Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.CCN(CC)CC.[S:20](Cl)([CH3:23])(=[O:22])=[O:21]>C(Cl)Cl>[NH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([CH2:3][CH2:2][NH:1][S:20]([CH3:23])(=[O:22])=[O:21])=[CH:5]1
Reactant: CS(=O)(=O)Cl
Reactant: NCCc1c[nH]c2ccccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NCCc1c[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A round bottom flask charged with tryptamine (2.0 g, 12.5 mmol) in DCM (20 mL) was added Et3N (3.5 mL, 25 mmol) under an atmosphere of Ar and cooled to 0° C. The solution was then added mesyl chloride (1.5 mL, 18.7 mmol) and the resulting reaction mixture was stir to RT for 2 h. The reaction was quenched with water (20 mL) and extracted with DCM (3×20 mL). The combined organic extracts were washed with brine (30 mL), dried over Na2SO4 and concentrated in vacuo. The desired product was purified via automated column chromatography method 2 (2.1 g, 70%) and isolated as a brown oil. 1H NMR (400 MHz, MeOD) δ 7.55 (d, J=7.6 Hz, 1H), 7.33 (d, J=8.0 Hz, 1H), 7.08 (m, 2H), 7.01 (td, J=8.0, 0.8 Hz, 1H), 3.35 (t, J=7.2 Hz, 2H), 2.99 (t, J=7.2 Hz, 2H), 2.76 (s, 3H). 13C NMR (100 MHz, MeOD) δ 138.28, 128.77, 123.91, 122.54, 119.85, 119.34, 112.93, 112.43, 45.09, 40.02, 27.60.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[S:9][C:10]=1[C:11]([CH:13]1[CH2:18][CH2:17][S:16][CH2:15][CH2:14]1)=[O:12].ClC1C=CC=C(C(OO)=[O:35])C=1.O>C(Cl)(Cl)Cl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])[S:9][C:10]=1[C:11]([CH:13]1[CH2:14][CH2:15][S:16](=[O:35])[CH2:17][CH2:18]1)=[O:12]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)Nc1nc(-c2ccco2)c(C(=O)C2CCSCC2)s1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)(C)OC(=O)Nc1nc(-c2ccco2)c(C(=O)C2CCS(=O)CC2)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.9 %

Procedure:
Compound 587 (500 mg, 1.27 mmol) was dissolved in chloroform (13 mL), and m-chloroperbenzoic acid (219 mg, 1.27 mmol) was added thereto, followed by stirring at room temperature for 3 hours. The reaction mixture was poured into water, followed by extraction with chloroform. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (ethyl acetate) to afford the entitled Compound 591 (359 mg, 69%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8](F)[C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5].[CH3:12][NH2:13]>C(O)C>[F:1][C:2]1[CH:9]=[C:8]([NH:13][CH3:12])[C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CN
Reactant: N#Cc1cc(F)c(F)cc1F
Solvent: CCO
Product: CNc1cc(F)c(C#N)cc1F
Reaction time: 3 h
Yield: 88.2 %

Procedure:
To a solution of 2,4,5-trifluorobenzonitrile (0.575 g, 3.7 mmol) in ethanol (20 ml) was added methylamine (30% aq, 4.2 ml, 37 mmol) and the mixture stirred for 3 h. The reaction mixture was then partitioned between diethyl ether (100 ml) and water (100 ml), and the aqueous layer re-extracted with diethyl ether (100 ml). The combined ether extract was washed with brine (200 ml), dried (MgSO4) and evaporated to give 2,5-difluoro-4-methylaminobenzonitrile (0.549 g, 89%), mp 160-163° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1F)[C:8]([OH:13])=[C:7]([CH:14]([OH:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:6]([CH3:21])=[CH:5]2.[Cl:22]C1C=CC(CC(=O)C)=CC=1>>[Cl:22][C:11]1[CH:10]=[C:9]2[C:4]([CH:5]=[C:6]([CH3:21])[C:7]([CH:14]([OH:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:8]2[OH:13])=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(O)c1c(C)cc2cc(Cl)c(F)cc2c1O
Reactant: CC(=O)Cc1ccc(Cl)cc1
Product: CCOC(=O)C(O)c1c(C)cc2ccc(Cl)cc2c1O

Procedure:
Prepared in a manner similar to ethyl 2-(6-chloro-7-fluoro-1-hydroxy-3-methylnaphthalen-2-yl)-2-hydroxyacetate of Example 99 except using 1-(4-chlorophenyl)propan-2-one. 1H-NMR: (400 MHz, CDCl3): δ 8.42 (s, broad, 1H), 8.18 (d, J=2.0 Hz, 1H), 7.59 (d, J=8.6 Hz, 1H), 7.38 (dd, J=8.6, 2.0 Hz, 1H), 7.18 (s, 1H), 5.68 (s, 1H), 4.33-4.10 (m, 2H), 2.53 (s, 3H), 1.20 (t, J=7.0 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8]C)=[CH:4][CH:3]=1.[Cl:10][CH2:11][C:12](Cl)=[O:13].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[C:6]([C:12](=[O:13])[CH2:11][Cl:10])[CH:7]=1
Reactant: COc1ccc(Br)cc1
Reactant: O=C(Cl)CCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(CCl)c1cc(Br)ccc1O
Temperature: 25 °C

Procedure:
To a solution of 4-bromoanisole (17.4 ml, 138 mmol) in dichloromethane (150 ml) was added chloroacetyl chloride (32 ml, 400 mmol) followed by aluminium chloride (60 g, 450 mmol) keeping the temperature below 30° C. The yellow solution was heated to reflux for 8 hours, cooled down to ambient temperature, then ice water was added very carefully. The organic layer was separated and the aqueous extracted once with dichloromethane. The combined organics were dried (sodium sulphate) then evaporated to give an oil which was purified by crystallisation from hexane. The title compound was obtained as a yellow solid (18 g, 52%). mp 80-82° C. 1H NMR (250 MHz, CDCl3) δ 4.69 (2H, s), 6.95 (1H, d, J=9 Hz), 7.60 (1H, dd, J=1 and 9 Hz), 7.80 (1H, d, J=2 Hz), 11.59 (1H, s).
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([S:18][CH2:19][CH2:20][CH2:21][NH:22]C(=O)OC(C)(C)C)[N:15]([CH2:30][CH:31]=[C:32]([CH3:34])[CH3:33])[C:14]=2[CH:35]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>O>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[NH2:22][CH2:21][CH2:20][CH2:19][S:18][C:16]1[N:15]([CH2:30][CH:31]=[C:32]([CH3:34])[CH3:33])[C:14]2[CH:35]=[C:10]([NH:9][C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:11]=[CH:12][C:13]=2[N:17]=1
Reactant: CC(C)=CCn1c(SCCCNC(=O)OC(C)(C)C)nc2ccc(NC(=O)c3ccccc3)cc21
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)=CCn1c(SCCCN)nc2ccc(NC(=O)c3ccccc3)cc21

Procedure:
33 mg (0.07 mmol) of tert-butyl {3-[6-benzoylamino-1-(3-methylbut-2-enyl)-1H-benzimidazol-2-ylsulfanyl]propyl}carbamate were dissolved in 102 μl of trifluoroacetic acid and 100 μl of water and stirred at room temperature for 6 hours. The reaction mixture was diluted with water and freeze-dried. 34 mg of the desired product were obtained in quantitative yield.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]([CH2:15][CH:16]([O:22][CH2:23][CH3:24])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:11]=[CH:12][C:13]=1[OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1C=CC(S(O[CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][C:41]([NH:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])=[CH:40][CH:39]=2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].O>CC(=O)CC>[CH2:1]([C:8]1[CH:9]=[C:10]([CH2:15][CH:16]([O:22][CH2:23][CH3:24])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:11]=[CH:12][C:13]=1[O:14][CH2:36][CH2:37][C:38]1[CH:39]=[CH:40][C:41]([NH:44][C:45]([O:47][C:48]([CH3:49])([CH3:51])[CH3:50])=[O:46])=[CH:42][CH:43]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Cc1ccc(O)c(Cc2ccccc2)c1)OCC
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(NC(=O)OC(C)(C)C)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CCOC(=O)C(Cc1ccc(OCCc2ccc(NC(=O)OC(C)(C)C)cc2)c(Cc2ccccc2)c1)OCC
Yield: 11.7 %

Procedure:
Ethyl 3-(3-benzyl-4-hydroxyphenyl)-2-ethoxypropanoate (2 g, 6 mmol), 2-{4-[(tert-butoxycarbonyl}amino]phenyl}ethyl 4-methylbenzenesulfonate (3.6 g, 9 mmol); was solved in 2-butanone (30 ml). PEG-400 (0.8 g) and potassium carbonate (2.6 g, 19 mmol) was added and the mixture was refluxed for 8 h. Water was added, the organic layer separated and evaporated. The residue was purified on silica gel using isooctane/ethylacetate 2:1 which yielded 0.38 g (0.7 mmol) of the title product.
Reaction SMILES: Cl.[C:2]1([NH:8][C:9]([NH:11][CH2:12][CH2:13][NH2:14])=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[O:22]1[CH2:36][CH:23]1[CH2:24][O:25][C:26]1[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=1[C:28]([O:30][CH3:31])=[O:29]>CO>[OH:22][CH:23]([CH2:36][NH:14][CH2:13][CH2:12][NH:11][C:9]([NH:8][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH2:24][O:25][C:26]1[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=1[C:28]([O:30][CH3:31])=[O:29]
Reactant: COC(=O)c1ccccc1OCC1CO1
Reactant: NCCNC(=O)Nc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1ccccc1OCC(O)CNCCNC(=O)Nc1ccccc1
Yield: 7.5 %

Procedure:
4.8 g of N-phenyl-N'-(2-aminoethyl)urea HCl salt (0.024 mole) was placed in 100 ml of methanol, and 2.5 g of triethylamine (0.024 mole) was added. While this reaction mixture was being stirred, a solution of 5 g of methyl 2-(2,3-epoxypropoxy)benzoate (0.024 mole) in 25 ml methanol was added slowly. The solution was then heated to reflux for 4 hours. The methanol was removed under reduced pressure and the resulting gel-like solid was dissolved in 100 ml of methylene chloride. The organic layer was washed twice with 100 ml of water and dried over anhydrous magnesium sulfate. Removal of the methylene chloride left an oil which was dissolved in 50 ml of methanol/ethyl ether (1:1) from which the product crystallized slowly upon refrigeration to afford 0.7 g (7.5%) of product having a melting point of 133°-134° C. The compound was identified by its NMR spectrum and elemental analysis.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:13])=[CH:5][C:6]=1[C:7]1[CH:11]=[CH:10][N:9]([CH3:12])[N:8]=1.C([Li])CCC.Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21]>O1CCCC1>[C:20]([C:10]1[N:9]([CH3:12])[N:8]=[C:7]([C:6]2[CH:5]=[C:4]([CH3:13])[NH:3][C:2]=2[CH3:1])[CH:11]=1)([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)Cl
Reactant: Cc1cc(-c2ccn(C)n2)c(C)[nH]1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(-c2cc(C)[nH]c2C)nn1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.9 %

Procedure:
A solution of 3-(2,5-dimethylpyrrolyl)-1-methyl-pyrazole (5.0 g, 28.6 mmol) in dry tetrahydrofuran (250 mL) was cooled to -78° C. Then, n-butyllithium (19.5 mL, 1.6M, 31.2 mmol) was added dropwise over 15 min followed by stirring for 2 h at -78° to -60° C. Ethyl chloroformate (3.58 mL, 37.5 mmol) was added and the solution was warmed to room temperature and stirred 1 h. The solvent was removed at reduced pressure and the residue was partitioned between ether and water. Phases were separated and the organic layer was washed with brine, filtered through a cone of sodium sulfate, and concentrated to leave an oil. This residue was chromatographed on Silica Woelm®TSC (600 g, 15% ether-hexane) to give after an 850 mL forerun, 0.18 of an impurity in 500 mL and 4.69 g of oil in 700 mL. The oil was kugelrohr distilled, 100° to 110° C., (0.15 mm) to give 4.24 g, 60% of 5-carboethoxy-3-(2,5-dimethylpyrrolyl)-1-methylpyrazole as a clear oil; IR (neat) 1728, 1546, 1494, 1273, 1252 cm-1.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([C:7]1[C:8]([Cl:32])=[C:9]([C:28]([Cl:31])=[CH:29][CH:30]=1)[CH2:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[C:19]([CH3:22])[CH:18]=[C:17]2[N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1)[CH3:6])=[O:4].[C:33](OC(=O)C)(=[O:35])[CH3:34].N1C=CC=CC=1>ClCCl>[C:33]([NH:1][CH2:2][C:3]([N:5]([C:7]1[C:8]([Cl:32])=[C:9]([C:28]([Cl:31])=[CH:29][CH:30]=1)[CH2:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[C:19]([CH3:22])[CH:18]=[C:17]2[N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1)[CH3:6])=[O:4])(=[O:35])[CH3:34]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(-n2ccnc2)c2cccc(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)c2n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)NCC(=O)N(C)c1ccc(Cl)c(COc2cccc3c(-n4ccnc4)cc(C)nc23)c1Cl
Reaction time: 3 h
Yield: 81.1 %

Procedure:
To a stirred solution of 8-[3-(N-glycyl-N-methylamino)-2,6-dichlorobenzyloxy]-4-(imidazol-1-yl)-2-methylquinoline (60 mg) in dichloromethane (0.6 ml) were added acetic anhydride (15.6 mg) and pyridine (15.1 mg) at ambient temperature, and the mixture was stirred for 3 hours at the same temperature. The mixture was concentrated in vacuo, and the residue was purified by preparative thin layer chromatography (chloroform:methanol, 10:1, v/v) to give 8-[3-(N-(acetylglycyl)-N-methylamino]-2,6-dichlorobenzyloxy]-4-(imidazol-1-yl)-2-methylquinoline (53 mg) as colorless amorphous.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.C(Cl)(=O)C(Cl)=O.[Br:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[C:31]([F:36])[CH:30]=1>C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:15])[NH:33][C:32]1[CH:34]=[CH:35][C:29]([Br:28])=[CH:30][C:31]=1[F:36])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)O
Reactant: Nc1ccc(Br)cc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)Nc1ccc(Br)cc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (3.8 g, 18 mmol) was dissolved in 150 mL dry diethyl ether under Ar, and the resulting solution was cooled in an ice water bath, while dry pyridine (8.6 mL, 106 mmol) was added, followed by the dropwise addition of oxalyl chloride (4.6 mL, 53 mmol). A precipitate formed immediately. The reaction was stirred vigorously at 0° C. for one hour, then at ambient temperature for one hour. 100 mL of diethyl ether were then added, and the solids wwere removed by filitration washing with diethyl ether. Concentrated the filtrates to an off-white oil. Redissolved oil in 50 mL dry DCM under Ar, cooled to 0° C., added 6 mL pyridine followed by 4-bromo-2-fluoroaniline (3.4 g, 17.7 mmol). The reaction was allowed to warm to ambient temperature, stirred for 3 hours then concentrated. Redissolved in 250 mL EtOAc, washed with 10% HCl (3×100 mL), brine (100 mL), dried with MgSO4, filtered and concentrated. Purified on a silica gel column eluted with 20% moving to 40% EtOAc in hexanes. Combined and concentrated pure fractions to yield title compound as a white solid. (3.2 g, 47%) APCI (AP−): 385.1, 387.1 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:5]([NH:7][OH:8])=[NH:6].[CH3:16][C:17]1[CH:25]=[N:24][CH:23]=[CH:22][C:18]=1[C:19](O)=O.C1C=CC2N(O)N=NC=2C=1.N=C=N.C(N(C(C)C)CC)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[N:6]=[C:19]([C:18]3[CH:22]=[CH:23][N:24]=[CH:25][C:17]=3[CH3:16])[O:8][N:7]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)Oc1ccc(C(=N)NO)cc1Cl
Reactant: Cc1cnccc1C(=O)O
Agent: N=C=N
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1cnccc1-c1nc(-c2ccc(OC(C)C)c(Cl)c2)no1
Temperature: 160 °C
Yield: 10.4 %

Procedure:
To a microwave vial charged with 3-chloro-N-hydroxy-4-isopropoxy-benzamidine (75 mg, 0.328 mmol), 3-methyl-isonicotinic acid (41 mg, 0.298 mmol), HOBt (46 mg, 0.298 mmol), PS-carbodiimide (720 mg, 0.894 mmol, loading 1.24 mmol/g) was added acetonitrile (3.5 mL) and diisopropylethylamine (156 μL, 0.894 mmol). The reaction vial was capped and heated at about 160° C. for about 30 minutes in a Biotage microwave. The reaction mixture was filtered and the resin was washed with acetonitrile (4 mL). Filtrate was concentrated to dryness. The crude product was purified via reverse phase HPLC (30-90% acetonitrile, 30 minute ramp) to give 10.2 mg (10%) of 4-[3-(3-chloro-4-isopropoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-3-methyl-pyridine.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4].[CH3:31][O:32][CH2:33][CH2:34][O:35][CH2:36]Cl>>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([O:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])=[CH:28][CH:29]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(O)cc1
Reactant: COCCOCCl
Product: COCCOCOc1ccc(Cn2c(C(=O)OC)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1

Procedure:
The present compound was synthesized by a method similar to that in Example 260 and using 6-bromo-2-(4-hydroxybenzyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (200 mg) and methoxyethoxymethylchloride. Colorless crystals (28 mg).
Reaction SMILES: [C:1]([Si:5]([CH3:8])([CH3:7])Cl)([CH3:4])([CH3:3])[CH3:2].[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16].N1C=CN=C1>CN(C=O)C>[C:1]([Si:5]([O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[F:9])([CH3:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccccc1F
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccccc1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
A 500 mL round bottom flask was charged with tert-butyldimethylchlorosilane (73.9 g, 491 mmol) (available from Aldrich), DMF (220 mL), 2-fluorophenol (41.3 mL, 446 mmol) (available from Aldrich), and imidazole (75.9 g, 1115 mmol). The pale yellow solution was stirred for 1.5 hours at 25° C. and diluted with hexanes (1 L). The organic phase was washed with water (1×300 mL), saturated aqueous NaHCO3 (3×300 mL), water (3×300 mL) and brine (1×300 mL). The organic phase was then dried (MgSO4), and concentrated to afford 84.A (101 g, 100% yield) as a colorless liquid. The crude product was used without further purification.
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH2:5][CH2:4][N:3]1[C:7](Cl)=[O:8].[Cl:10][C:11]1[CH:12]=[C:13]([C:19]2[C@H:28]3[C@H:23]([CH2:24][CH:25]=[CH:26][CH2:27]3)[C:22](=[O:29])[N:21]([CH:30]3[CH2:35][CH2:34][N:33](C(N4CCOCC4)=O)[CH2:32][CH2:31]3)[N:20]=2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]>>[Cl:10][C:11]1[CH:12]=[C:13]([C:19]2[C@H:28]3[C@H:23]([CH2:24][CH:25]=[CH:26][CH2:27]3)[C:22](=[O:29])[N:21]([CH:30]3[CH2:35][CH2:34][N:33]([C:7]([N:3]4[CH2:4][CH2:5][NH:6][C:2]4=[O:1])=[O:8])[CH2:32][CH2:31]3)[N:20]=2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: COc1ccc(C2=NN(C3CCN(C(=O)N4CCOCC4)CC3)C(=O)[C@H]3CC=CC[C@@H]23)cc1Cl
Reactant: O=C(Cl)N1CCNC1=O
Product: COc1ccc(C2=NN(C3CCN(C(=O)N4CCNC4=O)CC3)C(=O)[C@H]3CC=CC[C@@H]23)cc1Cl

Procedure:
Prepared from intermediate product A1 and 2-oxo-imidazolidine-1-carbonyl chloride as described for compound 1. M. p. 216–218° C.
Reaction SMILES: [Si](O[CH:9]1[CH2:13][CH2:12][C@@H:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[O:10]1)(C(C)(C)C)(C)C.C[Si]([Br:25])(C)C>C(Cl)Cl>[Br:25][CH:9]1[CH2:13][CH2:12][C@@H:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[O:10]1
Reactant: CC(C)(C)[Si](C)(C)OC1CC[C@@H](c2ccc(F)cc2)O1
Reactant: C[Si](C)(C)Br
Solvent: ClCCl
Product: Fc1ccc([C@@H]2CCC(Br)O2)cc1
Temperature: -70 °C
Reaction time: 1.5 h

Procedure:
(5S)-2-(t-Butyldimethylsilyloxy)-5-(4-fluorophenyl) tetrahydrofuran (212, 1 g, 3.4 mmol) was dissolved in 10 mL of dry methylene chloride (degassed by bubbling argon prior to use). This solution was cooled to −70° C. and, while stirring at the same temperature under dry argon, trimethylsilyl bromide (550 μL, 4.1 mmol) was added dropwise. The stirring was continued for an additional 1.5 hours to yield (5S)-2-bromo-5-(4-fluorophenyl) tetrahydrofuran which was used without isolation (see below). In a separate flask, 3-t-butyldimethylsilyloxy-but-1-yne (840 mg, 4.5 mmol) was dissolved in dry THF (10 mL). The solution was cooled to −60° C. and, while stirring at the same temperature under dry argon, n-butyllithium (1.8 mL of 2.5M solution in hexane, 4.5 mmol) was added dropwise. The stirring was continued for an additional 0.5 hours. The resulting solution was added dropwise, through a cannula to the stirred solution of the 2-bromotetrahydrofuran (made above) at −70° C. The stirring was continued at −78° C. for additional 1.5 hours. The reaction flask was then left in the freezer (−78° C.) over night (though the TLC did not show any change). The reaction mixture was poured into 2M solution of ammonium chloride (100 mL) and extracted with methylene chloride (3×75 mL). The solution was dried over sodium sulfate and the solvent removed in vacuo. The residue was purified via flash column chromatography (eluent, 10% ethyl acetate in hexane) to obtain two components. From the proton NMR analysis, the less polar one was identified as (2S,5S)-trans-2-(3-t-butyldimethylsilyloxy-but-1-ynyl)-5-(4-fluorophenyl) tetrahydrofuran (213, 765 mg, 65%). 1H-NNR (CDCl3) δ 7.29 (2H, m), 7.01 (2H, t, J=8.7 Hz), 5.09 (1H, t, J=7.1 Hz), 4.91-4.97 (2H, m), 4.55-4.62 (1H, m), 2.26-2.50 (2H, m), 2.05-2.17 (1H, m), 1.75-1.88 (1H, m), 1.38 (3H, d, J=6.6 Hz), 0.90 (9H,s), 0.12 (6H, s). The more polar component was assigned to be (2R,5S)-cis-2-(3-t-butyldimethylsilyloxy-but-1-ynyl)-5-(4-fluorophenyl) tetrahydrofuran (214, 190 mg, 16%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:32])[C:16]2[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Br:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41]Br)[CH:36]=1>>[C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:32])[C:16]2[CH:17]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:19]=[C:20]([O:22][CH2:41][C:37]3[CH:38]=[CH:39][CH:40]=[C:35]([Br:34])[CH:36]=3)[CH:21]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(O)cc(Oc3ccc(C#N)cc3)c2)CC1
Reactant: BrCc1cccc(Br)c1
Product: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(OCc3cccc(Br)c3)cc(Oc3ccc(C#N)cc3)c2)CC1
Yield: 85.5 %

Procedure:
Using 0.6 g (1.32 mmol) of {4-[3-(4-cyanophenoxy)-5-hydroxybenzoylamino]cyclohexyl}carbamic acid tert-butyl ester and 1-bromo-3-bromomethyl-benzene (0.33 g, 1.32 mmol) and following the procedure of Example 42(b) afforded 0.7 g of the required product. 1H NMR (DMSO-d6): δ 1.25 (4H, m), 1.4 (9H, s), 1.8 (4H, m), 3.2 (1H, m), 3.7 (1H, m), 5.2 (2H, s), 6.76 (1H, d), 7.0 (1H, s), 7.12 (2H, d), 7.2 (1H, s), 7.44 (3H, m), 7.56 (1H, d), 7.68 (1H, s), 7.84 (2H, d), 8.3 (1H, d).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]2[C:7]([CH2:10][C:11]([OH:13])=[O:12])=[CH:8][O:9][C:5]=2[CH:4]=1.C[O-].[Na+].[H][H]>CO>[CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]2[CH:7]([CH2:10][C:11]([OH:13])=[O:12])[CH2:8][O:9][C:5]=2[CH:4]=1
Reactant: [H][H]
Reactant: COc1ccc2c(CC(=O)O)coc2c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2c(c1)OCC2CC(=O)O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88.4 %

Procedure:
To a mixture of (1,5-cyclooctadiene)rhodium trifluoromethanesulfonate (5.9 mg) and (S,S)-Et-FerroTANE (5.5 mg) was added methanol (2.5 mL) sufficiently substituted by argon gas, and the mixture was stirred at room temperature for 15 min. This was added to a mixture of (6-methoxy-1-benzofuran-3-yl)acetic acid (51.5 mg) and sodium methoxide (7 mg), and the mixture was stirred at room temperature for 5 hr under 0.7 MPa hydrogen atmosphere. The reaction mixture was quantified by HPLC. As a result, the enantiomeric excess was 86.2%, and the yield was 88.4%.