Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[N:11][CH:10]=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)(=O)C.O>[C:1]1([CH:7]2[CH2:12][NH:11][CH2:10][CH2:9][NH:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2cnccn2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: c1ccc(C2CNCCN2)cc1
Reaction time: 4 h
Yield: 59.5 %

Procedure:
To a solution of 2-phenylpyrazine (11.64 gram, 74.53 mmol) in acetic acid (58.2 ml) was added palladium acetate Pd(OAc)2 (2.33 gram, 9.94 mmol). The mixture was hydrogenated at 50 psi for four hours. After the reaction was complete, the catalyst was filtered off and rinsed with a small portion of acetic acid. The filtrate was concentrated under house vacuum to give a brown-black solid which was suspended in deionized water (300 ml) and adjusted to pH 13 with 20% NaOH solution. The product was extracted from aqueous solution with EtOAc (200 ml, 3×), dried over MgSO4, filtered and evaporated to dryness to give 2-phenylpiperazine (7.2 gram). An additional 1.6 g of 2-phenylpiperazine was obtained by evaporating the aqueous fraction to a solid and triturating the solid with CH2Cl2. Total yield of 2-phenylpiperazine was 73%. The crude material was crystallized from EtOAc and hexane for characterization, m.p. 86°-88° C.; FAB mass [M+1]+ 163; Found, C, 74.04; H, 8.66; N, 17.15. Calcd. for C10H14N2, C, 74.04; H. 8.69; N, 17.26.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][CH:8]1[CH2:11][NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl:13][C:14]1[N:19]=[C:18](Cl)[CH:17]=[CH:16][N:15]=1.C(N(CC)CC)C>CO>[C:1]([O:5][C:6](=[O:12])[NH:7][CH:8]1[CH2:11][N:10]([C:16]2[CH:17]=[CH:18][N:19]=[C:14]([Cl:13])[N:15]=2)[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CNC1
Reactant: Clc1ccnc(Cl)n1
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CN(c2ccnc(Cl)n2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.9 %

Procedure:
A mixture of azetidin-3-yl-carbamic acid tert-butyl ester (635 mg, 3.4 mmol), 2,4-dichloropyrimidine (500 mg, 3.4 mmol) and triethylamine (0.5 ml, 3.6 mmol) in methanol (10 ml) was stirred at room temperature overnight. The mixture was concentrated and purified by column chromatography (0-40% ethyl acetate/petroleum ether) furnishing 561 mg title compound. MS: [M+H]+=283/285
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][C:17]=2[NH:26][C:27]2[C:36]3[C:31](=[CH:32][C:33]([CH:37]([CH3:39])[CH3:38])=[CH:34][CH:35]=3)[N:30]=[CH:29][N:28]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+].Cl>O1CCOCC1.O>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([OH:22])=[O:21])=[CH:18][C:17]=2[NH:26][C:27]2[C:36]3[C:31](=[CH:32][C:33]([CH:37]([CH3:39])[CH3:38])=[CH:34][CH:35]=3)[N:30]=[CH:29][N:28]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(Sc2ccc(NC(=O)OC(C)(C)C)cc2)c(Nc2ncnc3cc(C(C)C)ccc23)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)c1ccc2c(Nc3cc(C(=O)O)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2c1
Yield: 88 %

Procedure:
The product of Example 92D (0.505 g, 0.927 mmol) was suspended in 1,4-dioxane (6 mL), treated with a solution of lithium hydroxide monohydrate (0.078 g, 1.85 mmol) in water (3 mL) at room temperature, then heated at 50° for one hour. The reaction was diluted with water (25 mL), adjusted to pH 1 with 1N aqueous HCl, and extracted with ethyl acetate (50 mL). The organic extract was washed with water (25 mL) and brine (25 mL), dried over magnesium sulfate, filtered, and concentrated by rotary evaporation to afford the title compound as a light yellow solid (0.433 g, 0.816 mmol, 88%). 1H NMR (300 MHz, DMSO-D6) δ ppm 1.31 (d, J=6.99 Hz, 6 H) 1.48 (s, 9 H) 2.98-3.23 (m, 1 H) 6.92 (d, J=8.09 Hz, 1 H) 7.36 (d, J=8.46 Hz, 2 H) 7.54 (d, J=8.82 Hz, 2 H) 7.59 (d, J=11.77 Hz, 1 H) 7.73 (d, J=8.09 Hz, 1 H) 7.89 (s, 1 H) 8.34-8.49 (m, 2 H) 9.61 (s, 1 H) 9.94 (s, 1 H). MS (ESI+) m/z 531 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][C:7]=1[O:15][CH3:16].O.C(C(O)=[O:23])(F)(F)F>CC#N>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH2:13][OH:23])=[CH:8][C:7]=1[O:15][CH3:16]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Solvent: CC#N
Solvent: O
Product: COc1cc(C(=O)CO)ccc1OCCCCl

Procedure:
A solution of 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (4.3 g, 17.7 mmol), [bis(trifluoroacetoxy)iodolbenzene (15.6 g, 36.2 mmol), H2O (18 ml), CF3CO2H (2.8 ml) and CH3CN (90 ml) was refluxed for 3 hours. The CH3CN was removed under reduced pressure and the resulting yellow liquid was partitioned between H2O and CH2Cl2. The biphasic mixture was filtered, the organic phase collected, washed with saturated NaHCO3 solution and concentrated to afford 1.5 g of an amorphous brown solid. The solid was flash chromatographed on silica gel, eluting the column with 5% EtOAc/CH2Cl2. Concentration of similar fractions afforded 0.7 g of the compound as a pale yellow solid, m.p. 99°-101 ° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=O)[C:5]2=[O:12].F[C:14]1[CH:25]=C2C([O:21][C:22](=O)[NH:23][C:17]2=[CH:16][CH:15]=1)=O.FC1C=C2[NH:35]C(=O)OC(=O)C2=CC=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]=[C:6]1[C:5](=[O:12])[C:16]3[C:17]([N:23]1[C:22]2=[O:21])=[N:35][CH:25]=[CH:14][CH:15]=3
Reactant: O=c1[nH]c2cc(F)ccc2c(=O)o1
Reactant: O=c1[nH]c2ccc(F)cc2c(=O)o1
Reactant: O=C1Nc2ccc(F)cc2C1=O
Product: O=C1c2cccnc2-n2c1nc1ccc(F)cc1c2=O

Procedure:
Using the procedure in Example 36 and substituting 7-azaisatin (Example 10, J. Parrick et al., J. Chem. Soc. Perkin I 2009, 1989) for 5-fluoroisatin and 5-fluoroisatoic anhydride for 4-fluoroisatoic anhydride gives the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[Br:15]Br>C(O)(=O)C.O.[Fe]>[Br:15][C:8]1[CH:7]=[C:6]([C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)[CH:5]=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(-c2ccncc2)cc1
Reactant: BrBr
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(-c2ccncc2)cc1Br
Temperature: 60 °C
Reaction time: 1 h

Procedure:
4-(4-Methoxyphenyl)pyridine (1 g, 5.4 mmol) was dissolved in glacial acetic acid (6 ml). Iron powder (30 mg, 0.54 mmol) was added followed by a solution of bromine (0.36 ml) in glacial acetic acid (3 ml) slowly over 5 minutes. The resulting solution was stirred at 60° C. for 1 hour. A solution of bromine (0.13 ml) in glacial acetic acid (1 ml) was added and stirring was continued at 60° C. for 1.5 hours. The solution was allowed to cool to ambient temperature, diluted with water (20 ml). Excess bromine was destroyed by adding in sold sodium bisulphite until all the colour had disappeared. Solid sodium carbonate was added until the solution was basic and the resulting solution was then extracted with ethyl acetate (2×30 ml) and dried over sodium sulphate. Removal of the solvent gave an oil which was chromatographed on silica gel in diethyl ether giving the title compound as a clear oil (0.77 g, 54%). 1H NMR (250 MHz, CDCl3) δ 8.66-8.62 (2H, d, J=8.6 Hz), 7.87-7.86 (1H, d, J=2.2 Hz), 7.61-7.56 (1H, dd, J=8.5 Hz and 2.2 Hz), 7.48-7.46 (1H, d, J=8.5 Hz), 7.03-6.99 (2H, d, J=8.6 Hz), and 3.96 (3H, s). m/z (ES+) 264, 266 (M+1).
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[C:15]([C:18]1[CH:23]=[C:22]([Cl:24])[C:21]([NH:25][C:26](=[O:29])[CH2:27]Cl)=[C:20]([Cl:30])[CH:19]=1)(=[O:17])[CH3:16].C(N(CC)CC)C>CN(C)C=O>[C:15]([C:18]1[CH:19]=[C:20]([Cl:30])[C:21]([NH:25][C:26](=[O:29])[CH2:27][N:7]2[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:3][CH:2]2[CH3:1])=[C:22]([Cl:24])[CH:23]=1)(=[O:17])[CH3:16]
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1
Reactant: CC(=O)c1cc(Cl)c(NC(=O)CCl)c(Cl)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)c1cc(Cl)c(NC(=O)CN2CCN(C(=O)OC(C)(C)C)CC2C)c(Cl)c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of 12 parts of (1,1-dimethylethyl) 3-methyl-1-piperazinecarboxylate, 18.7 parts of N-(4-acetyl-2,6-dichlorophenyl)-2-chloroacetamide, 11.8 parts of N,N-diethylethanamine and 230 parts of N,N-dimethylformamide was stirred first for 8 hours at 70° C. and then over weekend at room temperature. The reaction mixture was evaporated and the residue was taken up in water. The product was extracted twice with dichloromethane. The combined extracts were washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using trichloromethane as eluent. The desired fraction was collected and the eluent was evaporated, yielding 27 parts (100%) of (1,1-dimethylethyl) 4-[2-[(4-acetyl-2,6-dichlorophenyl)amino]-2-oxoethyl]-3-methyl-1-piperazinecarboxylate as a residue (int. 21).
Reaction SMILES: [Li+].[OH-].[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@H:20]([CH2:38][C:39]3[CH:44]=[C:43]([C:45]([F:48])([F:47])[F:46])[C:42]([NH2:49])=[C:41]([Cl:50])[CH:40]=3)[C:21]([N:23]3[CH2:28][CH2:27][CH:26]([N:29]4[CH2:33][CH2:32][CH2:31][C@H:30]4[C:34]([O:36]C)=[O:35])[CH2:25][CH2:24]3)=[O:22])=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:51]=[CH:52][CH:53]=[CH:54][C:6]=2[NH:5]1.C(O)=O>O.C1COCC1>[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@H:20]([CH2:38][C:39]3[CH:44]=[C:43]([C:45]([F:47])([F:46])[F:48])[C:42]([NH2:49])=[C:41]([Cl:50])[CH:40]=3)[C:21]([N:23]3[CH2:24][CH2:25][CH:26]([N:29]4[CH2:33][CH2:32][CH2:31][C@H:30]4[C:34]([OH:36])=[O:35])[CH2:27][CH2:28]3)=[O:22])=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:51]=[CH:52][CH:53]=[CH:54][C:6]=2[NH:5]1
Reactant: COC(=O)[C@@H]1CCCN1C1CCN(C(=O)[C@@H](Cc2cc(Cl)c(N)c(C(F)(F)F)c2)OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: O=CO
Product: Nc1c(Cl)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCC[C@H]3C(=O)O)CC2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2.9 mg (0.12 mmol) LiOH in 1 mL water was added to a solution of 60 mg (0.08 mmol) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-((S)-2-methoxycarbonyl-pyrrolidin-1-yl)-piperidin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 3 mL THF and the reaction mixture was stirred overnight at RT. The solvent was eliminated in the nitrogen stream, the residue was taken up in 1 mL water, formic acid was added until an acidic reaction was obtained and the mixture was exhaustively extracted with EtOAc. The combined organic extracts were dried over Na2SO4, filtered and evaporated down i. vac. The residue was taken up in a little water and acetonitrile and freeze-dried.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([C:13]([CH3:36])([CH3:35])[C:14]([N:16]([C:18]2[C:19]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])=[N:20][C:21](S(C)(=O)=O)=[N:22][CH:23]=2)[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.O1[CH2:44][CH2:43]OCC1>>[F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([C:13]([CH3:36])([CH3:35])[C:14]([N:16]([CH3:17])[C:18]2[C:19]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])=[N:20][C:21]([N:22]3[CH2:44][CH2:43][N:16]([CH3:14])[CH2:18][CH2:23]3)=[N:22][CH:23]=2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: Cc1ccccc1-c1nc(S(C)(=O)=O)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: C1COCCO1
Product: Cc1ccccc1-c1nc(N2CCN(C)CC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 16 h
Yield: 143.5 %

Procedure:
To a solution of 0.5 g (0.89 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-(2-methanesulfonyl-4-o-tolyl-pyrimidin-5-yl)-N-methyl-isobutyramide in 10 ml dioxane 0.25 ml (2.23 mmol) 1-methylpiperazine was added. The reaction mixture was stirred for 16 hrs. After evaporation of the solvent, the residue was distributed between 50 ml CH2Cl2 and 50 ml H2O. The aqueous layer was extracted with 50 ml CH2Cl2, the combined organic layers dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/MeOH/NH4OH 110:10:1) to give 0.37 g (71%) 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-[2-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyrimidin-5-yl]-isobutyramide as a colorless solid, m.p. 149°151°, MS (ISP): 580.1 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[C:18]([F:20])[C:17]([O:21]CC3C=CC=CC=3)=[CH:16][C:15]=2[O:29]CC2C=CC=CC=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO>C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]=[C:11]([C:14]2[CH:19]=[C:18]([F:20])[C:17]([OH:21])=[CH:16][C:15]=2[OH:29])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(F)c(OCc3ccccc3)cc2OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC=C(c2cc(F)c(O)cc2O)CC1
Temperature: 25 °C
Reaction time: 29 h
Yield: 147.8 %

Procedure:
A mixture of 860 mg (0.42 mmol, 1 eq) of 4-(2,4-bis(benzyloxy)-5-fluorophenyl)piperidine-1-carboxylic acid tert-butyl ester at 35% in 10 ml of ethyl acetate, in the presence of 200 mg of palladium-on-charcoal at 10%, is stirred at ambient temperature under a hydrogen pressure of 5 bar for 17 hours. 5 ml of methanol are added and the reaction medium is stirred at ambient temperature under a hydrogen pressure of 5 bar for 29 hours. The reaction medium is filtered through filter paper and the filtrate is evaporated off. The residue is chromatographed on silica gel, elution being carried out with 60/40 heptane/ethyl acetate. 192 mg of 4-(5-fluoro-2,4-dihydroxyphenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester are obtained. Yield=100%.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[S:14][C:13]([C:15]([OH:17])=[O:16])=[CH:12][C:9]=3[NH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(NC(=NC(C)C)O[C:24]([CH3:27])([CH3:26])[CH3:25])(C)C.C1C(=O)N([Br:39])C(=O)C1>C1COCC1.C(Cl)Cl>[Br:39][C:11]1[NH:10][C:9]2[CH:12]=[C:13]([C:15]([O:17][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:16])[S:14][C:8]=2[C:7]=1[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(O)c1cc2[nH]cc(C3CCCCC3)c2s1
Reactant: CC(C)N=C(NC(C)C)OC(C)(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1cc2[nH]c(Br)c(C3CCCCC3)c2s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
A solution (0.2 M) of 6-cyclohexyl-4H-thieno[3,2-b]pyrrole-2-carboxylic acid (prepared as described in example 14, step 8) in THF was treated with tert-butyl N,N′-diisopropylimidocarbamate (2 eq.). The reaction mixture was heated to reflux for 1 h. After cooling down, the mixture was filtered trough a pad of silica gel and washed with AcOEt. Evaporation under reduced pressure of the filtrate gave a residue that was dissolved in DCM. The resulting solution (0.2 M) was cooled at 0° C. and treated with NBS (1 eq.). The reaction mixture was stirred at 0° C. for 1 h, then it was quenched with aqueous Na2S2O3 (saturated solution) and extracted with AcOEt. The combined organic phase was washed with aqueous Na2S2O3 (saturated solution) and brine and dried. Evaporation of the solvent under reduced pressure afforded the title compound (37%) as a solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][O:5][C:3]1=O.[F:8][C:9]([F:19])([F:18])[O:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=1)[NH2:14].C(OCC)C.O>C(OCC)C.CCCCCC>[F:8][C:9]([F:18])([F:19])[O:10][C:11]1[CH:12]=[C:13]([N:14]2[CH2:6][CH2:7][CH:2]([OH:1])[C:3]2=[O:5])[CH:15]=[CH:16][CH:17]=1
Reactant: O=C1OCCC1O
Reactant: Nc1cccc(OC(F)(F)F)c1
Solvent: CCOCC
Solvent: CCCCCC
Solvent: O
Product: O=C1C(O)CCN1c1cccc(OC(F)(F)F)c1
Temperature: 150 °C
Yield: 69.3 %

Procedure:
A mixture of alpha-hydroxy-gamma-butyrolactone (22.0 g) and 3-trifluoromethoxy aniline (19.0 g) was heated to 150° C. (bath temperature) for 48 hours. The mixture was allowed to cool and poured into a mixture of diethyl ether and water. After shaking, the ether layer was separated and the aqueous layer extracted with diethyl ether (x2). The combined ether extracts were washed with 2M hydrochloric acid, water and brine, then dried (MgSO4). The mixture was evaporated under reduced pressure to leave an oil, which on trituration with a mixture of diethyl ether/hexane gave the sub-title compound as an off-white solid (19.42 g).
Reaction SMILES: [C:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[C:12]([CH2:13]O)=[CH:11][N:10]=[CH:9]2)=[CH:5][C:4]=1[F:17])#[N:2].C1C=CC(P([N:32]=[N+:33]=[N-:34])(C2C=CC=CC=2)=O)=CC=1.C1CCN2C(=NCCC2)CC1>C1COCC1>[N:32]([CH2:13][C:12]1[N:8]([CH2:7][C:6]2[CH:15]=[CH:16][C:3]([C:1]#[N:2])=[C:4]([F:17])[CH:5]=2)[CH:9]=[N:10][CH:11]=1)=[N+:33]=[N-:34]
Reactant: N#Cc1ccc(Cn2cncc2CO)cc1F
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: N#Cc1ccc(Cn2cncc2CN=[N+]=[N-])cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 1-(4-cyano-3-fluorobenzyl)-5-(hydroxymethyl)imidazole, as described above in Example 4, Step F, (103 mg, 0.45 mmol) in dry THF (1 mL), at 0° C., under argon, were added DPPA (147 mg, 0.53 mmol) then DBU (75 mg, 0.49 mmol). The mixture was allowed to warm to ambient temperature and then stirred for 3 hrs. The mixture was then partitioned between H2O (10 mL) and CH2Cl2 (20 mL). The aqueous layer was extracted further with CH2Cl2 (2×15 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluting with a gradient of CHCl3-1% MeOH −0.1% NH4OH to CHCl3-5% MeOH −0.5% NH4OH, to yield the titled product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:34]=[C:33]([F:35])[C:13]([O:14][C:15]2[CH:16]=[C:17]([CH:21]=[C:22]([O:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][CH:26]=3)[CH:23]=2)[C:18](O)=[O:19])=[C:12]([F:36])[CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:37]([O:41][C:42](=[O:51])[NH:43][CH:44]1[CH2:49][CH2:48][CH:47]([NH2:50])[CH2:46][CH2:45]1)([CH3:40])([CH3:39])[CH3:38]>>[C:37]([O:41][C:42](=[O:51])[NH:43][CH:44]1[CH2:45][CH2:46][CH:47]([NH:50][C:18](=[O:19])[C:17]2[CH:21]=[C:22]([O:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][CH:26]=3)[CH:23]=[C:15]([O:14][C:13]3[C:12]([F:36])=[CH:11][C:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])=[CH:34][C:33]=3[F:35])[CH:16]=2)[CH2:48][CH2:49]1)([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Reactant: CC(C)(C)OC(=O)NCc1cc(F)c(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)O)c2)c(F)c1
Product: CC(C)(C)OC(=O)NCc1cc(F)c(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)NC3CCC(NC(=O)OC(C)(C)C)CC3)c2)c(F)c1
Yield: 48.1 %

Procedure:
3-[4-(tert-butoxycarbonylamino-methyl)-2,6-difluoro-phenoxy]-5-(4-cyano-phenoxy)-benzoic acid (0.6 g, 1.2 mmol) and (4-amino-cyclohexyl)-carbamic acid tert-butyl ester (0.28 g, 1.3 mmol) and other reagents as described in Example 9(e) were used to afford 0.4 g of the required product. 1H NMR (DMSO-d6): δ 1.24 (4H, m), 1.42 (18H, s), 1.8 (4H, m), 3.18 (1H, m), 3.64 (1H, m), 4.20 (2H, d), 6.74 (1H, d), 7.0 (1H, s), 7.16 (4H, m), 7.24 (1H, s), 7.38 (1H, s), 7.54 (1H, t), 7.88 (2H, d), 36 (1H, d).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[CH:6][C:7]=1[OH:8].C(N(CC)CC)C.[P:17](Cl)(Cl)([O:19][CH3:20])=[O:18]>CCOCC>[CH3:20][O:19][P:17]1(=[O:18])[O:8][C:7]2[CH:6]=[CH:5][C:4]([CH3:9])=[CH:3][C:2]=2[O:1]1
Reactant: COP(=O)(Cl)Cl
Reactant: Cc1ccc(O)c(O)c1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COP1(=O)Oc2ccc(C)cc2O1
Yield: 88.3 %

Procedure:
3,4-Dihydroxytoluene (1.686 g, 13.58 mM) was dissolved in 40 ml of ether and, using 2.748 g of triethylamine and 2.022 g of methyl dichlorophosphate, the reaction mixture was treated in the same manner as in Reference Example 5. There was obtained 2.400 g (88.4% yield) of 2-methoxy-5-methyl-2-oxo-1,3,2-benzodioxaphosphole as a viscous oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:20])[N:9]([C:13]3[CH:18]=[CH:17][C:16](I)=[CH:15][CH:14]=3)[CH2:10][CH2:11][O:12][C:6]=2[N:5]=[CH:4][N:3]=1.C[CH:22]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)[C:23]([OH:25])=[O:24].[C:33](=O)([O-])[O-].[Cs+].[Cs+].CN(C)CC(O)=O>O1CCOCC1.[Cu]I>[NH2:1][C:2]1[C:7]2[C:8](=[O:20])[N:9]([C:13]3[CH:18]=[CH:17][C:16]([O:32][C:29]4[CH:30]=[CH:31][C:26]([CH2:22][C:23]([O:25][CH3:33])=[O:24])=[CH:27][CH:28]=4)=[CH:15][CH:14]=3)[CH2:10][CH2:11][O:12][C:6]=2[N:5]=[CH:4][N:3]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C(=O)O)c1ccc(O)cc1
Reactant: Nc1ncnc2c1C(=O)N(c1ccc(I)cc1)CCO2
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: [Cs+]
Solvent: C1COCCO1
Product: COC(=O)Cc1ccc(Oc2ccc(N3CCOc4ncnc(N)c4C3=O)cc2)cc1

Procedure:
A stirred slurry of 4-amino-6-(4-iodophenyl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one (38 mg, 0.10 mmol), methyl 4-hydroxyphenylacetic acid (25 mg, 0.15 mmol), cesium carbonate (78 mg, 0.24 mmol), N,N-dimethyl glycine (10.3 mg, 0.10 mmol) and copper (I) iodide (6 mg, 0.03 mmol) in p-dioxane (0.4 mL) were heated at 90° C. for 18 hours. The reaction mixture was cooled, concentrated in vacuo and chromatographed (0-5% methanol: chloroform) to afford the title compound as a solid, 2.4 mg. 1H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 7.25 (d, 2H), 7.20 (d, 2H), 7.07 (d, 2H), 7.02 (d, 2H), 4.69 (m, 2H), 4.00 (m, 2H), 3.68 (s, 3H). m/z=421.2 (M+1). IC50 254 nM.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][O:10][CH2:11][CH2:12]Cl)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[N-:14]=[N+:15]=[N-:16].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH2:1]([O:3][P:4]([CH2:9][O:10][CH2:11][CH2:12][N:14]=[N+:15]=[N-:16])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOP(=O)(COCCCl)OCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOP(=O)(COCCN=[N+]=[N-])OCC

Procedure:
0,02 mol (2-chloroethoxy)methyl-phosphonic acid diethylester, 3 mmol tetrabutylammoniumbromide and 2,5 g sodiumazide are boiled in 50 ml toluol under reflux for 4 h. After cooling-off it is washed for three times with 25 ml water respectively. The watery phase may be extracted with toluol. The combined toluol phases are dried over sodiumsulfate and the solvent is removed in the vacuum. A yellow oil remains.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11]O.[Br:13]P(Br)Br>ClCCl>[Br:13][CH2:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[Cl:1]
Reactant: O=[N+]([O-])c1ccc(CO)c(Cl)c1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(CBr)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(2-chloro-4-nitrophenyl)methanol (707 mg, 3.73 mmol) was dissolved in dichloromethane (15 mL) at 0° C. under nitrogen. Tribromophosphane (0.7 mL, 7.46 mmol) was added dropwise. The resulting mixture was stirred at room temperature overnight. The reaction was quenched by addition of 10% NaHCO3 solution (2 mL). After 10 minutes, Na2SO4 (15 g) was added. The solvent was filtered and evaporated to provide 1-(bromomethyl)-2-chloro-4-nitrobenzene, which was used without further purification.