Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH:2]([Cl:24])[C:3]([NH:5][C@H:6]([CH2:22][F:23])[C@H:7]([OH:21])[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][NH:17][C:16](=[O:20])[CH:15]=2)=[CH:10][CH:9]=1)=[O:4].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:32][C:33]#[N:34]>CN(C)C=O.O>[Cl:24][CH:2]([Cl:1])[C:3]([NH:5][C@H:6]([CH2:22][F:23])[C@@H:7]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][N:17]([CH2:32][C:33]#[N:34])[C:16](=[O:20])[CH:15]=2)=[CH:12][CH:13]=1)[OH:21])=[O:4]
Reactant: N#CCCl
Reactant: O=C(N[C@H](CF)[C@H](O)c1ccc(-c2cc[nH]c(=O)c2)cc1)C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCn1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)cc1=O
Temperature: 65 °C
Yield: 58.7 %

Procedure:
A microwave tube is charged with the product of step 2, Example 20 (185 mg, 0.496 mmol) in dimethylformamide (4.9 mL), cesium carbonate (194 mg, 0.595 mmol) and chloroacetonitrile (313.7 uL, 4.957 mmol) were added under nitrogen, and the tube is capped. The reaction mixture is heated at 65° C. for 2.5 hours using the microwave (max power—100 W). The mixture is diluted with water (20 mL), extracted with ethylacetate (2×20 mL), and the combined organic phase is washed with water (3×15 mL), brine (15 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Purification by silica gel chromatography (40 g, 50-90% ethyl acetate/hexanes) gave the title compound (120 mg): 1H NMR (300 MHz, DMSO) δ 4.25 (m, 1.5H), 4.44 (m, 0.5H), 4.53 (m, 0.5H), 4.72 (m, 0.5H), 4.91 (m, 1H), 5.02 (s, 2H), 6.01 (d, 1H), 6.51 (s, 1H), 6.72 (dd, 1H), 6.77 (m, 1H), 7.47 (d, 2H), 7.70 (d, 2H), 7.83 (d, 1H), 8.60 (bd, 1H). MS (ESI+) m/z 412 [M+H].
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[CH3:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([CH3:33])[C:30]=1[O:31][CH3:32])[C:25](O)=[O:26]>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH:7]([NH:6][C:4]([CH2:3][NH:2][C:25](=[O:26])[C:24]2[CH:28]=[C:29]([CH3:33])[C:30]([O:31][CH3:32])=[C:22]([CH3:21])[CH:23]=2)=[O:5])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: COc1c(C)cc(C(=O)O)cc1C
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Agent: Cl
Product: COc1c(C)cc(C(=O)NCC(=O)NC(c2ccccc2)c2ccc(Cl)cc2)cc1C

Procedure:
Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) and 3,5-dimethyl-4-methoxybenzoic acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[OH:11].[C:13]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:18]=CC=C[CH:14]=1.C(O)(C)C.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[O:11][CH:13]([CH3:18])[CH3:14]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)c1ccc(C)cc1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: C1CCOC1
Solvent: CC(C)O
Product: COC(=O)c1ccc(C)cc1OC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 112 %

Procedure:
To a mixture of 2-hydroxy-4-methyl-benzoic acid methyl ester (1.0 g, 6.0 mmol), triphenylphosphine (1.9 g, 7.2 mmol), and isopropanol (0.72 g, 12.0 mmol) in THF (10.0 mL) is added DIAD (1.45 g, 7.2 mmol) dropwise at 0° C. The mixture is stirred at room temperature overnight. The mixture is evaporated to dryness under reduced pressure. The residue is partitioned between EtOAc (50 mL) and water (50 mL). The organic phase is washed with brine (50 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to a residue. The residue is purified by flash chromatography to afford the title compound as white solid (1.4 g, 96%). LC-ES/MS m/e 209.0 (M+1).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][C:8]([C:10]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:11]=1[CH2:12][CH2:13][C:14]([OH:16])=O)=[O:9])(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:35][C@H:36]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40].C(N(C(C)C)C(C)C)C>O1CCCC1>[C:1]([NH:4][CH2:5][CH2:6][CH2:7][C:8]([C:10]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:11]=1[CH2:12][CH2:13][C:14]([NH:35][C@H:36]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[O:16])=[O:9])(=[O:3])[CH3:2]
Reactant: CCOC(=O)CC[C@H](N)C(=O)OCC
Reactant: CC(=O)NCCCC(=O)c1ccc(Cl)cc1CCC(=O)O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CC[C@H](NC(=O)CCc1cc(Cl)ccc1C(=O)CCCNC(C)=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.10 g (0.01 mol) of 2-(4-acetamidobutyryl)-5-chlorohydrocinnamic acid and 1.70 g (0.015 mol) of 1,1'-carbonyldiimidazole are stirred at room temperature for 1 hour in 50 ml of tetrahydrofuran and 2.51 g (0.011 mol) of diethyl L-glutamate hydrochloride and 1.8 ml (0.011 mol) of N-ethyldiisopropylamine are then added thereto. After stirring at room temperature for 2 hours the solution is concentrated, extracted with methylene chloride/water, dried with sodium sulfate and the solvent is distilled in a vacuum. Chromatography on aluminum oxide with methylene chloride-methanol (97:3) and crystallization from ethyl acetate/hexane gives diethyl N-[2-(4-acetamidobutyryl)-5-chlorohydrocinnamoyl]-L-glutamate as white crystals with melting point 109°-111°.
Reaction SMILES: [O:1]1[CH2:22][CH:2]1[CH2:3][O:4][C:5]1[C:18]([CH3:19])=[C:17]([CH3:20])[CH:16]=[C:15]([CH3:21])[C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].[CH:23]([NH2:26])([CH3:25])[CH3:24]>CO>[C:7]([C:6]1[C:15]([CH3:21])=[CH:16][C:17]([CH3:20])=[C:18]([CH3:19])[C:5]=1[O:4][CH2:3][CH:2]([OH:1])[CH2:22][NH:26][CH:23]([CH3:25])[CH3:24])(=[O:8])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)N
Reactant: Cc1cc(C)c(C(=O)c2ccccc2)c(OCC2CO2)c1C
Solvent: CO
Product: Cc1cc(C)c(C(=O)c2ccccc2)c(OCC(O)CNC(C)C)c1C

Procedure:
A mixture of 2-(2,3-epoxypropoxy)-3,4,6-trimethylbenzophenone (10.0 g.), isopropylamine (10 ml.) and anhydrous methanol (100 ml.) was heated at reflux for 17 hours. The solution was evaporated in vacuo and the residue was dissolved in water (100 ml.) containing concentrated hydrochloric acid (6 ml.). The solution was filtered through charcoal and kieselguhr, adjusted to pH 11 by means of 2 N aqueous sodium hydroxide solution and extracted with ethyl acetate. The extract was washed 3 times with water, dried over anhydrous sodium sulphate and evaporated. The residue was recystallized from cyclohexane to give DL-1-(2-benzoyl-3,5,6-trimethylphenoxy)-2-hydroxy-3-isopropylaminopropane (6.6 g.), m.p. 121°-123° C.
Reaction SMILES: Br[C:2]1[C:10]2[S:9][C:8]([NH:11][C:12](=[O:16])[NH:13][CH2:14][CH3:15])=[N:7][C:6]=2[CH:5]=[C:4]([C:17]2[CH:18]=[N:19][C:20]([N:23]3[CH2:28][CH2:27][C:26]([CH3:34])([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][CH2:24]3)=[N:21][CH:22]=2)[CH:3]=1.C([Sn](CCCC)(CCCC)[C:40]([O:42][CH2:43][CH3:44])=[CH2:41])CCC.C(OC=C)=C>CN(C=O)C.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>[CH2:43]([O:42][C:40]([C:2]1[C:10]2[S:9][C:8]([NH:11][C:12](=[O:16])[NH:13][CH2:14][CH3:15])=[N:7][C:6]=2[CH:5]=[C:4]([C:17]2[CH:22]=[N:21][C:20]([N:23]3[CH2:28][CH2:27][C:26]([CH3:34])([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][CH2:24]3)=[N:19][CH:18]=2)[CH:3]=1)=[CH2:41])[CH3:44]
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(Br)c2s1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C=COC=C
Solvent: CN(C)C=O
Product: C=C(OCC)c1cc(-c2cnc(N3CCC(C)(C(=O)OCC)CC3)nc2)cc2nc(NC(=O)NCC)sc12
Temperature: 100 °C

Procedure:
The ethyl 1-[5-[7-bromo-2-(ethylcarbamoylamino)-1,3-benzothiazol-5-yl]pyrimidin-2-yl]-4-methyl-piperidine-4-carboxylate (1 g, 1.82 mmol) and tributyl-(1-ethoxy-vinyl)-stannane (1.31 g, 3.64 mmol) were dissolved in DMF (20 mL) and the mixture deoxygenated by bubbling N2 through the solution for 20 min. Pd(PPh3)4, (210 mg, 0.18 mmol) was added and the reaction heated to 100° C. for 4 h under a N2 atmosphere, at the end of which time LCMS indicated clean formation of the vinyl ether. The reaction was concentrated under reduced pressure then diluted with EtOAc, washed with water then brine, the organic layer dried (MgSO4), filtered and the solvent removed in vacuo to give the desired compound.
Reaction SMILES: [CH3:1][S:2]([C:5]1[O:9][C:8]([C@@H:10]([NH:13][S@@](C(C)(C)C)=O)[CH2:11][CH3:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[ClH:20].O1CCOCC1>CO>[ClH:20].[CH3:1][S:2]([C:5]1[O:9][C:8]([C@@H:10]([NH2:13])[CH2:11][CH3:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CC[C@H](N[S@](=O)C(C)(C)C)c1ccc(S(C)(=O)=O)o1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC[C@H](N)c1ccc(S(C)(=O)=O)o1
Reaction time: 1 h

Procedure:
To a solution of (R)-2-methyl-propane-2-sulfinic acid[(S)-1-(5-methanesulfonyl-furan-2-yl)-propyl]amide (0.530 g, 1.72 mmol) in methanol (5 mL) was added 4 N HCl in dioxane (2 mL, 8 mmol). After 1 hour, the mixture was concentrated in vacuo to afford (S)-1-(5-methanesulfonyl-furan-2-yl)-propylamine hydrochloride.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:13]([CH3:15])[CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.[F:39][C:40]1([F:45])[CH2:44][CH2:43][NH:42][CH2:41]1>CN(C=O)C>[F:39][C:40]1([F:45])[CH2:44][CH2:43][N:42]([C:10](=[O:12])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH:13]([CH3:15])[CH3:14])[CH2:41]1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: FC1(F)CCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC(F)(F)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 99.3 %

Procedure:
(S)-2-(Tert-butoxycarbonylamino)-3-methylbutanoic acid (1.1 g, 5.06 mmol), which is commercially available, and TBTU (1.63 g, 5.06 mmol) was mixed in DMF (10 mL). The mixture was cooled to 0° C. and TEA (2.105 mL, 15.19 mmol) was added. After 10 min was 3,3-difluoropyrrolidine hydrochloride (0.872 g, 6.08 mmol) added. The resultant mixture was stirred at rt over night. The mixture was concentrated and the residue dissolved in DCM (50 mL). The organic phase was washed with HCl (1M aq. solution, 100 mL), NaHCO3 (saturated, 2×100 mL) and brine (100 mL), filtered through a phase separator and concentrated under reduced pressure to give the title compound (1.54 g, 99%). The obtained crude product was used without further purification. 1H NMR (400 MHz, CD3OD) δ 0.77-1.09, 1.21, 1.43, 1.84-2.08, 2.22-2.69, 3.52-4.40. Total no of protons: 24. LCMS (M+H)+: 307.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][N:3]=1.[Br:11]C1(Br)C(=O)NC(=O)NC1=O>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH2:9][Br:11])=[CH:4][N:3]=1
Reactant: CC(=O)c1ccc(Cl)nc1
Reactant: O=C1NC(=O)C(Br)(Br)C(=O)N1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(CBr)c1ccc(Cl)nc1
Reaction time: 2 h
Yield: 72.8 %

Procedure:
A solution of 784 mg of 2-chloro-5-acetylpyridine in 10 mL of THF was added via canula to a solution of 1.44 g of dibromobarbituric acid (DBBA) in 10 mL of THF. The resultant solution was heated at 50°-55° C. for 12 h, and then an additional 0.72 g DBBA was added. After stirring at 50°-55° C. for 2.5 more hours, 0.36 g DBBA was added. The mixture was allowed to stir for 2 h at which point NMR analysis of an aliquot indicated 87% conversion. The reaction mixture was cooled, diluted with ethyl acetate, washed with two portions of saturated aqueous sodium bicarbonate, water, and brine, dried over magnesium sulfate and concentrated. Purification by flash chromatography (silica gel, 15% ethyl acetate/hexane) provided 0.86 g (73%) of the title compound as a white solid: 1H NMR (400 MHz, CDCl3) δ8.96 (d, 1H, J=2.6 Hz), 8.21 (dd, 1H, J=2.5, 8.3 Hz), 7.46 (d, 1H, J=8.4 Hz), 4.37 (s, 2H). The NMR also indicated the presence of the corresponding 2-bromo derivative. The ~4:1 mixture was carried on through the synthesis.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:12]([O-])=O)[C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[NH4+].[Cl-]>CCO.O.[Fe]>[NH2:12][C:4]1[C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: CC(=O)c1cc(Br)cc([N+](=O)[O-])c1O
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(=O)c1cc(Br)cc(N)c1O

Procedure:
A mixture of 1-(5-bromo-2-hydroxy-3-nitrophenyl)ethanone (25 g, 96 mmol), iron (27 g, 481 mmol), and NH4Cl (5.1 g, 96 mmol) in EtOH/H2O (5:1, 300 ml) was heated at reflux in 2 h, the mixture was cooled filtered the solid, the filtrate was concentrated, taken up in H2O, extracted with DCM (3×), dried over MgSO4, concentrated and purified by ISCO (10% EtOAc/Hexanes) to give the title compound as a yellow solid. MS (m+2): 232.1.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:18]1[C:23]([I:24])=[C:22]([CH:25]([O:27][C:28](=[O:30])[CH3:29])[CH3:26])[N:21]=[CH:20][N:19]=1>C1(C)C=CC=CC=1>[C:28]([O:27][CH:25]([C:22]1[N:21]=[CH:20][N:19]=[C:18]([NH:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:23]=1[I:24])[CH3:26])(=[O:30])[CH3:29]
Reactant: CC(=O)OC(C)c1ncnc(Cl)c1I
Reactant: NCCc1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(=O)OC(C)c1ncnc(NCCc2ccccc2)c1I
Temperature: 60 °C

Procedure:
In 20 ml of toluene were dissolved 2-phenylethylamine (0.6 g) and triethylamine (0.6 g), then, 4-chloro-6-(1-acetoxy-ethyl)-5-iodopyrimidine (1.7 g) was added to the solution, and the mixture was heated at about 60° C. for 3 hours while stirring.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O.[CH3:17][O:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1.C(O)(=O)C>C(O)(C)C>[CH3:17][O:18][C:19]1[CH:25]=[CH:24][C:22]([N:23]2[C:2]3[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=3[CH:8]=[C:9]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:21][CH:20]=1
Reactant: O=C(CC1CCCCC1=O)c1ccccc1
Reactant: COc1ccc(N)cc1
Solvent: CC(=O)O
Solvent: CC(C)O
Product: COc1ccc(-n2c(-c3ccccc3)cc3c2CCCC3)cc1

Procedure:
Following a procedure similar to that of Example 1C but using 64.9 g. of 2-(2-oxocyclohexyl)acetophenone and 37 g. of 4-methoxyaniline in 180 ml. glacial acetic acid there was obtained 80.9 g. of 1-(4-methoxyphenol)-2-phenol-4,5,6,7-tetrahydroindole; m.p. 132°-133°C. (isopropyl alcohol).
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].C(OCC)(=O)CC(OCC)=O.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[CH:24]=[CH:25][C:26](=[O:28])[CH3:27]>C(O)C>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[CH:24]1[CH2:3][C:2](=[O:1])[CH2:27][C:26](=[O:28])[CH2:25]1
Reactant: CC(=O)C=Cc1cc(Cl)ccc1Cl
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCOC(=O)CC(=O)OCC
Solvent: CCO
Product: O=C1CC(=O)CC(c2cc(Cl)ccc2Cl)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 20% sodium ethoxide in ethanol (6.2 g) were added at room temperature ethanol (150 ml) and diethyl malonate (14.6 g), and then added little by little 4-(2,5-dichlorophenyl)-3-buten-2-one (19.0 g). The mixture was stirred at room temperature for 30 minutes, refluxed for 2 hours and cooled. The solvent was evaporated, and to the residue was added water. The aqueous layer was washed with ethyl acetate and concentrated, and to the residue was added 2M sodium hydroxide (50 ml). The mixture was refluxed for 2 hours and cooled, and to the mixture was added 2.5M sulfuric acid (50 ml) for 15 minutes. The mixture was refluxed for 1.5 hours and cooled, and precipitated crystals were filtered and washed with water and toluene to give 5-(2,5-dichlorophenyl)cyclohexane-1,3-dione (9.9 g) as colorless crystals.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([O:27][CH2:28][CH2:29][O:30][CH3:31])[C:23]([O:25]C)=[O:24])=[CH:17][CH:16]=1)[CH3:11].[OH-].[Na+]>CO.O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([O:27][CH2:28][CH2:29][O:30][CH3:31])[C:23]([OH:25])=[O:24])=[CH:17][CH:16]=1)[CH3:11]
Reactant: COCCOC(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COCCOC(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)C(=O)O

Procedure:
A mixture of methyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-(2-methoxyethoxy)propanoate (1.08 g, Int. Patent Appl., Publication No. WO 9401420) and sodium hydroxide (253 mg) in methanol:water (1:1, 10 mL) was heated under reflux for 2 hours. After evaporation of the resultant mixture in vacuo, the residue was diluted with water, acidified to pH 5 with 2M hydrochloric acid and then extracted with ethyl acetate. Washing of the ethyl acetate extracts with water and drying (MgSO4) and evaporation gave the title compound as an oil which crystallised on trituration with diethyl ether/hexane. [Found C, 63.8; H, 6.5; N, 7.0%; M+ 414.1791. C22H26N2O6 requires C, 63.8; H, 6.3; N, 6.8%; M+ 414.1791]; δH (CDCl3) 2.91 (1H,dd), 3.15 (1H,dd), 3.34 (3H,s), 3.38 (3H,s), 3.41-3.69 (4H,m), 3.93 (2H,t), 4.05 (1H,dd), 4.21 (2H,t), 6.80 (2H,d) and 6.83-7.38 (6H m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:36]([O:38]C)=[O:37])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:14]=[C:13]([C:15]([NH:17][C:18]2[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=2)=[O:16])[CH:12]=[C:11]([O:24][C@@H:25]([CH3:35])[CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH:10]=1.O.[OH-].[Li+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:36]([OH:38])=[O:37])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:14]=[C:13]([C:15]([NH:17][C:18]2[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=2)=[O:16])[CH:12]=[C:11]([O:24][C@@H:25]([CH3:35])[CH2:26][O:27][Si:28]([C:31]([CH3:33])([CH3:34])[CH3:32])([CH3:30])[CH3:29])[CH:10]=1
Reactant: COC(=O)c1cnc(Oc2cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)cc(C(=O)Nc3ccn(C)n3)c2)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(Oc2ncc(C(=O)O)cc2Cl)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.8 %

Procedure:
To a solution of methyl 5-chloro-6-[(3-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenyl)oxy]pyridine-3-carboxylate (1.2 g, 2.09 mmol) in THF (50 mL) was added a solution of lithium hydroxide monohydrate (0.219 g, 5.22 mmol) in water (30 mL). The mixture was allowed to stir under RT overnight. The THF was removed in vacuo and the resulting solution was partitioned between water (50 mL) and ethyl acetate (75 mL), and the ethyl acetate layer separated, washed with brine and dried (MgSO4). The aqueous layer was then adjusted to pH 7 by addition of 1N hydrochloric acid (5.2 mL) and partitioned between ethyl acetate (75 mL). The ethyl acetate layer was separated, washed with brine and dried (MgSO4). The ethyl acetate layers were combined and evaporated to give the required product (1.1 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:15][CH:16]([CH2:19][CH3:20])[CH2:17]Br.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:15][CH:16]([CH2:19][CH3:20])[CH2:17][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCC(C)CBr
Reactant: Oc1ccc(-c2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCC(C)COc1ccc(-c2ccc(O)cc2)cc1
Yield: 19.1 %

Procedure:
A solution of 0.20 mole (37.2 g) of 4,4'-dihydroxybiphenyl, 0.10 mole (15.1 g) of the above 2-methyl-1-bromobutane, and 0.60 mole (33.7 g) of potassium carbonate in 300 ml of ethanol was refluxed for 16 hours. After the reaction, the reaction solution was filtered and concentrated, then purified by column chromatography to obtain 4.9 g of 4'-(2-methylbutoxy)-4-hydroxybiphenyl. (yield: 58%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([O:22][CH2:23][C:24]#[N:25])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1.S(C)C>C1COCC1>[NH2:25][CH2:24][CH2:23][O:22][C@@H:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCC#N)c2cccc(Cl)c2)C1
Solvent: CSC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCCN)c2cccc(Cl)c2)C1
Temperature: 25 °C

Procedure:
(R)-tert-butyl 3-((R)-(3-chlorophenyl)(cyanomethoxy)methyl)piperidine-1-carboxylate (36.8 g, 0.10 mol) was dissolved in anhydrous THF (350 mL), and the solution was heated under reflux under a nitrogen atmosphere. A solution of BH3.Me2S (30 mL, 0.30 mol) in THF was added drop wise, and stirring was continued under reflux overnight. The resulting solution was cooled to room temperature. The reaction was quenched by careful, drop wise addition of MeOH until bubbling ceased. After evaporation of the solution, the crude product was obtained (70 g), which was used for the next step without purification.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:15][CH:14]([C:16]([OH:18])=O)[CH2:13][CH2:12][C:11]=3[CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20]([NH2:23])[CH:21]=[CH2:22]>>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:15][CH:14]([C:16]([NH:23][CH2:20][CH:21]=[CH2:22])=[O:18])[CH2:13][CH2:12][C:11]=3[CH:19]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=CCN
Reactant: O=C(O)C1CCc2cc(-c3ccccc3)ccc2O1
Product: C=CCNC(=O)C1CCc2cc(-c3ccccc3)ccc2O1

Procedure:
4 Was prepared as a white solid, mp: 123°-124° C. from the ethyl ester of 3,4-dihydro-6-phenyl-2H-1-benzopyran-2-carboxylic acid (Witiak et al. (1975)) and 2-propenamine by the procedure described in the last paragraph of Example 2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH:10]2[C:13]([OH:15])=O)=[CH:5][CH:4]=1.[CH2:16]([C:18]1[S:22][C:21]([CH2:23][NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH:31]([CH3:33])[CH3:32])=[CH:27][CH:26]=2)=[CH:20][CH:19]=1)[CH3:17]>>[CH2:16]([C:18]1[S:22][C:21]([CH2:23][N:24]([C:25]2[CH:26]=[CH:27][C:28]([CH:31]([CH3:32])[CH3:33])=[CH:29][CH:30]=2)[C:13]([CH:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH2:7][CH2:8][CH2:9]2)=[O:15])=[CH:20][CH:19]=1)[CH3:17]
Reactant: COc1ccc2c(c1)C(C(=O)O)CCC2
Reactant: CCc1ccc(CNc2ccc(C(C)C)cc2)s1
Product: CCc1ccc(CN(C(=O)C2CCCc3ccc(OC)cc32)c2ccc(C(C)C)cc2)s1
Yield: 14.6 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.82 g) and [(5-ethylthiophen-2-yl)methyl](4-isopropylphenyl)amine (1.04 g) as starting materials, N-[(5-ethylthiophen-2-yl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.26 g) was obtained. MS (ESI)m/z: 448 [MH]+
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.[CH2:19]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1OB(O)O)[CH2:20][CH3:21].ClCCl>C(N(CC)CC)C>[CH2:19]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[O:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1)[CH2:20][CH3:21]
Reactant: CCCOCc1ccccc1OB(O)O
Reactant: COC(=O)C1=Cc2cc(O)ccc2S(=O)(=O)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCOCc1ccccc1Oc1ccc2c(c1)C=C(C(=O)OC)CCS2(=O)=O
Reaction time: 20 h
Yield: 20.9 %

Procedure:
To a mixture of methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.40 g), 2-propoxymethylphenylboric acid (0.80 g), cupric acetate (0.27 g), MS 4A (0.8 g) and dichloromethane (15 ml) was added at room temperature triethylamine (1.04 ml), and the resulting mixture was stirred for 20 hours. The reaction mixture was filtered to remove an insoluble material and the filtrate was concentrated under reduced pressure. The residue was subjected to separation and purification using column chromatography (ethyl acetate:hexane 1:2) to obtain methyl 7-(2-propoxymethylphenoxy)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.13 g) as a light yellow, oily substance.