Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([CH2:9][CH3:10])[CH:6]=[C:5]([O:11]C)[CH:4]=1.Br>C(O)(=O)C>[OH:2][C:3]1[CH:8]=[C:7]([CH2:9][CH3:10])[CH:6]=[C:5]([OH:11])[CH:4]=1
Reactant: CCc1cc(OC)cc(OC)c1
Agent: Br
Solvent: CC(=O)O
Product: CCc1cc(O)cc(O)c1
Temperature: 25 °C
Yield: 92.9 %

Procedure:
1,3-Dimethoxy-5-ethylbenzene (7.69 g) is dissolved in acetic acid (80 ml), and thereto is added with stirring 47% hydrobromic acid at room temperature. The mixture is refluxed for three hours, and the reaction mixture is cooled to room temperature. The mixture is concentrated to dryness under reduced pressure, and the residue is dissolved in ethyl acetate. The organic layer is washed successively with water and a saturated aqueous sodium chloride solution, dried, and concentrated under reduced pressure. The residue is recrystallized from diisopropyl ether-hexane to give 1,3-dihydroxy-5-ethylbenzene (5.94 g), m.p. 97-98° C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.ClC1C=CC(S(O[N:31]2[C:35]3[CH:36]=[C:37]([Cl:40])[CH:38]=[CH:39][C:34]=3[N:33]=[N:32]2)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][N:31]2[C:35]3[CH:36]=[C:37]([Cl:40])[CH:38]=[CH:39][C:34]=3[N:33]=[N:32]2)=[O:9])=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: O=S(=O)(On1nnc2ccc(Cl)cc21)c1ccc(Cl)cc1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(On1nnc2ccc(Cl)cc21)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 75.4 %

Procedure:
p-Nitrobenzoic acid (1.67 g) is dissolved in chloroform (20 ml) and thereto are added triethylamine (1.40 ml) under ice-cooling and further 1-(p-chlorobenzenesulfonyloxy)-6-chloro-1,2,3-benzotriazole (3.44 g) at room temperature. When the mixture is stirred at room temperature for 20 minutes, white crystals precipitate, and the mixture is further stirred for 7 hours. The precipitated crystals are separated by filtration to give white crystals of 1-(p-nitrobenzoyloxy)-6-chloro-1,2,3-benzotriazole (2.4 g), melting point: 198°-199° C. (decomp).
Reaction SMILES: [CH:1]1([C:4]2[C:5](=[O:17])[N:6]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:7]([CH3:10])[C:8]=2[CH3:9])[CH2:3][CH2:2]1.[Br:18]Br>O1CCOCC1.O.CCOC(C)=O>[Br:18][CH2:9][C:8]1[N:7]([CH3:10])[N:6]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:5](=[O:17])[C:4]=1[CH:1]1[CH2:3][CH2:2]1
Reactant: Cc1c(C2CC2)c(=O)n(-c2ccccc2)n1C
Reactant: BrBr
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1c(CBr)c(C2CC2)c(=O)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To 4-cyclopropyl-1,5-dimethyl-2-phenyl-1,2-dihydro-pyrazol-3-one (0.081 g) in a round bottom flask under argon in dioxane (1.5 mL) was added bromine (0.057 g). The reaction was stirred at ambient temperature for 2 days. The reaction was diluted with water and EtOAc and the phases were separated. The aqueous phase was extracted with more EtOAc and the combined organic phases were washed with brine, dried over sodium sulfate, filtered and evaporated in vacuo. The crude material was purified via ISCO combiflash chromatography (EtOAc/heptane) to afford the desired 5-Bromomethyl-4-cyclopropyl-1-methyl-2-phenyl-1,2-dihydro-pyrazol-3-one as a light brown solid. MS (ESI+): 307.1 ([M+H]+).
Reaction SMILES: [CH2:1]([C:5]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8]([CH3:17])([CH3:16])[NH:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[CH3:18][C:19]([N:27]=[C:28]=[O:29])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:20]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[CH3:20][C:19]([NH:27][C:28]([N:7]1[C:8]([CH3:16])([CH3:17])[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6]1)=[O:29])([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH3:18]
Reactant: CCCCC1=NNC(C)(C)C1c1ccccc1
Reactant: CC(C)(N=C=O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCC1=NN(C(=O)NC(C)(C)c2ccccc2)C(C)(C)C1c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 55 %

Procedure:
Crude 3-(n-Butyl)-5,5-dimethyl-4-phenyl-4,5-dihydropyrazole (Intermediate IV-1) (1.03 gram, 4.48 mmol maximally) was dissolved in toluene (10 ml) and treated with 1-methyl-1-phenyl-ethylisocyanate (Intermediate VII-2) (0.72 g, 4.48 mmol) and 2 drops of triethylamine and the resulting solution was stirred at room temperature for 16 hours. The solution was concentrated and purified using Sepacore equipment: (petroleum ether/diethyl ether=85/15 (v/v)) to give N-(1-methyl-1-phenyl-ethyl)-3-(n-butyl)-5,5-dimethyl-4-phenyl-4,5-dihydro-(1H)-pyrazole-1-carbox-amide as a colorless oil (0.97 gram, 55% yield). Rf (petroleum ether/diethyl ether=4/1 (v/v))˜0.3. 1H-NMR (400 MHz, CDCl3) δ 0.88 (t, J=7, 3H), 1.08 (s, 3H), 1.26-1.39 (m, 2H), 1.44 (s, 3H), 1.45-1.56 (m, 2H), 1.70 (s, 3H), 1.76 (s, 3H), 2.09-2.18 (m, 1H), 2.25-2.35 (m, 1H), 3.70 (s, 1H), 6.59 (br s, 1H), 7.03 (br d, J˜8 Hz, 2H), 7.20 (br t, J˜8 Hz, 1H), 7.26-7.36 (m, 5H), 7.44 (br d, J˜8 Hz, 2H).
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][N:7]=1)[C:3](Cl)=[O:4].[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[OH:23].C(=O)([O-])[O-].[K+].[K+]>CC(CC)=O>[CH3:1][N:2]([C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][N:7]=1)[C:3](=[O:4])[O:23][C:14]1[CH:15]=[CH:16][C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=1
Reactant: Cc1ccnc(N(C)C(=O)Cl)c1
Reactant: Oc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Cc1ccnc(N(C)C(=O)Oc2ccc3ccccc3c2)c1
Temperature: 25 °C
Yield: 81.2 %

Procedure:
A mixture of 1.85 g of N-methyl-N-(4-methyl-2-pyridyl)carbamoyl chloride, 1.44 g of 2-naphthol and 1.38 g of anhydrous potassium carbonate in methylethylketone was refluxed under heating for 48 hours. After the reaction mixture was cooled to room temperature, inorganic salts were removed by filtration and then methylethylketone was removed by distillation under a reduced pressure. The residue was purified by the column chromatography (silica gel, developed with ethyl acetate/benzene=1/9 (V/V) ), to obtain 2.37 g of oily 2-naphthyl N-methyl-N-(4-methyl-2-pyridyl)carbamate (yield 81%, refraction index nD25 1.6191). The elementary analysis of this material was as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:27][OH:28])[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18][CH:17]=2)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[S:29](Cl)([CH3:32])(=[O:31])=[O:30]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH:12]([CH2:27][O:28][S:29]([CH3:32])(=[O:31])=[O:30])[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18][CH:17]=2)=[O:14])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(NC(=O)C(CO)NS(=O)(=O)c2ccc(Cl)cc2)cc1
Reactant: CS(=O)(=O)Cl
Product: CCOC(=O)c1ccc(NC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c2ccc(Cl)cc2)cc1

Procedure:
The procedure described in Example 65 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-ethoxycarbonylphenyl)-3-hydroxypropanamide (1 g) was reacted with mesyl chloride to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-ethoxycarbonylphenyl)-3-methanesulfonyloxypropanamide (943 mg). CHCl3 was used for recrystallization.
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]([NH:16][C:17]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20]1[S:25]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=2)[CH2:30][CH2:29]1)(=[O:27])=[O:26])=[O:18])[Si](C(C)(C)C)(C)C.C(OCC)C>C(Cl)Cl>[OH:8][NH:16][C:17]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20]1[S:25]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=2)[CH2:30][CH2:29]1)(=[O:26])=[O:27])=[O:18]
Reactant: CC(C)(C)[Si](C)(C)ONC(=O)C1CCCCN1S(=O)(=O)N1CCN(c2ccc(Cl)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(NO)C1CCCCN1S(=O)(=O)N1CCN(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 67 %

Procedure:
Trifluoroacetic acid (few drops) was added to a solution of N-tert-butyldimethylsiloxy-1-[4-(4-chlorophenyl)piperazine-1-sulfonyl]pipeidine-2-(RS)-carboxamide (63 mg, 0.12 mmol), [prepared as described in Step 2 above], in methylene chloride (2 ml) and the reaction mixture was stirred at RT for 45 min. The organics were removed in vacuo and the residue was dissolved in methylene chloride (25 ml) and the washed with sat. sodium bicarbonate, brine, and dried over MgSO4. The solvent was removed in vacuo to give a foam which was redissolved in a minimum amount of methylene chloride. Diethyl ether was added and the resulting white precipitates were filtered to give N-hydroxy-1-[4-(4-chlorophenyl)-piperazine-1-sulfonyl]-piperidine-2-(RS)-carboxamide (67%).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:4][N:5]([CH3:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CC(C)([O-])C.[K+].Cl[C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1.[OH-].[Na+]>O.CN(C=O)C>[CH3:13][N:5]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:2]([O:1][C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=2)[C:3]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[N:4]1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: Cn1nc(-c2ccccc2)c(O)c1-c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nc(-c2ccccc2)c(Oc2ccc([N+](=O)[O-])cc2)c1-c1ccccc1
Temperature: 60 °C
Yield: 91.4 %

Procedure:
A solution of 4-hydroxy-1-methyl-3,5-diphenylpyrazole (10 g, 0.04 mole), potassium t-butoxide (4.5, 0.04 mole) and dry DMF (150 ml) is stirred and heated to 60° C. The green fluorescent solution is cooled to room temperature and p-chloronitrobenzene (6.0 g, 0.038 mole) is added. The dark green solution is heated at 60° C for 24 hours and then poured into water, made alkaline with 1N sodium hydroxide and extracted with ether. The ether layer is separated, washed well with water, dried and stripped in vacuo to give a bright-yellow solid 12.9 g (86.5%), m.p. 85° C to 110° C. The solid is chromatographed on silica gel with benzene to give a yellow crystalline solid 11.3 g, m.p. 74° C to 100° C. Recrystallization from methanol (185 ml) affords white crystals 5.5 g (37%) m.p. 120° C to 122° C.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]2[CH2:14][C@H:15]([OH:17])[CH2:16][C@H:10]2[CH2:9]1)C1C=CC=CC=1.[H][H]>[OH-].[OH-].[Pd+2].C(O)C>[CH2:9]1[NH:8][CH2:13][CH2:12][N:11]2[CH2:14][C@H:15]([OH:17])[CH2:16][C@@H:10]12
Reactant: O[C@@H]1C[C@H]2CN(Cc3ccccc3)CCN2C1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: O[C@@H]1C[C@H]2CNCCN2C1

Procedure:
A mixture of (7R,8aS)-2-benzyloctahydropyrrolo[1,2-a]pyrazin-7-ol (Example 54D, 1 g, 4.30 mmol) and ethanol (10 mL) were added to 20% palladium hydroxide on carbon, wet (0.100 g) in a pressure bottle. The mixture was stirred at 50° C. for 16 hours under 30 psi of hydrogen. The mixture was filtered through a nylon membrane to give a crude intermediate (7R,8aS)-octahydropyrrolo[1,2-a]pyrazin-7-ol. To a solution of crude (7R,8aS)-octahydropyrrolo[1,2-a]pyrazin-7-ol (1.422 g, 10 mmol) and triethylamine (1.62 g, 16 mmol) in dichloromethane (50 mL) was slowly added a solution of 3-(trifluoromethyl)benzoyl chloride (2.09 g, 10 mmol) in dichloromethane (3 mL). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated, diluted with ethyl acetate (100 mL), washed with water (20 mL), dried over sodium sulfate, and filtered. The organic solution was concentrated, and the residue was purified by chromatography on silica gel (dichloromethane/methanol=10:1) to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.43-1.63 (m, 2H), 2.10-2.27 (m, 3H), 2.50 (m, 1H), 2.80-3.00 (m, 2H), 3.20-3.50 (m, 2H), 4.22 (m, 1H), 4.42-4.60 (m, 1H), 4.80 (m, 1H), 7.70 (m, 3H), 7.82 (m, 1H); MS (ESI) m/z 315 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-:27].[K+]>C(O)(C)(C)C>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[O:27])[NH2:26])=[CH:21][CH:20]=3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(Oc3ccc(C#N)cc3)ccc2C1
Reactant: [OH-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)N1CCc2cc(Oc3ccc(C(N)=O)cc3)ccc2C1
Reaction time: 72 h
Yield: 45.4 %

Procedure:
Combine 6-(4-Cyano-phenoxy)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (1.93, 5.51 mmol), t-butyl alcohol (50 ml), and KOH (1.56 g, 27.6 mmol). After the reaction stirs for 72 hours at room temperature, concentrate under reduced pressure then add ethyl acetate. Wash the ethyl acetate with a brine solution and dry the organic layer over Na2SO4. After concentrating the organic layer under reduced pressure, the reaction affords 1.93 g, 2.50 mmol (95% yield) of the title compound as a white solid:
Reaction SMILES: [Na+:1].[OH:2][CH2:3][CH2:4][CH2:5][S:6]([O-:9])(=[O:8])=[O:7].[C:10](OC(=O)C)(=[O:12])[CH3:11]>>[Na+:1].[C:10]([O:2][CH2:3][CH2:4][CH2:5][S:6]([O-:9])(=[O:8])=[O:7])(=[O:12])[CH3:11]
Reactant: O=S(=O)([O-])CCCO
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Product: CC(=O)OCCCS(=O)(=O)[O-]

Procedure:
A mixture of 81 g (0.5 mol) of 3-hydroxy-1-propanesulfonic acid sodium salt and 250 ml of acetic anhydride is heated on the steam bath for 64 hrs and at reflux for 2 hrs. The dark solution is cooled and the solid is filtered, washed with ether and dried to give 82.8 g of 3-acetyloxy-1-propanesulfonic acid sodium salt.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:16])[CH2:14][OH:15])[CH:7]=[CH:6]2.ClC(Cl)(Cl)[C:19]([N:21]=C=O)=[O:20].CO.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:16])[CH2:14][O:15][C:19](=[O:20])[NH2:21])[CH:7]=[CH:6]2
Reactant: COc1ccc2cc([C@H](C)CO)ccc2c1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: COc1ccc2cc([C@H](C)COC(N)=O)ccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.3 %

Procedure:
To (S)-2-(6-methoxy-naphthalen-2-yl)-propan-ol (8.0 g, 37 mmol) in CH2Cl2 (200 mL) at 0° C. under N2 was added trichloroacetyl isocyanate (5.5 mL, 44 mmol). After the mixture was stirred at room temperature for 1 hr, the solvent was concentrated. The residue was treated MeOH (300 mL), water (40 mL) and potassium carbonate (21 g, 0.15 mol) and stirred at RT for 2 hrs to form white precipitate. The precipitate was collected by filtration and dissolved with CH2Cl2. The organic phase was washed with water, dried over MgSO4 and concentrated to give 5.5 g of white precipitate (57%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][NH2:20])=[CH:15][CH:14]=1.CN([CH:24]=[N:25][C:26](=O)[C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1)C>CO.C(O)(=O)C>[N:30]1[CH:31]=[CH:32][C:27]([C:26]2[N:19]([C:16]3[CH:15]=[CH:14][C:13]([O:12][CH2:11][C:2]4[CH:3]=[CH:4][C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[N:1]=4)=[CH:18][CH:17]=3)[N:20]=[CH:24][N:25]=2)=[CH:28][CH:29]=1
Reactant: CN(C)C=NC(=O)c1ccncc1
Reactant: NNc1ccc(OCc2ccc3ccccc3n2)cc1
Solvent: CC(=O)O
Solvent: CO
Product: c1ccc2nc(COc3ccc(-n4ncnc4-c4ccncc4)cc3)ccc2c1
Yield: 21.8 %

Procedure:
Isonicatinamide (4.15 g) was heated in 35 ml of N,N-Dimethylformamide diethyl acetal at reflux for 3 h. The reaction mixture was cooled to ambient temperature and concentrated to give 5.02 g of N-Dimethylaminomethylene-isonicotinamide. To a solution of [4-(Quinolin-2-ylmethoxy)-phenyl]-hydrazine (3.16 g) in methanol (30 mL) and acetic acid (2.5 mL) was added N-Dimethylaminomethylene-isonicotinamide (1.10 g) and the reaction mixture heated at reflux for 72 h. The reaction mixture was concentrated onto silica gel and purified by flash chromatography to provided the title compound (514 mg). 1H NMR (400 MHz, CDCl3) δ 8.60 (d, J=5.8 Hz, 2H), 8.22 (d, J=8.7 Hz, 1H), 8.10 (s, 1H), 8.07 (d, J=8.7 Hz, 1H), 7.85 (d, J=7.1 Hz, 1H), 7.76 (m, 1H), 7.66 (d, J=8.3 Hz, 1H), 7.56 (m, 1H), 7.56 (m, 1H), 7.38 (d, J=6.2 Hz, 2H), 7.26 (d, J=8.7 Hz, 2H), 7.11 (d, J=9.1 Hz, 2H), 5.42 (s, 2H); MS: (M+H m/z=380.3).
Reaction SMILES: C1(N2C(C(F)(F)F)=C(C3ON=C4C5C(CCC=34)=CC(C=C)=CC=5)C=N2)C=CC=CC=1.[CH:31]([C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][CH:42]=1)[C:39](=[N:43][OH:44])[CH2:38][CH2:37][CH2:36]2)=[CH2:32].[F:45][C:46]1[CH:47]=[CH:48][C:49]([N:52]2[C:56]([C:57]([F:60])([F:59])[F:58])=[C:55]([C:61](OCC)=O)[CH:54]=[N:53]2)=[N:50][CH:51]=1>>[F:45][C:46]1[CH:47]=[CH:48][C:49]([N:52]2[C:56]([C:57]([F:60])([F:59])[F:58])=[C:55]([C:61]3[O:44][N:43]=[C:39]4[C:40]5[C:35]([CH2:36][CH2:37][C:38]=34)=[CH:34][C:33]([CH:31]=[CH2:32])=[CH:42][CH:41]=5)[CH:54]=[N:53]2)=[N:50][CH:51]=1
Reactant: C=Cc1ccc2c(c1)CCCC2=NO
Reactant: CCOC(=O)c1cnn(-c2ccc(F)cn2)c1C(F)(F)F
Agent: C=Cc1ccc2c(c1)CCc1c-2noc1-c1cnn(-c2ccccc2)c1C(F)(F)F
Product: C=Cc1ccc2c(c1)CCc1c-2noc1-c1cnn(-c2ccc(F)cn2)c1C(F)(F)F

Procedure:
The titled compound was prepared using the experimental protocol described for Preparation 89A employing 6-vinyl-3,4-dihydronaphthalen-1(2H)-one oxime (I-1) and ethyl 1-(5-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (Preparation 122A) as starting materials. The compound had an HPLC retention time=3.93 min. (condition C); LC/MS M+1=426.9.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2[N:12]3[CH:13]=[CH:14][N:15]=[C:11]3[C:10]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:9][N:8]=2)=[CH:4][CH:3]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1.C(N(CC)CC)C>ClCCl>[F:23][C:24]([F:34])([F:35])[C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:6][C:7]3[N:12]4[CH:13]=[CH:14][N:15]=[C:11]4[C:10]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:9][N:8]=3)=[CH:21][CH:22]=2)=[O:30])=[CH:27][CH:26]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)Cc1cnc(Cc2ccc(N)cc2)n2ccnc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Cc1cnc(Cc2ccc(NC(=O)c3ccc(C(F)(F)F)cc3)cc2)n2ccnc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.5 %

Procedure:
A mixture of methyl [5-(4-aminobenzyl)imidazo[1,2-c]pyrimidin-8-yl]acetate (17 mg, 0.06 mmol), p-trifluoromethylbenzoyl chloride (0.01 mL, 0.07 mmol) and triethylamine (0.016 mL, 0.11 mmol) in dichloromethan (1 mL) was stirred at room temperature for 1 hour. The reaction was quenched with water, and extracted with chloroform. The extracts were washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative TLC (silica gel, chloroform:methanol, 95/5) to give methyl [5-(4-{[4-(trifluoromethyl)benzoyl]amino}benzyl)imidazo[1,2-c]pyrimidin-8-yl]acetate (21.5 mg, 80%) as slightly yellow solid.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[C:13]([NH:18][C@H:19]([C:21]3[N:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:25](=[O:33])[C:24]4=[C:34]([CH3:37])[CH:35]=[CH:36][N:23]4[N:22]=3)[CH3:20])=[N:14][CH:15]=[N:16][CH:17]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[C:13]([NH:18][C@H:19]([C:21]3[N:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:25](=[O:33])[C:24]4=[C:34]([CH3:37])[CH:35]=[CH:36][N:23]4[N:22]=3)[CH3:20])=[N:14][CH:15]=[N:16][CH:17]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(NC(=O)c2cncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1ccn2nc([C@H](C)Nc3ncncc3C(=O)Nc3cccc(O)c3)n(-c3ccccc3)c(=O)c12
Yield: 14 %

Procedure:
(S)—N-(3-Methoxyphenyl)-4-((1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carboxamide (80 mg, 72% purity, 0.12 mmol) was treated with boron tribromide (1M in dichloromethane, 0.6 ml, 0.6 mmol) in dichloromethane (2 ml) according to the method described in Example 23. The residue was purified using SP1® Purification System (0% to 10%, DCM-MeOH) to give 8 mg (14% yield) as a solid. Purity 95%.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[CH3:16][C:17]([OH:20])([CH3:19])[CH3:18].[NH:21]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C@H:22]([C:35](O)=[O:36])[CH2:23][NH:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[NH:21]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C@H:22]([C:35]([O:20][C:17]([CH3:19])([CH3:18])[CH3:16])=[O:36])[CH2:23][NH:24][C:25]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:26]
Reactant: CC(C)(C)O
Reactant: CC(C)(C)OC(=O)N[C@@H](CNC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CNC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 10 h
Yield: 83.9 %

Procedure:
To an ice-cold CH2Cl2 (60 mL) solution of DCC (9.78 g, 47.34 mmol), t-BuOH (17.54 g, 0.24 mol) and DMAP (0.29 g, 2.37 mmol); a CH2Cl2 (40 mL) solution of 2 (16.00 g, 47.34 mmol) was added slowly over 20 min. Then reaction mixture was allowed to stir 1 h at 0° C. and 10 h at 20° C. Precipitated urea was then filtered off and the filtrate evaporated in vacuo. The residue was taken up in CH2Cl2, and if necessary, filtered free of any further precipitated urea. The CH2Cl2 solution was washed twice with 10% citric acid solution and with saturated NaHCO3 solution, and then dried over Na2SO4. The residue obtained after evaporation of CH2Cl2 was purified by column chromatography to obtain the product as a clear viscous oil (15.67 g, 84% yield). 1H NMR (300 MHz, CDCl3) δ7.26 (5H), 5.53 (1H), 5.45 (1H), 5.02 (2H), 4.26-4.18 (1H), 3.59-3.46 (2H), 1.38 (9H), 1.37 (9H); 13C NMR (75 MHz, CDCl3) δ 169.9, 156.8, 155.8, 136.6, 128.7, 128.3, 82.8, 80.1, 66.9, 54.7, 43.3, 28.5, 28.1; ESI-LRMS m/z 395.2 (M+H)+, 417.2 (M+Na)+.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].P(=O)([O-])[O-].C([Li])CCC.[O:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH2:22][CH2:23][C:24](OC)=[O:25]>O1CCCC1.CCCCCC.C(O)(=O)C>[O:25]=[C:24]([CH2:23][CH2:22][C:18]1[O:17][CH:21]=[CH:20][CH:19]=1)[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: COC(=O)CCc1ccco1
Reactant: COP(C)(=O)OC
Agent: O=[PH]([O-])[O-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)CCc1ccco1)OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 32.8 %

Procedure:
A solution of 25 g (0.21 mole) dimethyl methylphosphonate (Aldrich) in 300 ml dry tetrahydrofuran was cooled to -78° in a dry nitrogen atmosphere. To the stirred phosphonate solution was added 80 ml of 2.67 M n-butyllithium in hexane solution (Alfa Inorganics, Inc.) dropwise over a period of 18 minutes at such a rate that the reaction temperature never rose above -65°. After an additional 5 minutes stirring at -78°, 16.0 g (.104 mole) methyl 3-(2-furyl)propionate was added dropwise at a rate that kept the reaction temperature less than -70° (20 minutes). After 3.5 hours at -78° the reaction mixture was allowed to warm to ambient temperature, neutralized with 6 ml acetic acid and rotary evaporated to a white gel. The gelatinous material was taken up in 75 ml water, the aqueous phase extracted with 100 ml portions of chloroform (3x), the combined organic extracts were backwashed (50 cc H2O), dried (MgSO4), and concentrated (water aspirator) to a crude residue and distilled, b.p. 148°-50° (0.5 mm) to give 8.4 g dimethyl 2-oxo-4-(2-furyl)butylphosphonate (2C).