Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C@@:3]([OH:13])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([OH:6])=O.[F:16][C:17]1[C:22]([CH2:23][NH2:24])=[CH:21][C:20]([CH3:25])=[CH:19][N:18]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>CN(C)C=O>[F:14][C:2]([F:1])([F:15])[C@@:3]([OH:13])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([NH:24][CH2:23][C:22]1[C:17]([F:16])=[N:18][CH:19]=[C:20]([CH3:25])[CH:21]=1)=[O:6]
Reactant: O=C(O)[C@](O)(c1ccccc1)C(F)(F)F
Reactant: Cc1cnc(F)c(CN)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cnc(F)c(CNC(=O)[C@](O)(c2ccccc2)C(F)(F)F)c1
Reaction time: 14 h

Procedure:
A solution of (2R)-3,3,3-trifluoro-2-hydroxy-2-phenylpropanoic acid (6-e with R=CF3 and R′=H, 105 mg, 0.48 mmol), the amine (2-e, 67 mg, 0.48 mmol) and diisopropylethylamine (415 uL, 2.4 mmol) in N,N-dimethylformamide (1 mL) was treated at room temperature with benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBop, 274 mg, 0.53 mmol). After 14 h, the reaction mixture was partitioned between ethyl acetate and 0.5N—NaOH. The aqueous layer was removed and the organic layer was washed with 0.5N—HCl. The aqueous layer was removed by filtering through a plastic frit. The organic layer was evaporated in vacuo to give the desired product (3-1); HRMS (M+H)=343.1059; 1H NMR (500 MHz, CDCl3) δ 7.89 (bs, 1 H), 7.63 (m, 2H), 7.43 (m, 3 H), 7.39 (d, 1 H, J=7.8 Hz), 6.67 (br, 1 H), 4.72 (m, 1 H), 4.48 (d, 2H, J=6.1 Hz), 2.26 (s, 3 H); compound 3-3 [(2R)-3,3,3-trifluoro-N-(2-fluoro-5-trifluoromethylbenzyl)-2-hydroxy-2-phenylpropanamide] was prepared by the same procedure (2-fluoro-5-trifluoromethylbenzylamine was purchased from Alfa Aesar); HRMS (M+H)=396.0825; 1H NMR (500 MHz, DMSO-6d) δ 8.95 (t, 1 H), 7.95 (s, 1 H), 7.65 (m, 3 H), 7.39 (m, 5 H), 4.40 (dq, 2 H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10](=[CH:11][C:12]3[NH:13][C:14]([CH3:27])=[C:15]([CH2:18][CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[C:16]=3[CH3:17])[C:9](=[O:28])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:29][C:30]1[CH:31]=[C:32]([NH2:37])[CH:33]=[CH:34][C:35]=1[F:36]>>[ClH:1].[Cl:29][C:30]1[CH:31]=[C:32]([NH:37][C:2]2[C:3]3[C:10](=[CH:11][C:12]4[NH:13][C:14]([CH3:27])=[C:15]([CH2:18][CH2:19][CH2:20][N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)[C:16]=4[CH3:17])[C:9](=[O:28])[NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:33]=[CH:34][C:35]=1[F:36]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: Cc1[nH]c(C=C2C(=O)Nc3ncnc(Cl)c32)c(C)c1CCCN1CCOCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3ncnc(Nc4ccc(F)c(Cl)c4)c32)c(C)c1CCCN1CCOCC1
Product: Cl
Yield: 10 %

Procedure:
The title compound (10% yield) was prepared from 4-chloro-5-[3,5-dimethyl-4-(3-morpholin-4-yl-propyl)-1H-pyrrol-2-ylmethylene]-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one and 3-chloro-4-fluoro-phenylamine according to the procedure described for Example 12.
Reaction SMILES: CC([N:5]([CH2:9][CH:10]([N:18]([OH:32])[C:19]([C:21]1[S:22][CH:23]=[C:24]([C:26]2[N:30]([CH3:31])[N:29]=[CH:28][CH:27]=2)[CH:25]=1)=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C(=O)[O-])(C)C.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]>C(Cl)Cl>[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34].[NH2:5][CH2:9][CH:10]([N:18]([OH:32])[C:19]([C:21]1[S:22][CH:23]=[C:24]([C:26]2[N:30]([CH3:31])[N:29]=[CH:28][CH:27]=2)[CH:25]=1)=[O:20])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Cn1nccc1-c1csc(C(=O)N(O)C(Cc2ccccc2)CN(C(=O)[O-])C(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1-c1csc(C(=O)N(O)C(CN)Cc2ccccc2)c1
Reaction time: 1 h
Yield: 64.8 %

Procedure:
1,1-Dimethylethyl[2-(hydroxy{[4-(1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate (84 mg, 0.19 mmol) was dissolved in DCM (2 mL) and treated with TFA (1 mL). The reaction was stirred over 1 h, and concentrated, and purified by reverse-phase HPLC (C18 column: H2O/CH3CN, 40-10%), and concentrated to afford the bis-TFA salt of the title compound (51.2 mg, 64.8%). LC-MS (ES) m/z 357 (M+H)+, 1H NMR (d4-MeOD, 400 MHz) δ ppm 8.03 (s, 1H), 7.94 (d, J=1.8 Hz, 1H), 7.52 (d, J=1.8 Hz, 1H), 6.46 (d, J=1.8 Hz, 1H), 7.34-7.18 (m, 5H), 5.16 (m, 1H), 3.95 (s, 3H), 3.38 (dd, J=13.1, 10.6 Hz, 1H), 3.17-3.11 (m, 2H), and 2.95 (dd, J=13.6, 6.6 Hz, 1H)
Reaction SMILES: [N:1]1([C:6](Cl)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:9]([O:13][C:14]([NH:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(N(CC)CC)C>ClCCl>[C:9]([O:13][C:14]([NH:16][CH:17]1[CH2:18][CH2:19][N:20]([C:6]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:7])[CH2:21][CH2:22]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=C(Cl)N1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)N2CCCC2)CC1
Reaction time: 72 h

Procedure:
1-Pyrrolidine carbonylchloride (1.10 g, 9.99 mmol) was dissolved in 400 ml if dichloromethane under N2. (Tert-butoxy)-N-(4-piperidyl)carboxamide (2.0 g, 9.99 mmol) and triethyl amine (1.40 mL, 9.99 mmol) were added and the reaction mixture was stirred for three days. The reaction was quenched with sat. NaHCO3 solution and extracted with dichloromethane. The combined organic phases were dried over MgSO4 and the solvent evaporated to give the product as a white solid. (2.63 g, 8.84 mmol, 89%).
Reaction SMILES: [N:1]1([C:7]2[C:8]3[S:28][C:27]([CH2:29][N:30]4[CH2:35][CH2:34][N:33]([C:36]([CH3:41])([CH3:40])[C:37]([NH2:39])=[O:38])[CH2:32][CH2:31]4)=[CH:26][C:9]=3[N:10]=[C:11]([Sn](CCCC)(CCCC)CCCC)[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[C:43]1[N:48]2[CH:49]=[CH:50][N:51]=[C:47]2[CH:46]=[CH:45][CH:44]=1>O1CCOCC1.S1C=CC=C1C([O-])=O.[Cu+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:51]1[CH:50]=[CH:49][N:48]2[C:43]([C:11]3[N:12]=[C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[C:8]4[S:28][C:27]([CH2:29][N:30]5[CH2:35][CH2:34][N:33]([C:36]([CH3:41])([CH3:40])[C:37]([NH2:39])=[O:38])[CH2:32][CH2:31]5)=[CH:26][C:9]=4[N:10]=3)=[CH:44][CH:45]=[CH:46][C:47]=12
Reactant: Brc1cccc2nccn12
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2sc(CN3CCN(C(C)(C)C(N)=O)CC3)cc2n1
Agent: [Cu+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])c1cccs1
Solvent: C1COCCO1
Product: CC(C)(C(N)=O)N1CCN(Cc2cc3nc(-c4cccc5nccn45)nc(N4CCOCC4)c3s2)CC1
Yield: 44.1 %

Procedure:
A mixture of 2-[4-(4-morpholin-4-yl-2-(tributylstannanyl)thieno[3,2-d]pyrimidin-6-ylmethyl)piperazin-1-yl]isobutyramide (0.35 g, 0.51 mmol), 5-bromoimidazo[1,2-a]pyridine (0.11 g, 0.56 mmol), copper(I) 2-thiophene carboxylate (0.019 g, 0.1 mmol) and Pd(PPh3)4 (0.059 g, 0.05 mmol) in dioxane (5 mL) was subjected to microwave irradiation at 140° C. for 20 min. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the desired product was eluted using 2 M NH3 in MeOH. The eluent was concentrated in vacuo and the residue was purified by flash chromatography (Si—PPC, MEOH:DCM, gradient 0:100 to 10:90). The residue was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the desired product was eluted using 2 M NH3 in MeOH. The solution was concentrated in vacuo and the residue was purified by reverse phase HPLC (Phenomenex Gemini 5u C 18, 20 mM triethylamine in water on a gradient of acetonitrile 75:25 to 2:98) to give 697 as a white powder (0.117 g, 45%). LCMS: RT=4.35 min, [M+H]+ 521.2. 1H NMR (400 MHz, DMSO-d6): δ 9.33 (d, J=1.1 Hz, 1 H); 8.04 (dd, J=7.5, 1.2 Hz, 1 H); 7.78 (dd, J=8.9, 1.1 Hz, 1 H); 7.74 (d, J=1.2 Hz, 1 H); 7.54 (s, 1 H); 7.41 (dd, J=8.9, 7.5 Hz, 1 H); 7.07 (d, J=3.5 Hz, 1 H); 6.95 (d, J=3.5 Hz, 1 H); 4.00 (t, J=4.7 Hz, 4 H); 3.89 (s, 2 H); 3.82 (t, J=4.7 Hz, 4 H); 2.56-2.54 (m, 4 H); 2.49-2.44 (m, 4 H); 1.08 (s, 6 H)
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O-:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.ClC1C=CC2SC(C=C3C=C(C)C4C(=CC=CC=4)O3)=[N+](CC)C=2C=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.ClC1C=CC2SC(SCC)=[N+](CC)C=2C=1.C(#N)C>C(N(CC)CC)C>[CH3:11][C:1]1[CH:6]=[CH:5][C:4]([S:7]([OH:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: CCSc1sc2ccc(Cl)cc2[n+]1CC
Agent: CC[n+]1c(C=C2C=C(C)c3ccccc3O2)sc2ccc(Cl)cc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)O)cc1
Yield: 211.5 %

Procedure:
5.2 g of 5-chloro-3-ethyl-2-{(4-methyl-2H-chromen-2-ylidene)methyl}-benzothiazolium p-toluenesulfonate and 4.3 g of 5-chloro-3-ethyl-2-ethylthiobenzothiazolium p-toluenesulfonate were added to 140 ml of acetonitrile and dissolved under heat, and then 4.5 ml of triethylamine was added thereto and reacted for 5 minutes. After cooling the precipitated crystals were separated by filtration and recrystallized from a mixed solvent of methanol/chloroform, to obtain 3.6 g of the desired p-toluenesulfonate product. Yield: 50%. Appearance: Brilliant brown crystal. M.p.: above 240° C. (decomposition). ##STR11##
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=1.[CH2:23]([O:25][P:26]([CH:31]([C:33]1[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=1)[OH:32])(=[O:30])[O:27][CH2:28][CH3:29])[CH3:24].[C:40](O)([C:42](F)(F)F)=O>CCO>[CH2:28]([O:27][P:26]([CH:31]([O:32][CH2:40][CH3:42])[C:33]1[CH:34]=[CH:35][C:36]([NH:39][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=3[C:11](=[O:12])[NH:13][CH3:14])[C:5]([C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=2)=[CH:37][CH:38]=1)(=[O:30])[O:25][CH2:23][CH3:24])[CH3:29]
Reactant: CCOP(=O)(OCC)C(O)c1ccc(N)cc1
Reactant: O=C(O)C(F)(F)F
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1C(F)(F)F
Solvent: CCO
Product: CCOC(c1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccccc3C(=O)NC)n2)cc1)P(=O)(OCC)OCC
Temperature: 105 °C
Reaction time: 0.75 h
Yield: 12 %

Procedure:
Under N2, a solution of 2-{[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-methylbenzamide (40.0 mg, 0.12 mmol) and diethyl[(4-aminophenyl)(hydroxy)methyl]-phosphonate (37.6 mg, 0.15 mmol) in a mixture of TFA (28 uL, 0.36 mmol) and EtOH (0.5 mL) was stirred at 105° C. for 45 min in a Biotage microwave reactor. The solvents were removed under reduced pressure and to the residue was added sat. NaHCO3 (aq) (2 mL) and DCM (5 mL). Layers were separated and the aqueous layer was extracted with DCM (3×5 mL). The combined organic phases were dried over MgSO4, concentrated, and purified by silica gel chromatography (5% 7 N NH3 in MeOH in DCM) to afford the desired product as a white-colored solid (8.4 mg, yield: 12%). 1H NMR (CD3OD, 400 MHz): δ=1.22 (dt, J=0.8, 7.6 Hz, 6H), 1.30 (t, J=7.2 Hz, 3H), 2.90 (s, 3H), 3.47-3.57 (m, 2H), 3.95-4.15 (m, 4H), 4.72 (d, J=16.0 Hz, 1H), 7.18 (dt, J=1.2, 7.6 Hz, 1H), 7.35 (dd, J=2.0, 8.4 Hz, 2H), 7.49 (dd, J=1.6, 8.8 Hz, 1H), 7.63-7.65 (m, 3H), 8.34 (s, 1H), 8.45 (m, 1H). MS (ES+): m/z 582.17 [MH+] HPLC: tR=3.44 min (OpenLynx, polar—5 min).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9](=[O:18])[C:10]2[CH:15]=[C:14]([OH:16])[CH:13]=[C:12]([OH:17])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C=O)C>[C:1]1([CH2:7][O:8][C:9](=[O:18])[C:10]2[CH:11]=[C:12]([O:17][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH3:20])[CH:13]=[C:14]([OH:16])[CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCCCCCCCCCCCCCCCCBr
Reactant: O=C(OCc1ccccc1)c1cc(O)cc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCCCOc1cc(O)cc(C(=O)OCc2ccccc2)c1
Yield: 36 %

Procedure:
A mixture of 30 g (0.123 mol) of 3,5-dihydroxybenzoic acid phenylmethyl ester, 40.9 g (0.123 mol) of 1-bromooctadecane, 17 g (0.123 mol) of anhydrous potassium carbonate in 500 ml of acetone and 10 ml of DMF was stirred at reflux for 25 hours. The reaction mixture was filtered and the filtrate was concentrated at reduced pressure to a solid. The residue was treated with water and the product was extracted with methylene chloride. The dried extract was concentrated at reduced pressure to a solid which was purified by HPLC using 1% ethyl acetate-methylene chloride to give 22 g (36% yield, mp 72°-75°) of 3-hydroxy-5-(octadecyloxy)benzoic acid phenylmethyl ester. The structure was confirmed by nmr and mass spectra.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([Li])[CH2:10]CC>>[OH:8][C:1]1[C:2]2[C:7](=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:10][CH:9]=1
Reactant: [Li]CCCC
Reactant: O=Cc1ccccc1
Product: OC1=CCc2ccccc21

Procedure:
Alternatively, compounds of formula I can be prepared as shown in Scheme 10. A benzaldehyde derivative 7-1 can be alkylated by treatment with n-butyllithium in the presence of N,N,N′-trimethylethane-1,2-diaminene followed by quenching with acrolein. The resulting semiacetal 10-1 can be converted to an olefin by treating with Ph3PCH3Br/n-butyllithium. Cyclization using Grubbs catalyst gives rise to 3-hydroxyindene derivative 10-3 which can be subjected to an oxidation using an oxidant such as pyridinium chlorochromate (PCC). Michael addition of intermediate 8-5 to the resulting ketone 10-4 affords intermediate 10-5. Following reduction of the ketone to alcohol, alkylation with R9I can be accomplished using a base such as sodium hydride. Removal of Boc followed by coupling with R1CO2H using a coupling agent such as EDCI/HOBt affords compounds of formula 10-7.
Reaction SMILES: ClC1C=C(Cl)C=CC=1C(=O)CCl.[C:13]1(=O)[NH:17][C:16](=O)[C:15]2=CC=CC=C12.C1(=O)OC(=O)CC1O.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.[NH2:38][C:39]1[N:44]=[C:43]([NH:45][CH2:46][CH2:47][NH:48][C:49]2[N:54]=[C:53]([C:55]3[CH:60]=[CH:59][C:58]([Cl:61])=[CH:57][C:56]=3[Cl:62])[C:52]([N:63]3[C:67](=[O:68])[CH:66]=CC3=O)=[CH:51][N:50]=2)[CH:42]=[CH:41][C:40]=1[N+:70]([O-:72])=[O:71]>>[NH2:38][C:39]1[N:44]=[C:43]([NH:45][CH2:46][CH2:47][NH:48][C:49]2[N:54]=[C:53]([C:55]3[CH:60]=[CH:59][C:58]([Cl:61])=[CH:57][C:56]=3[Cl:62])[C:52]([N:63]3[C:67](=[O:68])[CH2:66][CH:37]([N:32]4[CH2:15][CH2:16][N:17]([CH3:13])[CH2:34][CH2:33]4)[C:36]3=[O:35])=[CH:51][N:50]=2)[CH:42]=[CH:41][C:40]=1[N+:70]([O-:72])=[O:71]
Reactant: C1COCCN1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Nc1nc(NCCNc2ncc(N3C(=O)C=CC3=O)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Agent: O=C(CCl)c1ccc(Cl)cc1Cl
Agent: O=C1CC(O)C(=O)O1
Product: CN1CCN(C2CC(=O)N(c3cnc(NCCNc4ccc([N+](=O)[O-])c(N)n4)nc3-c3ccc(Cl)cc3Cl)C2=O)CC1

Procedure:
1-[2-({2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}amino)-4-(2,4-dichlorophenyl-pyrimidin-5-yl]-3-(4-methylpiperazinyl)pyrrolidine-2,5-dione was made in accordance with the foregoing procedures through steps A using 1-(2,4-dichlorophenyl)-2-chloroethan-1-one and phthalimide, B, C using amino{2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}-carboxamidine, D, E, K using malic anhydride, and F. Large excess of morpholine was added to clean fractions of 1-[2-({2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}amino)-4-(2,4-dichlorophenyl)pyrimidin-5-yl]-3-pyrroline-2,5-dione concentrated in vacuo, and purified by column chromatography eluting with 5-10% methanol/methylene chloride.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:4]=[C:3]1[C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1.[Na].[CH2:29](N(CC)CC)C.S(Cl)(Cl)=O>ClCl.CO>[CH3:29][O:24][C:23](=[O:25])[C:22]1[CH:21]=[CH:20][C:19]([C:3]2[N:2]([CH3:1])[C:6]([C:7]3[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=3)=[C:5]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:4]=2)=[CH:27][CH:26]=1
Reactant: Cn1c(-c2ccc(C(=O)O)cc2)nc(-c2ccccc2)c1-c1ccncc1
Reactant: CCN(CC)CC
Agent: ClCl
Agent: [Na]
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)c1ccc(-c2nc(-c3ccccc3)c(-c3ccncc3)n2C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 8 %

Procedure:
To a suspension of 4-[1-methyl-4-phenyl-5(4-pyridyl)-imidazol-2-yl]benzoic acid, sodium salt (20 mg, 0.06 mmol) [See Ex. 5 above] in CH2 Cl2 (2 mL.) was added triethylamine (24 mL, 0.17 mmol), followed by thionyl chloride (10 mL, 0.14 mmol). The reaction mixture was stirred at rt for 30 min, at which time MeOH (0.5 mL) was added. The mixture was stirred at rt for an additional 2 h and concentrated under reduced pressure. The residue was purified by flash chromatography, eluting with a solvent gradient of 0-1% MeOH/CHCl3 and recrystallized from EtOAc to afford the title compound as an off-white crystalline solid (1.6 mg, 8%): mp 208°-209° C.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[CH2:13]([CH:15]1[O:17][CH2:16]1)Br.O>CN(C=O)C>[O:17]1[CH2:16][CH:15]1[CH2:13][N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6]
Reactant: BrCC1CO1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CC1CO1
Temperature: 120 °C
Reaction time: 3 h
Yield: 51.2 %

Procedure:
Step1: To a suspension of potassium phthalimide (5.0 g, 27 mmol) in DMF (75 ml) was added epibromohydrin (2.5 ml, 29 mmol), and the mixture was stirred at 120° C. for 3 h. After adding water, the mixture was extracted with (hexane/ethyl acetate=3/1), washed with brine, dried over magnesium sulfate, and then filtered. Concentrating under vacuum gave N-(2,3-epoxypropyl)phthalimide (2.81 g, 51%) which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:18]([O-:20])=O)=[C:6]([C:8]2[C:9]([C:14](OC)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=1.[H][H]>CO.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:18]([OH:20])[C:14](=[O:15])[C:9]3[C:8](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]=2[CH:7]=1
Reactant: COC(=O)c1ccccc1-c1cc(F)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=c1c2ccccc2c2cc(F)ccc2n1O
Yield: 98.1 %

Procedure:
To a solution of the product of Example 37a (methyl 5′-fluoro-2′-nitrobiphenyl-2-carboxylate, 56.79 mg, 0.206 mmol) in methanol (9 mL) was added 10% palladium on carbon (15.6 mg, 0.015 mmol). The flask was fitted with a hydrogen balloon and de-gassed three times with hydrogen. The reaction mixture was stirred, diluted with dimethylformamide, and filtered. The filtrate was concentrated to provide 2-fluoro-5-hydroxyphenanthridin-6(5H)-one (37b, 46.36 mg, 0.202 mmol, 98% yield).
Reaction SMILES: [F:1][C:2]([F:21])([C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]#[N:13])=[CH:8][CH:7]=1)=[O:4].[N-:22]=[N+:23]=[N-:24].[Na+].[Cl-].[NH4+].CN(C)C=O>O>[F:1][C:2]([F:21])([C:14]([F:19])([F:20])[C:15]([F:18])([F:16])[F:17])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[NH:24][N:23]=[N:22][N:13]=2)=[CH:8][CH:7]=1)=[O:4]
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(NC(=O)C(F)(F)C(F)(F)C(F)(F)F)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(-c2nnn[nH]2)cc1)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
A mixture of 2,2,3,3,4,4,4-heptafluoro-N-[4-(cyano)phenyl]butanamide (1.5 g,) sodium azide (1.55 g), ammonium chloride (1.28 g) and dimethylformamide (20 mL) was heated in a 130°-135° C. oil bath overnight. The reaction mixture was then poured onto 200 mL of water and the resulting solid was filtered off and recrystallized from ethanol. The product was dried at 100° C. overnight using an abderhalden (drying pistol) to give the title compound, m.p. 266°-268° C.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:3]=1[O:4][CH:5]([CH3:9])[C:6](Cl)=[O:7].[Mg].[C:16]([O:24][CH2:25][CH3:26])(=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C(OCC)(=O)CC(OCC)=O>CCOCC>[CH2:21]([O:20][C:18](=[O:19])[CH:17]([C:6](=[O:7])[CH:5]([O:4][C:3]1[CH:10]=[CH:11][C:12]([Cl:14])=[CH:13][C:2]=1[Cl:1])[CH3:9])[C:16]([O:24][CH2:25][CH3:26])=[O:23])[CH3:22]
Reactant: CC(Oc1ccc(Cl)cc1Cl)C(=O)Cl
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Mg]
Solvent: CCOCC
Product: CCOC(=O)C(C(=O)OCC)C(=O)C(C)Oc1ccc(Cl)cc1Cl
Yield: 76 %

Procedure:
A mixture of 25 g of 2-(2',4'-dichloro-phenoxy)-propionyl chloride and 30 ml of ether is added dropwise to a 35% etheral solution of magnesium-diethyl malonate prepared from 17.6 g of diethyl malonate. When the addition of the acid chloride is completed the reaction mixture is heated to boiling for an hour and worked up as described in Example 1. Thus 29 g of the desired compound are obtained in the form of a yellow oil, yield 76%, nD25 =1,355.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([NH:13][C:14](=[O:25])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([OH:23])=[C:17](O)[CH:16]=3)[CH:10]=[N:9]2)=[C:5]([CH3:26])[O:4][N:3]=1.[C:27](=[O:30])([O-])[O-].[Cs+].[Cs+].Br[CH:34](Br)C>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([NH:13][C:14]([C:15]3[CH:16]=[C:17]([O:30][CH3:27])[C:18]4[O:23][CH2:34][CH2:22][O:21][C:19]=4[CH:20]=3)=[O:25])[CH:10]=[N:9]2)=[C:5]([CH3:26])[O:4][N:3]=1
Reactant: O=C([O-])[O-]
Reactant: CC(Br)Br
Reactant: COc1cc(C(=O)Nc2cnn(Cc3c(C)noc3C)c2)cc(O)c1O
Agent: [Cs+]
Product: COc1cc(C(=O)Nc2cnn(Cc3c(C)noc3C)c2)cc2c1OCCO2
Yield: 20 %

Procedure:
Prepared as in Example 4-92 from N-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-3,4-dihydroxy-5-methoxybenzamide (Example 4-73), cesium carbonate and dibromoethane. Yield 20%. MS M+H calculated 385.1, found 385.1.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][O:20][CH:21]1[CH2:25][CH2:24][N:23]([C:26]2[N:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=2)[CH2:22]1>>[CH3:19][O:20][CH:21]1[CH2:25][CH2:24][N:23]([C:26]2[N:31]=[CH:30][C:29]([NH:32][C:12]([C:10]3[N:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[O:8][C:9]=3[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:28][CH:27]=2)[CH2:22]1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: COC1CCN(c2ccc(N)cn2)C1
Product: COC1CCN(c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cn2)C1

Procedure:
With a procedure similar to example 16 above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(3-methoxy-pyrrolidin-1-yl)-pyridin-3-yl]-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and 6-(3-methoxy-pyrrolidin-1-yl)-pyridin-3-ylamine. LCMS calcd for C21H19F3N4O3 (m/e) 432, obsd 433 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH:15]([CH2:17][C:18]4[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[CH:21]=[CH:20][CH:19]=4)[CH2:14][CH2:13][CH2:12][C:11]=3[C:10]([CH2:28][OH:29])=[N:9]2)=[CH:4][CH:3]=1.N1[CH:35]=[CH:34]C=CC=1.[OH2:36].Cl>C(Cl)Cl>[C:34]([O:29][CH2:28][C:10]1[C:11]2[CH2:12][CH2:13][CH2:14][CH:15]([CH2:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=[CH:20][CH:19]=3)[C:16]=2[N:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:9]=1)(=[O:36])[CH3:35]
Reactant: O
Reactant: c1ccncc1
Reactant: OCc1nn(-c2ccc(F)cc2)c2c1CCCC2Cc1cccc2ccccc12
Agent: Cl
Solvent: ClCCl
Product: CC(=O)OCc1nn(-c2ccc(F)cc2)c2c1CCCC2Cc1cccc2ccccc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
1-(4-Fluorophenyl)-7-[(1-naphthyl)methyl]-4,5,6,7-tetrahydro-1H-indazole-3-methanol (CP 366, 0.864 mmol, 0.334 g) and 0.077 mL (1.35 mmol, 0.085 g) of pyridine were dissolved in 3 mL of CH2Cl2 and cooled to 0° C. under N2Acetyl chloride (1.08 mmol, 0.107 g, 0.109 mL) was added and the solution was stirred at 0° C. for 2 h. Water and 2N aqueous HCl were added and the mixture was extracted with ether. The organic layer was washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4 and concentrated to give 0.350 g (94%) of the title compound as an off-white solid. Recrystallization from EtOAc:hexanes afforded 0.084 g of analytically pure white solid, m.p. 142°-144° C.; 1H NMR (CDCl3, 300 MHz) 1.5-2.1 (complex, 4H), 2.13 (s, 3H), 2.52 (m, 1H), 2.71 (m, 1H), 2.84 (dd, 1H, J=11.1, 13.8), 3.14 (dd, 1H, J=4.1, 13.8), 3.38 (m, 1H), 5.16 (s, 2H), 7.10 (d, 2H, J=8.0), 7.2-7.5 (complex, 7H). 7.68 (d, 1H, J=8.2), 7.79 (d, 1H, J=8.0); IR (KBr) 1733, 1516, 1222 cm-1 ; MS (DCI) m/z 429 (base), 369. Anal. Calcd. for Calcd. for C27H25FN2O2 : C, 75.68; H, 5.88; N, 6.54. Found: C, 75.46; H, 5.83; N, 6.29.