Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH2:17][OH:18])[C:13]([O:15][CH3:16])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:19]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH3:19])[C@@H:12]([CH2:17][OH:18])[C:13]([O:15][CH3:16])=[O:14])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)[C@H](CO)NS(=O)(=O)c1ccc(F)cc1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CO)N(C)S(=O)(=O)c1ccc(F)cc1
Temperature: 50 °C

Procedure:
A solution of 2A (2 g, 7.2 mmol) in DMF (20 mL) was added with an. K2CO3 (1.5 mol eq, 1.49 g) and, after few minutes, iodomethane (1.2 mol eq, 0.8 ml) was added and the mixture heated at 50° C. for 12 h. The solvent was removed under reduced pressure, water was added to the residue (100 mL) and the aqueous phase extracted with EtOAc (3×40 mL). The combined organic phases were dried over Na2SO4 and evaporated under reduced pressure to obtain 3A as a pale yellow oil (2.3 g, quantitative yield). 1HNMR (DMSO, 200 MHz) δ 2.82 (s, 3H), 3.50 (s, 3H), 3.69 (m, 3H), 4.60 (t, 1H, J=6), 5.12 (t, 1H, J=6.1), 7.44 (m, 2H), 7.83 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[N:13]([CH3:16])[C:12](=[O:17])[CH:11]=[N:10]2)=[C:4]([F:18])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].F[C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1>CN(C)C=O>[Cl:1][C:2]1[C:7]([O:8][C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=2)=[CH:6][C:5]([N:9]2[C:14](=[O:15])[N:13]([CH3:16])[C:12](=[O:17])[CH:11]=[N:10]2)=[C:4]([F:18])[CH:3]=1
Reactant: Cn1c(=O)cnn(-c2cc(O)c(Cl)cc2F)c1=O
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(=O)cnn(-c2cc(Oc3ccc([N+](=O)[O-])cc3)c(Cl)cc2F)c1=O

Procedure:
2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione is reacted with potassium carbonate and 4-fluoronitrobenzene in N,N-dimethylformamide to form 2-[4-chloro-2-fluoro-5-(4-nitrophenoxy)phenyl]-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione. 2-[4-chloro-2-fluoro-5-(4-nitrophenoxy)phenyl]-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione is reduced with iron powder in acetic acid and water to produce 2-[5-(4-aminophenoxy)-4-chloro-2-fluorophenyl]-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione. To a mixture of 2-[5-(4-aminophenoxy)-4-chloro-2-fluorophenyl]-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione in hydrochloric acid is added acetone. The mixture is cooled to about 5° C., and in succession a solution of sodium nitrite in water and methyl acrylate is added. The resultant mixture is stirred for 15-30 minutes. Thereafter, copper (I) chloride is added slowly. This mixture is stirred at room temperature for approximately 30 minutes and then is poured into ice water. Extraction with an organic solvent (e.g., ethyl acetate) and subsequent purification yields methyl 2-chloro-3-[4-[2-chloro-4-fluoro-5-(4-methyl-3,5-dioxo-2H,4H-1,2,4-triazin-2-yl)-phenoxy]phenyl]-propionate.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=O)[C:5]=12.Cl.[CH3:13][C:14]([C:17]1[C:22]([F:23])=[CH:21][C:20]([O:24][C@@H:25]2[CH2:28][C@H:27]([NH2:29])[CH2:26]2)=[CH:19][C:18]=1[F:30])([CH3:16])[CH3:15]>>[CH3:16][C:14]([C:17]1[C:18]([F:30])=[CH:19][C:20]([O:24][C@@H:25]2[CH2:26][C@H:27]([NH:29][CH2:10][C:6]3[C:5]4[N:4]([CH:3]=[CH:2][N:1]=4)[CH:9]=[CH:8][CH:7]=3)[CH2:28]2)=[CH:21][C:22]=1[F:23])([CH3:13])[CH3:15]
Reactant: O=Cc1cccn2ccnc12
Reactant: CC(C)(C)c1c(F)cc(O[C@H]2C[C@@H](N)C2)cc1F
Agent: Cl
Product: CC(C)(C)c1c(F)cc(O[C@H]2C[C@@H](NCc3cccn4ccnc34)C2)cc1F

Procedure:
Prepared similarly to Example 1 from imidazo[1,2-a]pyridine-8-carbaldehyde and cis-3-{[4-(1,1-dimethylethyl)-3,5-difluorophenyl]oxy}cyclobutanamine hydrochloride. LCMS (System B): tRET=3.28 min; MH+ 386
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:22]=[N:21][C:14]3[O:15][CH2:16][C:17](=[O:20])[N:18]([CH3:19])[C:13]=3[CH:12]=2)=[O:10])=[C:4]([Cl:23])[CH:3]=1.[H-].[Na+].[CH3:26]I>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:26])[C:9]([C:11]2[CH:22]=[N:21][C:14]3[O:15][CH2:16][C:17](=[O:20])[N:18]([CH3:19])[C:13]=3[CH:12]=2)=[O:10])=[C:4]([Cl:23])[CH:3]=1
Reactant: CI
Reactant: CN1C(=O)COc2ncc(C(=O)Cc3ccc(Br)cc3Cl)cc21
Agent: [H-]
Agent: [Na+]
Product: CC(C(=O)c1cnc2c(c1)N(C)C(=O)CO2)c1ccc(Br)cc1Cl

Procedure:
In analogy to Example 1, step 2, 7-[2-(4-bromo-2-chloro-phenyl)-acetyl]-1-methyl-1H-pyrido[2,3-b][1,4]oxazin-2-one was reacted with sodium hydride and methyl iodide to give the title compound as a light yellow oil. MS (m/e, ISP neg. ion)=407.2 [M−H+].
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH:4]=1.[CH2:21]([O:23][P:24]([O:28]CC)[O:25][CH2:26][CH3:27])[CH3:22]>>[Si:14]([O:13][C:5]1[CH:4]=[C:3]([CH2:2][P:24]([O:25][CH2:26][CH3:27])([O:23][CH2:21][CH3:22])=[O:28])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CCOP(OCC)OCC
Reactant: COC(=O)c1ccc(CBr)cc1O[Si](C)(C)C(C)(C)C
Product: CCOP(=O)(Cc1ccc(C(=O)OC)c(O[Si](C)(C)C(C)(C)C)c1)OCC
Temperature: 130 °C
Reaction time: 24 h
Yield: 66.1 %

Procedure:
A mixture of methyl 4-(bromomethyl)-2-{[tert-butyl(dimethyl)silyl]oxy}benzoate (0.30 g) and triethylphosphite (0.17 g) was mixed at 25° C. and then stirred at 130° C. for 24 hours. The reaction liquid was concentrated under reduced pressure and azeotroped with toluene twice (30 mL×2). The residue was purified by silica gel column chromatography (automatic purification device, hexane:EtOAc=40:60 to 10:90) to obtain methyl 2-{[tert-butyl(dimethyl)silyl]oxy}-4-[(diethoxyphosphoryl)methyl]benzoate (0.23 g) as a colorless liquid
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH:3]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[N:13]1[CH:17]=[C:16]([CH3:18])[CH:15]=[N:14]1)[OH:4].[NH2:21][C:22]1[N:27]=[C:26]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][C@H:35]([NH:39]C(OC(C)(C)C)=O)[C:36]([OH:38])=[O:37])=[CH:30][CH:29]=2)[CH:25]=[C:24](Cl)[N:23]=1.O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:39][C@@H:35]([CH2:34][C:31]1[CH:32]=[CH:33][C:28]([C:26]2[CH:25]=[C:24]([O:4][CH:3]([C:5]3[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=3[N:13]3[CH:17]=[C:16]([CH3:18])[CH:15]=[N:14]3)[C:2]([F:19])([F:1])[F:20])[N:23]=[C:22]([NH2:21])[N:27]=2)=[CH:29][CH:30]=1)[C:36]([OH:38])=[O:37]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cc(Cl)nc(N)n2)cc1)C(=O)O
Reactant: COc1ccc(-n2cc(C)cn2)c(C(O)C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-n2cc(C)cn2)c(C(Oc2cc(-c3ccc(C[C@H](N)C(=O)O)cc3)nc(N)n2)C(F)(F)F)c1
Temperature: 180 °C
Reaction time: 0.5 h

Procedure:
2,2,2-Trifluoro-1-[5-methoxy-2-(4-methyl-pyrazol-1-yl)-phenyl]-ethanol (0.090 g, 0.31 mmol), (S)-3-[4-(2-amino-6-chloro-pyrimidine-4-yl)-phenyl]-2-tert-butoxycarbonylamino-propionic acid (0.122 g, 0.31 mmol), 1,4-dioxane (2 ml), Cs2CO3 (0.503 g, 1.55 mmol) were combined in a microwave vial and heated to 180° C. for 45 min. The mixture was filtered and concentrated. To the residue, 5% methanol in DCM (50 ml) was added. The mixture was filtered. The filtrate was concentrated to give crude product which was taken in 20% TFA in DCM (30 ml) and stirred for 30 minutes at room temperature. LCMS indicated the completion of the reaction with desired product. The reaction mixture was concentrated to give crude product, which was dissolved in MeOH and H2O (1:1), and purified by preparative HPLC using MeOH/H2O/TFA as solvent system to give (S)-2-amino-3-[4-(2-amino-6-{2,2,2-trifluoro-1-[5-methoxy-2-(4-methyl-pyrazol-1-yl)-phenyl]-ethoxy]-pyrimidin-4-yl)-phenyl]-propionic acid.
Reaction SMILES: [NH:1]1[CH:8]=[C:7]([CH2:9][C:10]([OH:12])=O)[C:5](=[O:6])[NH:4][C:2]1=[O:3].CN1CCOCC1.[C:20]([CH:27]([NH2:36])[CH2:28][NH:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].F[B-](F)(F)F.O=C1C2C=CC=CC=2N=NN1OC(N(C)C)=[N+](C)C>C(OCC)(=O)C.CN(C=O)C>[C:20]([CH:27]([NH2:36])[CH2:28][N:29]([C:10](=[O:12])[CH2:9][C:7]1[C:5](=[O:6])[NH:4][C:2](=[O:3])[NH:1][CH:8]=1)[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]
Reactant: O=C(O)Cc1c[nH]c(=O)[nH]c1=O
Reactant: CCOC(=O)CNCC(N)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc2c1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)CN(CC(N)C(=O)OC(C)(C)C)C(=O)Cc1c[nH]c(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Uracil-5-ylacetic acid (34, 1.0 g, 5.9 mmol) was transferred to a round bottomed flask equipped with a septum through which a flow of nitrogen was applied. Dry DMF (10 ml) and N-methylmorpholine (1.9 ml, 17.6 mmol) were transferred to the flask and the mixture was cooled to 0° C. Ethyl N-(2-BOC-aminoethyl)glycinate (1.6 g, 6.5 mmol) and O-(3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl)-N,N,N′,N′-tetramethyl uronium tetrafluoroborate (TDBTU, 2.5 g, 7.0 mmol) were added to the mixture. The reaction mixture was stirred for 3 hours at 0° C. and was then poured into ethyl acetate (300 ml). The resultant suspension was washed with saturated aqueous potassium hydrogen sulfate (2×50 ml), saturated aqueous sodium bicarbonate (2×50 ml) and with brine (1×50 ml). The organic phase was dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue was stirred overnight in dichloromethane (10 ml) and diethyl ether (40 ml). The resultant precipitate was isolated by filtration, washed once with diethyl ether and dried to give 1.13 g (48%) of the title compound as white crystals.
Reaction SMILES: [F:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[C:5]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][C:12]=2[F:19])=[C:4]([C:20]([NH:22][O:23][CH2:24][CH2:25][O:26]C=C)=[O:21])[CH:3]=1.Cl.[OH-].[Na+]>CCO.CCOC(C)=O.O>[F:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[C:5]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][C:12]=2[F:19])=[C:4]([C:20]([NH:22][O:23][CH2:24][CH2:25][OH:26])=[O:21])[CH:3]=1
Reactant: C=COCCONC(=O)c1cc(F)c(=O)n(C)c1Nc1ccc(SC)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: CSc1ccc(Nc2c(C(=O)NOCCO)cc(F)c(=O)n2C)c(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.7 %

Procedure:
To a solution of 5-fluoro-2-(2-fluoro-4-(methylthio)phenylamino)-1-methyl-6-oxo-N-(2-(vinyloxy)ethoxy)-1,6-dihydropyridine-3-carboxamide (0.121 g, 0.294 mmol) in EtOH (3 mL) was added 2 M HCl (0.75 mL). The reaction mixture was stirred at room temperature for 16 hours. The pH of the reaction mixture was adjusted to pH 7 with 1 M NaOH. The reaction mixture was diluted with EtOAc and H2O. The organic layer was separated and washed with saturated NaCl. The combined aqueous layers were back extracted with EtOAc (1×). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. Purification by silica gel flash column chromatography (methylene chloride/MeOH, 15:1) gave 5-fluoro-2-(2-fluoro-4-(methylthio)phenylamino)-N-(2-hydroxyethoxy)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (0.079 g; 70% over two steps) as a white solid. MS ESI (+) m/z 386 (M+1) pattern detected; 1H NMR (400 MHz, DMSO-d6) δ 11.54 (br s, 1H), 9.65 (br s, 1H), 7.65 (d, 1H), 7.23 (dd, 1H), 6.99 (dd, 1H), 6.81 (t, 1H), 4.67 (t, 1H), 3.74 (t, 2H), 3.51 (q, 2H), 3.25 (s, 3H), 2.46 (s, 3H).
Reaction SMILES: [C:1]([C:6]1([CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH2:11][CH2:10][N:9]([C:12](=[O:31])[C@H:13]([NH:23]C(=O)OC(C)(C)C)[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:8][CH2:7]1)(=[O:5])[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>C(Cl)Cl.FC(F)(F)C(O)=O>[NH2:23][C@H:13]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)[C:12]([N:9]1[CH2:10][CH2:11][C:6]([C:1](=[O:5])[CH2:2][CH2:3][CH3:4])([CH:32]2[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]2)[CH2:7][CH2:8]1)=[O:31]
Reactant: CCCC(=O)C1(C2CCCCC2)CCN(C(=O)[C@@H](Cc2ccc(OC)cc2)NC(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCC(=O)C1(C2CCCCC2)CCN(C(=O)[C@H](N)Cc2ccc(OC)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.1 %

Procedure:
0.43 g (0.84 mmol) of tert-butyl [(R)-2-(4-butyryl-4-cyclohexylpiperidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]carbamate is diluted in 8 ml of DCM and 2 ml of trifluoroacetic acid. The solution is stirred for 1 hour 30 minutes at room temperature and then poured into 1N sodium hydroxide solution and extracted with dichloromethane. The organic phase is dried, filtered and then concentrated. 300 mg of 1-{1-[(R)-2-amino-3-(4-methoxyphenyl)propionyl]-4-cyclohexylpiperidin-4-yl}butan-1-one in the form of a colourless oil are obtained in a yield of 86%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]([OH:12])[CH:6]=1)[CH3:2].BrC[C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[C:19]#[N:20]>>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([O:11][C:16]2[CH:23]=[CH:22][CH:21]=[C:18]([C:19]#[N:20])[CH:17]=2)[CH:8]=[C:7]([O:12][C:16]2[CH:23]=[CH:22][CH:21]=[C:18]([C:19]#[N:20])[CH:17]=2)[CH:6]=1)[CH3:2]
Reactant: N#Cc1cccc(CBr)c1
Reactant: CCOC(=O)c1cc(O)cc(O)c1
Product: CCOC(=O)c1cc(Oc2cccc(C#N)c2)cc(Oc2cccc(C#N)c2)c1
Yield: 75.3 %

Procedure:
3,5-Dihydroxy benzoic acid ethyl ester (1.45 g, 7.95 mmol) and 3-bromomethyl-benzonitrile (6.23 g, 31.8 mmol) and other reagents as described in Example 75(a) were used to afford 2.3 g of the required product. 1H NMR (DMSO-d6): 1.15 (3H, t), 4.15 (2H, q), 5.3 (4H, s), 7.0 (1H, s), 7.18 (2H, s), 7.64 (4H, d), 7.86 (4H, d).
Reaction SMILES: [O:1]1[CH:8]2[CH:2]1[CH2:3][CH2:4][N:5]([C:13](=[O:30])[C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])=[CH:16][CH:15]=1)[C:6]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=12.Cl.[CH3:32][NH:33][CH3:34].C(N(CC)CC)C>CO>[CH3:32][N:33]([CH3:34])[C@@H:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]([C:13](=[O:30])[C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])=[CH:18][CH:19]=2)[CH2:4][CH2:3][C@H:2]1[OH:1]
Reactant: O=C(Nc1ccc(C(=O)N2CCC3OC3c3ccccc32)cc1)c1ccccc1Cl
Reactant: CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CN(C)[C@@H]1c2ccccc2N(C(=O)c2ccc(NC(=O)c3ccccc3Cl)cc2)CC[C@H]1O
Yield: 68.6 %

Procedure:
A mixture of 4,5-epoxy-1-[4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.5 g), dimethylamine hydrochloride (2.6 g), triethylamine (4.5 g) and methanol (15 ml) is refluxed for 19 hours. After completion of the reaction, the solvent is distilled off and the resulting residue is dissolved in dichloromethane. The mixture is washed successively with water and saturated saline solution. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=50:1), and recrystallized from ethanol/diethyl ether to give trans-5-dimethylamino-4-hydroxy-1-[4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.38 g) as colorless needles, m.p. 180-182° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[CH:5]=[C:6]([CH3:8])[CH:7]=1.C(N=P1(N(CC)CC)N(C)CCCN1C)(C)(C)C.[CH2:38](Br)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C(#N)C>[CH2:38]([N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]([C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[CH:5]=2)([OH:19])[C:10]1=[O:18])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: Cc1cc(C)cc(C2(O)C(=O)Nc3ccccc32)c1
Reactant: BrCc1ccccc1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CC#N
Product: Cc1cc(C)cc(C2(O)C(=O)N(Cc3ccccc3)c3ccccc32)c1
Yield: 99 %

Procedure:
Using a method similar to Preparation 17 with 3-(3,5-dimethyl-phenyl)-3-hydroxy-1,3-dihydro-indol-2-one (50 mg, 0.20 mmol), 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine (0.065 ml, 0.22 mmol) and benzyl bromide (0.024 mL, 0.20 mmol) in acetonitrile (1 mL) gives 68 mg (100%) of the title compound which was used without further purification.
Reaction SMILES: ClCCl.[OH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:21]C)=[CH:18][CH:19]=3)[CH2:14][CH2:13][C:12]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:7][CH:6]=1.B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(OCC)(=O)C.CCCCCC.CCCCCCC>[OH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([OH:21])=[CH:18][CH:19]=3)[CH2:14][CH2:13][C:12]=2[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:7][CH:6]=1
Reactant: COc1ccc2c(c1)CCC(c1ccccc1)=C2c1ccc(O)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Oc1ccc(C2=C(c3ccccc3)CCc3cc(O)ccc32)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 98.1 %

Procedure:
In a reaction vessel, 2.3 ml of dichloromethane was added to the 4-(4-hydroxyphenyl)-7-methoxy-3-phenyl-1,2-dihydronaphthalene (7, 29.7 mg, 0.090 mM) obtained in the above Step (4), and the reaction system was cooled to 0° C. Next, 0.45 ml of a 1 M heptane solution including five equivalents of boron bromide (BBr3) was added. After 1.5 hr had elapsed, thin layer chromatography (n-hexane:ethyl acetate=3:1) was carried out on part of the reaction product, and after confirming that no spot was detected corresponding to the above 4-(4-hydroxyphenyl)-7-methoxy-3-phenyl-1,2-dihydronaphthalene, an aqueous NaHCO3 solution was added and the reaction was stopped. After extracting the reaction product with dichloromethane and ethyl acetate, the organic layer was washed with water and a saturated saline solution, and the organic layer was dried with anhydrous sodium sulfate. After concentrating the organic layer, thin layer chromatography (n-hexane:ethyl acetate 3:1) was carried out, and 27.9 mg of 4-(4-hydroxyphenyl)-7-hydroxy-3-phenyl-1,2-dihydronaphthalene (8) was obtained. The yield was quantitative.
Reaction SMILES: [C-:1]#[N:2].[Na+].FC(F)(F)C(O)=O.Br[CH2:12][C:13]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16].O>CS(C)=O>[C:1]([CH2:12][C:13]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16])#[N:2]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1CBr
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: COC(=O)c1ccc([N+](=O)[O-])cc1CC#N
Reaction time: 1 h
Yield: 26.6 %

Procedure:
To a suspension of sodium cyanide (6.3 g) in DMSO (200 ml) was added trifluoroacetic acid (6.6 ml) under water-cooling, methyl 2-(bromomethyl)-4-nitrobenzoate (J. Med. Chem., 42, 3510-3519 (1999)) (11.8 g) synthesized separately was added, and the mixture was stirred for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (ethyl acetate/hexane=1/10 to 1/3) to give a crude product of the title compound as a pale-yellow powder (2.52 g, 27%). The obtained crude product was used for the next reaction without further purification.
Reaction SMILES: [S:1]1[CH2:5][CH:4]([C:6]([NH2:8])=O)[NH:3][CH2:2]1.[Cl:9][CH2:10][C:11](Cl)=[O:12]>>[Cl:9][CH2:10][C:11]([N:3]1[C@@H:4]([C:6]#[N:8])[CH2:5][S:1][CH2:2]1)=[O:12]
Reactant: O=C(Cl)CCl
Reactant: NC(=O)C1CSCN1
Product: N#C[C@H]1CSCN1C(=O)CCl
Yield: 59.1 %

Procedure:
In a similar procedure as employed in the Intermediate Example 1, the thiazolidine-4-carboxylic acid amide (102 mg) obtained above was reacted with chloroacetyl chloride (105 mg) and then subjected to dehydration reaction to give the title compound (87 mg, Y.:59%).
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[F:22][C:23]([F:38])([F:37])[CH2:24][CH:25]([CH3:36])[CH:26]([C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=1)[CH2:27][OH:28].[OH2:39]>CN(C=O)C>[F:22][C:23]([F:37])([F:38])[CH2:24][CH:25]([CH3:36])[CH:26]([C:29]1[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=1)[C:27]([OH:39])=[O:28]
Reactant: Cc1ccc(C(CO)C(C)CC(F)(F)F)cc1
Reactant: O
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Product: Cc1ccc(C(C(=O)O)C(C)CC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
26.7 g (71.1 mmol) of pyridinium dichromate were added to 5 g (20.3 mmol) of 5,5,5-trifluoro-3-methyl-2-(4-methylphenyl)pentan-1-ol in 83 ml of DMF, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was subsequently added to 100 ml of water, the organic phase was separated off and the aqueous phase was extracted six more times with diethyl ether. The combined organic phases were extracted five times with 0.5 M aqueous sodium hydroxide solution. The combined aqueous-basic phases were then acidified to about pH 3 with 3 M hydrochloric acid and extracted six times with ethyl acetate. The combined ethyl acetate phases were dried over magnesium sulfate and filtered, and the solvent was removed under reduced pressure. This gave 3.79 g (14.56 mmol, 71% of theory) of the title compound as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[N+:13]([O-])([OH:15])=[O:14]>OS(O)(=O)=O>[Br:1][C:2]1[CH:3]=[C:4]([N+:13]([O-:15])=[O:14])[C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1cc(Br)ccc1O
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(Br)cc([N+](=O)[O-])c1O
Yield: 85.3 %

Procedure:
To a mixture of methyl 5-bromo-2-hydroxybenzoate (150 g, 0.65 mol) in concentrated H2SO4 (320 mL) below 0° C. was added dropwise a mixture of concentrated HNO3 (69.2 g, 0.71 mol) and concentrated H2SO4 (97 mL) with stirring below 5° C. After the addition, the mixture was stirred at this temperature for 3 hr. The reaction mixture was poured into crash ice and the precipitate was collected, washed with cold water, hot ethanol and dried to give methyl 5-bromo-2-hydroxy-3-nitrobenzoate (153 g, yield 85%). 1H-NMR (400 MHz, CDCl3-d) δ 4.04 (s, 3H), 8.25 (d, J=2.4 Hz, 1H), 8.28 (d, J=2.4 Hz, 1H), 11.92 (s, 1H); LC-MS (ESI) m/z 278 [M+1]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9]([C:13]2[CH:18]=[CH:17][C:16]([O:19]CC3C=CC=CC=3)=[CH:15][C:14]=2[O:27]CC2C=CC=CC=2)(O)[CH2:8][CH2:7]1)=[O:5])[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][CH:9]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=2[OH:27])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(O)(c2ccc(OCc3ccccc3)cc2OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)N1CCC(c2ccc(O)cc2O)CC1
Reaction time: 2 h
Yield: 87 %

Procedure:
1 g of 4-(2,4-bis(benzyloxy)phenyl)-4-hydroxypiperidine-1-carboxylic acid ethyl ester is dissolved in a mixture of 50 ml of methanol, and then 0.5 g of palladium-on-charcoal at 10% is added. The reaction mixture is stirred for 2 hours under a hydrogen atmosphere. The reaction mixture is filtered and the residue is then crystallized with dichloromethane. 0.5 g of 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid ethyl ester is obtained. Yield=86%.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[C:16]1[C:17]2[S:28][C:27]([C:29]([O:31][CH3:32])=[O:30])=[CH:26][C:18]=2[N:19]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:20]=1>C(Cl)Cl>[Br:1][C:20]1[N:19]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[C:18]2[CH:26]=[C:27]([C:29]([O:31][CH3:32])=[O:30])[S:28][C:17]=2[C:16]=1[CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH:10]1[F:9]
Reactant: COC(=O)Cn1cc(C2CCCCC2F)c2sc(C(=O)OC)cc21
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: COC(=O)Cn1c(Br)c(C2CCCCC2F)c2sc(C(=O)OC)cc21
Reaction time: 1 h
Yield: 100 %

Procedure:
N-bromo succinimide (1.5 eq.) was added at 0° C. to a 0.1M solution of methyl 6-(2-fluorocyclohexyl)-4-(2-methoxy-2-oxoethyl)-4H-thieno[3,2-b]pyrrole-2-carboxylate in dry DCM, and the mixture was stirred for 1 h. After dilution with EtOAc, the organic layer was washed with aq. Na2S2O3-solution and brine, dried over Na2SO4 and concentrated i. vac. Yield: 100%. 1H-NMR (300 MHz, CDCl3, 300 K, δ) 7.58 (s, 1H), 4.88 (d, 1H, J 17.9), 4.79 (d, 1H, J 17.9), 4.64 (dtd, 1H, J 49.3, 10.6, 4.4), 3.88 (s, 3H), 3.78 (s, 3H), 2.94-2.83 (m, 1H), 2.28-2.24 (m, 1H), 1.99-1.33 (m, 7H); MS (ES+) m/z 432, 434 (M+H)+.