Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:23])[C:9]2[CH:22]=[CH:21][C:12]3[C:13]([C:17]([NH:19][CH3:20])=[O:18])=[C:14]([CH3:16])[O:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:24][N:25]([CH3:33])[C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][CH:32]=1)[NH2:29]>CN(C=O)C>[CH3:24][N:25]([CH3:33])[C:26]1[CH:27]=[C:28]([NH:29][C:2]2[N:7]=[C:6]([N:8]([CH3:23])[C:9]3[CH:22]=[CH:21][C:12]4[C:13]([C:17]([NH:19][CH3:20])=[O:18])=[C:14]([CH3:16])[O:15][C:11]=4[CH:10]=3)[CH:5]=[CH:4][N:3]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: CNC(=O)c1c(C)oc2cc(N(C)c3ccnc(Cl)n3)ccc12
Reactant: CN(C)c1cccc(N)c1
Solvent: CN(C)C=O
Product: CNC(=O)c1c(C)oc2cc(N(C)c3ccnc(Nc4cccc(N(C)C)c4)n3)ccc12
Temperature: 60 °C
Reaction time: 5 h
Yield: 78 %

Procedure:
6-((2-chloropyrimidin-4-yl)(methyl)amino)-N,2-dimethylbenzofuran-3-carboxamide (0.1 mmol) and 3-dimethylaminoaniline (0.1 mmol) were dissolved in 0.5 ml DMF. To this was added p-TsOH monohydrate (0.2 mmol). The reaction mixture was stirred at 60° C. for 5 hours, and subjected to extraction with EtOAc. Then water was added and the mixture was subjected to extraction with ethyl acetate. The organic layer was washed with water and brine sequentially, dried over anhydrous Na2SO4, and concentrated. The resulting residue was purified by column chromatography to provide the title product in a yield of 78%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[C:10]([O:17][CH3:18])[CH:9]=2)=[CH:4][CH:3]=1.Cl.[CH2:20]([O:22][C:23](=[O:26])[CH2:24][NH2:25])[CH3:21].CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.CCOC(C)=O.CN(C=O)C>[CH2:20]([O:22][C:23](=[O:26])[CH2:24][NH:25][C:14]([C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[CH:9][C:10]=1[O:17][CH3:18])=[O:16])[CH3:21]
Reactant: CCOC(=O)CN
Reactant: COc1cc(-c2ccc(Cl)cc2)ccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CNC(=O)c1ccc(-c2ccc(Cl)cc2)cc1OC
Reaction time: 16 h
Yield: 85 %

Procedure:
To a solution of 4′-chloro-3-methoxy-biphenyl-4-carboxylic acid, 9, (0.325 g, 1.24 mmol) in CH2Cl2 (5 mL) and DMF (1.5 mL) at room temperature under N2 is added glycine ethyl ester hydrochloride (0.19 g, 1.36 mmol), 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide (EDCI) (0.261 g, 1.36 mmol), 1-hydroxybenzotriazole (HOBt) (0.033 g, 0.248 mmol) and diisopropylethylamine (DIPEA) (0.432 ml, 2.28 mmol). The resulting suspension is stirred for 16 hours after which the reaction mixture is diluted with EtOAc and washed with 1M HCl, 1M NaOH and saturated aqueous NaCl. The organic phase is separated, dried (MgSO4), filtered and concentrated under reduced pressure. The crude material is purified over silica (hexanes:EtOAc 1:1) to afford 0.364 g (85% yield) of the desired product as a colorless solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.51 (1 H, br s), 8.28 (1 H, d, J=8.1 Hz), 7.53-7.57 (2 H, m), 7.42-7.46 (2 H, m), 7.27 (1 H, dd, J=8.1, 1.6 Hz), 7.14 (1 H, d, J=1.5 Hz), 4.29 (2 H, d, J=4.8 Hz), 4.28 (2 H, q, J=7.1 Hz), 4.09 (3 H, s), 1.34 (3 H, t, J=7.2 Hz). HPLC-MS: m/z 348 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH3:10])[CH3:9].[Mg].II.[CH3:14][C:15]([CH3:35])([CH3:34])[CH2:16][C:17]([NH:19][C:20]1[C:21]([CH3:33])=[C:22]([CH3:32])[C:23]2[O:27][C:26]([CH3:29])([CH3:28])[C:25](=[O:30])[C:24]=2[CH:31]=1)=[O:18]>C1COCC1>[OH:30][C:25]1([C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([CH:8]([CH3:10])[CH3:9])[CH:2]=2)[C:24]2[CH:31]=[C:20]([NH:19][C:17](=[O:18])[CH2:16][C:15]([CH3:35])([CH3:34])[CH3:14])[C:21]([CH3:33])=[C:22]([CH3:32])[C:23]=2[O:27][C:26]1([CH3:28])[CH3:29]
Reactant: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2=O
Reactant: CC(C)c1ccccc1Br
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2(O)c1cccc(C(C)C)c1
Yield: 16.2 %

Procedure:
A solution of 1-bromo-2-isopropylbenzene (1.20 g, 6.03 mmol) in THF (5 mL) was added dropwise under an argon atmosphere to a mixture of magnesium (147 mg, 6.03 mmol) and a catalytic amount of iodine, and the mixture was stirred at 70° C. for 30 minutes. To the reaction solution was added dropwise a solution of 3,3-dimethyl-N-(2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)butanamide (350 mg, 1.15 mmol) obtained in Reference Example 65 in THF (3 mL), and the mixture was refluxed with heating for 12 hours. The reaction solution was added to ice and the product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2) to obtain 79 mg (yield: 16%) of N-(3-hydroxy-3-(3-isopropylphenyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide. To a solution of the compound (79 mg, 0.19 mmol) in trifluoroacetic acid (1 mL) was added with ice-cooling triethylsilane (44 mg, 0.38 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction solution was added to water and the product was extracted with ethyl acetate. The organic layer was washed with an aqueous 1 N sodium hydroxide solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2) to obtain 39 mg (yield: 51%) of the title compound. Yield: 51%. Melting point: 188-189° C. (ethyl acetate-hexane).
Reaction SMILES: Br[C:2]1C=CO[C:3]=1C(O)=O.[Br:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[C:14]([OH:16])=[O:15]>>[Br:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[C:14]([O:16][CH2:2][CH3:3])=[O:15]
Reactant: COc1ccc(C(=O)O)cc1Br
Reactant: O=C(O)c1occc1Br
Product: CCOC(=O)c1ccc(OC)c(Br)c1

Procedure:
A reaction was carried out in the same manner as in Reference Example 1 except that the 3-bromo-2-furancarboxylic acid used in Reference Example 1 was replaced with 3-bromo-4-methoxybenzoic acid (4.62 g). The crude product was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/10), thereby giving 4.65 g of ethyl 3-bromo-4-methoxybenzoate.
Reaction SMILES: [CH:1]1([C:11]([OH:13])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:14]([C:16]1[S:20][C:19]([CH2:21][NH:22][C:23]2[CH:28]=[CH:27][C:26]([CH:29]([CH3:31])[CH3:30])=[CH:25][CH:24]=2)=[CH:18][CH:17]=1)[CH3:15]>>[CH2:14]([C:16]1[S:20][C:19]([CH2:21][N:22]([C:23]2[CH:24]=[CH:25][C:26]([CH:29]([CH3:30])[CH3:31])=[CH:27][CH:28]=2)[C:11]([CH:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)=[O:13])=[CH:18][CH:17]=1)[CH3:15]
Reactant: O=C(O)C1CCCc2ccccc21
Reactant: CCc1ccc(CNc2ccc(C(C)C)cc2)s1
Product: CCc1ccc(CN(C(=O)C2CCCc3ccccc32)c2ccc(C(C)C)cc2)s1
Yield: 10.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.7 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)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.18 g) was obtained.
Reaction SMILES: Cl[CH2:2][C:3]1[S:7][C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[N:17]([CH3:26])[S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:20])=[O:19])=[N:5][CH:4]=1.C(N(CC)CC)C.Cl.[CH2:35]1[CH:40]2[CH2:41][NH:42][CH2:43][CH2:44][N:39]2[C:38](=[O:45])[CH2:37][O:36]1.CN(C)C=O>O>[CH3:26][N:17]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[NH:9][C:8]([C:6]1[S:7][C:3]([CH2:2][N:42]3[CH2:43][CH2:44][N:39]4[CH:40]([CH2:35][O:36][CH2:37][C:38]4=[O:45])[CH2:41]3)=[CH:4][N:5]=1)=[CH:16]2)[S:18]([C:21]1[S:22][CH:23]=[CH:24][CH:25]=1)(=[O:20])=[O:19]
Reactant: CN(c1cccc2cc(-c3ncc(CCl)s3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: O=C1COCC2CNCCN12
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CN(c1cccc2cc(-c3ncc(CN4CCN5C(=O)COCC5C4)s3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.2 %

Procedure:
A mixture of N-{2-[5-(chloromethyl)-1,3-thiazol-2-yl]-1H-indol-7-yl}-N-methylthiophene-2-sulfonamide (150 mg), triethylamine (150 μL), hexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-one hydrochloride (135 mg) and N,N-dimethylformamide (2 ml) was stirred at room temperature for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography to give the title compound (85 mg, yield 45%) as a colorless amorphous form from a fraction eluted with ethyl acetate. MS 544 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)[N:3]=1.[NH2:28][C:29]1[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][C:30]=1[C:31]([NH:33][CH3:34])=[O:32]>>[C:39]([C:36]1[CH:37]=[CH:38][C:29]([NH:28][C:2]2[C:7]([C:8]([F:10])([F:9])[F:11])=[CH:6][N:5]=[C:4]([NH:12][C:13]3[CH:14]=[CH:15][C:16]([CH2:17][P:18](=[O:25])([O:19][CH2:20][CH3:21])[O:22][CH2:23][CH3:24])=[CH:26][CH:27]=3)[N:3]=2)=[C:30]([C:31](=[O:32])[NH:33][CH3:34])[CH:35]=1)#[N:40]
Reactant: CNC(=O)c1cc(C#N)ccc1N
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(C#N)cc3C(=O)NC)n2)cc1)OCC
Yield: 21.8 %

Procedure:
The title compound was prepared using the procedure from Example 102 (Diethyl (4-{[4-{[4-fluoro-2-(methylcarbamoyl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-benzyl)phosphonate) with diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate (10.0 mg, 0.0236 mmol) and 2-amino-5-cyano-N-methylbenzamide (Compound 150A, 8.3 mg, 0.0472 mmol). The crude mixture was purified by MDP to obtain the title compound as white solid (2.9 mg, 22% yield). 1H NMR (400 MHz, CD3OD) δ=1.28 (t, J=7.1 Hz, 6H), 2.92 (s, 3H), 3.26 (d, J=21.5 Hz, 2H), 4.07 (qd, J=7.3, 7.1 Hz, 4H), 7.28 (dd, J=8.8, 2.5 Hz, 2H), 7.56 (d, J=6.3 Hz, 2H), 7.76 (d, J=8.6 Hz, 1H), 8.04 (d, J=1.8 Hz, 1H), 8.42 (s, 1H), 8.88 (br. s., 1H). MS (ES+): m/z 563.17 (100) [MH+]; HPLC: tR=1.04 min (UPLC, purity).
Reaction SMILES: C(OC([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:22]3[S:26][N:25]=[CH:24][CH:23]=3)[C:19]3[C:27](=[O:37])[N:28](C(OC(C)(C)C)=O)[CH2:29][C:18]=3[C:17]=2[F:38])[CH2:13][CH2:12][O:11][CH2:10]1)=O)(C)(C)C.Cl.O1CCOCC1.CCO>CO>[NH2:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:22]3[S:26][N:25]=[CH:24][CH:23]=3)[C:19]3[C:27](=[O:37])[NH:28][CH2:29][C:18]=3[C:17]=2[F:38])[CH2:13][CH2:12][O:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(-c2ccns2)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Solvent: CO
Product: N[C@H]1COCC[C@H]1Nc1nc(-c2ccns2)c2c(c1F)CNC2=O
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 63.2 %

Procedure:
To a stirred solution of tert-butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-7-fluoro-4-(isothiazol-5-yl)-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (65.8 mg, 0.120 mmol) in MeOH (1.0 mL) was added 4N HCl/dioxane (1.0 mL, 4.00 mmol). The reaction mixture was heated to 60° C. for 1 hour and was subsequently concentrated in vacuo. The residue was triturated with EtOAc and filtered. The filter cake was washed with EtOAc to give a yellow solid, which was suspended into EtOH. The mixture was stirred at 80° C. for 30 minutes and allowed to cool to room temperature. The resulting precipitate was collected by filtration and washed with EtOH to give a hydrochloride salt of the title compound as an off-white solid (26.5 mg, 57%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.74-1.85 (m, 1H), 2.08-2.23 (m, 1H), 3.56-3.68 (m, 1H), 3.80 (d, J=11.23 Hz, 2H), 3.96-4.11 (m, 2H), 4.29-4.39 (m, 1H), 4.42-4.55 (m, 2H), 7.49 (d, J=5.37 Hz, 1H), 8.08 (br s, 3H), 8.63 (s, 1H), 8.71 (s, 1H), 8.96 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C15H16FN5O2S, 350. found, 350.
Reaction SMILES: [F:1][CH2:2][CH2:3][NH2:4].[C:5]([C:8]1[C:9]([C:29]([F:32])([F:31])[F:30])=[N:10][N:11]([CH2:13][C:14]([NH:16][C:17]2[S:21][C:20]3[CH2:22][CH2:23][CH2:24][CH2:25][C:19]=3[C:18]=2[C:26]([NH2:28])=[O:27])=[O:15])[CH:12]=1)(=O)[CH3:6].C([BH3-])#N.[Na+]>CO.CC(O)=O>[F:1][CH2:2][CH2:3][NH:4][CH:5]([C:8]1[C:9]([C:29]([F:31])([F:32])[F:30])=[N:10][N:11]([CH2:13][C:14]([NH:16][C:17]2[S:21][C:20]3[CH2:22][CH2:23][CH2:24][CH2:25][C:19]=3[C:18]=2[C:26]([NH2:28])=[O:27])=[O:15])[CH:12]=1)[CH3:6]
Reactant: CC(=O)c1cn(CC(=O)Nc2sc3c(c2C(N)=O)CCCC3)nc1C(F)(F)F
Reactant: NCCF
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(NCCF)c1cn(CC(=O)Nc2sc3c(c2C(N)=O)CCCC3)nc1C(F)(F)F
Temperature: 100 °C
Yield: 5 %

Procedure:
To a solution of 2-fluoroethanamine (107 mg, 1.689 mmol) in MeOH (1.5 mL), AcOH was added until the pH reached 5. 2-(2-(4-acetyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (50 mg, 0.121 mmol) was added before the addition of sodium cyanoborohydride (7.58 mg, 0.121 mmol). The reaction was heated by microwave irradiation to 100° C. for 20 min. The reaction mixture was filtered before purification by preparative reverse phase HPLC. The product fractions were acidified to pH 4 before applying to a strong cation exchange cartridge (500 mg). The cartridge was washed with DCM/MeOH (1:1) before eluting the product with 2M NH3 in MeOH. The solvent was removed in vacuo to give the title compound (2.9 mg, 0.006 mmol, 5%).
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9](O)[CH2:10][N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)[CH:8]=[CH:7][CH:6]=[CH:5]C=1.CN(C)[CH:19]=[O:20]>>[C:9]1([C:9]2([CH2:10][N:11]3[CH:15]=[N:14][CH:13]=[N:12]3)[CH2:3][CH2:8][C:7]32[CH2:6][CH2:5]3)[CH:3]=[CH:8][CH2:7][O:20][CH:19]=1
Reactant: CN(C)C=O
Reactant: OC(Cn1cncn1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Product: C1=CC(C2(Cn3cncn3)CCC23CC3)=COC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 9.9 %

Procedure:
33.2 mg (0,496 mmole) of sodium hydride (as a 60% w/w dispersion in mineral oil) was added, whilst ice-cooling, to a solution of 69.8 mg (0.207 mmole) of 1-[1-methanesulfonyloxymethyl)cyclopropan-1-yl]-1-phenyl-2-(1H-1,2,4-triazol-1-yl)ethanol in dimethylformamide, and the resulting mixture was stirred at room temperature for 2 hours. At the end of this time, the reaction mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The resulting residue was subjected to column chromatography through silica gel, eluted with a 1:1 by volume mixture of hexane and ethyl acetate, to afford 5 mg (yield 9.9%) of the title compound as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][CH2:14][C:13](=O)[C:12]=3[CH:19]=2)=[CH:4][CH:3]=1.[BH4-].[Na+].O>C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][CH:14]=[CH:13][C:12]=3[CH:19]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C(=O)CCCO3)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccc(-c2ccc3c(c2)C=CCCO3)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.3 %

Procedure:
To 7-(4-methylphenyl)-2,3,4,5-tetrahydro-1-benzooxepin-5-one (1 g) dissolved in ethanol (50 ml) was added under ice cooling sodium borohydride (0.3 g). The resulting mixture was stirred at room temperature for 30 minutes, was mixed with water and was concentrated. The residue was extracted with ethyl acetate, and the organic layer was washed with water and was then concentrated. To the residue dissolved in bis(2-methoxyethyl)ether (20 ml) was added hydrochloric acid (5 ml), and the resulting mixture was stirred with heating at 75° C. for one hour. The reaction mixture was poured into water and was extracted with ethyl acetate. The organic layer was washed with water and an aqueous saturated solution of sodium chloride, was then dried with anhydrous magnesium sulfate and was evaporated to remove the solvent. The precipitate was collected by filtration using hexane to obtain 7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine (0.78 g) as colorless crystals.
Reaction SMILES: [CH:1]1([CH:7]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([N:31]([CH3:39])[CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])=[O:30])=[CH:25][CH:24]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)[O:10][C:9]=2[CH3:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)C.CCCCCC>[CH:1]1([CH:7]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]([N:31]([CH3:39])[CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:30])=[CH:27][CH:28]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)[O:10][C:9]=2[CH3:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2cc(-c3ccc(OC)nc3)oc2C)C2CCCCC2)cc1
Solvent: CCCCCC
Solvent: CCO
Product: COc1ccc(-c2cc(C(Nc3ccc(C(=O)N(C)CCC(=O)O)cc3)C3CCCCC3)c(C)o2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.7 %

Procedure:
Ethyl 3-[{[4-({cyclohexyl[5-(6-methoxypyridin-3-yl)-2-methylfuran-3-yl]methyl}amino)phenyl]carbonyl}(methyl)amino]propanoate (1388 mg) which is a synthetic intermediate in Example 133 was dissolved in ethanol-hexane (6:4, volume ratio), and the solution was subjected to HPLC using CHIRALPAK AD (50 mmID×500 mL, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.) and eluted with ethanol-hexane (6:4, volume ratio) as mobile phase at 30° C., a flow rate 60 mL/min. The fractions showing a peak with retention time 29 min were collected, and concentrated. The obtained amorphous compound (681 mg) was dissolved in ethanol (3 mL) and tetrahydrofuran (3 mL), 1N lithium hydroxide (2.5 mL) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (20 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (601 mg, 94%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([P:13]([C:26]2[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[C:28]([O:36][CH3:37])[CH:27]=2)[C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].OO.S([O-])([O-])=[O:41].[Na+].[Na+]>C(Cl)Cl.C(O)C>[CH3:21][O:20][C:18]1[CH:19]=[C:14]([P:13](=[O:41])([C:5]2[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:26]2[CH:27]=[C:28]([O:36][CH3:37])[C:29]([O:34][CH3:35])=[C:30]([O:32][CH3:33])[CH:31]=2)[CH:15]=[C:16]([O:24][CH3:25])[C:17]=1[O:22][CH3:23]
Reactant: O=S([O-])[O-]
Reactant: COc1cc(P(c2cc(OC)c(OC)c(OC)c2)c2cc(OC)c(OC)c(OC)c2)cc(OC)c1OC
Agent: OO
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: COc1cc(P(=O)(c2cc(OC)c(OC)c(OC)c2)c2cc(OC)c(OC)c(OC)c2)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
31.6 g (59.3 mmol) of tris(3,4,5-trimethoxyphenyl)phosphine were dissolved in a mixture of 100 ml of methylene chloride and 150 ml of ethanol in a 500 ml four-necked sulphonation flask having a thermometer, mechanical stirrer, 100 ml dropping funnel and condenser. 6.8 g (60 mmol) of 30% hydrogen peroxide were added dropwise to the resulting solution within 15 min., with the reaction temperature being held at 15-20° C. Shortly after completion of the dropwise addition of hydrogen peroxide the reaction had finished according to TLC. The reaction solution obtained was treated with 5 ml of saturated sodium sulphite solution, following which peroxide could no longer be detected in the reaction mixture. The reaction mixture was treated with 200 ml of methylene chloride and extracted twice with 300 ml of deionized water. The combined phases were re-extracted with 300 ml of methylene chloride, washed with 300 ml of saturated sodium chloride solution, dried over magnesium sulphate, filtered and treated with 200 ml of hexane. The solution obtained was concentrated on a RV at 50° C./600 mbar, with crystallization setting in. After stirring at 0° C. for 2 h. the crystalline material was filtered off under suction, washed twice with 50 ml of hexane and dried for 2 h. at 100° C. in a HV. 13.0 g of tris(3,4,5-trimethoxyphenyl)phosphine oxide were isolated at a first crystallizate. A further 12.7 g of tris(3,4,5-trimethoxyphenyl)phosphine oxide were obtained from the mother liquor as a second crystallizate. Both crystallizates were identical and uniform. The total yield of tris(3,4,5-trimethoxyphenyl)phosphine oxide was 25.7 g (79%).
Reaction SMILES: [F:1][C:2]1[C:7]([Cl:8])=[C:6]([F:9])[C:5]([Br:10])=[CH:4][C:3]=1[N+:11]([O-])=O>O1CCCC1.[Re]>[F:1][C:2]1[C:7]([Cl:8])=[C:6]([F:9])[C:5]([Br:10])=[CH:4][C:3]=1[NH2:11]
Reactant: O=[N+]([O-])c1cc(Br)c(F)c(Cl)c1F
Agent: [Re]
Solvent: C1CCOC1
Product: Nc1cc(Br)c(F)c(Cl)c1F

Procedure:
7.6 g of 2,4-difluoro-3-chloro-5-bromonitrobenzene are dissolved in 80 ml of tetrahydrofuran and hydrogenated at from +20° to 25° C. over a period of 4 hours in the presence of 1.7 g of 5% rhenium-on-carbon (hydrogen absorbed: 1.88 l). The reaction mixture is filtered, the solvent is removed by distillation, and the residue is suspended in hexane and filtered off with suction. The title compound of formula ##STR12## is obtained in the form of colourless crystals; m.p. 86°-88° C.
Reaction SMILES: N1[C:10]2[C:5](=[CH:6]C=CC=2)[CH2:4][CH2:3][CH2:2]1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CC(C)=O>[CH3:6][C:5]1([CH3:10])[CH2:4][CH:3]([CH3:2])[CH:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH2:16]2)[NH:11]1
Reactant: Nc1ccccc1
Reactant: c1ccc2c(c1)CCCN2
Solvent: CC(C)=O
Product: CC1CC(C)(C)NC2=CC=CCC21

Procedure:
The tetrahydroquinoline skeleton can be dehydration-condensed with aniline and acetone and then the obtained product is reduced to obtain corresponding 2,2,4-trimethyltetrahydroquinoline according to a method described in Organic Synthesis Collective Volume, Vol. III, p. 328.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18]Br>CN(C)C=O>[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][N:5]1[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]1
Reactant: OC1CCNCC1
Reactant: Clc1ccccc1CBr
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: OC1CCN(Cc2ccccc2Cl)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
0.202 g (0.002 mol) of 4-hydroxypiperidine, 1.22 ml (0.0088 mol) of triethylamine and 0.43 g (0.0021 mol) of 2-chlorobenzyl bromide were dissolved in 5 ml of dimethylform-amide and stirred at room temperature for 2 hrs. The solvent was distilled off and the residue was taken up in dichloromethane and washed with saturated bicarbonate solution and sodium chloride solution. The organic phase was dried over sodium sulfate and concentrated. 0.28 g (62%) 1-(2-chloro-benzyl)-piperidin-4-ol was obtained as a colorless oil.