Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7](OC2C=C3C(=CC=2)OC(C2C=CC=CC=2)CC3)=[N:8][CH:9]=1)([O-:3])=[O:2].[F:27][C:28]1[CH:29]=[C:30]([CH:35]2[CH2:44][CH2:43][C:42]3[C:37](=[CH:38][CH:39]=[C:40]([OH:45])[CH:41]=3)[O:36]2)[CH:31]=[C:32]([F:34])[CH:33]=1>>[F:27][C:28]1[CH:29]=[C:30]([CH:35]2[CH2:44][CH2:43][C:42]3[C:37](=[CH:38][CH:39]=[C:40]([O:45][C:7]4[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=4)[CH:41]=3)[O:36]2)[CH:31]=[C:32]([F:34])[CH:33]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Reactant: Oc1ccc2c(c1)CCC(c1cc(F)cc(F)c1)O2
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2cc(F)cc(F)c2)O3)nc1

Procedure:
2-[2-(3,5-Difluorophenyl)chroman-6-yloxy]-5-nitropyridine was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 340 mg of 2-(3,5-difluorophenyl)chroman-6-ol. The product was purified on preparative TLC-plate covered with silica gel using toluene-ethyl acetate as an eluant and then crystallised from 2-propanol. 1H NMR (400 MHz, d6-DMSO) δ:9.04 (d, 1H, J 2.9 Hz), 8.60 (dd, 1H, J 9.1, 2.9 Hz), 7.23-7.19 (m, 4H), 7.01-6.95 (m, 3H), 5.18 (dd, 1H, J 10.0, 2.1 Hz), 2.97 (ddd, 1H, J −16.9, 10.9, 5.7 Hz), 2.76 (ddd, 1H, J −16.9, 8.4, 4.7 Hz), 2.22 (m, 1H), 1.99 (m, 1H).
Reaction SMILES: [O:1]=[C:2]([NH:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)[CH2:3][CH2:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][C@H:8]1[CH:9]=O)=[O:6].Cl.[NH2:24][OH:25].N1C=CC=CC=1>CN(C=O)C>[O:1]=[C:2]([NH:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)[CH2:3][CH2:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][C@H:8]1[CH:9]=[N:24][OH:25])=[O:6]
Reactant: NO
Reactant: O=C[C@@H]1CCCN1C(=O)CCC(=O)NCc1ccc(Cl)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(CCC(=O)N1CCC[C@H]1C=NO)NCc1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a solution of N-[4-oxo-4-(4-chlorobenzylamino)butanoyl]-L-prolinal (304 mg) in DMF (2.5 ml) were added hydroxylamine hydrochloride (75 mg) and pyridine (90 μl), and the mixture was stirred at 70° C. for 2 hours. To a solution of crude (2S)-1-[4-oxo-4-(4-chlorobenzylamino)butanoyl]-2-pyrrolidinecarboxaldehyde oxime as obtained by subjecting the reaction mixture to concentration under reduced pressure, in methylene chloride (4 ml) were added pyridine (0.16 ml) and acetic anhydride (0.19 ml), and the mixture was stirred at room temperature for 5 hours. The reaction mixture was treated in the same manner as in Example 15 to give 249 mg of (2S)-1-[4-oxo-4-(4-chlorobenzylamino)butanoyl]-2-pyrrolidinecarboxaldehyde O-acetyloxime.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[CH3:27])=[C:9]([C:14]2[N:18]([CH3:19])[N:17]=[N:16][N:15]=2)[CH:10]=[CH:11][CH:12]=[O:13])=[C:4]([CH3:28])[CH:3]=1.[C:29]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])(=[O:34])[CH2:30][C:31]([CH3:33])=[O:32].[H-].[Na+].C([Li])CCC>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[CH3:27])=[C:9]([C:14]2[N:18]([CH3:19])[N:17]=[N:16][N:15]=2)[CH:10]=[CH:11][CH:12]([OH:13])[CH2:33][C:31](=[O:32])[CH2:30][C:29]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[C:4]([CH3:28])[CH:3]=1
Reactant: Cc1cc(F)ccc1C(=C(C=CC=O)c1nnnn1C)c1ccc(F)cc1C
Reactant: CC(=O)CC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1C(=C(C=CC(O)CC(=O)CC(=O)OC(C)(C)C)c1nnnn1C)c1ccc(F)cc1C
Temperature: -30 °C
Reaction time: 1.5 h

Procedure:
To a solution of 5,5-bis(4-fluoro-2-methylphenyl)-4-(1-methyl-1H-tetrazol-5-yl)-2,4-pentadienal (1.0 g, 2.5 mmoles) in tetrahydrofuran at -50° C. was added the dianion of t-butyl acetoacetate (2.5 mL of a 1M solution, 2.5 mmoles) prepared by adding t-butyl acetoacetate (4.0 g, 25.0 mmoles) in tetrahydrofuran (4 mL) to a suspension of sodium hydride (1.0 g of 60% dispersion, 25.0 mmoles) in tetrahydrofuran at -5° C. followed by cooling to -30° C. and the addition of butyl lithium (11.4 mL of 2.2M solution, 25 mmoles). After stirring for 1.5 hours, analytical TLC indicated starting aldehyde and another 0.5 mL of dianion solution was added. The solution was stirred an additional 0.5 hour and quenched with 1N hydrochloric acid. The mixture was extracted with methylene chloride. The extracts were dried and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with methanol in methylene chloride to produce 0.6 g of the title compound; m.p.=65° -72° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]([CH2:23][CH:24]([O:29][Si](C(C)(C)C)(C)C)[C:25]([F:28])([F:27])[F:26])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]([F:22])([F:21])[CH:18]([F:20])[F:19])[CH:11]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:43][C:44]1[CH:49]=[CH:48][C:47]([OH:50])=[CH:46][C:45]=1[CH2:51][CH3:52].C1(C(O)=O)C2C(=CC=CC=2)C=CC=1>CC(N(C)C)=O.C1(C)C=CC=CC=1>[Cl:43][C:44]1[CH:49]=[CH:48][C:47]([O:50][C:2]2[CH:3]=[C:4]([N:8]([CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]([F:22])([F:21])[CH:18]([F:19])[F:20])[CH:11]=3)[CH2:23][CH:24]([OH:29])[C:25]([F:27])([F:26])[F:28])[CH:5]=[CH:6][CH:7]=2)=[CH:46][C:45]=1[CH2:51][CH3:52]
Reactant: CCc1cc(O)ccc1Cl
Reactant: CC(C)(C)[Si](C)(C)OC(CN(Cc1cccc(OC(F)(F)C(F)F)c1)c1cccc(Br)c1)C(F)(F)F
Agent: O=C(O)c1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: Cc1ccccc1
Product: CCc1cc(Oc2cccc(N(Cc3cccc(OC(F)(F)C(F)F)c3)CC(O)C(F)(F)F)c2)ccc1Cl
Yield: 23.1 %

Procedure:
A solution of N-(3-bromophenyl)-N-[2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-3,3,3-trifluoropropyl]-3-(1,1,2,2-tetrafluoroethoxy)benzenemethanamine (75 mg, 0.124 mmol), cesium carbonate (81 mg, 0.248 mmol), 4-chloro-3-ethylphenol (44 mg, 0.358 mmol), copper triflate benzene complex (6.24 mg, 10 mol %), 1-naphthoic acid (43 mg, 0.248 mmol) in 2:1 toluene:dimethylacetamide (3.0 mL) was heated at 105° C. for 96 hours. The reaction mixture was filtered through celite, and the solvent was evaporated. The residue was purified by reverse phase chromatography eluting with 50-90% acetonitrile in water to afford 16.2 mg (23%) of the desired 3-[[3-(4-chloro-3-ethylphenoxy)phenyl]-[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as an orange oil. HRMS calcd. for C26H23ClF7NO3: 566.1332 [M+H]+, found: 566.1332. 1H NMR (CDCl3) δ1.18 (t, 3H), 2.69 (q, 2H), 3.50-3.61 (m, 1H), 3.87 (dd, 1H), 4.28-4.39 (m, 1H), 4.63 (s, 2H), 5.88 (tt, 1H), 6.32-6.40 (m, 2H), 6.48 (dd, 1H), 6.69 (dd, 1H), 6.87 (d, 1H), 7.0-7.34 (m, 5H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:13][CH2:12][C@H:11]([NH2:14])[CH2:10]2)[CH:6]=[CH:7][CH:8]=1.Cl[C:16]1[N:24]=[CH:23][N:22]=[C:21]2[C:17]=1[N:18]=[CH:19][N:20]2[C@H:25]1[C@H:32]2[C@H:28]([O:29][C:30]([CH3:34])([CH3:33])[O:31]2)[C@@H:27]([CH2:35][F:36])[CH2:26]1.CCN(CC)CC>CCO>[Cl:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:13][CH2:12][C@H:11]([NH:14][C:16]3[N:24]=[CH:23][N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][N:20]4[C@H:25]3[C@H:32]4[C@H:28]([O:29][C:30]([CH3:33])([CH3:34])[O:31]4)[C@@H:27]([CH2:35][F:36])[CH2:26]3)[CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: N[C@H]1CCN(c2cccc(Cl)c2)C1
Reactant: CC1(C)O[C@@H]2[C@@H](CF)C[C@@H](n3cnc4c(Cl)ncnc43)[C@@H]2O1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC1(C)O[C@@H]2[C@@H](CF)C[C@@H](n3cnc4c(N[C@H]5CCN(c6cccc(Cl)c6)C5)ncnc43)[C@@H]2O1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
1-(3-Chloro-phenyl)-pyrrolidin-3(S)-ylamine hydrochloride (300 mg, 1.29 mmoles) prepared as in step 4 of example 1 and 6-chloro-9-((3aS,4R,6S,6aR)-6-fluoromethyl-2,2-dimethyl-tetrahydro-cyclopenta-1,3-dioxol-4-yl)-9H-purine (420 mg, 1.29 mmoles) prepared as described above were combined in EtOH (12 ml), NEt3 (730 μl, 5.15 mmoles) was then added and the resulting brown solution was stirred at reflux under an argon atmosphere. After 22 h, the reaction mixture was cooled to room temperature, evaporated to dryness, the residue was partitioned between water and EtOAc, the aqueous layer was separated and extracted two times with EtOAc. The combined organic layers are washed with brine and dried over magnesium sulfate. The filtrate is concentrated under reduced pressure to give a residue which is purified by flash chromatography on silica gel eluting with 40% EtOAc in cyclohexane followed by 5% MeOH in CH2Cl2 to yield [(S)-1-(3-chloro-phenyl)-pyrrolidin-3-yl]-[9-((3aS,4R,6S,6aR)-6-fluoromethyl-2,2-dimethyl -tetrahydro-cyclopenta-1,3-dioxol-4-yl)-9H-purin-6-yl]-amine
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:29])[N:4]([C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=2[CH3:28])[C:22](O)=[O:23])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].[CH2:30]([CH2:32][NH2:33])[OH:31].CCN=C=NCCCN(C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[C:3](=[O:29])[N:4]([C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=2[CH3:28])[C:22]([NH:33][CH2:32][CH2:30][OH:31])=[O:23])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: Cc1ccc(C(=O)O)cc1-n1c(C)cc(OCc2ccc(F)cc2F)c(Br)c1=O
Reactant: NCCO
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C(=O)NCCO)cc1-n1c(C)cc(OCc2ccc(F)cc2F)c(Br)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 721.1 %

Procedure:
3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoic acid (from Step 4 above) (1.9 g, 4.10 mmol) was dissolved in 20 ml of CH2Cl2. Ethanolamine (297 μl, 4.92 mmol) was added, followed, in order, by EDCI (0.764 g, 4.92 mmol), 1-hydroxybenzotriazole (0.6659, 4.92 mmol) and triethylamine (1.14 ml, 8.20 mmol). The reaction was stirred at room temperature overnight. The reaction was quenched with NH4Cl and extracted 3 times with ethyl acetate. The combined organic layer was then washed with saturated NaHCO3 (aq.) and extracted 3 times with ethyl acetate. The organic layers were combined and washed with H2O and extracted 3 times with ethyl acetate. The organic layers were combined and dried over Na2SO4 and evaporated. The resulting residue was triturated with diethyl ether/hexane to obtain a solid, which was dried in vacuo to give a white solid (15 g, 72%). 1H NMR (300 MHz, CDCl3) δ 7.93 (dd, J=7.85, 1.61 Hz, 1H), 7.65 (d, J=1.61 Hz, 1H), 7.62 (app q, J=8.26 Hz, 1H), 7.40 (d, J=8.06 Hz, 1H), 7.39-7.30 (m, 1H), 7.03-6.97 (m, 1H), 6.88-6.81 (m, 1H), 6.25 (s, 1H), 5.20 (s, 2H), 3.70-3.52 (m, 1H), 3.16-3.12 (m, 2H), 2.10 (s, 3H), 1.98 (s, 3H); ES-MS m/z 507 (M+H). ES-HRMS m/z 507.0719 (M+H calcd for C23H22BrF2N2O4 requires 507.0726).
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=C2N=NN(O)C2=CC=1.O.[C:23]([CH2:25][C:26]([OH:28])=O)#[N:24].[CH3:29][C:30]([CH3:55])([CH3:54])[C:31]([C:33]1[C:41]2[C:36](=[N:37][CH:38]=[C:39]([C:42]3[CH:47]=[CH:46][CH:45]=[C:44]([N:48]4[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]4)[CH:43]=3)[N:40]=2)[NH:35][CH:34]=1)=[O:32].C(N(C(C)C)CC)(C)C>ClCCl>[CH3:29][C:30]([CH3:55])([CH3:54])[C:31]([C:33]1[C:41]2[C:36](=[N:37][CH:38]=[C:39]([C:42]3[CH:43]=[C:44]([N:48]4[CH2:53][CH2:52][N:51]([C:26](=[O:28])[CH2:25][C:23]#[N:24])[CH2:50][CH2:49]4)[CH:45]=[CH:46][CH:47]=3)[N:40]=2)[NH:35][CH:34]=1)=[O:32]
Reactant: CC(C)(C)C(=O)c1c[nH]c2ncc(-c3cccc(N4CCNCC4)c3)nc12
Reactant: N#CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(-c3cccc(N4CCN(C(=O)CC#N)CC4)c3)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.7 %

Procedure:
Dichloromethane (1 mL) was added to a mixture of EDCI (0.181 g, 0.945 mmol), HOBT monohydrate (0.128 g, 0.945 mmol), cyanoacetic acid (0.060 g, 0.71 mmol), and 2,2-Dimethyl-1-[2-(3-piperazin-1-yl-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-propan-1-one (0.1718 g, 0.473 mmol) under argon. Diisopropylethylamine (DIPEA, 0.41 mL; 0.304 g, 2.36 mmol) was subsequently added and the reaction was stirred overnight at ambient temperature. The reaction was quenched with saturated aqueous NaHCO3 and extracted 3 times with dichloromethane. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. Preparative thin layer chromatography afforded 0.0402 g (20% yield) of 3-(4-{3-[7-(2,2-Dimethyl-propionyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-phenyl}-piperazin-1-yl)-3-oxo-propionitrile as an off-white solid.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:9]([OH:11])=O)[CH2:4][CH2:5][CH2:6][CH2:7][NH2:8].[OH-].[Na+]>C(O)C>[NH2:2][CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1=[O:11]
Reactant: NCCCC[C@H](N)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC1CCCCNC1=O
Temperature: 200 °C

Procedure:
50 mmols of L-lysine hydrochloride 1 is neutralized with 50 mmols of NaOH and then 200 ml of ethanol is added. This mixture is heated to 200° C. for eight hours. The yield of α-amino-ε-caprolactam 2 produced by this reaction is about 47%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[NH:11][NH:10][C:9]2=[O:14])=[CH:4][CH:3]=1.[OH-].[Na+].[Cl:17][C:18]([Cl:22])([Cl:21])[S:19]Cl>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:9](=[O:14])[N:10]([S:19][C:18]([Cl:22])([Cl:21])[Cl:17])[N:11]([S:19][C:18]([Cl:22])([Cl:21])[Cl:17])[C:12]2=[O:13])=[CH:6][CH:7]=1
Reactant: O=c1[nH][nH]c(=O)n1-c1ccc(Cl)cc1
Reactant: ClSC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1n(-c2ccc(Cl)cc2)c(=O)n(SC(Cl)(Cl)Cl)n1SC(Cl)(Cl)Cl

Procedure:
To a solution of 42.2g (0.2 mole) 4-(4-chlorophenyl)urazole in 200 ml water was added a solution of 16g (0.4 mole) sodium hydroxide in 20 ml water. A mixture of 74.4g (0.4 mole) trichloromethylsulfenyl chloride and 3g of an emulsifier solution (as in example 1) in 50 ml water was added dropwise to the above basic solution while keeping the reaction mixture at 0° C. The reactants were mixed so that the reaction mixture was kept at a pH greater than 7. The precipitate that was formed was collected on a filter and the filter cake was washed with water. After drying, triturating with ethyl ether, and recrystallizing from benzene-cyclohexane (1:1, by volume) there was obtained 42g (64%) of 4-(4-chlorophenyl)-1, 2-bis(trichloromethylthio)urazole having a melting point of 169° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(C1C=CC(S([O-])(=O)=O)=CC=1)(=O)C.[Na+].[CH3:28][N:29]([CH3:33])[CH2:30][CH2:31][NH2:32]>O>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:32][CH2:31][CH2:30][N:29]([CH3:33])[CH3:28])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CN(C)CCN
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Agent: CC(=O)c1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Solvent: O
Product: CC(=O)c1ccc(S(=O)(=O)NCCN(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The damp 4-acetylbenzenesulfonyl chloride from 100 g. of sodium 4-acetylbenzenesulfonate is added to a solution of 83 g. of N,N-dimethylethylenediamine in 730 ml. of water. The mixture is stirred at room temperature for 16 hours, cooled, and the precipitate of 4-acetyl-N-(2-dimethylaminoethyl)benzenesulfonamide collected by filtration, washed with water and dried; m.p. 87-89° C. after crystallization from 2-propanol/hexane.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@@H:2]([C:10]([N:12]1[CH2:26][CH2:25][CH2:24][C@H:13]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C1(OC)C=CC=CC=1.[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45]>ClCCl>[NH2:1][C@@H:2]([C:10]([N:12]1[CH2:26][CH2:25][CH2:24][C@H:13]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:42][C:43]([C:44]([OH:46])=[O:45])([F:48])[F:47]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: N[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 3 h
Yield: 85 %

Procedure:
To a stirring solution of Boc-D-Phe-Pro-OBn (68 g, 150 mmol) in dichloromethane (50 mL) at 0° C., was added anisole (20 mL) followed by trifluoroacetic acid (400 mL). After stirring for 3 hours, the solvents were evaporated in vacuo and the thick oily residue was dissolved in diethyl ether (1.5 L) and refrigerated (72 hours). The white precipitate was filtered, washed with diethyl ether (300 mL) and dried to yield 59.4 g (85%) of white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:16]([NH2:19])(=[O:18])=[O:17])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C@H:10]1[O:15][CH2:14][CH2:13][NH:12][CH2:11]1.CO.C(O[C:25]1(O[Si](C)(C)C)[CH2:27][CH2:26]1)C.C([BH3-])#N.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([S:16]([NH2:19])(=[O:18])=[O:17])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C@H:10]1[O:15][CH2:14][CH2:13][N:12]([CH:25]2[CH2:27][CH2:26]2)[CH2:11]1
Reactant: NS(=O)(=O)c1cnc(OC[C@@H]2CNCCO2)c(Cl)c1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: NS(=O)(=O)c1cnc(OC[C@@H]2CN(C3CC3)CCO2)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of EXAMPLE 244B (250 mg), anhydrous methanol (6 mL), (1-ethoxycyclopropoxy)trimethylsilane (0.474 mL), and acetic acid (0.509 mL) was heated at 70° C. for 30 minutes. After cooling to ambient temperature, sodium cyanoborohydride (112 mg) was added and the mixture was stirred for 18 hours. Additional sodium cyanoborohydride (75 mg) was added and stirring was continued 18 hours. The reaction was concentrated and the residue was partitioned between methylene chloride and saturated sodium bicarbonate solution. The crude product was isolated from the dried methylene chloride layer and was purified on silica gel and was eluted with a 1, 2.5, 5, 10% methanol in methylene chloride step gradient to provide the title compound.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[C:8]([C:15]2[C:16]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[N:17][NH:18][CH:19]=2)[N:7]=1)[CH:2]([CH3:4])[CH3:3].[H-].[Na+].Cl.[O:30]1[CH2:35][CH2:34][N:33]([CH2:36][CH2:37]Cl)[CH2:32][CH2:31]1>CN(C=O)C>[CH2:1]([NH:5][C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[C:8]([C:15]2[C:16]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)=[N:17][NH:18][C:19]=2[CH:36]([N:33]2[CH2:34][CH2:35][O:30][CH2:31][CH2:32]2)[CH3:37])[N:7]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CNc1nc(-c2c[nH]nc2-c2ccc(F)cc2)ccc1[N+](=O)[O-]
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)CNc1nc(-c2c(-c3ccc(F)cc3)n[nH]c2C(C)N2CCOCC2)ccc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 81.9 %

Procedure:
Treat a solution of 2-isobutylamino-3-nitro-6-[3-(4-fluorophenyl)pyrazol-4-yl]pyridine (1.25 g, 3.52 mmol) in dry DMF (15 mL) with 95% NaH (0.36 g, 14.3 mmol) at 0° C. for 15 min. Add morpholinoethylchloride hydrochloride (0.983 g, 5.28 mmol) and slowly warm to RT. Add additional NaH (0.36 g, 14.3 mmol), after 1 h and stir the reaction mixture for 24 h. Quench with MeOH (1 mL) and dilute with water (30 mL). Extract with EtOAc (100 mL), dry with MgSO4, and concentrate. Purify the residue (silica gel chromatography, eluting with hexanes:EtOAc 1:2) to give the title compound (1.35 g, 81%).
Reaction SMILES: C1C2C(=CC=CC=2)C=CC=1[C:11]1[CH:12]=[C:13]([CH:24]=[CH:25][CH:26]=1)[CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=O.F>>[C:11]1([C:11]2[CH:26]=[CH:25][C:24]3[C:17](=[O:19])[C:16]4[C:15](=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:14][C:13]=3[CH:12]=2)[CH:12]=[CH:13][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(O)c1ccccc1Cc1cccc(-c2ccc3ccccc3c2)c1
Agent: F
Product: O=C1c2ccccc2Cc2cc(-c3ccccc3)ccc21
Yield: 144.7 %

Procedure:
First, 11.7 g of 2-[3-(2-naphthyl)benzyl]benzoic acid were added to 250 mL of liquid hydrogen fluoride, and then the mixture was stirred until hydrogen fluoride evaporated. The residue was dissolved in chloroform, and then the solution was sequentially washed with water, an aqueous solution of ammonium hydroxide, and water. After the chloroform solution had been dried with magnesium sulfate, the solvent was removed by distillation under reduced pressure. The residue was crystallized with methanol, and was then recrystallized with cyclohexane and acetone. Thus, 6.76 g of 2-phenyl-10-anthrone were obtained (in 61% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([F:39])[C:12]=1[CH:13]=[CH:14][C:15]1[N:16]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[C:17]([C:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([O:30][CH3:31])[CH:24]=2)([CH3:22])[CH3:21])=[CH:18][N:19]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].N#N>CCO.O=[Pt]=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([F:39])[C:12]=1[CH2:13][CH2:14][C:15]1[N:16]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[C:17]([C:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([O:30][CH3:31])[CH:24]=2)([CH3:21])[CH3:22])=[CH:18][N:19]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)c1cc(F)c(C=Cc2ncc(C(C)(C)c3ccc(Cl)c(OC)c3)n2-c2ccc(F)cc2)c(Cl)c1
Agent: O=[Pt]=O
Agent: N#N
Solvent: CCO
Product: CCOC(=O)c1cc(F)c(CCc2ncc(C(C)(C)c3ccc(Cl)c(OC)c3)n2-c2ccc(F)cc2)c(Cl)c1
Reaction time: 8 h
Yield: 68.1 %

Procedure:
A solution of ethyl 3-chloro-4-(2-(5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-yl)vinyl)-5-fluorobenzoate (224 mg, 0.392 mmol) in EtOH (10 mL) was degassed using N2 for 5-10 minutes prior to the addition of PtO2 (42 mg, 0.184 mmol). The resulting suspension was pressurized with 70 psi H2 and agitated overnight. The catalyst was removed by filtration through Celite™ and eluting with more EtOH. The filtrate was concentrated in vacuo to provide ethyl 3-chloro-4-(2-(5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-yl)ethyl)-5-fluorobenzoate (153 mg, 68%) as a gray oil. 1H NMR (400 MHz, CDCl3) δ 7.87-7.61 (m, 1H), 7.50 (td, J=9.4, 1.4 Hz, 1H), 7.15 (d, J=8.4 Hz, 1H), 7.11-6.98 (m, 1H), 6.98-6.65 (m, 2H), 6.65-6.32 (m, 4H), 4.38 (dq, J=21.4, 7.1 Hz, 2H), 3.74 (d, J=3.3 Hz, 3H), 3.25-2.83 (m, 2H), 2.52 (dd, J=16.6, 8.9 Hz, 2H), 1.50 (s, 6H), 1.39 (dt, J=14.3, 7.2 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]([O:12][C:13]2[C:18]([F:19])=[CH:17][C:16]([CH2:20][NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:15][C:14]=2[F:29])[CH:6]=1)[CH3:2].F[C:32]1[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[CH:34][CH:33]=1>>[CH2:1]([O:3][C:4](=[O:30])[C:5]1[CH:10]=[C:9]([O:11][C:32]2[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[CH:34][CH:33]=2)[CH:8]=[C:7]([O:12][C:13]2[C:18]([F:19])=[CH:17][C:16]([CH2:20][NH:21][C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])=[CH:15][C:14]=2[F:29])[CH:6]=1)[CH3:2]
Reactant: N#Cc1ccc(F)cc1
Reactant: CCOC(=O)c1cc(O)cc(Oc2c(F)cc(CNC(=O)OC(C)(C)C)cc2F)c1
Product: CCOC(=O)c1cc(Oc2ccc(C#N)cc2)cc(Oc2c(F)cc(CNC(=O)OC(C)(C)C)cc2F)c1
Yield: 48.5 %

Procedure:
Using 0.5 g (1.18 mmol) of 3-[4-(tert-butoxycarbonylamino-methyl)-2,6-difluoro-phenoxy]-5-hydroxy-benzoic acid ethyl ester and 4-fluorobenzonitrile (0.21 g, 1.77 mmol) and following the procedure of Example 42(b) afforded 0.3 g of the required product. 1H NMR (DMSO-d6): δ 1.25 (3H, t), 1.42 (9H, s), 4.2 (2H, d), 4.28 (2H, q), 7.22 (6H, m), 7.32 (1H, s), 7.54 (1H, t), 7.90 (2H, d).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([C:21]2[S:22][C:23]([F:26])=[CH:24][N:25]=2)=[N:10]1.C1C(=O)N([Br:34])C(=O)C1>>[Br:34][CH2:20][C:13]1[NH:12][C:11]([C:21]2[S:22][C:23]([F:26])=[CH:24][N:25]=2)=[N:10][CH:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C1=C(C)NC(c2ncc(F)s2)=NC1c1ccc(Cl)cc1Cl
Product: CCOC(=O)C1=C(CBr)NC(c2ncc(F)s2)=NC1c1ccc(Cl)cc1Cl
Yield: 68.9 %

Procedure:
Ethyl 4-(2,4-dichlorophenyl)-2-(5-fluorothiazol-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate (0.44 g, 1.06 mmol) was reacted with NBS (0.19 g, 1.06 mmol) according to the procedure as described in Example 1, Step B to give the title compound as a yellow solid (0.36 g, 70%). The compound was characterized by the following spectroscopic data: