Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=O)[CH2:10][N:9]=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[C:7]=2[CH:20]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22]>N1C=CC=CC=1>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[S:22])[CH2:10][N:9]=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[C:7]=2[CH:20]=1
Reactant: CSc1ccc2c(c1)C(c1ccccn1)=NCC(=O)N2
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: CSc1ccc2c(c1)C(c1ccccn1)=NCC(=S)N2

Procedure:
A stirred solution of 7-methylthio-1,3-dihydro-5-(2-pyridyl)-2H-1,4-benzodiazepin-2-one (0.0206 mole) in dry pyridine (400 ml.) was treated with phosphorus pentasulfide (5.05 g.), warmed, under nitrogen, at 110°-120° C. for 1 hour, cooled and concentrated in vacuo. Residual pyridine was removed by the successive addition of xylene and toluene to the residue with concentration after each addition. The resulting residue was mixed with dilute sodium carbonate and extracted with chloroform. The chloroform extract was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was crystallized to give 7-methylthio-1,3-dihydro-5-(2-pyridyl)-2H-1,4-benzodiazepine-2-thione.
Reaction SMILES: OC[CH2:3][CH2:4][CH2:5][C:6]1[S:10][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:7]=1.[I-:15]>>[I:15][CH2:3][CH2:4][CH2:5][C:6]1[S:10][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:7]=1
Reactant: COC(=O)c1ccc(CCCCO)s1
Reactant: [I-]
Product: COC(=O)c1ccc(CCCI)s1

Procedure:
Methyl 5-(4-hydroxybutyl)thiophene-2-carboxylate 112 (1.07 g, 4.99 mmol) was converted to 1.61 g (99%) iodide 113 according to the procedures described in Example 5.
Reaction SMILES: O.NN.[C:4]([O:8][C:9](=[O:38])[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][N:27]3C(=O)C4C(=CC=CC=4)C3=O)=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:13][CH2:12]1)([CH3:7])([CH3:6])[CH3:5]>C(O)C>[C:4]([O:8][C:9](=[O:38])[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([S:17]([C:20]2[CH:21]=[CH:22][C:23]([CH2:26][NH2:27])=[CH:24][CH:25]=2)(=[O:19])=[O:18])[CH2:13][CH2:12]1)([CH3:7])([CH3:5])[CH3:6]
Reactant: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccc(CN3C(=O)c4ccccc4C3=O)cc2)CC1
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccc(CN)cc2)CC1
Temperature: 70 °C
Reaction time: 4 h
Yield: 98.1 %

Procedure:
Hydrazine monohydrate (0.11 ml, 2.4 mmol) was added to a stirred solution of {1-[4-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-benzenesulfonyl]-piperidin-4-yl}-carbamic acid tert-butyl ester (0.4 g, 0.8 mmol) in ethanol (10 ml), the mixture was heated to 70° C. and stirred at this temperature for 4 hours. After this time, the precipitate was removed by filtration and the filtrate was concentrated. The resulting residue was triturated with DCM and the resulting precipitate was collected by filtration and dried under vacuum to give the title compound (0.29 g, 98% yield) as a white solid. Tr=1.38 min, m/z (ES+) (M+Na)+ 392.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][C:7]=1[C:8]#[N:9].Cl[C:20]1[CH:30]=[C:24]2[N:25]([CH3:29])[CH2:26][CH2:27][CH2:28][N:23]2[C:22](=[O:31])[N:21]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:13]=[CH:12][C:11]([CH2:14][O:15][C:20]2[CH:30]=[C:24]3[N:25]([CH3:29])[CH2:26][CH2:27][CH2:28][N:23]3[C:22](=[O:31])[N:21]=2)=[CH:10][C:7]=1[C:8]#[N:9]
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: N#Cc1cc(CO)ccc1Oc1cccc(F)c1
Product: CN1CCCn2c1cc(OCc1ccc(Oc3cccc(F)c3)c(C#N)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from 2-(3-fluorophenoxy)-5-(hydroxymethyl)benzonitrile and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: N[CH2:2][O:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([CH3:18])=[C:15]([OH:17])[CH:16]=2)[N:5]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:26][CH:27]=[C:28]([CH3:30])[CH3:29]>CC(C)=O>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([CH3:18])=[C:15]([O:17][CH2:26][CH:27]=[C:28]([CH3:30])[CH3:29])[CH:16]=2)[N:5]=1
Reactant: Cc1ccc(Nc2nccc(OCN)n2)cc1O
Reactant: CC(C)=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COc1ccnc(Nc2ccc(C)c(OCC=C(C)C)c2)n1
Yield: 62 %

Procedure:
Following the general procedure for O-alkylation of 2-R-5-(heteroaryl-2-ylamino)phenol, 5-(4-aminomethoxypyrimidin-2-ylamino)-2-methylphenol (15 mg, 0.07 mmol) and Cs2CO3 (21 mg, 0.07 mmol) in acetone (1 mL) was treated with 4-bromo-2-methyl-2-butene (7.5 μL, 0.22 mmol) at room temperature. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAC 8/2) in 62% yield (12 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[Cl:30][CH2:31][CH2:32][O:33][C:34]1[CH:35]=[C:36]([CH:38]=[CH:39][CH:40]=1)[NH2:37]>C(O)(C)C.Cl>[Cl:30][CH2:31][CH2:32][O:33][C:34]1[CH:35]=[C:36]([NH:37][C:2]2[N:7]=[C:6]([C:8]3[C:9]([C:17]4[CH:18]=[C:19]([NH:23][C:24](=[O:29])[C:25]([F:26])([F:27])[F:28])[CH:20]=[CH:21][CH:22]=4)=[N:10][N:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=34)[CH:5]=[CH:4][N:3]=2)[CH:38]=[CH:39][CH:40]=1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)C(F)(F)F
Reactant: Nc1cccc(OCCCl)c1
Agent: Cl
Solvent: CC(C)O
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(OCCCl)c3)n2)c1)C(F)(F)F
Temperature: 85 °C
Yield: 78.9 %

Procedure:
N-{3-[3-(2-Chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,2,2-trifluoroacetamide (1.0 g, 2.75 mmol) was stirred in 20 ml of isopropanol, 3-[(2-chloroethyl)oxy]aniline (0.494 g, 2.89 mmol) was added along with 3 drops of conc. HCl and heated to 85° C. for 18 h. The mixture was filtered hot and washed with isopropanol. The product obtained was the HCl salt as a yellow solid (1.2 g, 74% yield). ES-LCMS m/z 553 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[O:17]([CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)S(C(F)(F)F)(=O)=O>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]=[C:10]([N:11]1[CH:15]=[N:14][CH:13]=[N:12]1)[O:17][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: O=C(Cn1cncn1)c1ccc(Cl)cc1Cl
Reactant: O=S(=O)(OC1CCCCC1)C(F)(F)F
Product: Clc1ccc(C=C(OC2CCCCC2)n2cncn2)c(Cl)c1

Procedure:
Analogously to Example 1a,b, after reacting 1-(2,4-dichlorophenyl)-2-[1,2,4]triazol-1-yl-ethanone with cyclohexyl triflate there was obtained 1-[2-(2,4-dichloro-phenyl)-1-cyclohexyloxy-vinyl]-1H-[1,2,4]triazole as a white solid with m.p. 84° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O)=[O:14].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CO>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH:13]=[O:14])=[CH:3][CH:4]=1
Reactant: COC(=O)Cc1ccc(Br)cc1
Reactant: O=Cc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)Cc1ccc(-c2ccccc2C=O)cc1

Procedure:
Methyl (4-bromophenyl)acetate (5.9 g), (2-formylphenyl)boronic acid (5.0 g) and potassium carbonate (10.8 g) were combined in a mixture of toluene and methanol [9:1] (50 mL). The resulting mixture was degassed by bubbling nitrogen though for 1 hour. Tetrakis(triphenylphosphine)palladium(0) (1.5 g) was added and the reaction heated to reflux for 12 hours, under nitrogen. The reaction mixture was filtered through a pad of Celite, the filter pad was washed with ethyl acetate and the combined filtrates evaporated. Purification on silica, eluting with a gradient 0 to 10% ethyl acetate in iso-hexane.
Reaction SMILES: [I:1][C:2]1[N:3]=[CH:4][N:5](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:6]=1.Br[CH2:27][C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][C:29]=1[F:36]>C(#N)C>[F:36][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][C:28]=1[CH2:27][N:3]1[C:2]([I:1])=[CH:6][N:5]=[CH:4]1)[C:32]#[N:33]
Reactant: N#Cc1ccc(CBr)c(F)c1
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: CC#N
Product: N#Cc1ccc(Cn2cncc2I)c(F)c1
Temperature: 25 °C
Reaction time: 168 h

Procedure:
A mixture of 4-iodo-1-trityl-1H-imidazole (17.1 g, 39.2 mmol) and 4-bromomethyl-3-fluorobenzonitrile (9.65 g, 45.08 mmol) in 150 mL of dry acetonitrile is stirred at room temperature for 7 days. After concentration, the residue is mixed with methanol, and heated to reflux for 1.5 h. The solvent is subsequently removed and the residue is treated with 1M HCl (300 mL). The resulting suspension is filtered and the washed with HCl (1 M). The combined solution is adjusted to PH 9-10 by saturated NaHCO3 solution. The resulting precipitation is collected by filtration, dried in vacuum oven. MS (ESI) m/z (M+H) 328.1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH:8]2[O:12]C(=O)[N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:9]2[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH:5]=[CH:4][CH:3]=1.CO.[OH-].[Na+].O>CO>[Cl:1][C:2]1[N:7]=[C:6]([CH:8]([OH:12])[CH:9]([NH:10][C:14](=[O:15])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:24][CH:23]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)OC(c2cccc(Cl)n2)C1Cc1ccc(C(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1cccc(Cl)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.4 %

Procedure:
To 1,1-dimethylethyl(4RS,5RS)-5-(6-chloro-2-pyridyl)-2-oxo-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidine-3-carboxylate (677 mg, 1.46 mmol) in methanol (3.5 ml) was added 0.5N sodium hydroxide methanol solution (3.5 ml, 1.75 mmol) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. To the reaction solution was added water (50 ml), and the mixture was extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from diisopropyl ether-hexane to give the title compound (550 mg, 57%).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:4]3[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6](=S)[C:5]=3[CH:19]=[CH:20][CH:21]=2.[N:22]1([CH2:27][CH2:28][CH2:29][NH2:30])[CH:26]=[CH:25][N:24]=[CH:23]1.C(O)C>CN(C)C=O>[Cl:1][C:2]1[C:3]2[C:4]3[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6](=[N:30][CH2:29][CH2:28][CH2:27][N:22]1[CH:26]=[CH:25][N:24]=[CH:23]1)[C:5]=3[CH:19]=[CH:20][CH:21]=2
Reactant: S=C1c2cccc3c(Cl)ccc(c23)N1Cc1ccccc1
Reactant: NCCCn1ccnc1
Solvent: CCO
Solvent: CN(C)C=O
Product: Clc1ccc2c3c(cccc13)C(=NCCCn1ccnc1)N2Cc1ccccc1
Yield: 64.8 %

Procedure:
A mixture of 3.1 g of 6-chloro-1-(phenylmethyl)benz[cd]indole-2(1H)-thione (Cr), 1.4 g of 1H-imidazole-1-propanamine, 250 ml of ethanol, 75 ml of dimethylformamide, and 3.5 g of mercuric acetate is reacted as described in Example 3, giving 2.6 g of the desired product, mp 147°-149° C.
Reaction SMILES: [C:1]([C:4]1[C:12]2[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][C:7]=2[S:6][C:5]=1[NH:20][C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)=[O:22])(=[O:3])[NH2:2].[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34]>C(Cl)Cl>[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([NH:23][C:21](=[O:22])[NH:20][C:5]2[S:6][C:7]3[CH2:8][NH:9][CH2:10][CH2:11][C:12]=3[C:4]=2[C:1]([NH2:2])=[O:3])=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc(NC(=O)Nc3ccc(Cl)cc3)c2C(N)=O)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1c(NC(=O)Nc2ccc(Cl)cc2)sc2c1CCNC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
To a solution of compound A3 (16.0 g, 35.5 mmol) in methylene chloride (100 mL) was added trifluoroacetic acid (30.0 mL, 392 mmol) dropwise over 5 min at 0° C. After the addition complete, the reaction mixture was warmed to room temperature and stirred for 4 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was triturated with ethyl acetate (75 mL) to afford compound A4 as an off-white solid (16.5 g, quantitative yield): 1H NMR (500 MHz, DMSO-d6) δ 10.97 (s, 1H), 10.24 (s, 1H), 9.17 (bs, 2H), 7.60-7.12 (m, 6H), 4.25 (s, 2H), 3.37-3.34 (m, 2H), 3.01-2.98 (m, 2H). MS (M+H) 351.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[NH:19][N:18]=[N:17][N:16]=2)=[CH:5][CH:4]=1.[CH2:20]([CH2:24][C:25](=O)[CH3:26])[C:21]([CH3:23])=O.CC(O)=O>C(O)C>[CH3:26][C:25]1[N:1]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:15]3[NH:19][N:18]=[N:17][N:16]=3)=[CH:5][CH:4]=2)[C:21]([CH3:23])=[CH:20][CH:24]=1
Reactant: CC(=O)CCC(C)=O
Reactant: NCc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1ccc(C)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 54 %

Procedure:
2.8 g of (4a) (9.7 mmol), 1.1 g of acetonylacetone (9.7 mmol) and 0.5 mL of glacial AcOH in 50 mL of absolute ethanol are mixed under a nitrogen atmosphere. The mixture is heated to reflux for 6 h, the solvent is evaporated, the residue is redissolved with chloroform and water, the organic phase is washed with water, dried with Na2SO4 and evaporated. Product: 1.7 g. Formula: C20H19N5 (m.w. 329.41). Yield 54%.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:15]=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:17]=1[OH:18])[C:8]([C:10]1[CH:14]=[CH:13][NH:12][CH:11]=1)=[O:9])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:25]I>CN(C)C=O>[CH3:25][N:12]1[CH:13]=[CH:14][C:10]([C:8](=[O:9])[C:7]2[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:17]([OH:18])=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:15]=2)=[CH:11]1
Reactant: CC(C)(C)c1cc(C(=O)c2cc[nH]c2)cc(C(C)(C)C)c1O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccc(C(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.6 %

Procedure:
2 G (6.6 mmol) of 3-(3,5-di-t-butyl-4-hydroxybenzoyl)pyrrole were added to a stirred suspension of 640 mg (13 mmol) of sodium hydride (50% in mineral oil) in 20 ml of anhydrous dimethylformamide. After 1 hour at room temperature, 0.415 ml (6.68 mmol) of methyl iodide was added, and stirring at room temperature was continued for an additional hour. Nitrogen was then bubbled through the reaction mixture for 10 minutes and thereafter the reaction mixture was partitioned between methylene chloride and water. The organic phase was washed with water, dried and evaporated in vacuo. Purification of the crude product by t.l.c. using hexane:ethyl acetate (80:20) afforded 1.439 g (69%) of the title compound, which was recrystallized from methylene chloride-hexane (mp 135.5°-136.5° C.).
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[N+:11]([C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1)([O-])=O>>[NH2:11][C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=1)[O:20][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1
Reactant: ClCCN1CCOCC1
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: Cl
Product: Nc1cccc(OCCN2CCOCC2)c1

Procedure:
By the method of examples 2 and 3, 4-(2-chloroethyl)morpholine hydrochloride and 3-nitrophenol were converted into the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:10]=1[CH2:11][C@@H:12]([C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[I:41]Cl.S(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([O:8][C:9]1[C:34]([F:35])=[CH:33][C:32]([I:41])=[CH:31][C:10]=1[CH2:11][C@@H:12]([C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccc(F)c1OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: ClI
Agent: O=C([O-])O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cc(I)cc(F)c1OCc1ccccc1)C(=O)OCc1ccccc1
Reaction time: 72 h

Procedure:
12.5 g (26.1 mmol) of benzyl 2-(benzyloxy)-N-(tert-butoxycarbonyl)-3-fluoro-L-phenylalaninate are introduced into 200 ml of dichloromethane, and 8.76 g (104 mmol) of sodium bicarbonate are added. 8.46 g (52.4 mmol) of iodine monochloride in 10 ml of dichloromethane are slowly added dropwise. After 72 h, 300 ml of a 5% sodium bisulfite solution are added. The phases are separated and the organic phase is extracted with water. The organic phase is concentrated and the residue is purified on silica gel (cyclohexane:ethyl acetate 6:1).
Reaction SMILES: [BH4-].[Na+].[CH3:3][N:4]1[C:9](=[O:10])[C:8]2[C:11](SC3SC=CC=3)=[C:12]([CH:14]=[O:15])[S:13][C:7]=2[N:6]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:5]1=[O:26]>CO.O>[OH:15][CH2:14][C:12]1[S:13][C:7]2[N:6]([CH2:22][CH:23]([CH3:24])[CH3:25])[C:5](=[O:26])[N:4]([CH3:3])[C:9](=[O:10])[C:8]=2[C:11]=1[CH2:14][C:12]1[S:13][CH:7]=[CH:8][CH:11]=1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(Sc3cccs3)c(C=O)sc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(Cc3cccs3)c(CO)sc21
Reaction time: 24 h
Yield: 104.4 %

Procedure:
Sodium borohydride (0.06 g) was added to 1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-2,4-dioxo-5-(2-thienylthio)-thieno[2,3-d]pyrimidine-6-carboxaldehyde (0.25 g) in methanol (25 ml) and the mixture was stirred for 24 hours. The reaction was diluted with water (30 ml) and was then extracted with ethyl acetate (3×50 ml). The organic phases were washed with brine and dried over magnesium sulfate, filtered and evaporated to leave a green oil. Purification by chromatography (1:4 ethyl acetate:isohexane) gave the subtitle compound as a yellow foam (0.125 g).
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[O:28])[CH2:12][CH2:13][C:14]1[N:15]=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([OH:27])[CH:20]=2)[O:17][CH:18]=1.Br[CH:30]([CH3:32])[CH3:31]>>[F:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[O:28])[CH2:12][CH2:13][C:14]1[N:15]=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH:30]([CH3:32])[CH3:31])[CH:20]=2)[O:17][CH:18]=1
Reactant: CC(C)Br
Reactant: COc1ccc(-c2nc(CCC(=O)c3ccccc3OCCF)co2)cc1O
Product: COc1ccc(-c2nc(CCC(=O)c3ccccc3OCCF)co2)cc1OC(C)C

Procedure:
Using the compound obtained in Example 271 and 2-bromopropane, white powdery 1-(2-fluoroethoxyphenyl)-3-[2-(3-isopropoxy-4-methoxyphenyl)oxazol-4-yl]propan-1-one was obtained following the procedure of Example 3.
Reaction SMILES: [CH3:1][C@H:2]([CH2:6][CH2:7][CH2:8][C@H:9]([CH3:16])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[C:3]([OH:5])=[O:4].[N+](=[CH2:19])=[N-]>CCOCC>[CH3:19][O:4][C:3](=[O:5])[C@H:2]([CH3:1])[CH2:6][CH2:7][CH2:8][C@H:9]([CH3:16])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14]
Reactant: C=[N+]=[N-]
Reactant: CC(C)CCC[C@@H](C)CCC[C@@H](C)C(=O)O
Solvent: CCOCC
Product: COC(=O)[C@H](C)CCC[C@H](C)CCCC(C)C

Procedure:
2(R),6(R),10-trimethylundecanoic acid (270 mg., [α]D25 -8.64°) was dissolved in ether and treated with an excess of etheral solution of diazomethane at 23° C. for 2.0 hour. The crude product was subjected to evaporative distillation at 98°-101°/0.15 mm Hg to give 247 mg. of 2(R), 6(R),10-trimethylundecanoic acid methyl ester as a colorless oil, [α]D25 - 11.30° (c 1.1065, CHCl 3).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH:12](NC(C)C)(C)[CH3:13].[Li]CCCC.BrCCBr>O1CCCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([CH2:13][CH2:12]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Cc2ccc(Br)cc2N1
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: BrCCBr
Solvent: C1CCOC1
Product: O=C1Nc2cc(Br)ccc2C12CC2
Temperature: 0 °C
Reaction time: 20 h

Procedure:
A solution of 6-bromoindolin-2-one (2 g, 9.43 mmol) and diisopropylamine (2.00 g, 2.82 ml, 19.8 mmol) in tetrahydrofuran (16 ml) was cooled to −25° C. and a solution of nBuLi (1.6 M in hexane, 23.6 ml, 37.7 mmol) was added dropwise. The reaction mixture was warmed to 0° C. and a solution of 1,2-dibromoethane (5.32 g, 2.44 ml, 28.3 mmol) in tetrahydrofuran (2 ml) was added dropwise. The reaction mixture was warmed to room temperature, stirred for 20 hours and carefully quenched with brine (2 ml) and conc. HCl (2 ml, ice bath). The reaction mixture was diluted with tert-butyl methyl ether and water. The aqueous phase was extracted with tert-butyl methyl ether, the combined organic phases were washed with brine and dried over sodium sulfate. The solvent was evaporated and the residue purified by silica gel chromatography using ethyl acetate/heptane as eluent. The title compound was obtained as red crystals (1.11 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:16][CH2:15][CH2:14][C@:13]([CH2:23][C:24]([CH3:26])=[CH2:25])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:36])C=1>C(Cl)Cl.C(OC)(C)(C)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:16][CH2:15][CH2:14][C@:13]([CH2:23][C:24]3([CH3:26])[CH2:25][O:36]3)([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(C)C[C@]1(c2ccccc2)CCCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: C[C@@H](c1ccc(Br)cc1)N1CCC[C@](CC2(C)CO2)(c2ccccc2)OC1=O
Yield: 90 %

Procedure:
To a solution of (S)-3-((S)-1-(4-bromophenyl)ethyl)-7-(2-methylallyl)-7-phenyl-1,3-oxazepan-2-one (300 mg, 0.7 mmol) in dry CH2Cl2 (20 mL) was added m-CPBA (605 mg, 3.5 mmol) at room temperature. The reaction mixture was stirred until the starting material was completed. The mixture was diluted with (CH3)3COCH3 (30 mL), washed by 30% Na2S2O3, and NaHCO3 (aq.) for three times, dried over Na2SO4, filtered, and concentrated to give (7S)-3-((S)-1-(4-bromophenyl)ethyl)-7-((2-methyloxiran-2-yl)methyl)-7-phenyl-1,3-oxazepan-2-one (280 mg, 90%), which was used directly for the next step without further purification.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[CH:33]=[C:32]([C:37]([C:42]1[N:43]=[CH:44][N:45]([C:47]([C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH:46]=1)([OH:41])[CH:38]([CH3:40])[CH3:39])[CH:31]=[CH:30]2)(C(C)(C)C)(C)C>C1COCC1>[OH:41][C:37]([C:32]1[CH:33]=[C:34]2[C:29](=[CH:30][CH:31]=1)[CH:28]=[C:27]([OH:26])[CH:36]=[CH:35]2)([C:42]1[N:43]=[CH:44][N:45]([C:47]([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH:46]=1)[CH:38]([CH3:39])[CH3:40]
Reactant: CC(C)C(O)(c1ccc2cc(O[Si](C)(C)C(C)(C)C)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)C(O)(c1ccc2cc(O)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
A solution of tetrabutylammonium fluoride in THF (1 M, 100 mL) was added to a solution of 1-(6-tert-butyldimethylsilyloxy-2-naphthyl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol (35.0 g) in THF (100 ml) at 0° C. and the mixture was stirred at room temperature for 1 h. The solvent was evaporated, and water was added to the residue. The precipitate was filtered, washed with diethyl ether and water to give the titled compound (28.3 g) as a colorless powder.