Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Si](C1C=CC=CC=1)(C1C=CC=CC=1)[O:6][C:7]1[CH:45]=[CH:44][C:10]([O:11][CH2:12][C@@H:13]([OH:43])[CH2:14][NH:15][CH2:16][CH2:17][C:18]2[CH:42]=[CH:41][C:21]([NH:22][CH:23]3[CH2:28][CH2:27][N:26]([C:29]([NH:31][CH2:32][C:33]4[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=4[F:40])=[O:30])[CH2:25][CH2:24]3)=[CH:20][CH:19]=2)=[CH:9][CH:8]=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[F:40][C:34]1[CH:35]=[CH:36][C:37]([F:39])=[CH:38][C:33]=1[CH2:32][NH:31][C:29]([N:26]1[CH2:27][CH2:28][CH:23]([NH:22][C:21]2[CH:41]=[CH:42][C:18]([CH2:17][CH2:16][NH:15][CH2:14][C@H:13]([OH:43])[CH2:12][O:11][C:10]3[CH:9]=[CH:8][C:7]([OH:6])=[CH:45][CH:44]=3)=[CH:19][CH:20]=2)[CH2:24][CH2:25]1)=[O:30]
Reactant: CC(C)(C)[Si](Oc1ccc(OC[C@@H](O)CNCCc2ccc(NC3CCN(C(=O)NCc4cc(F)ccc4F)CC3)cc2)cc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(NCc1cc(F)ccc1F)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 44.8 %

Procedure:
4-[4-(2-{[(2S)-3-(4-{[tert-Butyl (diphenyl)silyl]oxy}phenoxy)-2-hydroxypropyl]amino}ethyl)anilino]-N-(2,5-difluorobenzyl)-1-piperidinecarboxamide (0.238 g, 0.29 mmol) was reacted according to Procedure H (eluant: 5:1 chloroform-methanol containing 1% ammonium hydroxide) to give the title compound (0.075 g, 0.13 mmol).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH:16]2[CH2:18][CH2:17]2)[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH2:23])([CH3:4])([CH3:3])[CH3:2].C([O:29][C:30](=O)[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2[CH:45]=[CH:44][N:43]=[C:42]([CH3:46])[CH:41]=2)[CH:35]=1)=[O:33])(C)(C)C>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH:16]2[CH2:17][CH2:18]2)[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:30](=[O:29])[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2[CH:45]=[CH:44][N:43]=[C:42]([CH3:46])[CH:41]=2)[CH:35]=1)=[O:33])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC2CC2)c(C(F)(F)F)cc1N
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(OCC4CC4)cc3NC(=O)OC(C)(C)C)c2)ccn1

Procedure:
The title compound was prepared from (2-amino-5-cyclopropylmethoxy-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J29) (260 mg, 0.75 mmol) and 3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K12) (234 mg, 0.75 mmol) according to the general procedure M. Obtained as an amorphous yellow substance (325 mg, 74%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:17]([NH2:19])=[C:16]([O:20][CH3:21])[C:15]([O:22][CH3:23])=[CH:14][C:13]=3[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:24](N1C=CN=C1)(N1C=CN=C1)=[O:25]>ClCCCl>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:9]3[C:18]4[C:13]([N:12]=[CH:11][N:10]=3)=[CH:14][C:15]([O:22][CH3:23])=[C:16]([O:20][CH3:21])[C:17]=4[NH:19][C:24]2=[O:25])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2ncnc(Nc3cccc(Br)c3)c2c(N)c1OC
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCCl
Product: COc1cc2ncnc3c2c(c1OC)NC(=O)N3c1cccc(Br)c1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
To a solution of N4-(3-bromo-phenyl)-6,7-dimethoxy-quinazoline-4,5-diamine (0.15 g, 0.40 mmol) (from Example 6, Step B, supra) in 1,2-dichloroethane (50 mL) was added 1,1′-carbonyldiimidazole (0.65 g, 4.0 mmol) (Aldrich). The reaction mixture was heated with stirring at 90° C. for 4 hours. The solvents were evaporated and the residue was purified by chromatography using EtOAc/CH2Cl2/Et3N (1:1:0.05) as eluent to give the desired 3-(3-bromo-phenyl)-8,9-dimethoxy-1H,3H-1,3,4,6-tetraaza-phenalen-2-one as a brown solid. (Yield 0.12 g, 75%).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)=[N:7][CH:8]=1.[OH-].[Na+].C(O)COCCO.Cl>O>[OH:2][C:3]1[CH:4]=[N:5][C:6]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:14]=2)=[N:7][CH:8]=1
Reactant: COc1cnc(-c2ccc(OCc3ccccc3)cc2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: Oc1cnc(-c2ccc(OCc3ccccc3)cc2)nc1
Yield: 91 %

Procedure:
A mixture of 8.42 g of 5-methoxy-2-(4-benzyloxyphenyl)pyrimidine, 6.9 g of sodium hydroxide, and 84 ml of diethylene glycol was heated at 190° to 200° C. for 2 hours. After cooling, the reaction mixture was poured into 300 ml of water, neutralized with a 1% hydrochloric acid aqueous solution, and extracted with ethyl acetate. Distillation of the extract to remove ethyl acetate gave 7.3 g (26.2 mmol; percent yield: 91.8%) of 5-hydroxy-2-(4-benzyloxyphenyl)pyrimidine.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:10][C:9](Cl)=[N:8][C:7]=1[C:12]([F:15])([F:14])[F:13])=[O:5])[CH3:2].[C:16]1([OH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Na]>CN(C=O)C.CCOCC>[O:22]([C:9]1[O:10][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:7]([C:12]([F:15])([F:14])[F:13])[N:8]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)c1oc(Cl)nc1C(F)(F)F
Reactant: Oc1ccccc1
Agent: [Na]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)c1oc(Oc2ccccc2)nc1C(F)(F)F
Reaction time: 1 h

Procedure:
The compound of Example 5, ethyl 2-chloro-4-trifluoromethyl-5-oxazolecarboxylate (4.87 g; 0.02 mol) was added to a mixture of sodium phenol in 100 ml DMF. The reaction was allowed to progress at ambient temperature for 1 hour. Gas chromatographic analysis, at this point, indicated the completion of the reaction. The dark brown liquid was then slurried in ether and washed 5 times with NaOH (5%) and H2O. The resulting brown liquid was dried (MgSO4) and concentrated in vacuo to yield 5.2 g of a brown semi-solid. Bulb to bulb distillation at 75° C./25 mm gave 1.7 g of a colorless oil. Further distillation at 130° C./0.25 mm gave 2.8 g of a white solid. Recrystallization from methylcyclohexane gave 1.08 g of pure white solid, ethyl 2-phenoxy-4-trifluoromethyl-5-oxazolecarboxylate, mp 75°-77° C., yield 18%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:6]([Cl:10])[C:7]=1OC.Br[C:21]([C:23]([F:26])([F:25])[F:24])=[CH2:22].C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:10][C:6]1[CH:5]=[C:4]([C:21]([C:23]([F:26])([F:25])[F:24])=[CH2:22])[CH:3]=[C:2]([Cl:1])[C:7]=1[C:23]([F:26])([F:25])[F:24]
Reactant: COc1c(Cl)cc(B2OC(C)(C)C(C)(C)O2)cc1Cl
Reactant: C=C(Br)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: C=C(c1cc(Cl)c(C(F)(F)F)c(Cl)c1)C(F)(F)F
Temperature: 70 °C
Yield: 81.4 %

Procedure:
A mixture of 2-(3,5-dichloro-4-(methoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.4 g, 1.33 mmol), 2-bromo-3,3,3-trifluoroprop-1-ene (0.28 g, 1.59 mmol), Cs2CO3 (1.33 mL, 2M, 2.66 mmol) and Pd(PPh3)2Cl2 (28 mg) in THF (30 mL) was heated at 70° C. in a sealed tube for 4 h. The mixture was cooled to rt and partitioned between ether and H2O. The aqueous layer was extracted with EA and the combined organic layers were dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by column chromatography over silica gel eluted with hexanes to give 1,3-dichloro-2-(trifluoromethyl)-5-(3,3,3-trifluoro-prop-1-en-2-yl)benzene (0.2 g, yield 56%) as colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.39 (s, 2 H), 6.00 (s, 1 H), 5.78 (s, 1 H), 3.93 (s, 3 H) ppm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=O)[NH2:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.C(Cl)(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[N:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=O)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C#N)CC1
Yield: 67.9 %

Procedure:
To a solution of 4-carbamoylpiperidine-1-carboxylic acid tert-butyl ester (5.6 g) in a mixture of tetrahydrofuran (110 ml) and carbon tetrachloride (90 ml) was added triphenylphosphine (24.4 g), and the mixture was stirred under reflux for 1.5 hours. After completion of the reaction, the reaction mixture was filtrated and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) and dried under reduced pressure to give the title compound (3.5 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][NH:5]1.C(N(C(C)C)CC)(C)C.Cl[C:19]1[N:24]([CH3:25])[C:23](=[O:26])[C:22]([C:27]2[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=2)=[C:21]([C:34]2[CH:39]=[CH:38][N:37]=[C:36]([Cl:40])[CH:35]=2)[N:20]=1>ClCCl>[Cl:40][C:36]1[CH:35]=[C:34]([C:21]2[N:20]=[C:19]([N:5]3[CH2:6][CH2:7][CH2:8][CH:4]3[CH2:3][O:2][CH3:1])[N:24]([CH3:25])[C:23](=[O:26])[C:22]=2[C:27]2[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=2)[CH:39]=[CH:38][N:37]=1
Reactant: COC[C@@H]1CCCN1
Reactant: Cc1cccc(-c2c(-c3ccnc(Cl)c3)nc(Cl)n(C)c2=O)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCC1CCCN1c1nc(-c2ccnc(Cl)c2)c(-c2cccc(C)c2)c(=O)n1C
Reaction time: 0.17 h

Procedure:
To a 100 mL RBF, was added (S)-2-methoxymethyl-pyrrolidine (0.172 g, 1.5 mmol), and 50 mL dichloromethane at 0° C. under nitrogen. 0.35 mL diisopropylethylamine (2.0 mmol) was added drop wise, and stirred for 10 min. 2-Chloro-6-(2-chloropyridin-4-yl)-3-methyl-5-m-tolyl-3H-pyrimidin-4-one (0.345 g, 1.0 mmol) was added in one portion, and stirred at 0° C. to rt for 12 h. The mixture was diluted with 100 mL dichloromethane, washed with sat. NaHCO3 and brine. After purified by flash chromatography, the title compound was obtained in 0.40 g as pale yellow solid. MS (ES+): 425 (M+H)+.
Reaction SMILES: [N+](C1C=CC=CC=1C1C=CC(C[N:17]2[C:21]([CH2:22][O:23][CH3:24])=[C:20]([Cl:25])[N:19]=[C:18]2[CH2:26][CH2:27][CH2:28][CH3:29])=CC=1)([O-])=O.C(O)(=O)C>[Fe].CO>[CH2:26]([C:18]1[NH:17][C:21]([CH2:22][O:23][CH3:24])=[C:20]([Cl:25])[N:19]=1)[CH2:27][CH2:28][CH3:29]
Reactant: CCCCc1nc(Cl)c(COC)n1Cc1ccc(-c2ccccc2[N+](=O)[O-])cc1
Agent: [Fe]
Solvent: CO
Solvent: CC(=O)O
Product: CCCCc1nc(Cl)c(COC)[nH]1

Procedure:
A solution of 4.40 g of 1-[(2'-nitrobiphenyl-4-yl)methyl]-2-butyl-4-chloro-5-methoxymethylimidazole, 2.10 g of iron powder, 4.25 mL of glacial acetic acid, and 200 mL of methanol was refluxed for 5 hours. After cooling, the solvent was removed in vacuo, and the residue was dissolved in ethyl acetate. The precipitated iron salts were removed by filtration through Celite®, and the resulting solution was washed with water and brine, dried over anhydrous sodium sulfate and concentrated. Column chromatography on silica gel (elution: 10-30% ethyl acetate/benzene) furnished 2.95 g of 1-[2'-aminobiphenyl-4-yl)methyl]-2-butyl-4-chloro-5-methoxymethylimidazole; NMR (200 MHz, CDCl3): δ7.43 (d, 2H); 7.19-7.04 (m, 4H); 6.80 (m, 2H); 5.19 (s, 2H); 4.33 (s, 2H); 3.70 (br s, 1H); 3.28 (s, 3H); 2.59 (t, 2H); 1.67 (quint., 2H); 1.34 (sext., 2H); 0.87 (t, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].Cl.[NH:12]1[CH2:17][CH2:16][C:15](O)([OH:18])[CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>ClCCl.O>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:12]1[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]1)=[O:5]
Reactant: OC1(O)CCNCC1
Reactant: Cc1ccccc1C(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: Cc1ccccc1C(=O)N1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.2 %

Procedure:
To a solution of 2-methylbenzoyl chloride (800 mg, 5.2 mmol) in 5 mL of DICHLOROMETHANE was added a mixture of piperidine-4,4-diol hydrochloride salt 800 mg, 5.2 mmol) and potassium carbonate (716 mg, 5.2 mmol) in 5 mL H2O and stirred at room temperature for 2 hours. Layers were separated and aqueous layer was extracted with dichloromethane (3×10 mL). Organic layers were combined, dried, filtered and the filtrate was concentrated in vacuo to give the tile compound (1.2 g) as light yellow oil. MS (M+1): 218.0
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.CN1C(=O)CCC1.[OH-].[K+].[CH:25]([C:27]1[CH:28]=[CH:29][C:30]([CH2:33][CH2:34][CH2:35][N:36]2C(=O)C3C(=CC=CC=3)C2=O)=[N:31][CH:32]=1)=[CH2:26]>O>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:26][CH2:25][C:27]3[CH:28]=[CH:29][C:30]([CH2:33][CH2:34][CH2:35][NH2:36])=[N:31][CH:32]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: C=Cc1ccc(CCCN2C(=O)c3ccccc3C2=O)nc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(CCCN)nc2)CCN(C)C1
Temperature: 120 °C
Reaction time: 12 h
Yield: 44.1 %

Procedure:
2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.005 mol) was taken into NMP (3 mL), and to it was added finely crushed KOH (280 mg, 0.005 mol) and 2-(3-(5-vinylpyridin-2-yl)propyl)isoindoline-1,3-dione (146 mg, 0.005 mol). The reaction was heated at 120° C. for 12 h. The reaction was monitored by LCMS. After 12 h, 2 mL of water was added to the reaction mixture and heated at 120° C. for 12 h. The reaction was monitored by LCMS. After completion of reaction the mixture was cooled and water was added, followed by extraction with EtOAc. The organic extract was dried over sodium sulfate and concentrated under vacuum to yield 800 mg of crude product. 1HNMR (CDCl3, Oxalate salt) d (ppm): 8.17 (s, 1H), 7.22 (s, 1H), 1.18 (d, 1H), 7.15 (d, 1H), 6.95 (m, 2H), 4.20 (t, 2H), 3.70 (s, 2H), 3.0 (t, 2H), 2.90 (t, 2H), 2.80 (t, 2H), 2.70 (t, 2H), 2.58 (s, 3H), 2.40 (s, 3H), 2.37 (m, 2H), 1.80 (t, 2H).
Reaction SMILES: [C:1]([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([O:17][CH3:18])[C:13]([S:15][CH3:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1)(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:27])C=1>>[C:1]([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([O:17][CH3:18])[C:13]([S:15]([CH3:16])=[O:27])=[CH:14][C:7]=2[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cc2c(cc1SC)CCN(C(C)=O)CC2
Product: COc1cc2c(cc1S(C)=O)CCN(C(C)=O)CC2

Procedure:
Following the general procedure of Example 4, 3-acetyl-8-methoxy-7-methylthio-2,3,4,5-tetrahydro-1H3-benzazepine is reacted with one equivalent of 3-chloroperbenzoic acid to give 3-acetyl-8-methoxy-7-methylsulfinyl-2,3,4,5-tetrahydro-1H-3-benzazepine. Following the procedure of Example 4, 3-acetyl-8-methoxy-7-methylsulfinyl-2,3,4,5-tetrahydro-1H-3-benzazepine is reacted with 3N hydrochloric acid to give 8-methoxy-7-methylsulfinyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride. This methoxy compound is treated with pyridine hydrochloride to give 8-hydroxy-7-methylsulfinyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[C:16]([Cl:18])[N:15]=[C:14]([Cl:19])[CH:13]=2)[N:3]=1.[Cl:20][C:21]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:22]=1[NH2:23]>>[Cl:20][C:21]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:22]=1[NH:23][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[C:16]([Cl:18])[N:15]=[C:14]([Cl:19])[CH:13]=2)[N:3]=1
Reactant: COc1ccc(Cl)c(N)c1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cc(Cl)nc(Cl)c2)n1
Product: COc1ccc(Cl)c(Nc2cc(C(F)(F)F)nc(-c3cc(Cl)nc(Cl)c3)n2)c1

Procedure:
The title compound was prepared from 4-chloro-2-(2,6-dichloro-4-pyridinyl)-6-trifluoromethyl-pyrimidine (52 mg, 0.159 mmol) and 2-chloro-5-methoxyaniline (40 mg, 0.255 mmol) similar to Example 160 and was isolated as a yellow crystalline solid (13 mg, 0.029 mmol, 18%). 1H NMR (CDCl3): 8.27 (s, 2H), 7.76 (s, br, 1H), 7.40 (s, 1H), 7.38 (s, 1H), 7.02 (s, 1H), 6.77 (m, 1H), 3.90 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[C:10]1(=[O:16])[O:15][C:13](=[O:14])[CH:12]=[CH:11]1.O>CN(C=O)C>[C:7]([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:10]([CH:11]=[CH:12][C:13]([OH:15])=[O:14])=[O:16])([OH:9])=[O:8]
Reactant: O=C1C=CC(=O)O1
Reactant: NCCCCCC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)C=CC(=O)NCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
6-Aminocaproic acid (10.1 g, 81.6 mmol) was added to maleic anhydride (8.09 g, 82.6 mmol), in 100 mL of anhydrous DMF. The mixture was stirred at room temperature for 24 h and poured into 250 mL of water. White precipitate was filtered, washed with ether and dried (15 g, 86%). 1H NMR (DMSO-d6): δ 1.27-1.33 (2H, m), 1.45-1.54 (4H, m), 2.21 (2H, t, J=7.3), 3.18 (2H, q, J=6.7), 6.24 (1H, d, J=13.0), 6.42 (1H, d, J=12.5), 9.11 (1H, br s), 13.6 (1H, br).
Reaction SMILES: [CH:1]([Mg]Cl)([CH3:3])[CH3:2].[Cl:6][C:7]1[C:15]2[N:14]=[C:13]3[N:16]([C:20]4[C:21]([CH3:28])=[N:22][C:23](Cl)=[N:24][C:25]=4[CH3:26])[CH2:17][CH2:18][CH2:19][N:12]3[C:11]=2[C:10]([CH:29]([O:34][CH:35]([F:37])[F:36])[C:30]([F:33])([F:32])[F:31])=[CH:9][CH:8]=1.FC(F)(F)C(O)=O>O1CCCC1.[Cl-].[NH4+].Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:6][C:7]1[C:15]2[N:14]=[C:13]3[N:16]([C:20]4[C:25]([CH3:26])=[N:24][C:23]([CH:1]([CH3:3])[CH3:2])=[N:22][C:21]=4[CH3:28])[CH2:17][CH2:18][CH2:19][N:12]3[C:11]=2[C:10]([CH:29]([O:34][CH:35]([F:36])[F:37])[C:30]([F:33])([F:32])[F:31])=[CH:9][CH:8]=1
Reactant: Cc1nc(Cl)nc(C)c1N1CCCn2c1nc1c(Cl)ccc(C(OC(F)F)C(F)(F)F)c12
Reactant: CC(C)[Mg]Cl
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: Cc1nc(C(C)C)nc(C)c1N1CCCn2c1nc1c(Cl)ccc(C(OC(F)F)C(F)(F)F)c12
Temperature: 25 °C
Reaction time: 14 h

Procedure:
i-Propylmagnesium chloride (1.0 M solution in tetrahydrofuran, 0.76 mL, 0.760 mmol) was added dropwise to a stirred suspension of 9-chloro-1-(2-chloro-4,6-dimethylpyrimidin-5-yl)-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole (189 mg, 0.381 mmol) and [1,3-bis(diphenylphosphino)propane]dichloronickel (20.7 mg, 0.0381 mmol) in tetrahydrofuran (1.5 mL) at 0° C., and the mixture was stirred at room temperature for 14 hr. The mixture was diluted with aqueous ammonium chloride and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 50-100% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was purified by preparative HPLC to give a mixture containing an intermediate of the title compound as the trifluoroacetic acid salt. The mixture was washed with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/n-hexane to give the title compound as a colorless crystal (19.1 mg, 0.0379 mmol, 10%).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:31])[CH:14]([P:23]([O:28][CH2:29][CH3:30])([O:25][CH2:26][CH3:27])=[O:24])[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(C)(C)C>ClCCl>[CH2:29]([O:28][P:23]([CH:14]([CH2:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:13]([OH:31])=[O:12])([O:25][CH2:26][CH3:27])=[O:24])[CH3:30]
Reactant: CCOP(=O)(OCC)C(CCc1ccccc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOP(=O)(OCC)C(CCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (4 mL) was added drop wise to a stirring solution of 2-(diethoxy-phosphoryl)-4-phenyl-butyric acid tert-butyl ester (1.00 g, 2.81 mmol) in anhydrous dichloromethane (16 ml). The mixture was stirred for 2 hours at room temperature followed by the removal of the solvent. The crude residue was purified by flash chromatography (100% dichloromethane-2.5% methanol in dichloromethane) to afford the desired compound as a yellowish oil. 1H NMR (CDCl3, 400 MHz) δ 11.21 (br s, 1H), 7.29–7.14 (m, 5H), 4.24–4.12 (m, 4H), 3.09–3.00 (m, 1H), 2.82–2.75 (m, 1H), 2.64–2.57 (m, 1H), 2.35–2.27 (m, 1H), 2.15–2.11 (m, 1H), 1.31–1.25 (m, 6H); 13C (CDCl3, 100 MHz) δ 170.4, 140.4, 128.4, 128.3, 126.1, 63.4, 63.2, 45.1, 43.8, 34.0, 28.5, 16.0; 31p (CDCl3, 400 MHz) δ 24.3; HRMS calcd. for C14H21O5P 300.1127. found 300.1129.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13](F)[C:12]=1[N+:18]([O-:20])=[O:19].C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[F:10][C:11]1[C:12]([N+:18]([O-:20])=[O:19])=[C:13]([NH:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)CCN
Reactant: O=[N+]([O-])c1c(F)cccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)CCNc1cccc(F)c1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
A round bottomed flask was charged with ethyl 3-aminopropanoate hydrochloride (1 g, 6.51 mmol), 1,3-difluoro-2-nitrobenzene (1.036 g, 6.51 mmol), potassium carbonate (2.70 g, 19.53 mmol), and a stirbar. THF (35 mL, 0.2 M) was added, and the mixture was stirred at 100° C. overnight. The mixture was concentrated with celite and purified by silica gel chromatography (eluting with hexanes/ethyl acetate) to yield ethyl 3-(3-fluoro-2-nitrophenylamino)propionate as a yellow amorphous solid (1.473 g, 5.75 mmol, 88%).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:11]([O:13][C:14](=[O:24])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:17]=1[Cl:23])[CH3:12]>CCO.O1CCOCC1>[CH2:11]([O:13][C:14](=[O:24])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:18][C:17]=1[Cl:23])[CH3:12]
Reactant: CCOC(=O)Cc1ccc(N)cc1Cl
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: C1COCCO1
Solvent: CCO
Product: CCOC(=O)Cc1ccc(Nc2ncccc2[N+](=O)[O-])cc1Cl
Temperature: 25 °C

Procedure:
A mixture of 2-chloro-3-nitro-pyridine (0.600 g, 3.80 mmol) (Aldrich) and (4-amino-2-chloro-phenyl)-acetic acid ethyl ester (see WO 97/21665) (0.800 g 3.80 mmol) in EtOH/dioxane (20 mL; 1:1, v/v) is stirred and refluxed for 72 h. The mixture is allowed to cool to rt and concentrated in vacuo. The crude material is purified by silica gel column chromatography (Hexane/EtOAc, 7/3) to afford a red solid, which upon trituration with Et2O provides the title compound as an orange solid: ES-MS: 336.0 [M+H]+; single peak at tR=5.59 min (System 1); Rf=0.39 (Hexane/EtOAc, 7:3).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:21])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[CH:7][C:6]=1[C:22]1[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=1.Br[CH2:29][CH2:30][C:31]([F:34])([F:33])[F:32].C(N(CC)CC)C>CN(C=O)C>[CH3:20][O:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[C:12]([NH:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][NH:1][CH2:29][CH2:30][C:31]([F:34])([F:33])[F:32])=[C:6]([C:22]2[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=2)[CH:7]=1)=[O:21]
Reactant: FC(F)(F)CCBr
Reactant: COc1cccc(C(=O)Nc2ccc(OCCN)c(-c3ccnn3C)c2)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cccc(C(=O)Nc2ccc(OCCNCCC(F)(F)F)c(-c3ccnn3C)c2)c1
Temperature: 150 °C
Yield: 2.3 %

Procedure:
A mixture of N-(4-(2-aminoethoxy)-3-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-methoxybenzamide (14.5 mg, 81.9 μmol), 3-bromo-1,1,1-trifluoropropane (30 mg, 81.9 μmol) and triethylamine (34.2 μL, 246 μmol) in DMF was heated to 150° C. for 1 hour under microwave irradiation in a heavy-walled sealed tube. The crude product was purified by PLC. The proper fractions were collected and lyophilized to afford the title compound as a brown solid in 2.3% yield. LCMS m/z (%)=463 (M+H, 100). 1H NMR (400 MHz, MeOH-d4) δ 2.6 (m, 2H) 3.2 (dd, J=15.4, 7.8 Hz, 2H) 3.5 (m, 2H) 3.8 (s, 3H) 3.9 (s, 3H) 4.4 (m, 2H) 6.4 (d, J=2.0 Hz, 1H) 7.2 (dd, J=8.6, 3.5 Hz, 1H) 7.3 (d, J=9.1 Hz, 1H) 7.4 (t, J=8.1 Hz, 1H) 7.5 (m, 2H) 7.6 (d, J=2.0 Hz, 1H) 7.7 (d, J=2.5 Hz, 1H) 7.9 (dd, J=9.1, 2.5 Hz, 1H).