Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.S(=O)(=O)(O)O.II.[I:22](O)(=O)=O>O.C(O)(=O)C>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([I:22])=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1
Reactant: [O-][I+2]([O-])O
Reactant: Brc1ccc2c(c1)Cc1ccccc1-2
Agent: II
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: Brc1ccc2c(c1)Cc1cc(I)ccc1-2
Temperature: 85 °C
Yield: 317 %

Procedure:
A mixture of 2-bromofluorene (12.61 g, 50 mmol), acetic acid (125 mL), water (9 mL), concentrated sulfuric-acid (4 mL), iodine (5.1 g, 20.1 mmol) and iodic acid (2.2 g, 12.5 mmol) was heated at 80-90° C. for 2 hours, cooled and filtered. The solids were washed with acetic acid (100 mL) and water (500 mL), to yield the product 14.7 g (79% yield), m.p. 179-185° C. Mass Spec: m/z 418 (M+ diiodo), 370, 372 (M+ iodobromo), 322, 324,326 (M+ dibromo).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:28])[C:10]([N:13]2[C:18](=[O:19])[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:16]([CH2:26]Br)OC2)([CH3:12])[CH3:11])[CH:5]=[CH:6][CH:7]=1.[I-:29].[Na+].C[C:32](C)=[O:33]>CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:28])[C:10]([N:13]2[C:18](=[O:19])[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:16]([CH2:26][I:29])[CH2:32][O:33]2)([CH3:11])[CH3:12])[CH:5]=[CH:6][CH:7]=1
Reactant: [I-]
Reactant: CC(C)(C(=O)Nc1cccc(Cl)c1)N1COC(CBr)=C(c2ccccc2)C1=O
Reactant: CC(C)=O
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)(C(=O)Nc1cccc(Cl)c1)N1OCC(CI)=C(c2ccccc2)C1=O

Procedure:
A mixture of N-(3-chlorophenyl)-2-(6-bromomethyl-2,3-dihydro-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanamide (compound 8, 0.2 g) and sodium iodide (0.065 g) in acetone was heated under reflux for 18 hours, then evaporated to give a residue which was redissolved in ether. The ethereal solution was washed in turn with saturated aqueous sodium thiosulphate solution and water, dried (magnesium sulphate) and evaporated under reduced pressure to leave a residue which was purified by dry column chromatography on silica, eluting with ethyl acetate/dichloromethane to give N-(3-chlorophenyl)-2-(2,3-dihydro-6-iodomethyl-4-oxo-5-phenyl-4H-2,3-oxazin-3-yl)-2-methylpropanamide (compound 9, 0.04 g) as a white solid, m.p. 134.6-136.6° C.
Reaction SMILES: CS(O[CH2:6][CH:7]1[O:19][C:18]2[C:9](=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:20])[CH2:12][CH2:11]3)[CH2:8]1)(=O)=O.[N-:21]=[N+:22]=[N-:23].[Na+].O>CN(C)C=O>[N:21]([CH2:6][CH:7]1[O:19][C:18]2[C:9](=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:20])[CH2:12][CH2:11]3)[CH2:8]1)=[N+:22]=[N-:23]
Reactant: CS(=O)(=O)OCC1Cc2c(ccc3c2CCC(=O)N3)O1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC1Cc2c(ccc3c2CCC(=O)N3)O1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
The compound obtained in Example 160 (0.691 g, 2.32 mmol) and sodium azide (1.51 g) were suspended in dimethylformamide (14 ml) and stirred at 120° C. for 2 hours. The suspension was cooled and poured into water, followed by extraction with chloroform. The chloroform phase was washed with water and dried over sodium sulfate. When the solvent was distilled off under reduced pressure, 0.553 g of the pale yellow crystals of the title compound was obtained (97.4%, mp.: 157°-158° C.).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[NH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22].[SH:24][CH2:25][C:26](O)=[O:27]>C1C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([CH:8]2[N:18]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:26](=[O:27])[CH2:25][S:24]2)[CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCC(=O)O
Reactant: O=C(O)CS
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Solvent: c1ccccc1
Product: CC(C)(C)c1cc(C2SCC(=O)N2CCC(=O)O)cc(C(C)(C)C)c1O
Yield: 67.4 %

Procedure:
In benzene (500 ml) were suspended 3,5-di-tert-butyl-4-hydroxybenzaldehyde (50.0 g) and β-alanine (20.0 g) under a nitrogen atmosphere. A Dean-Stark trap was fitted to the reactor, and the suspension was refluxed for 1 hour. After allowing the mixture to cool, α-mercaptoacetic acid (23.6 g) was added, then the mixture was further refluxed for 24 hours. After removal of benzene by evaporation, water (500 ml) was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (eluent; chloroform-methanol, 98:2) to afford 54.6 g (67%) of 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-(2-carboxyethyl)-1,3-thiazolidin-4-one as colorless crystals. mp 164-165° C. NMR (CDCl3, 200 MHz) δ: 1.42 (18H, s), 2.2-2.5 (1H, m), 2.5-2.8 (1H, m), 3.0-3.3 (1H, m), 3.5-4.0 (3H, m), 5.33 (1H, s), 5.64 (1H, s), 7.09 (2H, s), 8.5 (1H, brs)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[C:12]2[C:18](=[O:20])[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:28][C:29]([O:31][CH3:32])=[O:30]>CC#N>[C:18]([C:12]1[C:11]2[C:15](=[CH:16][CH:17]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:10]=2)[N:14]([CH2:28][C:29]([O:31][CH3:32])=[O:30])[N:13]=1)(=[O:20])[CH3:19]
Reactant: COC(=O)CBr
Reactant: CC(=O)c1n[nH]c2ccc(OCc3ccccc3)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)Cn1nc(C(C)=O)c2cc(OCc3ccccc3)ccc21
Temperature: 90 °C
Reaction time: 1.5 h

Procedure:
To 1-(5-(benzyloxy)-1H-indazol-3-yl)ethanone (3.50 g, 13.1 mmol) in CH3CN (100 mL) was added K2CO3 (4.54 g, 32.9 mmol) and methyl 2-bromoacetate (1.33 mL, 14.5 mmol). The reaction mixture was stirred at 90° C. for 90 min. Then was filtered and the residue was washed with CH3CN. Volatiles were evaporated and the crude mixture was purified by flash column chromatography on silica gel (c-hexane/EtOAc 1:1 to 1:3). TLC, Rf (c-hexane/EtOAc 1:3)=0.64; MS (LC/MS): 339.0 [M+H]+, 361.0 [M+Na]+; tR (HPLC conditions e): 5.09 min.
Reaction SMILES: [O:1]1[C:5]2([CH2:15][CH2:14][C:8]3([CH2:12][CH2:11][NH:10][C:9]3=[O:13])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Br[C:17]1[CH:22]=[CH:21][C:20]([CH:23]([OH:27])[CH:24]([F:26])[F:25])=[CH:19][CH:18]=1>>[F:25][CH:24]([F:26])[CH:23]([C:20]1[CH:19]=[CH:18][C:17]([N:10]2[CH2:11][CH2:12][C:8]3([CH2:14][CH2:15][C:5]4([O:4][CH2:3][CH2:2][O:1]4)[CH2:6][CH2:7]3)[C:9]2=[O:13])=[CH:22][CH:21]=1)[OH:27]
Reactant: OC(c1ccc(Br)cc1)C(F)F
Reactant: O=C1NCCC12CCC1(CC2)OCCO1
Product: O=C1N(c2ccc(C(O)C(F)F)cc2)CCC12CCC1(CC2)OCCO1

Procedure:
The title compound was prepared in analogy to example 133, step 4 from 1,4-dioxa-10-aza-dispiro[4.2.4.2]tetradecan-9-one (described in example 133, step 3) and 1-(4-bromo-phenyl)-2,2-difluoro-ethanol as yellow solid. MS (m/e): 368.166 [MH+].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:13]3[CH:14]=[C:15]([C:19]([O:21][CH3:22])=[S:20])[S:16][C:17]=3[CH3:18])[S:11][CH:12]=2)=[CH:4][CH:3]=1.CN1[CH2:29][CH2:28]OCC1.[C:30]1(C)[CH:35]=C[C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1.CO>ClCCl>[C:28]1([CH3:29])[C:33]([S:36]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[N:9]=[C:10]([C:13]4[CH:14]=[C:15]([C:19]([O:21][CH3:22])=[S:20])[S:16][C:17]=4[CH3:18])[S:11][CH:12]=3)=[CH:4][CH:3]=2)(=[O:38])=[O:37])=[CH:32][CH:31]=[CH:30][CH:35]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=S)c1cc(-c2nc(-c3ccc(N)cc3)cs2)c(C)s1
Reactant: CN1CCOCC1
Solvent: CO
Solvent: ClCCl
Product: COC(=S)c1cc(-c2nc(-c3ccc(NS(=O)(=O)c4ccccc4C)cc3)cs2)c(C)s1
Temperature: 25 °C
Reaction time: 120 h
Yield: 44.4 %

Procedure:
Methyl 4-(4-{4-{4-(toluenesulfonyl)amino]phenyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate: Methyl 4-(4-(4-aminophenyl)(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate (33 mg, 0.09 mmol) was dissolved in dry dichloromethane (5 mL). To this, N-methyl morpholine (10 μL, 0.09 mmol) and p-toluenesulfonyl chloride (17 mg, 0.09 mmol) was added and the mixture was stirred at room temperature for 5 days. Workup was carried out as in Example 134, step (c). Trituration with dichloromethane and methanol gave methyl 4-(4-{4-[(toluenesulfonyl)amino]phenyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate (20 mg, 43%) as a brown solid. 1H-NMR (DMSO-d6; 300 MHz) δ 10.39 (s, 1H), 8.19 (s, 1H), 8.05 (s, 1H), 7.91 and 7.18 (AB quartet, 2H, J=8.7 Hz), 7.68 and 7.35 (AB quartet, 2H, J=8.2 Hz), 3.85 (s, 3H), 2.74 (s, 3H), 2.27 (s, 3H). Mass spectrum (MALDI-TOF, CHCA matrix, m/z): Calcd. for C23H20N2O4S4, 517.2 (M+H), found 517.0.
Reaction SMILES: CC([O-])(C)C.[K+].C([O:12][N:13]=O)CC(C)C.[CH2:15]1[CH2:25][C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16]1.Cl>C1COCC1>[C:23]1(=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][C:25]1=[N:13][OH:12]
Reactant: CC(C)CCON=O
Reactant: O=C1CCCc2ccccc21
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1C(=NO)CCc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the mixture of t-BuOK (1.2 eq.) in THF at 0° C. was added a solution of isoamylnitrite (1.2 eq.) and α-tetralone (Aldrich) (1.0 eq.) in THF dropwise. The reaction mixture was warmed to RT and stirred at RT for 2 h. The reaction mixture was stripped to dryness, mixed with ice-cooled HCl (1M), extracted with EtOAc, washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified with flash chromatography (silica gel, 2:1 hexane/EtOAc) to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.Cl[CH:11](Cl)[C:12](O)([CH3:14])[CH3:13].[OH-:17].[Na+]>[Br-].C([N+](C)(C)C)CCCCCCCCCCCCCCC.CCOCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:12]([CH3:14])([CH3:13])[CH:11]=[O:17])=[CH:5][CH:4]=1
Reactant: CC(C)(O)C(Cl)Cl
Reactant: COc1ccc(O)cc1
Reactant: [OH-]
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: [Br-]
Agent: [Na+]
Solvent: CCOCC
Product: COc1ccc(OC(C)(C)C=O)cc1
Reaction time: 18 h

Procedure:
A solution of 4-methoxyphenol, (21.72 g, 0.175 mol), in aqueous sodium hydroxide solution, (5.8M, 30 ml), was treated with cetyltrimethyl ammonium bromide, (0.255 g, 0.7 mmol), followed by a solution of 1,1-dichloro-2-hydroxy-2-methylpropane, (5.01 g, 35 mmol), in ether, (70 ml). The mixture was stirred under an argon atmosphere for 18 hours then diluted with ether, (100 ml), and extracted with aqueous sodium hydroxide solution, (2M, 4×50 ml), to remove unreacted phenol. The combined aqueous extracts were extracted with ether, (100 ml), and the organic phase was washed with aqueous sodium hydroxide solution, (2M, 50 ml), and water, (100 ml). The combined organic extracts were dried, (MgSO4), concentrated and purified by flash column chromatography, eluting with ethyl acetate/hexane, (10%, v/v), to give 2-(4-methoxyphenoxy)-2-methylpropanal, (3.61 g), as an oil; NMR: 1.36(6H,s), 3.76(3H,s), 6.7-6.9(4 H,m) and 9.85(1H,s).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].[CH2:11](I)[CH2:12][CH3:13].NC1C=CSC=1C(OC)=O.C(I)CCC>>[CH2:11]([NH:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8])[CH2:12][CH3:13]
Reactant: COC(=O)c1ccsc1N
Reactant: CCCI
Agent: COC(=O)c1sccc1N
Solvent: CCCCI
Product: CCCNc1sccc1C(=O)OC
Yield: 54 %

Procedure:
In the same manner as in Reference Example 1-1), methyl 2-aminothiophene-3-carboxylate [Chem. Bet. 98, 3571 (1965)]and n-propyl iodide were used in place of methyl 3-aminothiophene-2-carboxylate and n-butyl iodide to obtain 10.76 g (54.0%) of Compound (h-1).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12]O)[N:11]=1.P(Br)(Br)[Br:15]>CCOCC.C(OCC)(=O)C>[Br:15][CH2:12][C:10]1[N:11]=[C:7]([CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[S:8][CH:9]=1
Reactant: COCCOCc1nc(CO)cs1
Reactant: BrP(Br)Br
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COCCOCc1nc(CBr)cs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.6 %

Procedure:
A solution of (2-((2-methoxyethoxy)methyl)thiazol-4-yl)methanol (0.35 g, 1.72 mmol) in ether (15 mL) was treated with PBr3 (0.1 mL, 1.06 mmol) at RT. There is formation of a precipitate. The reaction was stirred at RT for 18 hours, then diluted with ethyl acetate and washed with sat. NaHCO3 (1×) and brine (1×), dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (3×10 cm, 20% ethyl acetate/CH2Cl2) to give the title material (0.233 g, 51%) as a clear oil. 1H NMR (CDCl3, 400 MHz) δ ppm: 7.27 (s, 1H), 4.83 (s, 2H), 4.55 (s, 2H), 3.73-3.76 (m, 2H), 3.57-3.60 (m, 2H), 3.39 (s, 3H).
Reaction SMILES: C([C:3]1[C:8]([O:9][C:10]2[C:11]([CH3:21])=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][C:14]=3[F:20])=[CH:7][CH:6]=[CH:5][N:4]=1)#N.[CH3:22][Mg]Cl.Cl.[C:26](=[O:29])(O)[O-].[Na+]>O1CCCC1>[CH3:21][C:11]1[C:10]([O:9][C:8]2[C:3]([C:26](=[O:29])[CH3:22])=[N:4][CH:5]=[CH:6][CH:7]=2)=[CH:19][C:18]2[C:13](=[C:14]([F:20])[CH:15]=[CH:16][CH:17]=2)[N:12]=1
Reactant: Cc1nc2c(F)cccc2cc1Oc1cccnc1C#N
Reactant: C[Mg]Cl
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)c1ncccc1Oc1cc2cccc(F)c2nc1C
Reaction time: 2 h

Procedure:
2.51 g of 3-(2-cyano-pyridin-3-yloxy)-8-fluoro-2-methylquinoline were dissolved in 30 ml of dehydrated tetrahydrofuran. 3.6 ml of a 3 M tetrahydrofuran solution of methylmagnesium chloride were dropped therein while cooling with ice followed by stirring the reaction solution for 2 hours while continuing to cool with ice. Subsequently, the reaction solution was added to 1 N hydrochloric acid solution followed by neutralizing with aqueous sodium bicarbonate and then extracting with ethyl acetate. The extract was washed with saturated saline and dried with magnesium sulfate followed by distilling off the solvent under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 1.7 g of 1-[3-(2-methyl-8-fluoroquinolin-3-yloxy)-pyridin-2-yl]-ethanone.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[OH:10].[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[Si:11]([O:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[Cl:1])[CH:6]=[O:7])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=Cc1ccc(Cl)c(O)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)Oc1cc(C=O)ccc1Cl
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A mixture of 4-chloro-3-hydroxy-benzaldehyde* (0.354 g), 4-N,N-dimethylaminopyridine (0.028 g), tert-butyldimethylsilyl chloride (0.409 g) and triethylamine (0.473ml) in DCM (15 ml) was stirred at room temperature under nitrogen for 19 h. The mixture was quenched with saturated aqueous sodium bicarbonate and extracted with diethyl ether. The combined organic extracts were concentrated under reduced pressure to give an oil which was purified using SPE (silica, eluting with cyclohexane followed by 10% to 30% ethyl acetate:cyclohexane) to give the title compound (0.42 g) as an oil. *Kelley, J; Linn, J; Selway, J. W. T., J. Med. Chem. (1989), 32(8), 1757-63.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH:5](C)[CH2:6][NH:7][CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)[CH3:2].[Cl:15][C:16]1[N:21]=[C:20](Cl)[C:19]([N+:23]([O-:25])=[O:24])=[CH:18][N:17]=1.[C:26](=O)(O)[O-].[K+]>O.C(OCC)C>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH:6]([N:7]([C:18]1[C:19]([N+:23]([O-:25])=[O:24])=[CH:20][N:21]=[C:16]([Cl:15])[N:17]=1)[CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12]1)[CH3:26])[CH3:2]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: O=C([O-])O
Reactant: CCOC(=O)C(C)CNC1CCCC1
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)CC(C)N(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.1 %

Procedure:
A solution of 1.99 g (0.010 mole) of (rac)-3-cyclopentylamino-2-methyl-propanoic acid ethyl ester in 25 mL of water was added dropwise to a solution of 1.94 g (0.010 mole) of 2,4-dichloro-5-nitro-pyrimidine in 25 mL of ethyl ether. At 0 degrees, 2.0 g (0.020 mole) of potassium bicarbonate was added. The mixture was stirred at ambient temperature for 3 hours. The layers were then separated, and the aqueous layer extracted twice with 30 mL of ether. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with hexanes-ethyl acetate (100:0-80:20) gave 3.0 g of (rac)-3-[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclopentyl-amino]-butanoic acid ethyl ester (IV-1)
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:30][NH:31][CH3:32])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:41][C:42]1[S:43][C:44]([Cl:50])=[CH:45][C:46]=1[C:47](Cl)=[O:48]>C(Cl)Cl.CCOC(C)=O>[C:1]([O:5][C:6](=[O:33])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:30][N:31]([C:47]([C:46]1[CH:45]=[C:44]([Cl:50])[S:43][C:42]=1[Cl:41])=[O:48])[CH3:32])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNCc1cc(OCCc2nc(-c3ccccc3)oc2C)ccc1CCC(=O)OC(C)(C)C
Reactant: O=C(Cl)c1cc(Cl)sc1Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCC(=O)OC(C)(C)C)c(CN(C)C(=O)c2cc(Cl)sc2Cl)c1

Procedure:
A solution of 3-{2-methylaminomethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid tert-butyl ester (37 mg, 0.083 mmol) in CH2Cl2 (5 mL) was treated with triethylamine (0.035 mL, 0.25 mmol) then 2,5-dichloro-thiophene-3-carbonyl chloride (0.054 mL, 0.25 mmol) and stirred at ambient temperature overnight. The mixture was diluted with EtOAc (25 mL) and washed with brine (3×10 mL). The organic layer was dried (Na2SO4) and concentrated to the title compound (50 mg, 96%). MS (ES) m/z 629, 631 [M+1].
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH:12]2[CH2:16][N:15]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)[C:14](=[O:25])[N:13]2[CH2:26][CH2:27][CH3:28])=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl.CCOCC.O>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH:12]2[CH2:16][N:15]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=3)[C:14](=[O:25])[N:13]2[CH2:26][CH2:27][CH3:28])=[CH:5][CH:4]=1
Reactant: CCCN1C(=O)N(Cc2ccc(C)cc2)CC1CCCc1ccc(OC)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Solvent: CCOCC
Product: CCCN1C(=O)N(Cc2ccc(C)cc2)CC1CCCc1ccc(O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 58.4 %

Procedure:
A solution of 4-[3-(4-methoxy-phenyl)-propyl]-1-(4-methyl-benzyl)-3-propyl-imidazolidin-2-one (1.22 g, assume 3.21 mmol) was dissolved in dry CH2Cl2 (25 mL), cooled to 0° C. and then treated dropwise with BBr3 (2.41 g, 9.63 mmol). The reaction was stirred at 0° C. for 1 h. The reaction mixture was diluted with Et2O and water, the organic layer was dried (MgSO4), and the solvent removed in vacuo to give crude product that was purified by flash chromatography using 1:1 hexanes:EtOAc to afford 0.687 g (68%) 4-[3-(4-hydroxy-phenyl)-propyl]-1-(4-methyl-benzyl)-3-propyl-imidazolidin-2-one. MS (ES+) Calc'd for C23H31N2O2 (M+1) 367. Found m/z 367 (100%). 1H NMR.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][CH2:8][CH2:9][OH:10].C(N(CC)CC)C.ClCCl>O>[CH3:6][O:7][CH2:8][CH2:9][O:10][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: COCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methanesulfonyl chloride (15 g, 0.13 mol) was added to a mixture of 2-methoxy ethanol (10 g, 0.13 mol), triethylamine (26.5 g, 0.26 mol) and dichloromethane (150 g) at 0° C. After being stirred at room temperature overnight, water (100 g) was added to the reaction mixture. The layers were separated and the organic layer was concentrated in vacuo at room temperature. This gave 13.1 g (65%) of the title mesylate as an oil. 1H NMR analysis supports the stated structure. *Previously reported in Tetrahedron 1995, 51, 4867-4890.
Reaction SMILES: Br[CH2:2][O:3][CH3:4].[OH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([CH:16]=[O:17])[CH:10]=[CH:9]2.[H-].[Na+].O>C(COC)OC.C(OC(=O)C)C>[CH3:4][O:3][CH2:2][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([CH:16]=[O:17])[CH:10]=[CH:9]2
Reactant: COCBr
Reactant: O=Cc1ccc2cc(O)ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: COCOc1ccc2cc(C=O)ccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Bromomethyl-methylether (1.50 mL, 18.3 mmol) was added dropwise to a stirred suspension of 6-hydroxy-2-naphthaldehyde (2.1 g, 12.2 mmol) and sodium hydride (0.73 g, 18.3 mmol) in dimethoxyethane at 0° C. The mixture was stirred for 1 h at room temperature. After the complete addition water was carefully added and it was entracte with ethylacetate (3×), dried over MgSO4 and concentrated in vacuo; yellow solid; yield: 2.64 g (91%);
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[OH:11].NC1C=CC=C(Cl)C=1O>>[NH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[OH:11]
Reactant: Cc1cccc([N+](=O)[O-])c1O
Agent: Nc1cccc(Cl)c1O
Product: Cc1cccc(N)c1O

Procedure:
2-amino-6-methylphenol was prepared from 2-methyl-6-nitrophenol (0.500 g, 3.26 mmol) in a manner similar to that described for 2-amino-6-chlorophenol. The compound was formed as a black solid (0.030 g, 8%). RP-HPLC (25 to 100% CH3CN in 0.1 N aqueous ammonium acetate over 10 min at 1 mL/min using a Hypersil HS C18, 100 Å, 5 μm, 250×4.6 mm column) tr=5.78 min., 86%; m/z 123 (MH+).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH2:8][CH2:7]2)(=O)[CH3:2].[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.[CH2:22](OCC)C>C(OCC)(=O)C>[CH2:9]1[C:10]2[C:6](=[CH:5][C:4]([CH:1]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH2:13][N:20]([CH3:22])[CH2:2]3)=[CH:12][CH:11]=2)[CH2:7][CH2:8]1
Reactant: NCc1ccccc1
Reactant: CC(=O)c1ccc2c(c1)CCC2
Reactant: CCOCC
Agent: Cl
Solvent: CCOC(C)=O
Product: CN1Cc2ccccc2C(c2ccc3c(c2)CCC3)C1

Procedure:
4-Indan-5-yl-2-methyl-1,2,3,4-tetrahydroisoquinoline was prepared from 5-acetylindane and benzylamine as described in Example 58 (Steps A to D). It was dissolved in ethyl acetate and treated with 2 M hydrogen chloride in diethyl ether (2 equiv) to give the corresponding hydrochloride salt (2.15 g, 99.4% AUC HPLC): 1H NMR (300 MHz, CDCl3) δ1H NMR (300 MHz, MeOD) δ 7.22-7.34 (m, 4H), 7.11 (s, 1H), 7.02 (d, J=6.9 Hz, 1H), 6.91 (d, J=6.9 Hz, 3H), 4.54-4.66 (m, 3H), 3.81-3.87 (m, 1H), 3.51 (t, J=12.3 Hz, 1H), 3.10 (s, 3H), 2.87-2.94 (m, 4H), 2.03-2.14 (m, 2H), EI MS m/z=264 [C19H21N+H]+Anal. Calcd. for C19H22ClN: C, 76.11; H, 7.40; N, 4.67. Found: C, 75.87; H, 7.57; N, 4.52.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.[F:13][C:14]([F:24])([CH2:20][CH2:21][CH2:22][CH3:23])[C:15](OCC)=[O:16].OS(O)(=O)=O>O1CCCC1.CCCCC>[CH3:4][O:3][P:2]([CH2:1][C:15](=[O:16])[C:14]([F:24])([F:13])[CH2:20][CH2:21][CH2:22][CH3:23])(=[O:7])[O:5][CH3:6]
Reactant: COP(C)(=O)OC
Reactant: CCCCC(F)(F)C(=O)OCC
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCCCC(F)(F)C(=O)CP(=O)(OC)OC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 44.1 %

Procedure:
A solution of dimethyl methylphosphonoate (6.5 g, 80 mmol, 2.2 equiv) in tetrahydrofuran (100 mL) was cooled to −78° C. and n-butyllithium (2.5 M in hexanes, 14 mL, 36 mmol, 1 equiv) was added dropwise. The solution was stirred at −78° C. for 30 min and ethyl 2,2-difluorohexanoate (6.5 g, 36 mmol, 1 equiv) was added dropwise. The solution was stirred at −78° C. for 1 h and warmed to 0° C. over 1 h. Pentane (100 mL) was added followed by the dropwise addition of 2M H2SO4 to pH=6. The aqueous layer was separated and extracted with pentane (3×15 mL). The organics were combined, dried over sodium sulfate, filtered, and concentrated to dryness under vacuum on a rotary evaporator. The crude oil was purified by column chromatography using methyl tert-butyl ether as eluant to afford 4.1 g of 26 as a yellow oil (44%).