Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[O:29]1[CH2:33][CH2:32][CH:31]([CH2:34][NH2:35])[CH2:30]1>>[CH3:28][N:4]1[C:3]([CH2:2][NH:35][CH2:34][CH:31]2[CH2:32][CH2:33][O:29][CH2:30]2)=[N:11][C:10]2[C:5]1=[N:6][C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])=[N:8][C:9]=2[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: NCC1CCOC1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CNCC3CCOC3)n(C)c2n1

Procedure:
4-(8-(Bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine (50 mg) was reacted with (tetrahydrofuran-3-yl)methanamine via General Procedure E to give 6.9 mg of 297 following reverse phase purification. MS (Q1) 463.2 (M)+
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7]P(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O)([CH3:4])([CH3:3])[CH3:2].[Br:25][C:26]1[CH:27]=[C:28]([CH:32]=O)[S:29][C:30]=1[Br:31]>C1COCC1.CO>[C:1]([O:5][C:6](=[O:24])/[CH:7]=[CH:32]\[C:28]1[S:29][C:30]([Br:31])=[C:26]([Br:25])[CH:27]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)CP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: O=Cc1cc(Br)c(Br)s1
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)/C=C\c1cc(Br)c(Br)s1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
(Diphenoxy-phosphoryl)-acetic acid tert-butyl ester (8.49 g, 24.4 mmol) was dissolved in THF (519 ml) and cooled to −78° C. followed by the addition of triton B (13.3 ml, 40% by wt. in MeOH). After 15 minutes a solution of 4,5-Dibromo-thiophene-2-carbaldehyde (7.0 g, 25.9 mmol) in THF (20 ml) was added and the reaction was stirred for 1 hour. Next, the reaction mixture was quenched with sat. NH4Cl (250 ml), diluted with H2O (500 ml), and extracted with EtOAc (2×300 ml). The organic layers were washed with water (2×200 ml), brine (100 ml), and dried (MgSO4). The crude was passed through a plug of silica gel with EtOAc providing the desired product 9.2 g (96%) as a 4:1 mixture of cis:trans. MS calculated for C10H12BrNS−H 367, observed M-tBu 309, 311, 313.
Reaction SMILES: [CH3:1][NH:2][NH2:3].[Cl:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[C:12](=O)[C:13]([CH3:19])=[C:14](SC)[S:15][CH3:16]>C(#N)C>[Cl:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[C:12]1[C:13]([CH3:19])=[C:14]([S:15][CH3:16])[N:2]([CH3:1])[N:3]=1
Reactant: CSC(SC)=C(C)C(=O)c1ccc(Cl)cc1Cl
Reactant: CNN
Solvent: CC#N
Product: CSc1c(C)c(-c2ccc(Cl)cc2Cl)nn1C
Temperature: 80 °C

Procedure:
0.138 g (0.003 mol) of methyl hydrazine is added to a solution of 0.614 g (0.002 mol) of 1-(2,4-dichlorophenyl)-3,3-bis(methylthio)-2-methyl-2-propen-1-one in 10 ml of acetonitrile and the reaction mixture is heated at 80° C. for 8 hours. The mixture is then concentrated in vacuo and the residue is taken up in ether, washed with water and dried over sodium sulfate. After the ether phase has been concentrated by evaporation, the residue is purified by column chromatography over silica gel with hexane/ethyl acetate 2/1 as eluant. The desired product is obtained in a yield of 0.425 g (74.0%) in the form of a white solid having a melting point of 65-66° C. (recrystallised from hexane).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][C:20]([F:29])=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:28])[C:15]=3[O:14]2)(=O)=O)=CC=1.[N-:30]=[N+:31]=[N-:32].[Na+]>>[N:30]([CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[CH:19][C:20]([F:29])=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])[C:15]=2[O:14]1)=[N+:31]=[N-:32]
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3ccc(F)c(-c4ccccc4C)c3O2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: Cc1ccccc1-c1c(F)ccc2c1OC(CN=[N+]=[N-])C2
Yield: 86 %

Procedure:
Treatment of 1-bromo-2-methylbenzene (10.06 g, 58.84 mmol) with (2-fluoro-6-methyoxyphenyl)boronic acid (5.0 g, 29.42 mol tetrakis(triphenylphosphine)palladium(0) (2.5 g, 2.16 mmol), and sodium carbonate (6.2 g, 58.84 mmol) generally according to the procedure described for Intermediate 37 provided 2.35 g (37%) of 6-fluoro-2′-methylbiphenyl-2-yl methyl ether. A solution of 6-fluoro-2′-methylbiphenyl-2-yl methyl ether (2.35 g, 10.86 mmol) in hydrogen bromide (40 mL, 30 wt. % in acetic acid) was heated to 55° C. for 12 h. The reaction mixture was concentrated under in vacuo and the crude residue diluted with ethyl acetate (200 mL). The organic layer was carefully extracted with saturated bicarbonate solution (3×200 mL) was dried (magnesium sulfate), and the solvent was removed in vacuo to provide a crude oil. Treatment of 6-fluoro-2′-methybiphenyl-2-ol (2.17 g, 10.84 mmol) with sodium hydride (0.65 g, 16.26 mmol, 60 wt. %) and allyl bromide (0.96 g, 16.26 mmol), followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 3-allyl-6-fluoro-2′-methylbiphenyl-2-ol. Treatment of 3-allyl-6-fluoro-2′-methylbiphenyl-2-ol (1.77 g, 7.3 mmol) with 3-chloroperoxybenzoic acid (3.2 g, 10.96 mmol, 77%) followed by potassium carbonate (1.2 g, 8.76 mmol) generally according to the procedure described for Intermediate 9 afforded 1.5 g (80%) of (±)-[6-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanol. Treatment of (±)-[6-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanol (1.5 g, 5.81 mmol) with p-toluenesulfonyl chloride (1.66 g, 8.71 mol) generally according to the procedure described for Intermediate 10 gave 2.17 g (90%) of (±)-[6-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. Treatment of (±)-[6-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.23 g, 0.56 mmol) with sodium azide (0.23 g, 3.54 mmol) generally according to the procedure described for Intermediate 98 afforded 0.135 g, (86%) of (±)-2-(azidomethyl)-6-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran. Treatment of (±)-2-(azidomethyl)-6-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran (0.135 g, 0.4 mmol) in tetrahydrofuran (10 mL) with polymer-supported triphenylphosphine (0.30 g, 0.9 mmol) generally according to the procedure described for Example 154 provided 0.11 g (67%) of (±)-{[6-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine as a white solid, hydrochloride salt. mp 216-218° C.
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[N:8][C:9]([N+:23]([O-])=O)=[C:10]([O:11][C@@H:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=3[Cl:22])[CH3:13])[C:5]=2[O:4][CH:3]=1.Cl>CCO.CCOC(C)=O.[Fe]>[Br:1][C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH2:23])=[C:10]([O:11][C@@H:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=3[Cl:22])[CH3:13])[C:5]=2[O:4][CH:3]=1
Reactant: C[C@@H](Oc1c([N+](=O)[O-])ncc2c(Br)coc12)c1c(Cl)ccc(F)c1Cl
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: C[C@@H](Oc1c(N)ncc2c(Br)coc12)c1c(Cl)ccc(F)c1Cl
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
To a solution of 3-bromo-7-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-6-nitrofuro[3,2-c]pyridine (1.00 g, 2.22 mmol) in EtOH (10 mL) was added iron (0.62 g, 11.1 mmol), followed by 0.1 N aq. HCl (1.1 mL, 0.11 mmol) at 95° C. (bath temp). The resulting mixture was stirred at this temperature for 30 min. Additional 0.1 N aq. HCl (1.1 mL, 0.11 mmol) was added and the mixture was refluxed for another 30 min. TLC and LC-MS showed the reaction was complete. The mixture was diluted with EtOAc (100 mL) and the solid was filtered off through a pad of Celite. The mother liquor was washed with brine (3×25 mL) and dried over anhydrous sodium sulfate. Evaporation of solvents under reduced pressure afforded the title compound as a light-yellow semi-solid (930 mg, 100% yield). 1H NMR (CDCl3, 400 MHz): δ=1.87 (d, J=6.6 Hz, 3H), 5.15 (br s, 2H), 6.55 (q, J=6.6 Hz, 1H), 7.06 (dd, J=9.1, 8.1 Hz, 1H), 7.27 (dd, J=9.1, 5.1 Hz, 1H), 7.44 (s, 1H), 7.96 (s, 1H). MS (ES+): 418.91/420.86/422.89 [MH+].
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH3:15])=O.CSC.B>>[CH3:15][O:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[CH2:7][NH:6][CH2:4][C:3]1[CH:16]=[CH:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:2]=1[NH2:1]
Reactant: COc1ccccc1CNC(=O)c1ccc([N+](=O)[O-])cc1N
Agent: B
Solvent: CSC
Product: COc1ccccc1CNCc1ccc([N+](=O)[O-])cc1N

Procedure:
The title compound was synthesized according to EXAMPLE 63, section 1.6 starting from 2-amino-N-(2-methoxybenzyl)-4-nitrobenzamide and borane-dimethyl sulfide.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[N:6][N:7]([CH3:17])[C:8]=2[C:9]2[CH:10]=[C:11]([C:14]([OH:16])=O)[S:12][CH:13]=2)[CH2:3][CH2:2]1.[NH2:18][C@@H:19]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]([F:42])([F:41])[F:40])[CH2:20][N:21]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]1=[O:31].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[CH:1]1([C:4]2[CH:5]=[N:6][N:7]([CH3:17])[C:8]=2[C:9]2[CH:10]=[C:11]([C:14]([NH:18][C@@H:19]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:39]([F:42])([F:40])[F:41])[CH2:20][N:21]3[C:29](=[O:30])[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:22]3=[O:31])=[O:16])[S:12][CH:13]=2)[CH2:2][CH2:3]1
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Reactant: Cn1ncc(C2CC2)c1-c1csc(C(=O)O)c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cn1ncc(C2CC2)c1-c1csc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.8 %

Procedure:
To a 50 mL round-bottomed flask was added 4-(4-cyclopropyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (105 mg, 0.42 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (152 mg, 0.39 mmol) [prepared according to Preparation 6] and PyBrop (246 mg, 0.52 mmol) in Chloroform (6 mL). DIEA (370 μL, 2.19 mmol) was added and the mixture stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (171 mg, 66%): LC-MS (ES) m/z=579 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4](=[CH:9][CH:10]=[CH:11]OC)[C:5]([O:7][CH3:8])=[O:6].[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[C:16]1([NH:15]/[CH:11]=[CH:10]/[CH:9]=[C:4]([C:3]([O:2][CH3:1])=[O:14])[C:5]([O:7][CH3:8])=[O:6])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1ccccc1
Reactant: COC=CC=C(C(=O)OC)C(=O)OC
Solvent: C1CCOC1
Product: COC(=O)C(=C/C=C/Nc1ccccc1)C(=O)OC
Temperature: 60 °C
Yield: 57.4 %

Procedure:
To a solution of 2-(3-methoxyallylidene)malonic acid dimethyl ester (Acros Organics, 200 mg, 1.0 mmol) in THF (2 mL) at rt was added aniline (300 mg, 3.2 mmol) and the reaction mixture was heated at 60° C. for 8.5 h. Purification of the reaction mixture by preparative HPLC provided the desired product (150 mg, 57%) as a yellow solid. 1H NMR (DMSO-d6) δ 10.16 (d, 1H, J=12.7 Hz), 8.06 (t, 1H, J=12.7 Hz), 7.74 (d, 1H, J=12.7 Hz), 7.30 (t, 2H, J=8.7 Hz), 7.16 (d, 2H, J=7.7 Hz), 6.98 (t, 1H, J=7.7 Hz), 6.35 (t, 1H, J=12.1 Hz), 3.69 (s, 3H), 3.65 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:11]([N:19]=[C:20]=[O:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CC(C)=O>[C:4]([C:3]1[CH:6]=[CH:7][C:8]([OH:10])=[CH:9][C:2]=1[NH:1][C:20]([NH:19][C:11](=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:21])#[N:5]
Reactant: O=C=NC(=O)c1ccccc1
Reactant: N#Cc1ccc(O)cc1N
Solvent: CC(C)=O
Product: N#Cc1ccc(O)cc1NC(=O)NC(=O)c1ccccc1

Procedure:
Prepared as in Example 53a, but refluxed in acetone instead of 1,4-dioxane, from 2-amino-4-hydroxybenzonitrile and benzoyl isocyanate as a yellow solid (399 mg, 94%). MS 281 (MH1).
Reaction SMILES: C([O:5][C:6]([CH:8]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[N:9]1[C:13]2[CH:14]=[C:15]([I:18])[CH:16]=[CH:17][C:12]=2[N:11](C(OC(C)(C)C)=O)[C:10]1=[O:26])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[I:18][C:15]1[CH:16]=[CH:17][C:12]2[NH:11][C:10](=[O:26])[N:9]([CH:8]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:6]([OH:7])=[O:5])[C:13]=2[CH:14]=1
Reactant: CC(C)(C)OC(=O)C(c1ccccc1)n1c(=O)n(C(=O)OC(C)(C)C)c2ccc(I)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)C(c1ccccc1)n1c(=O)[nH]c2ccc(I)cc21
Temperature: 25 °C

Procedure:
1.50 g (2.73 mmol) of tert-butyl 3-(tert-butoxycarbonylphenylmethyl)-5-iodo-2-oxo-2,3-dihydrobenzimidazole-1-carboxylate (XIIb) were dissolved in dichloromethane (16 ml) and, while stirring at room temperature, trifluoroacetic acid (10 ml) was added. The reaction solution was stirred for 2 h and then the solvent and excess trifluoroacetic acid were removed in vacuo. The residue was taken up again in toluene, concentrated in vacuo and then dried in vacuo. Yield: 1.10 g (100%) of yellow solid.
Reaction SMILES: [N:1]1([CH2:6]N2C3C=CC=CC=3N=C2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:16][O:17][C:18](=[O:30])[C:19]1[CH:24]=[C:23]([CH2:25]Br)[CH:22]=[CH:21][C:20]=1[N+:27]([O-:29])=[O:28]>CN(C)C=O.[Zn]>[CH3:16][O:17][C:18](=[O:30])[C:19]1[CH:24]=[C:23]([CH2:25][CH2:6][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:22]=[CH:21][C:20]=1[N+:27]([O-:29])=[O:28]
Reactant: COC(=O)c1cc(CBr)ccc1[N+](=O)[O-]
Reactant: c1ccc2c(c1)ncn2CN1CCCC1
Agent: [Zn]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(CCN2CCCC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixture of zinc powder (1.05 g, 16.05 mmol) and 1-pyrrolidin-1-ylmethyl-1H-benzoimidazole (2.95 g, 14.59 mmol) in N,N-dimethyl formamide (40 mL) under a nitrogen atmosphere was added 5-bromomethyl-2-nitro-benzoic acid methyl ester (4.0 g, 14.59 mmol). The reaction mixture was stirred at room temperature for 24 hours, then quenched at 0° C. with an ice-cold 25% aqueous solution of ammonium hydroxide (108 mL). The stirring was continued until most of the solid had dissolved. Undissolved solid was filtered off and the filtrate was extracted with diethyl ether. The combined organic layers were washed with 1 N aqueous sodium hydroxide, then water, and were dried over anhydrous sodium sulfate and concentrated under high vacuum to give 2-nitro-5-(2-pyrrolidin-1-yl-ethyl)-benzoic acid methyl ester as an orange oil. Yield: 1.3 g (32%). The crude material was used for the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:20][C:21](=[O:23])[CH3:22])C=CC=CC=1>C(Cl)Cl.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=CC(=O)C)C=CC=CC=1>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6](/[CH:7]=[CH:20]/[C:21](=[O:23])[CH3:22])=[CH:5][CH:4]=1
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Product: CC(=O)/C=C/c1ccc(C(F)(F)F)cc1
Reaction time: 5 h
Yield: 91.8 %

Procedure:
4-(Trifluoromethyl)benzaldehyde (25.0 g, 144 mmol) was taken up in 500 mL of DCM. 1-Triphenylphosphoranylidene-2-propanone (48.0 g, 151 mmol) was added. After 5 hours, an additional 3 g of 1-triphenylphosphoranylidene-2-propanone was added. The mixture was stirred for 10 hours. The solvent was removed under reduced pressure, and the residue was triturated with 500 mL of 5% EtOAc/hexanes. The mixture was filtered, removing a large amount of P(O)Ph3. The residue was taken up in 300 mL of 2.5% EtOAc/hexanes and filtered through a pad of silica. The mixture was concentrated under reduced pressure and the residue was found to be (E)-4-(4-(trifluoromethyl)phenyl)but-3-en-2-one (28.3 g, 92.0% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.68-7.60 (m, 4H), 7.52 (d, J=16.43 Hz, 1H), 6.78 (d, J=16.4 Hz, 1H), 2.41 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[CH3:5].C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[CH:21]=[CH2:22]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:13])[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:22][CH:21]=[CH2:20])=[CH:8][CH:7]=1)[CH3:5]
Reactant: COC(=O)C(C)c1ccc(O)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCOc1ccc(C(C)C(=O)OC)cc1
Temperature: 80 °C

Procedure:
A solution of the product of Example 46A (2.6 g, 12 mmol) in anhydrous dimethylformamide (20 mL) was treated with potassium carbonate (3.3 g, 24 mmol) and allyl bromide (1.2 mL, 13 mmol), and reaction heated for 16 hours at 80° C. Reaction mixture cooled and diluted with ethyl acetate. Mixture washed with water and brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. Residue purified by normal phase HPLC on silica gel eluting with 3% ethyl acetate/hexane to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[N:10]=[CH:9]2)=[CH:4][C:3]=1[F:22].N1C=CC=CC=1.Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>ClCCl.C(=O)(O)[O-].[Na+]>[CH2:33]([O:32][C:30]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH2:13][O:14][Si:15]([C:18]([CH3:19])([CH3:21])[CH3:20])([CH3:16])[CH3:17])[N:10]=[CH:9]2)=[CH:4][C:3]=1[F:22])=[O:31])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OCc1cn(-c2ccc(N)c(F)c2)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)OCc1cn(-c2ccc(NC(=O)OCc3ccccc3)c(F)c2)cn1
Temperature: -20 °C

Procedure:
1-Amino-4-(4-t-butyldimethylsilyloxymethylimidazol-1-yl)fluorobenzene (36.1 g) was dissolved in dry dichloromethane (450 ml), treated with pyridine (11.3 ml), then stirred under argon while cooling to −20° C. Benzyl chloroformate (17.7 ml) in dichloromethane (50 ml) was added dropwise, maintaining the temperature. The mixture was then allowed to warm to ambient temperature over 1 hour, then stirred for a further 1.5 hours. The mixture was diluted with aqueous sodium bicarbonate (250 ml), and the organic layer separated. A further extraction with dichloromethane (200 ml) was made, the combined organic layers dried over magnesium sulfate, and solvent evaporated. The resulting oil was re-evaporated with toluene, and purified by chromatography on silica (500 g) in a sinter column, eluting with a gradient from CH2Cl2 to 50% EtOAc in CH2Cl2. Evaporation, then re-evaporation with toluene gave solid product (51 g).
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH2:9][NH:8][CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CNC.CN(C)[P:17](N(C)C)N(C)C>>[N:1]12[P:17]3[N:4]([CH2:5][CH2:6][CH2:7][N:8]3[CH2:9][CH2:10][CH2:11]1)[CH2:3][CH2:2]2
Reactant: CN(C)P(N(C)C)N(C)C
Reactant: C1CNCCCNCCNC1
Agent: CNC
Product: C1CN2CCCN3CCN(C1)P23
Temperature: 125 °C
Yield: 75.2 %

Procedure:
A mixture of 3.62 g of 1,4,8-triazacycloundecane and 3.75 g of hexamethylphosphorous triamide is heated to 125° C. with stirring and held at this temperature for 2 hours, by which time evolution of dimethylamine is complete. Evolution is vigorous for the first 45 minutes. Distillation affords 3.20 g (75%) 1,4,8-triaza-12-phosphatricyclo[6.3.1.04,12 ]dodecane as a water-white liquid which boils at 73°-75° C. at 0.30 mm.
Reaction SMILES: C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)=[O:28])=[CH:23][CH:22]=1.[Br:36]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:36][CH2:35][C:32]1[CH:33]=[CH:34][C:29]([C:27]([C:24]2[CH:23]=[CH:22][C:21]([O:20][CH3:19])=[CH:26][CH:25]=2)=[O:28])=[CH:30][CH:31]=1
Reactant: COc1ccc(C(=O)c2ccc(C)cc2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(C(=O)c2ccc(CBr)cc2)cc1
Yield: 29.2 %

Procedure:
Benzoyl peroxide (1 g) was added to a solution of 4-methoxyphenyl-4-methylphenyl methanone (22.6 g) and N-bromosuccinimide (17.8 g) in CCl4 (100 ml). The mixture was heated under reflux for 3.25 h, then cooled to 0°. The precipitated succinimide was filtered off, the filtrate evaporated and the residue purified by crystallisation from cyclohexane to give the title compound (8.9 g), m.p. 76°-78°.
Reaction SMILES: C(NC(C)C)(C)C.[F:8][CH2:9][C@@H:10]1[CH2:14][N:13]([C@@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])[C:12](=[O:23])[CH2:11]1.S([O-])([O-])(=[O:26])=S.[Na+].[Na+]>O1CCCC1>[F:8][CH2:9][C@H:10]1[CH2:14][N:13]([C@@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])[C:12](=[O:23])[C@@H:11]1[OH:26]
Reactant: C[C@H](c1ccccc1)N1C[C@@H](CF)CC1=O
Reactant: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N1C[C@H](CF)[C@@H](O)C1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 73 %

Procedure:
In an atmosphere of nitrogen and at −78° C., 1.66 N n-butyllithium-hexane solution (7.08 ml) was added dropwise to a tetrahydrofuran (20 ml) solution of diisopropylamine (1.65 ml, 11.75 mmol), and the mixture was stirred at 0° C. for 5 minutes. The reaction solution was cooled to −78° C. and added dropwise to a tetrahydrofuran (20 ml) solution of 4-(S)-fluoromethyl-N-[1-(R)-phenylethyl]-2-pyrrolidone (2.00 g, 9.04 mmol) at −78° C. in an atmosphere of nitrogen. After 15 minutes of stirring at the same temperature, degassing was effected under a reduced pressure, the atmosphere in the reaction container was replaced with oxygen gas and then the reaction mixture was stirred at the same temperature in an atmosphere of oxygen. After completion of the reaction, the reaction solution was mixed with 5% sodium thiosulfate aqueous solution, tetrahydrofuran was evaporated, the thus obtained residue was extracted with ethyl acetate (150 ml×3) and then the resulting organic layers were combined and dried over sodium sulfate. The solvent was evaporated and the thus obtained residue was subjected to a silica gel chromatography to give 1.57 g (73%) of the title compound from the eluate of 3% methanol-chloroform in the form of white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]([CH3:25])=[C:11]([CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)[N:12]=1.C(O)(=O)C>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]([CH3:25])=[C:11]([CH2:13][CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([NH2:22])=[CH:20][CH:21]=2)[N:12]=1
Reactant: Cc1oc(-c2ccccc2Cl)nc1CCOc1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: CC(=O)O
Product: Cc1oc(-c2ccccc2Cl)nc1CCOc1ccc(N)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Reduced iron (10.6 g) was added portionwise mixture of 4-{2-[2-(2-chlorophenyl)-5-methyl-4-oxazolyl]ethoxy}nitrobenzene (22.9 g), acetic acid (150 ml) and water (50 ml) at 70° C. After stirring at 80° C. for 2 hours, the insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. Water was added to the filtrate, and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated to give 4-{2-[2-(2-chlorophenyl)-5-methyl-4-oxazolyl]ethoxy}aniline as a crude oily material (20.5 g, 97.6%). NMR δppm in CDCl3 : 2.35(3H, s), 2.93(2H, t, J=7 Hz), 3.77(2H, s), 4.15(2H, t, J=7 Hz), 6.56(2H, d, J=9 Hz), 6.75(2H, d, J= 9 Hz), 7.2 to 7.5(3H, m), 7.9 (1H, m).