Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[C:13]([N:32]1[CH:36]=[C:35]([CH2:37][OH:38])[N:34]=[CH:33]1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[N+:39]([C:42]1[CH:43]=[C:44](O)[CH:45]=[CH:46][CH:47]=1)([O-:41])=[O:40].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[N+:39]([C:42]1[CH:47]=[C:46]([CH:45]=[CH:44][CH:43]=1)[O:38][CH2:37][C:35]1[N:34]=[CH:33][N:32]([C:13]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:36]=1)([O-:41])=[O:40]
Reactant: OCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccc(OCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.2 %

Procedure:
To a solution of diethyl azodicarboxylate (2.1 mL) in tetrahydrofuran (THF) (40 mL) was added (1-trityl-1H-imidazole-4-yl)methanol (2.23 g, prepared as described in J. Med. Chem. (1977)20:721) and 3-nitrophenol (2 g). To this mixture at 0° C. was added dropwise a solution of triphenyl phosphine (3.44 g) in THF (60 mL). The reaction mixture was stirred at room temperature overnight. After evaporation of the solvent the residue was chromatographed on silica gel eluting with ethyl acetate:hexane (40:60) to isolate 4-(3-nitro-phenoxymethyl)-1-trityl-1H-imidazole (2 g).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[S:19][CH:18]=[CH:17][N:5]2[C:6](=[O:16])[C:7]=1[C:8]1[CH:15]=[CH:14][C:11](C#N)=[CH:10][CH:9]=1.[F:20][C:21]([F:33])([F:32])[O:22]C1C=CC(B(O)O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+].FC1C=C(C2C(=O)N3C=CSC3=NC=2C)C=C(F)C=1>C1(C)C=CC=CC=1.O.C(O)C>[CH3:1][C:2]1[N:3]=[C:4]2[S:19][CH:18]=[CH:17][N:5]2[C:6](=[O:16])[C:7]=1[C:8]1[CH:15]=[CH:14][C:11]([O:22][C:21]([F:33])([F:32])[F:20])=[CH:10][CH:9]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: Cc1nc2sccn2c(=O)c1-c1ccc(C#N)cc1
Agent: Cc1nc2sccn2c(=O)c1-c1cc(F)cc(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1nc2sccn2c(=O)c1-c1ccc(OC(F)(F)F)cc1
Yield: 68.8 %

Procedure:
The title compound was prepared by coupling reaction of Step 2 of Intermediate 4 (9.5 g, 37.312 mmol) with 4-(trifluoromethoxy)phenyl boronic acid (9.5 g, 32.523 mmol) in the presence of Pd[(C6H5)3P]4 (1.5 g, 1.301 mmol) and sodium carbonate (20.6 g, 195.13 mol) in a mixture of toluene, ethanol and water according to the procedure described in Intermediate 3, step 3 yielded 7.3 g of the desired compound as a pale yellow solid; IR (KBr) 3088, 1658, 1646, 1513, 1269, 1160 cm−1; 1H NMR (300 MHz, DMSO-d6) δ 2.18 (s, 3H), 7.42-7.4 (m, 4H), 7.53 (d, J=4.8 Hz, 1H), 8.01 (d, J=4.8 Hz, 1H); ESI-MS (m/z) 327.16 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+].[C:15](Cl)(=[O:24])[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>O1CCOCC1.O>[C:4]1([CH2:3][C@H:2]([NH:1][C:15](=[O:24])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:10]([OH:12])=[O:11])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=C(Cl)CCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(CCc1ccccc1)N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 79.9 %

Procedure:
L-phenylalanine (2 a) was dissolved in a mixed solvent of dioxane:water=1:1 (20 ml), and the reaction system was cooled to 0° C. The solution was added with 1 N aqueous sodium hydroxide (12.1 ml), and further added dropwise with 1 N aqueous sodium hydroxide (12.1 ml) and hydrocinnamoyl chloride (1.98 ml) simultaneously over 25 minutes, and then stirred at 0° C. for 2 hours. 1 N Hydrochloric acid was added to the mixture to adjust the pH to 3, and the precipitated crystals were washed with water and diethyl ether to obtain 3-phenyl-(2S)-(3-phenylpropanoylamino)propanoic acid (2.9 g, 79.9%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:10]([O-])=O)[C:5]([NH2:9])=[N:6][C:7]=1[I:8].O.O.[Sn](Cl)Cl.O.[F-].[K+]>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[N:6][C:7]=1[I:8]
Reactant: Nc1nc(I)c(Cl)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: [F-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Nc1cc(Cl)c(I)nc1N
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 5-chloro-6-iodo-3-nitropyridin-2-amine (18.9 g, 63.1 mmol) in EtOH (100 mL) was added tin (II) chloride dihydrate (57 g, 252 mmol). The mixture was heated at 70° C. for 0.5 h. The r×n was warmed to rt and treated with a slurry of 150 mL water and 60 g KF and stirred for 0.5 h. The mixture was then partitioned between ethyl acetate (300 mL) and water (300 mL). The ethyl acetate layer was washed with brine, dried over magnesium sulfate and filtered through a 100 g pad of silica gel. The filtrate was concentrated and dried under vacuum to give an off-white solid, which was used in next step without further purification. LC-MS: calculated for C5H5ClIN3 269.47, observed m/e: 269.99 (M+H)+ (Rt 1.35/5 min)
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:16]=[C:15]([CH2:17][OH:18])[CH:14]=[CH:13][CH:12]=3)[S:10][C:3]=12.[CH3:19][C:20]1[NH:21][C:22]2[C:27]([CH:28]=1)=[CH:26][C:25]([NH2:29])=[CH:24][CH:23]=2>>[CH3:19][C:20]1[NH:21][C:22]2[C:27]([CH:28]=1)=[CH:26][C:25]([NH:29][C:2]1[CH:7]=[CH:6][N:5]=[C:4]3[CH:8]=[C:9]([C:11]4[N:16]=[C:15]([CH2:17][OH:18])[CH:14]=[CH:13][CH:12]=4)[S:10][C:3]=13)=[CH:24][CH:23]=2
Reactant: OCc1cccc(-c2cc3nccc(Cl)c3s2)n1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Product: Cc1cc2cc(Nc3ccnc4cc(-c5cccc(CO)n5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from [6-(7-chloro-thieno[3,2-b]pyridin-2-yl)-pyridin-2-yl]-methanol and 2-methyl-5-aminoindole by the procedure analogous to example 148(c) above. 1H NMR (400 MHz, CD3OD) δ8.10 (d, 1H), 7.90 (s, 1H), 7.83 (m, 2H), 7.44 (m, 1H), 7.36 (s, 1H), 7.30 (d, 1H), 6.90 (d, 1H), 6.60 (d, 1H), 6.12 (s, 1H), 3.57 (s, 2H), 2.42 (s, 3H); RP18-HPLC RT: 4.59 minutes; API MS: 387 (M+1).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([O:33][CH3:34])[C:23]=3[O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:18]2=[O:35])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.[C].[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([O:33][CH3:34])[C:23]=3[O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:18]2=[O:35])=[CH:11][CH:10]=1
Reactant: [H][H]
Reactant: CCCCCOc1c(OC)ccc2c(=O)n(CCc3ccc(OCc4ccccc4)cc3)ccc12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCOc1c(OC)ccc2c(=O)n(CCc3ccc(O)cc3)ccc12
Temperature: 25 °C
Yield: 68.7 %

Procedure:
2-[2-(4-Benzyloxyphenyl)ethyl]-6-methoxy-5-pentyloxy-2H-isoquinolin-1-one (1.21 g, 2.6 mmol, 1.0 eq) was dissolved in ethyl acetate (12 ml), and 10% palladium-carbon catalyst (300 mg, water content 50%) was added. The mixture was stirred in a stream of hydrogen for 4 hours. The reaction mixture was cooled to room temperature and filtered through Celite. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by column chromatography on silica gel (ethyl acetate/hexane=1/1-ethyl acetate) to give 2-[2-(4-hydroxyphenyl)ethyl]-6-methoxy-5-pentyloxy-2H-isoquinolin-1-one (681.8 mg, 68.7%) as colorless crystals.
Reaction SMILES: [NH3:1].Cl[C:3]1[N:8]=[C:7]([Cl:9])[CH:6]=[C:5]([O:10][C:11]([F:14])([F:13])[F:12])[N:4]=1>C(OC)(C)(C)C>[NH2:1][C:3]1[N:8]=[C:7]([Cl:9])[CH:6]=[C:5]([O:10][C:11]([F:14])([F:13])[F:12])[N:4]=1
Reactant: FC(F)(F)Oc1cc(Cl)nc(Cl)n1
Reactant: N
Solvent: COC(C)(C)C
Product: Nc1nc(Cl)cc(OC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4.3 g (0.25 mol) of gaseous ammonia were passed over the course of 45 minutes into a stirred mixture of 23.3 g (0.1 mol) of 2,4-dichloro-6-trifluoromethoxypyrimidine and 150 ml of methyl tert.-butyl ether at -50° to -45° C. The mixture was stirred at -50° C. for 30 minutes, at -30° C. for 1 hour and at 25° C. for 1 hour. The precipitate was filtered off with suction, washed with water and dried, resulting in 5.4 g (33.1% of theory) of 4-amino-2,4-dichloropyrimidine of melting point 270°-272° C. as by-product. The filtrate was washed with water, dried and concentrated under reduced pressure, and the residue was chromatographed with 5:1 petroleum ether/ether, the initial fractions yielding 3 g (12.8% of theory) of starting material as a colorless oil, and subsequent fractions containing 9 g (42% of theory) of the title compound as colorless crystals of melting point 55°-56° C. Conversion was 48.3%.
Reaction SMILES: C[O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[NH2:11].C[O:14][C:15](=O)[CH:16]([CH3:19])[CH2:17]O.[OH-].[Na+]>Cl>[OH:14][CH2:15][CH:16]([C:19]1[NH:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([C:3]([OH:2])=[O:12])[C:5]=2[N:11]=1)[CH3:17]
Reactant: COC(=O)c1cccc(N)c1N
Reactant: COC(=O)C(C)CO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(CO)c1nc2c(C(=O)O)cccc2[nH]1
Temperature: 90 °C
Reaction time: 24 h
Yield: 25.8 %

Procedure:
To a solution of 2,3-diaminobenzoic acid methyl ester (2.1 g, 14.1 mmol) in 4 M HCl (90 mL) was added 2-methyl-3-hydroxypropionic acid methyl ester (5 g, 42.3 mmol). The mixture was stirred at ˜90° C. for 24 h. It was neutralized by use of aqueous sodium hydroxide solution to pH ˜3, and concentrated to dryness. The residue was suspended in methanol, and filtered through a filter paper. After the filtrate was concentrated, the remaining solid residue was dissolved in water and washed with ethyl acetate. The aqueous solution was evaporated in vacuo yielding the title intermediate as a pale yellow oil (˜800 mg). The crude product was used in the next step without further purification. (m/z): [M+H]+ calcd for C11H12N2O3 221.09. found 221.3. 1H-NMR (CD3OD) δ (ppm) 8.1 (d, 1H), 7.9 (m, 1H), 7.6 (t, 1H), 3.8 (m, 2H), 3.6 (m, 1H), 1.4 (d, 3H).
Reaction SMILES: [OH:1][C@H:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].[CH3:9]O>CCCCCC>[OH:1][C@H:2]([CH:6]([CH3:8])[CH3:7])[C:3]([O:5][CH3:9])=[O:4]
Reactant: CC(C)[C@@H](O)C(=O)O
Reactant: CO
Solvent: CCCCCC
Product: COC(=O)[C@H](O)C(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 30 %

Procedure:
To a solution of (R)-2-hydroxy-3-methylbutanoic acid (5.0 gm, 42.2 mmol) in methanol was added a solution of TMS CH2N2 (2M) in hexane (65 mL), at 0° C., over 20 min. The reaction mixture was stirred at 0° C. for 1 h. The reaction was concentrated with a bath temperature of 20° C. and vacuum greater than 50 mm Hg. Purification via silica gel chromatography using 2-100% EtOAc in hexanes gave the ester as a yellow oil (438 mg, 12.7 mmol, 30% yield). 1H NMR (400 MHz, DMSO-d6) δ 5.30 (d, J=5.1 Hz, 1H), 3.81 (t, J=0.8 Hz, 1H), 3.63H), 1.94-1.86 (m, 1H), 0.88-0.82 (m, 6H).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[S:4][C:3]=1[C:11]([NH2:13])=O.P(Cl)(Cl)(Cl)=O.C(=O)([O-])[O-].[Na+].[Na+].C(Cl)Cl>C(#N)C>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[S:4][C:3]=1[C:11]#[N:13]
Reactant: NC(=O)c1sc2cnccc2c1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CC#N
Product: N#Cc1sc2cnccc2c1Br
Temperature: 85 °C
Yield: 29.4 %

Procedure:
To a suspension of 3-bromothieno[2,3-c]pyridine-2-carboxamide (750 mg, 2.92 mmol) in acetonitrile (20 mL) was added phosphorus oxychloride (816 μL, 8.75 mmol) and the mixture was heated under N2 for 1 hour at 85° C. The same portion of phosphorus oxychloride was added every hour at 85° C. for a total of 6 h. The crude mixture was poured into saturated aqueous sodium carbonate on ice, to reach pH 7-8. DCM was added. The mixture was filtered to remove inorganic salts and the organic layer was separated. The DCM layer was washed with brine and dried over anhydrous Na2SO4. Purification by ISCO chromatography (100% DCM) afforded 205 mg (29%) of the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ 9.31-9.36 (m, 1 H), 8.71 (d, J=5.8 Hz, 1 H), 7.93 (dd, J=5.6, 1.0 Hz, 1 H); MS (ESI): 239.42, 241.35 [M+H]+; HPLC tR=1.04 min (HPLC: Analytical—2 min).
Reaction SMILES: NC1C=CC=CC=1.[C:8]([C:12]1[CH:13]=[C:14]([CH:31]=[C:32]([C:35]([CH3:38])([CH3:37])[CH3:36])[C:33]=1[OH:34])[C:15]([O:17][CH2:18][CH2:19][C:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([NH2:30])[CH:24]=1)=[O:21])=[O:16])([CH3:11])([CH3:10])[CH3:9].[CH2:39]([O:43][C:44]1[CH:49]=[CH:48][C:47]([C:50](=[O:57])[CH2:51][C:52](OCC)=[O:53])=[CH:46][CH:45]=1)[CH2:40][CH2:41][CH3:42]>C1(C)C(C)=CC=CC=1>[C:35]([C:32]1[CH:31]=[C:14]([CH:13]=[C:12]([C:8]([CH3:10])([CH3:11])[CH3:9])[C:33]=1[OH:34])[C:15]([O:17][CH2:18][CH2:19][C:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([NH:30][C:52](=[O:53])[CH2:51][C:50]([C:47]2[CH:48]=[CH:49][C:44]([O:43][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:45][CH:46]=2)=[O:57])[CH:24]=1)=[O:21])=[O:16])([CH3:38])([CH3:37])[CH3:36]
Reactant: CC(C)(C)c1cc(C(=O)OCCC(=O)Oc2ccc(Cl)c(N)c2)cc(C(C)(C)C)c1O
Reactant: CCCCOc1ccc(C(=O)CC(=O)OCC)cc1
Solvent: Cc1ccccc1C
Solvent: Nc1ccccc1
Product: CCCCOc1ccc(C(=O)CC(=O)Nc2cc(OC(=O)CCOC(=O)c3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)ccc2Cl)cc1
Reaction time: 5 h
Yield: 82.2 %

Procedure:
A solution of the aniline from (c) (19.8 g, 44.2 mmole) and the β-ketoester from (e) (13.0 g, 44.2 mmole) in xylene (160 ml) were heated under reflux, using a Dean & Stark apparatus, for 5 hours. Over the final hour, the volume of the mixture was reduced to 75 ml by distillation. 60-80 petroleum ether (300 ml) was added with cooling and the solid collected by filtration. The product was isolated as a brown solid (24.2 g, 82%). m.p. 94-96%.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C@H:17]3[CH2:22][CH2:21][NH:20][CH2:19][C@@H:18]3[C:23]([O:25][CH3:26])=[O:24])=[O:16])[CH2:11][CH2:10]2)=[C:5]([CH3:27])[CH:4]=1)#[N:2].C(#N)C.C(N(CC)CC)C.[CH:38]1[CH:43]=[CH:42][C:41]([O:44][C:45](OC2C=CC=CC=2)=[N:46][C:47]#[N:48])=[CH:40][CH:39]=1>>[C:47](/[N:46]=[C:45](\[O:44][C:41]1[CH:42]=[CH:43][CH:38]=[CH:39][CH:40]=1)/[N:20]1[CH2:21][CH2:22][C@H:17]([C:15]([N:12]2[CH2:13][CH2:14][N:9]([C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=3[CH3:27])[CH2:10][CH2:11]2)=[O:16])[C@@H:18]([C:23]([O:25][CH3:26])=[O:24])[CH2:19]1)#[N:48]
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Reactant: COC(=O)[C@H]1CNCC[C@@H]1C(=O)N1CCN(c2ccc(C#N)cc2C)CC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1CN(/C(=N/C#N)Oc2ccccc2)CC[C@@H]1C(=O)N1CCN(c2ccc(C#N)cc2C)CC1
Temperature: 85 °C

Procedure:
To a stirred solution of methyl(3R,4S)-4-[4-(4-cyano-2-methylphenyl)piperazin-1-yl]carbonylpiperidine-3-carboxylate (386.500 mg, 1.04334E-3 mol) in anhydrous acetonitrile (6.000 mL, 0.1149 mol) at rt was added triethylamine (0.2923 mL, 0.002087 mol) and diphenyl cyanocarbonimidate (384.4 mg, 0.001565 mol). The reaction mixture was heated to reflux (oil bath temperature: 85° C.) for 5 hrs. The reaction mixture was concentrated in vacuo. The residue was purified by Combiflash with 40-90% EtOAc/Hex to give the product (60% in yield). MS (ESI): (M+H)+=515.
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][C:3]=1[NH:4][C:5]1[C:6]([C:13]([OH:15])=[O:14])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1.N1C=CC=CC=1.FC(F)(F)C(O[C:32]1[C:37]([F:38])=[C:36]([F:39])[C:35]([F:40])=[C:34]([F:41])[C:33]=1[F:42])=O>CC(N(C)C)=O.CCOC(C)=O>[F:1][C:2]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][C:3]=1[NH:4][C:5]1[C:6]([C:13]([O:15][C:32]2[C:33]([F:42])=[C:34]([F:41])[C:35]([F:40])=[C:36]([F:39])[C:37]=2[F:38])=[O:14])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1
Reactant: Cn1cc(C(=O)O)c(Nc2ccc(I)cc2F)cc1=O
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: c1ccncc1
Product: Cn1cc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)c(Nc2ccc(I)cc2F)cc1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-(2-Fluoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylic acid (894 mg, 2.30 mmol) and pyridine (909 mg, 11.5 mmol) were dissolved in DMA (15 mL). To this mixture was added pentafluorophenyl trifluoroacetate (3.22 g, 11.5 mmol) then the solution was allowed to stir at R.T. for 2 h. The DMA solution was diluted with EtOAc (150 mL), which was washed sequentially with 1 M HCl (2×100 mL), water (100 mL), sat. NaHCO3 (2×100 mL), and brine (100 mL). The EtOAc fraction was then dried (Na2SO4) and the solvent removed under reduced pressure to yield a viscous oil which was purified by column chromatography on silica gel (50% EtOAc/PE as eluant). This afforded 2,3,4,5,6-pentafluorophenyl-4-(2-fluoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylate as a cream foam (1.22 g, 96%) which was used directly in subsequent steps. 1H NMR [(CD3)2SO, 400 MHz] δ 9.03 (s, 1H), 8.70 (s, 1H), 7.79 (dd, J=10.1, 1.9 Hz, 1H), 7.62 (br dd, J=8.4, 1.0 Hz, 1H), 7.29 (t, J=8.4 Hz, 1H), 5.36 (d, J=1.6 Hz, 1H), 3.45 (s, 3H). LCMS (APCI+) calcd for C19H9F6N2O3 555 (MH+), found 555.
Reaction SMILES: [Mg:1].C(C1C=C([Br:12])C=CC=1)=C(C)C.CO[C:15]1[CH:24]=[CH:23][C:22]2[C:17](=C[CH:19]=[C:20]([CH:25]=O)[CH:21]=2)[CH:16]=1>C1COCC1>[CH:21]([C:22]1[CH:17]=[C:16]([Mg:1][Br:12])[CH:15]=[CH:24][CH:23]=1)=[C:20]([CH3:25])[CH3:19]
Reactant: COc1ccc2cc(C=O)ccc2c1
Reactant: CC(C)=Cc1cccc(Br)c1
Reactant: [Mg]
Solvent: C1CCOC1
Product: CC(C)=Cc1cccc([Mg]Br)c1
Reaction time: 18 h

Procedure:
To a suspension of Rieke magnesium (0.12 g, 4.74 mmol; commercially available suspension) in dry THF (4.61 mL) was added neat 3-(iso-buten-1-yl)-phenylbromide (1.0 g, 4.74 mmol) at such a rate as to maintain a steady reflux. After the arylbromide was completely added, the reaction was refluxed under nitrogen for 0.5 hours. The solution was allowed to settle for 18 hours and the supernatant was determined to have a 0.56 m titer for active grignard by tritrating a known quantity of 2-methoxynaphthalene-6-carboxaldehyde.
Reaction SMILES: O=P(Cl)(Cl)Cl.[F:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[N:16]1[CH:20]=[CH:19][CH:18]=[CH:17]1.CN([CH:24]=[O:25])C>>[F:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[N:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[CH:24]=[O:25]
Reactant: O=[N+]([O-])c1ccc(F)c(-n2cccc2)c1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cccn1-c1cc([N+](=O)[O-])ccc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 54 %

Procedure:
Anhydrous DMF (0.82 mL, 10.67 mmol) and POCl3 (0.96 mL, 10.67 mmol) were combined at 0° C. in a 50 mL round bottomed flask. The suspension was warmed to ambient temperature and treated with 1-(2-fluoro-5-nitrophenyl)-1H-pyrrole (2.0 g, 9.7 mmol) as a light yellow solution in anhydrous DMF (8 mL). The resulting mixture was vigorously stirred at room temperature for 5 hours. TLC analysis of the mixture after 5 hours showed the complete conversion of the starting material to the product. The reaction mixture was transferred to a separatory funnel and partitioned (EtOAc//H2O). The organic phase was washed with H2O (3×50 mL), brine (3×50 mL), dried over Na2SO4 and evaporated in vacuo to give a brown residue. The residue was purified by flash chromatography (hexanes 1:1 EtOAc/hexanes) to furnish the title compound as a white solid (1.2 g, 54%).
Reaction SMILES: [CH3:1][Si:2]([CH2:5][CH2:6][O:7][CH2:8]Cl)([CH3:4])[CH3:3].[OH:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1.CCN(CC)CC.CCOCC>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][Si:2]([CH2:5][CH2:6][O:7][CH2:8][O:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1)([CH3:4])[CH3:3]
Reactant: C[Si](C)(C)CCOCCl
Reactant: N#Cc1ccc(O)cc1
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[Si](C)(C)CCOCOc1ccc(C#N)cc1
Temperature: 25 °C
Yield: 45.2 %

Procedure:
To a solution of 1.63 ml (9.23 mmol) of SEM-Cl in 10 ml of dry DCM were added 1.00 g (8.39 mmol) of 4-hydroxy benzonitrile, 103 mg (0.84 mmol) of DMAP and 2.34 ml (16.8 mmol) of Et3N, stirring at RT under N2. After stirring overnight, 10 ml of ether were added and the solids filtered off. The filtrate was evaporated and the product purified by flash chromatography (20% ethyl acetate in petrol), obtaining 945 mg (3.79 mmol, 48%) of a colourless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([CH:12]([CH3:14])[CH3:13])[N:3]=1.[NH:15]1[CH:19]=[CH:18][N:17]=[CH:16]1>C(#N)C>[N:15]1([C:2]2[N:7]=[C:6]([N:15]3[CH:19]=[CH:18][N:17]=[CH:16]3)[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([CH:12]([CH3:14])[CH3:13])[N:3]=2)[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: CC(C)c1nc(Cl)nc(Cl)c1[N+](=O)[O-]
Reactant: c1c[nH]cn1
Solvent: CC#N
Product: CC(C)c1nc(-n2ccnc2)nc(-n2ccnc2)c1[N+](=O)[O-]

Procedure:
Combine 29 g (0.12 mol) of 2,4-dichloro-5-nitro-6-(2-propyl)-pyrimidine with 42 g (0.62 mol) of imidazole in 500 mL of acetonitrile, and stir at room temperature for 24 h. Remove the solvent under vacuum, slurry the residue in 500 mL of CH2Cl2 and wash with 4×500 mL 10% K2CO3. Dry the organic portion over MgSO4, treat with charcoal, filter and concentrate the filtrate to dryness under vacuum to afford 2,4-bis(1H-imidazol-1-yl)-5-nitro-6-(2-propyl) pyrimidine.
Reaction SMILES: [CH:1]([NH:5][C:6]([NH2:8])=[O:7])([CH2:3][CH3:4])[CH3:2].Cl[CH:10]([C:16]([C:18]([F:21])([F:20])[F:19])=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12]>>[CH3:2][CH:1]([NH:5][C:6]1[O:7][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:16]([C:18]([F:19])([F:21])[F:20])[N:8]=1)[CH2:3][CH3:4]
Reactant: CCOC(=O)C(Cl)C(=O)C(F)(F)F
Reactant: CCC(C)NC(N)=O
Product: CCOC(=O)c1oc(NC(C)CC)nc1C(F)(F)F
Yield: 28.5 %

Procedure:
By the procedure of Example 4, 6.96 g (60 mmol) of sec-butyl urea was reacted with 10.9 g (50 mmol) of ethyl 2-chloro-4,4,4-trifluoroacetoacetate at 140°-150° C. for 3 hours. The product was separated and then Kugelrohr distilled to yield 4.0 g of a colorless oil product (b.p.=100° C. @ 0.25 mm Hg) identified in Table I.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([NH:9][C:10]2[N:15]=[CH:14][N:13]=[C:12]([O:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)[C:11]=2[O:29][CH3:30])=[C:4]([CH3:31])[CH:3]=1.[OH2:32].C[S:34]([CH3:36])=[O:35]>>[CH3:8][C:6]1[C:5]([NH:9][C:10]2[N:15]=[CH:14][N:13]=[C:12]([O:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)[C:11]=2[O:29][CH3:30])=[C:4]([CH3:31])[CH:3]=[C:2]([S:34]([CH3:36])(=[O:32])=[O:35])[N:7]=1
Reactant: O
Reactant: COc1c(Nc2c(C)cc(Br)nc2C)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Reactant: CS(C)=O
Product: COc1c(Nc2c(C)cc(S(C)(=O)=O)nc2C)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Temperature: 150 °C

Procedure:
To a solution of isopropyl 4-(6-(6-bromo-2,4-dimethylpyridin-3-ylamino)-5-methoxypyrimidin-4-yloxy)piperidine-1-carboxylate (500 mg, 1.0 mmol) in 10 ml of DMSO, were added sodium sulfinate (0.36 g, 3.5 mmol), (CuOTf)2PhH (0.051 g, 0.10 mmol), and N,N′-dimethylethylamine (0.018 g, 0.20 mmol) at an ambient temperature. The reaction was heated to 150° C. for 8 hrs. The reaction was cooled to room temperature and poured into H2O. The organics were extracted with ethyl acetate and dried over MgSO4. The ethyl acetate was concentrated under vacuum and purified over SiO2 to afford isopropyl 4-(6-(2,4-dimethyl-6-(methylsulfonyl)pyridin-3-ylamino)-5-methoxypyrimidin-4-yloxy)piperidine-1-carboxy-late. 1HNMR (CDCl3, 400 MHz) δ 1.24 (d, J=1.6 Hz, 6H), 1.75-1.81 (m, 2H), 1.98-2.02 (m, 2H), 2.25 (s, 3H), 2.65 (s, 3H), 3.21 (s, 3H), 3.52-3.65 (m, 2H), 3.65-3.75 (m, 1H), 3.84 (s, 3H), 5.21-5.35 (m, 1H), 7.78 (s, 1H), 7.79 (s, 1H), 8.89 (s, 1H). Exact mass calculated for C22H31N5O6S 493.58 found 494.5 (MH+).