layers are separated and the aqueous layer is extracted with EtOAc (15 ml). The combined extracts are washed with brine (15 ml), dried (Na2SO4) and evaporated. PTLC separation of the residue with 10% MeOH in CH2Cl2 provides the title compound (119) as a white solid; LC-MS, M+1 351.1; 1H-NMR (CDCl3) δ: 8.10 (dd, 1H), 7.85 (q, 1H), 7.66 (d, 1H), 7.44 (d, 1H), 7.20 (d, 1H), 7.12 (d, 1H), 6.86 (dd, 1H), 6.02 (s, 2H), 3.01–3.07 (m, 2H), 2.69 (s, 3H), 1.60–1.67 (m, 2H), 0.94 (t, 3H).
Reaction SMILES: [CH3:1][O-].[Na+].[Cl:4][C:5]1[C:15]([Cl:16])=[C:14]([C:17](=O)[C:18](=[CH2:20])[CH3:19])[CH:13]=[CH:12][C:6]=1[O:7][CH2:8][C:9]([OH:11])=[O:10].[CH2:22]([OH:24])[CH3:23]>C(OCC)(=O)CC(C)=O>[Cl:4][C:5]1[C:15]([Cl:16])=[C:14]([C:17]2[CH:18]([CH3:20])[CH2:19][CH2:1][C:22](=[O:24])[CH:23]=2)[CH:13]=[CH:12][C:6]=1[O:7][CH2:8][C:9]([OH:11])=[O:10]
Reactant: C=C(C)C(=O)c1ccc(OCC(=O)O)c(Cl)c1Cl
Reactant: C[O-]
Reactant: CCO
Agent: [Na+]
Solvent: CCOC(=O)CC(C)=O
Product: CC1CCC(=O)C=C1c1ccc(OCC(=O)O)c(Cl)c1Cl

Procedure:
To a stirred solution of sodium methoxide (2.0 g, 0.037 mole) in ethanol (60 ml) and ethyl acetoacetate (4.86 ml) was added [2,3-dichloro-4-(2-methylene-1-oxopropyl)phenoxy]acetic acid (4.8 g, 0.017 mole). The reaction mixture was heated at reflux for 3 hours then the solvent was distilled at reduced pressure. The residue was dissolved in water, acidified with hydrochloric acid, extracted with ether, washed with water, extracted in sodium bicarbonate and acidified to get a precipitate which was filtered, rinsed with water, dried, and recrystallized from 500 ml toluene to give 2,3-dichloro-4-(6-methyl-3-oxo-1-cyclohexen-1-yl)phenoxy]acetic acid which melted at 185° C.
Reaction SMILES: Cl.[CH2:2]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:12][C:13]([OH:15])=O)[CH2:8][CH2:7]2)[CH2:5][O:4][O:3]1.[NH2:16][C@@H:17]([CH2:35][O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[CH:23][CH:22]=1)=[O:19]>>[CH2:5]1[C:6]2([CH2:7][CH2:8][N:9]([CH2:12][C:13]([NH:16][C@@H:17]([CH2:35][O:36][CH2:37][C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:18]([NH:20][C:21]3[CH:22]=[CH:23][C:24]([O:27][C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)=[CH:25][CH:26]=3)=[O:19])=[O:15])[CH2:10][CH2:11]2)[CH2:2][O:3][O:4]1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: O=C(O)CN1CCC2(CC1)COOC2
Agent: Cl
Product: O=C(CN1CCC2(CC1)COOC2)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 48.1 %

Procedure:
Proceeding as in Example 1, but substituting 2-(2,3-dioxa-8-azaspiro[4.5]decan-8-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 219, (2S)-2-(2-(2,3-dioxa-8-azaspiro[4.5]decan-8-yl)acetamido)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide (21.7 mg, 48.1%); Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.21 (s, 1H), 8.00 (d, 1H), 7.60 (d, 2H), 7.27-7.33 (m, 5H), 7.20-7.23 (m, 2H), 6.98-7.04 (m, 4H), 4.68-4.70 (m, 1H), 4.52 (s, 2H), 3.88 (s, 4H), 3.69-3.79 (m, 2H), 3.00 (s, 2H), 2.51-2.54 (m, 4H), 2.63-2.65 (m, 4H). MS (EI) for C31H34FN3O6. found 564.6 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:26])[CH:6]=[CH:7][C:8]=1[C:9]1[O:10][C:11]([C:14]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[N:12][N:13]=1.[CH:27](O)=[O:28]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:26][CH:27]=[O:28])[CH:6]=[CH:7][C:8]=1[C:9]1[O:10][C:11]([C:14]2[C:15]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[N:16][O:17][C:18]=2[CH3:19])=[N:12][N:13]=1
Reactant: O=CO
Reactant: COc1cc(N)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Product: COc1cc(NC=O)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Temperature: 90 °C
Reaction time: 2 h
Yield: 9.8 %

Procedure:
A mixture of 3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenylamine (200 mg, 0.57 mmol) and formic acid (2.1 mL, 55.6 mmol) was stirred at 90° C. for 2 h. After concentration purification of the residue by chromatography (SiO2, heptane:ethyl acetate:methanol=50:50:0 to 0:95:5) afforded the title compound (21 mg, 10%) as a yellow solid. MS: m/e=377.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]([C:9]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:10]=2[C:11](O)=[O:12])=O)=[CH:5][CH:4]=1.O.[NH2:22][NH2:23]>>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]2[C:9]3[C:10](=[CH:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)[C:11](=[O:12])[NH:23][N:22]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)c2cc(C)ccc2C(=O)O)cc1
Reactant: NN
Solvent: O
Product: COc1ccc(-c2n[nH]c(=O)c3ccc(C)cc23)cc1

Procedure:
This compound is obtained according to the procedure described in 1.2. by reacting unpurified 2-(4-methoxybenzoyl)-4-methylbenzoic acid with hydrazine hydrate.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]1[CH2:11][C:10](=[O:12])[CH:9]=[CH:8][CH2:7]1)(=[O:3])[CH3:2].C(O[CH2:18][N:19]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:20][Si](C)(C)C)CCC.C(=O)([O-])[O-].[K+].[K+]>FC(F)(F)C(O)=O.ClCCl>[C:1]([O:4][CH2:5][CH:6]1[CH2:7][CH:8]2[CH:9]([CH2:18][N:19]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:20]2)[C:10](=[O:12])[CH2:11]1)(=[O:3])[CH3:2]
Reactant: CCCCOCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: CC(=O)OCC1CC=CC(=O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)OCC1CC(=O)C2CN(Cc3ccccc3)CC2C1
Reaction time: 1 h
Yield: 70.4 %

Procedure:
Two drops of trifluoroacetic acid are added to a solution of 6.5 g of 5-acetoxymethylcyclohex-2-en-1-one and 14 g of N-butoxymethyl-N-trimethylsilylmethylbenzylamine [prepared according to the method described by Y. Tarao et al., Chem. Pharm. Bull., 33., 2762 (1985)] in 60 cm3 of dry dichloromethane. On reaching reflux, the reaction mixture is maintained at the same temperature for 30 minutes and then left at 20° C. for one hour. After addition of 1.0 g of potassium carbonate, the suspension obtained is filtered, and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The oily residue obtained is chromatographed on a silica gel column (particle size 0.06-0.2 mm, height 42 cm) in a mixture of cyclohexane and ethyl acetate (40:60 by volume) and then in ethyl acetate. 8.2 g of (3aRS,6SR,7aSR)-6-acetoxymethyl-2-benzylperhydroisoindol-4-one are obtained in the form of a yellowish oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:17][CH:18]([CH3:20])[CH3:19])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:29][C:30](Br)=[O:31].[CH2:33]([NH:40][CH3:41])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:17][CH:18]([CH3:20])[CH3:19])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:29][C:30]([N:40]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH3:41])=[O:31]
Reactant: O=C(Br)CBr
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC(C)C)cc32)cc1OC
Reactant: CNCc1ccccc1
Product: COc1ccc(CC2c3cc(OC(C)C)c(OC)cc3CCN2CC(=O)N(C)Cc2ccccc2)cc1OC

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with N-benzyl-N-methyl-amine