Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:14]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH3:15].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(OCC)(=O)C>[CH2:14]([N:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:11](=[O:13])[CH2:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)[CH3:15]
Reactant: CCCCCCCNCC
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCN(CC)C(=O)Cc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h

Procedure:
A mixture of p-nitrophenylacetic acid (7.14 g, 0.0394 mol), ethylheptylamine (5.64 g, 0.0394 mol) and 1-hydroxybenzotriazole (6.0 g, 0.044 mol) in 35 ml of dimethylformamide (DMF), under nitrogen, is cooled in an ice bath. The mixture is then treated with the 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) (7.68 g, 0.04 mol) in portions over 15 min. The mixture is stirred in the cold for 1 hr and at room temperature overnight. The mixture is diluted with 400 ml of ethyl acetate and washed twice with saturated NaHCO3. (Each wash is back extracted with ethyl acetate.) The pooled organic extract is washed sequentially with water (50 ml), 1N KHSO4 solution (3×50 ml), water (50 ml) and finally brine (50 ml). It is dried (Na2SO4) and concentrated in vacuo to yield the title compound. This residue is treated with Et2O-pentane, a solid filtered off and the filtrate concentrated in vacuo. The residue is chromatographed over 1400 ml of silica gel with 25% EtOAc-SSB with 42 ml fractions being collected. Fractions at approximately 70-104 yield the title compound as an oil.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][N:15]2C(=O)C3=CC=CC=C3C2=O)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]>C(O)C.[OH-].[Na+]>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][CH2:14][NH2:15])=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(CCCN2C(=O)c3ccccc3C2=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCc1ccc(CCCN)cc1
Yield: 53 %

Procedure:
A solution of N-3-(4-pentylphenyl)propylphthalimide (41.1 g, 123 mmol) and hydrazinemonohydrate (9.0 ml, 185 mmol) in ethanol (300 ml) was refluxed for 3 hours. The reaction mixture was dissolved in 5N aqueous sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate anhydride, and the organic layer was concentrated to give the object compound as an oily substance. 13.5 g, (yield 53%)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]2[C:21]3[C:16](=[CH:17][C:18]([N:22]([CH3:24])[CH3:23])=[CH:19][CH:20]=3)[O:15][CH:14]([OH:25])[CH2:13]2)[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9].CN(C1C=CC=CN=1)C.N1C=CC=CC=1.[C:41](OC(=O)C)(=[O:43])[CH3:42]>ClCCl>[C:41]([O:25][CH:14]1[CH2:13][CH:12]([C:4]2[CH:5]=[C:6]([O:10][CH3:11])[C:7]([O:8][CH3:9])=[C:2]([Br:1])[CH:3]=2)[C:21]2[C:16](=[CH:17][C:18]([N:22]([CH3:23])[CH3:24])=[CH:19][CH:20]=2)[O:15]1)(=[O:43])[CH3:42]
Reactant: COc1cc(C2CC(O)Oc3cc(N(C)C)ccc32)cc(Br)c1OC
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(C2CC(OC(C)=O)Oc3cc(N(C)C)ccc32)cc(Br)c1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-(3-bromo-4,5-dimethoxyphenyl)-7-dimethylamino-2-hydroxy-chroman (9 mg, 0.022 mmol), dimethylamino-pyridine (catalytic) and pyridine (0.1 ml) in dichloromethane at 0° C. was added acetic anhydride (0.05 ml). The mixture was stirred overnight at room temperature. To the mixture was added ice and the mixture was extracted with dichloromethane. The extract was washed with 1N HCl, saturated NaHCO3 and saturated sodium chloride solution, dried and the solvent was evaporated. The title compound was obtained upon chromatography of the crude material over a bond-elute (hexane:ethyl acetate=9:1 and 4:1 as eluent) (6.0 mg; 61%). 1H NMR (CD3OD): 6.99 (d, J=1.9 Hz), 6.86 (broad signal) and 6.85 (d, J=1.8 Hz) (2H), 6.72 (d, J=8.8 Hz) and 6.54 (d, J=8.5 Hz) (1H), 6.47 (t, J=2.3 Hz) and 6.42 (dd, J=2.2, 9.2 Hz) (1H), 6.35 (overlapping dd, J=2.5, 8.7 Hz) (1H), 6.26 (d, J=2.3 Hz) and 6.22 (d, J=2.5 Hz) (1H), 4.14 (overlapping dd, J=6.0, 11.9 Hz; 1H), 3.76-3.80 (s, 6H), 2.87 and 2.91 (s each, 6H), 2.40-2.45 and 2.11-2.32 (m each; 2H), 2.08 and 1.79 (s each, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][CH2:5][NH:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[S:8].Br[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=1)=O>C(O)C>[Br:27][C:24]1[CH:25]=[CH:26][C:21]([C:19]2[N:6]([CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:16])[C:7](=[N:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[S:8][CH:18]=2)=[CH:22][CH:23]=1
Reactant: CN(C)CCCNC(=S)Nc1ccccc1
Reactant: O=C(CBr)c1ccc(Br)cc1
Solvent: CCO
Product: CN(C)CCCn1c(-c2ccc(Br)cc2)csc1=Nc1ccccc1
Yield: 59.1 %

Procedure:
A mixture of N-[3-(dimethylamino)propyl]-N′-phenylthiourea (800 mg) obtained in Reference Example 3 as described below and 2-bromo-4′-bromoacetophenone (1.09 g) in ethanol (30 ml) was heated with reflux under nitrogen atmosphere. Nine hours thereafter, the reaction mixture was concentrated under reduced pressure, and to the residue was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with chloroform. The organic layer was washed with a saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol (50:1)), and crystallized from isopropyl alcohol to give the title compound (830 mg)
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.II.C(O[I:20](C1C=CC=CC=1)OC(=O)C)(=O)C.C(OC(=O)C)(=O)C.S(=O)(=O)(O)O>C(O)(=O)C>[I:20][C:4]1[CH:5]=[CH:6][C:1]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:2][CH:3]=1
Reactant: O=C(O)CCCCc1ccccc1
Reactant: CC(=O)OI(OC(C)=O)c1ccccc1
Agent: II
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C(O)CCCCc1ccc(I)cc1
Reaction time: 2 h
Yield: 129.1 %

Procedure:
5-Phenylpentanoic acid (50.0 g, 0.28 mol), iodine (37.77 g, 0.149 mol) and (diacetoxyiodo)benzene (48.0 g, 0.149 mol) are suspended in a mixture of glacial acetic acid (500 mL) and acetic anhydride (500 mL). Concentrated sulfuric acid (2 mL) is added and the suspension stirred for 2 h in the dark, during which the red colour fades. The solvent is removed under reduced pressure until approximately 80 ml remained, and the residue poured into ice-water (1 L) containing sodium metabisulfite (8 g). the resulting precipitate is stirred for 30 min, and then filtered. The crude product is recrystallised from ethanol/water, and then from acetic acid/water to afford the product (58.5 g). NMR showed the expected signals.
Reaction SMILES: [ClH:1].O1CCOCC1.C(OC(=O)[NH:14][CH2:15][CH2:16][C:17](=[O:38])[NH:18][CH2:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH2:22][N:23]([CH:30]1[CH2:35][CH2:34][C:33](=[O:36])[NH:32][C:31]1=[O:37])[C:24]2=[O:29])(C)(C)C>C(Cl)Cl.CN(C=O)C>[ClH:1].[NH2:14][CH2:15][CH2:16][C:17]([NH:18][CH2:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH2:22][N:23]([CH:30]1[CH2:35][CH2:34][C:33](=[O:36])[NH:32][C:31]1=[O:37])[C:24]2=[O:29])=[O:38]
Reactant: CC(C)(C)OC(=O)NCCC(=O)NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: C1COCCO1
Product: NCCC(=O)NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Temperature: 25 °C
Reaction time: 168 h
Yield: 74 %

Procedure:
4N HCl/dioxane (3.4 mL) was added to a stirred solution of (2-{[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-carbamoyl}-ethyl)-carbamic acid t-butyl ester (1.5 g, 3.4 mmol) in CH2Cl2 (50 mL) and DMF (25 mL). The mixture was stirred at room temperature for 7 days. The mixture was filtered to give 3-amino-N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-propionamide hydrochloride (1.0 g, 74%) as a white solid: mp 249-251° C.; 1H NMR (DMSO-d6) δ 2.00-2.04 (m, 1H), 2.37-2.65 (m, 4H, 2CH2), 2.86-2.99 (m, 3H), 4.34-4.57 (m, 4H, 2CH2), 5.11-5.18 (dd, J=4.8 and 13.1 Hz, 1H, CH), 7.46-7.64 (m, 3H, Ar), 8.02 (s, 3H, NH3), 8.78 (t, J=5.3 Hz, 1H, NH), 11.01 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.57, 31.17, 31.94, 35.09, 39.02, 46.21, 51.57, 121.71, 128.27, 130.81, 131.65, 134.28, 140.14, 167.99, 169.47, 170.96, 172.83; Anal. calcd. for C17H21N4O4Cl: C, 52.38; H, 5.69; N, 14.37; Cl, 9.09. Found: C, 52.31; H, 5.56; N, 14.19; Cl, 9.01.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:20][C@H:21]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)[CH3:22]>>[Cl:1][C:2]1[CH:10]=[C:6]([C:7]([NH:20][C@H:21]([C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=2)[CH3:22])=[O:9])[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)=[N:4][CH:3]=1
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: O=C(O)c1cc(Cl)cnc1Cc1cccc(Cl)c1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Cc2cccc(Cl)c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 5-chloro-2-(3-chlorobenzyl)nicotinic acid (step 2) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 3 of Example 5): 1H-NMR (CDCl3) δ 9.19 (1H, d, J=7.7 Hz), 8.65 (1H, d, J=2.4 Hz), 7.98–7.92 (3H, m), 7.51 (2H, d, J=8.4 Hz), 7.23–7.18 (3H, m), 7.09–7.06 (1H, m), 5.20–5.10 (1H, m), 4.18 (1H, d, J=14.2 Hz), 4.12 (1H, d, J=14.2 Hz), 3.85 (3H, s), 1.42 (3H, d, J=7.0 Hz); MS (ESI) m/z 443 (M+H)+, 441 (M−H)−.
Reaction SMILES: CC1NC([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:11]([O:13][CH3:14])=[O:12])=C(C)N=1.I[C:20]1[NH:24][C:23]([C:25]2([CH3:29])[CH2:28][O:27][CH2:26]2)=[N:22][C:21]=1[C:30]#[N:31].IC1NC(C)=NC=1C>>[C:30]([C:21]1[N:22]=[C:23]([C:25]2([CH3:29])[CH2:28][O:27][CH2:26]2)[NH:24][C:20]=1[C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=1[CH3:18])[C:11]([O:13][CH3:14])=[O:12])#[N:31]
Reactant: CC1(c2nc(C#N)c(I)[nH]2)COC1
Reactant: COC(=O)c1ccc(C)c(-c2[nH]c(C)nc2C)c1
Agent: Cc1nc(C)c(I)[nH]1
Product: COC(=O)c1ccc(C)c(-c2[nH]c(C3(C)COC3)nc2C#N)c1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 5.6, except 5-iodo-2-(3-methyloxetan-3-yl)-1H-imidazole-4-carbonitrile (compound 202.3) was used in place of 5-iodo-2,4-dimethyl-1H-imidazole (compound 5.5). m/z (ES+) 312 (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:27])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13](=[O:18])[C:14]([O:16]C)=O)=[C:5]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:4]=1[C:23]([O:25][CH3:26])=[O:24].[OH-].[NH4+:29].[Na+].[Cl-]>C(Cl)Cl>[F:1][CH:2]([F:27])[C:3]1[N:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[C:6]([C:13](=[O:18])[C:14]([NH2:29])=[O:16])=[C:5]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:4]=1[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)C(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1CC(C)C
Reactant: [NH4+]
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(=O)C(N)=O)c1CC(C)C
Reaction time: 2 h

Procedure:
To 16.5 g of methyl 6-(difluoromethyl)-4-(2-methylpropyl)-5-(methoxycarbonyl)-2-(trifluoromethyl)-a-oxo-3-pyridineacetate (prepared by example E of U.S. Pat. No. 5,298,479) in 60 ml of methylene chloride was added 25 ml of concentrated ammonium hydroxide. The reaction mixture was stirred for 2 h and the aqueous layer was saturated with NaCl and the organic was extracted into methylene chloride. The methylene chloride layer was dried (MgSO4) and concentrated in vacuo. The residue was recrystallized from 20% EtOAc-benzene to give 12.5 g of 6-(difluoromethyl) -4-(2-methylpropyl)-5-(methoxy-carbonyl)-2-(trifluoromethyl)-a-oxo-3-pyridineacetamide. A mixture of 2.4 g of this material, 2.0 g of phosphorus pentasulfide, 2 g of Celite and 16 ml of toluene was held at reflux for 2h. The mixture was filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (20% EtOAc in hexane) to give an oil which crystallized from 3% EtOAc in hexane as a solid.
Reaction SMILES: CC([S@@]([NH:7][C@:8]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([F:38])([F:37])[F:36])=[CH:25][CH:24]=1)([CH2:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)[C:9]([F:12])([F:11])[F:10])=O)(C)C.Cl>CO.O1CCOCC1>[NH2:7][C@@:8]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([F:36])([F:37])[F:38])=[CH:25][CH:24]=1)([C:9]([F:12])([F:11])[F:10])[CH2:13][C:14]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)=[O:22]
Reactant: Cc1ccc(C(=O)C[C@](N[S@@](=O)C(C)(C)C)(c2ccc(OCCCCCC(F)(F)F)cc2)C(F)(F)F)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1ccc(C(=O)C[C@](N)(c2ccc(OCCCCCC(F)(F)F)cc2)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
To a solution of Intermediate 8D (482 mg, 0.852 mmol) in MeOH (4 mL) was added 4 M HCl (1 mL, 4.00 mmol) in dioxane. The resulting mixture was stirred at rt for 2 h and then concentrated. The residue was taken up in EtOAc, washed with saturated NaHCO3 and brine, dried (MgSO4), filtered and concentrated to afford Intermediate (386 mg, 58%) as a colorless oil, which was used for the subsequent reaction without further purification. LCMS Anal. Calc'd for C23H25F6NO2 461.18, found [M+H] 461.9.
Reaction SMILES: [CH2:1]([N:3]([CH2:21][CH3:22])[C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([NH:13][C:14](=[O:20])[O:15][C:16](C)(C)C)CO)=[CH:6][CH:5]=1)[CH3:2].S(Cl)(Cl)=O.[F-].[Cs+].[NH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]1[NH2:36].[CH:37](O)=O>[Cu](I)I>[NH:29]1[C:30]2[CH:35]=[CH:34][C:33]([N:13]3[C@@H:10]([C:7]4[CH:6]=[CH:5][C:4]([N:3]([CH2:1][CH3:2])[CH2:21][CH3:22])=[CH:9][CH:8]=4)[CH2:16][O:15][C:14]3=[O:20])=[CH:32][C:31]=2[N:36]=[CH:37]1
Reactant: CCN(CC)c1ccc([C@H](CO)NC(=O)OC(C)(C)C)cc1
Reactant: NC1CCCCC1N
Reactant: O=CO
Agent: I[Cu]I
Agent: [Cs+]
Agent: [F-]
Solvent: O=S(Cl)Cl
Product: CCN(CC)c1ccc([C@H]2COC(=O)N2c2ccc3[nH]cnc3c2)cc1

Procedure:
The compound was synthesized according to method 6 starting from tert-butyl (R)-1-(4-(diethylamino)phenyl)-2-hydroxyethylcarbamate (0.500 g, 21.623 mmol), thionyl chloride (0.95 mL, 12.98 mmol, 4-bromol, 2-diamino benzene (219 mg, 1.175 mmol), cesium fluoride (324 mg, 2.136 mmoles) and copper iodide (30 mg, 0.160 mmoles), 1,2-diaminocyclohexane (0.02, 0.1602 mmoles), formic acid (5 mL). Yield: 0.05 g (0.6%). MS m/z 351.4 (M+H)+; 1H-NMR (400 MHz, DMSO-d6): δ 12.44 (d, 1H); 8.17 (d, 1H); 7.56-7.13 (m, 5H); 6.55 (d, 2H); 5.54 (t, 1H); 4.75 (t, 1H); 4.09 (t, 1H); 3.39-3.20 (m, 4H); 1.23-0.98 (m, 6H), HPLC (λ=214 nm, [A]: rt 6.04 min (97.7%).
Reaction SMILES: Br[CH:2]([C:5](=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]#[N:4].[NH2:13][C:14]([NH2:16])=[S:15].II.[NH4+].[OH-]>O>[NH2:16][C:14]1[S:15][C:2]([C:3]#[N:4])=[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:13]=1
Reactant: N#CC(Br)C(=O)c1ccccc1
Reactant: NC(N)=S
Agent: II
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: N#Cc1sc(N)nc1-c1ccccc1

Procedure:
2-Bromo-3-oxo-3-phenylpropionitrile (0.5 g, 3.4 mmol) was mixed with thiourea (0.52 g, 6.8 mmol) and iodine (0.43 g, 3.4 mmol) and the mixture was heated on a steam bath for 12 h. It was then diluted with water and made alkaline with saturated aqueous NH4OH, and extracted with ethyl acetate. The organic phases were washed with water and brine, dried over sodium sulfate, and evaporated to dryness to give the crude product, which was used in the next reaction without any further purification. Yield: 0.2 g, 29%.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16](C(F)(F)F)[CH:15]=2)=[CH:4][N:3]=1.[F:24]C1C=CC=CC=1C(N)CCN>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[C:5]([C:14]2[CH:19]=[CH:18][C:17]([F:24])=[CH:16][CH:15]=2)=[CH:4][N:3]=1
Reactant: FC(F)(F)c1cccc(-c2cnc(Cl)nc2-c2ccncc2)c1
Reactant: NCCC(N)c1ccccc1F
Product: Fc1ccc(-c2cnc(Cl)nc2-c2ccncc2)cc1

Procedure:
2-Chloro-4-(4-pyridyl)-5-(3-trifluoromethylphenyl)-pyrimidine and 1-(2-fluorophenyl)-1,3-propanediamine were reacted according to the General Procedure, Step C (100° C. for 30 min) to give the title compound. MS (m/z): 468.4 (M+H)+; C25H21F4N5 requir. 467.5 (free base).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[NH:8][N:9]=[C:10]2[C:15]=1[CH:14]=[CH:13][CH:12]=[C:11]2[C:16]([F:19])([F:18])[F:17].[F:20][C:21]1[CH:28]=[C:27]([F:29])[CH:26]=[C:25](F)[C:22]=1[CH2:23]Br>CN(C=O)C>[F:20][C:21]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:22]=1[CH2:23][N:8]1[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[C:15]2[C:10]([C:11]([C:16]([F:19])([F:17])[F:18])=[CH:12][CH:13]=[CH:14]2)=[N:9]1
Reactant: Fc1cc(F)c(CBr)c(F)c1
Reactant: FC(F)(F)c1cccc2c(-c3ccccn3)[nH]nc12
Solvent: CN(C)C=O
Product: Fc1ccc(Cn2nc3c(C(F)(F)F)cccc3c2-c2ccccn2)c(F)c1
Reaction time: 120 h
Yield: 12.1 %

Procedure:
Then a solution of 3-pyridin-2-yl-7-(trifluoromethyl)-2H-indazole (0.183 g, 0.7 mmol) and 2,4,6-trifluorobenzyl bromide (0.203 g, 0.9 mmol) in DMF (5 mL) was heated at 120° C. After 5 days, the reaction mixture was partitioned with EtOAc and water. Organics were washed with water (3×), then brine and dried over MgSO4, then stripped and the resulting crude product was flashed by reverse phase HPLC to afford the title compound (0.033 g, 5%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[F:13][C:14]([F:19])([F:18])[CH2:15][CH2:16]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CCOC(C)=O>[F:13][C:14]([F:19])([F:18])[CH2:15][CH2:16][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2
Reactant: OCCC(F)(F)F
Reactant: O=C1CCCc2cc(O)ccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1CCCc2cc(OCCC(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.5 %

Procedure:
6-Hydroxy-1-tetralone (3.5 g, 21.6 mmol), 3,3,3-trifluoro-1-propanol (4.93 g, 43.2 mmol) and triphenylphosphine (11.3 g, 43.2 mmol) were combined in THF (80 mL). DIAD (8.7 g, 43.2 mmol) was added, and the reaction stirred overnight at rt. The solution was diluted with EtOAc (100 mL) and washed with brine. Organics were dried (MgSO4) and concentrated. Purification by silica gel chromatography (10-50% EtOAc/hexanes) gave 2.93 g (53%) of the title compound as a clear oil. 1H NMR (400 MHz, DMSO-d6): δ 8.02 (d, 1H, J=8.7 Hz), 6.82 (dd, 1H, J=8.7, 2.5 Hz), 6.71 (d, 1H, J=2.4 Hz), 4.25 (t, 2H, J=6.6 Hz), 2.93 (t, 2H, J=6.1 Hz), 2.59-2.71 (m, 4H), 2.08-2.16 (m, 2H). [M+H] calc'd for C13H13F3O2, 259; found 259.
Reaction SMILES: [CH2:1]([O:9][N:10]1[C:15]([CH3:17])([CH3:16])[CH2:14][CH:13]([OH:18])[CH2:12][C:11]1([CH3:20])[CH3:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:21](Cl)(=[O:25])[C:22]([CH3:24])=[CH2:23].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:9][N:10]1[C:15]([CH3:17])([CH3:16])[CH2:14][CH:13]([O:18][C:21](=[O:25])[C:22]([CH3:24])=[CH2:23])[CH2:12][C:11]1([CH3:19])[CH3:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: C=C(C)C(=O)Cl
Reactant: CCCCCCCCON1C(C)(C)CC(O)CC1(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)C(=O)OC1CC(C)(C)N(OCCCCCCCC)C(C)(C)C1

Procedure:
The procedure of Example 3 is repeated using 1-octyloxy-4-hydroxy-2,2,6,6-tetramethylpiperidine, methacryloyl chloride and triethylamine in methylene chloride to afford the title compound as a colorless oil. Analyses by nmr, ir and ms give data consistent with the desired structure.
Reaction SMILES: CC1(C)[O:9][C:8](=[O:10])[C:5]2([CH2:7][CH2:6]2)[C:4](=[O:11])O1.[CH3:13][O:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>C(O)C>[CH3:13][O:14][C:15]1[CH:21]=[CH:20][C:18]([N:19]2[CH2:6][CH2:7][CH:5]([C:8]([OH:9])=[O:10])[C:4]2=[O:11])=[CH:17][CH:16]=1
Reactant: COc1ccc(N)cc1
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Solvent: CCO
Product: COc1ccc(N2CCC(C(=O)O)C2=O)cc1
Yield: 15.9 %

Procedure:
A mixture of 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (0.500 g; 2.94 mmol) and 4-methoxyaniline (1.09 g; 8.82 mmol) in ethanol (3 mL) was irradiated in a microwave oven for 3 minutes at 100° C. The mixture was concentrated under reduced pressure and the residue was dissolved in a solution of sodium hydroxide 6N, washed with dichloromethane, acidified with a solution of hydrochloric acid 6N to pH=2, extracted with ethyl acetate dried and concentrated under reduced pressure to yield 0.11 g (16%) of a pale pink solid which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:4].CI.[H-].[Na+].[CH3:34]COC(C)=O>CN(C=O)C.C1COCC1>[CH3:1][O:2][C:3]([C@H:5]1[CH2:9][C@@H:8]([O:10][CH3:34])[CH2:7][N:6]1[C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:4]
Reactant: COC(=O)[C@H]1C[C@@H](O)CN1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)[C@H]1C[C@@H](OC)CN1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 26 h

Procedure:
Into a solution of 2 (5.71 g, 14.7 mmol) in anhydrous DMF (20 mL) and anhydrous THF (20 mL) was added MeI (3.67 mL, 58.9 mmol). The solution was cooled to 0° C. in an ice bath and NaH (0.766 g, 19.2 mmol) was added in one portion. The mixture was stirred at RT for 26 h before adding EtOAc and washing sequentially with water and brine. The organic layer was dried over MgSO4 and concentrated under reduced pressure. Purification of the crude material by flash chromatography revealed 3 (4.67 g, 79%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-])=O)[CH:10]=1)[C:5]([OH:7])=[O:6].O>CO.Cl.[Pd]>[ClH:1].[NH2:11][C:9]1[CH:8]=[C:4]([CH:3]=[C:2]([Cl:1])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1cc(Cl)cc([N+](=O)[O-])c1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Product: Nc1cc(Cl)cc(C(=O)O)c1
Reaction time: 0.5 h

Procedure:
A mixture of 3-chloro-5-nitrobenzoic acid (10.0 g) and 10% Pd/C (0.3 g) in MeOH (100 mL) and 6N HCl (30 mL) was shaken under 30 psi H2 in a Parr apparatus for 30 min, then filtered through Celite and evaporated. The residue was crystallized from 6N HCl to yield the product. More highly purified material was obtained by a second crystallization from water. 1H-NMR (d4-CD3OD): δ 7.24 (1H, dd, J=1.4, 2.0 Hz), 7.20 (1H, dd, J=1.6, 2.0 Hz), 6.87 (1H, t, J=2.0 Hz). 13C-NMR (d4-CD3OD): δ 167.6, 149.5, 134.3, 132.7, 117.8, 117.4, 113.9.