Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([O:13][CH:14]([C:23]([F:26])([F:25])[F:24])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH2:21][CH3:22])=[O:12])=[C:7]([F:27])[CH:6]=1)(=O)C.C(O)C.C(N)C1C=CC=CC=1>O>[OH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([O:13][CH:14]([C:23]([F:24])([F:25])[F:26])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH2:21][CH3:22])=[O:12])=[C:7]([F:27])[CH:6]=1
Reactant: CCOCCCCCC(OC(=O)c1ccc(OC(C)=O)cc1F)C(F)(F)F
Solvent: O
Solvent: NCc1ccccc1
Solvent: CCO
Product: CCOCCCCCC(OC(=O)c1ccc(O)cc1F)C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A reactor was charged with 1 g of 4-acetoxy-2-fluoro-1-(6-ethoxy-1-trifluoromethylhexyloxycarbonyl)-benzene, 15 ml of ethanol and 0.6 g of benzylamine, and the mixture was stirred at room temperature for 5 hours. After the reaction, the reaction mixture solution was poured into water and subjected to extraction with dichloromethane. An organic layer was consecutively washed with a hydrochloric acid aqueous solution and with water, and dried over anhydrous sodium sulfate. The solvent was removed to give a crude 4-hydroxy-2-fluoro-1-(6-ethoxy-1-trifluoromethylhexyloxycarbonyl)benzene. This product was analyzed by thin film chromatography to show that benzylacetamide was co-present in addition to the end product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([N+:17]([O-])=O)[CH:16]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[F:13].[Cl-].[NH4+].O.C(O)C>C1COCC1.[Fe]>[Br:1][C:2]1[CH:16]=[C:15]([CH:14]=[C:4]([O:5][C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=2[F:13])[CH:3]=1)[NH2:17]
Reactant: O=[N+]([O-])c1cc(Br)cc(Oc2ccc(F)cc2F)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: Nc1cc(Br)cc(Oc2ccc(F)cc2F)c1
Yield: 100 %

Procedure:
A mixture of 1-(3-bromo-5-nitrophenoxy)-2,4-difluorobenzene (54 mg, 0.16 mmol), ammonium chloride (18 mg, 0.32 mmol), and iron powder (45 mg, 0.80 mmol) suspended in THF (300 uL), water (100 uL) and ethanol (300 uL) was heated to 100° C. using microwave irradiation (normal) for 3 h. The crude reaction mixture was filtered through a short plug of celite; the celite plug was washed with MeOH (˜5 mL). The resulting filtrate was concentrated in vacuo. The resulting residue was diluted with EtOAc (50 ml) and washed with saturated bicarbonate solution (aq), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude solid was purified by silica gel column chromatography using a gradient of EtOAc (5 to 20%) in hexanes to afford the title compound (48 mg, 100%) as a yellow solid. LCMS (M+H)+=301.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[CH:5][C:4]=1[CH2:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.N1C=CC=CC=1.ClCCCl.[CH3:30][O:31][C:32]1[C:33]([CH3:49])=[C:34]([CH3:48])[C:35]2[O:40][C:39]([CH2:42][C:43](Cl)=[O:44])([CH3:41])[CH2:38][CH2:37][C:36]=2[C:46]=1[CH3:47]>O>[CH3:30][O:31][C:32]1[C:33]([CH3:49])=[C:34]([CH3:48])[C:35]2[O:40][C:39]([CH2:42][C:43]([N:17]3[CH2:16][CH2:15][N:14]([CH2:13][C:4]4[CH:5]=[CH:6][C:7]([O:11][CH3:12])=[C:8]([O:9][CH3:10])[C:3]=4[O:2][CH3:1])[CH2:19][CH2:18]3)=[O:44])([CH3:41])[CH2:38][CH2:37][C:36]=2[C:46]=1[CH3:47]
Reactant: COc1ccc(CN2CCNCC2)c(OC)c1OC
Reactant: COc1c(C)c(C)c2c(c1C)CCC(C)(CC(=O)Cl)O2
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCCl
Product: COc1ccc(CN2CCN(C(=O)CC3(C)CCc4c(C)c(OC)c(C)c(C)c4O3)CC2)c(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.6 %

Procedure:
To a solution composed of 2.54 g (0.01 mol) of 1-(2,3,4-trimethoxyphenyl)methylpiperazine, 0.95 g of pyridine and 50 ml of 1,2-dichloroethane was added 3.56 g (0.012 mol) of the (3,4-dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-benzopyran-2-yl)acetyl chloride prepared above and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with diethyl ether. The extract was washed with water and then with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and filtered. Low-boiling substances were distilled off from the filtrate under reduced pressure and the residue was purified by silica gel column chromatography. The eluate was further purified by recrystallization from a 95:5 (v/v) mixture of hexane and ethyl acetate to give 1.4 g of 1-[(3,4-dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-benzopyran-2-yl)acetyl]-4-(2,3,4-trimethoxybenzyl)piperazine [Compound (28)] having the following physical characteristics.
Reaction SMILES: [CH2:1]([N:3]([CH2:28][CH3:29])[CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]3[CH:15]=[CH:16][C:17]([O:19][CH2:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:18][C:13]=3[S:12][C:11]=2[CH:27]=1)[CH3:2].C1C[O:33]CC1>>[CH2:28]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]3[CH:15]=[CH:16][C:17]([O:19][CH2:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:18][C:13]=3[S:12](=[O:33])[C:11]=2[CH:27]=1)[CH3:29]
Reactant: C1CCOC1
Reactant: CCN(CC)CCOc1ccc2c(c1)sc1cc(OCCN(CC)CC)ccc12
Product: CCN(CC)CCOc1ccc2c(c1)S(=O)c1cc(OCCN(CC)CC)ccc1-2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a cooled solution (0° C.) of the product of Example 16A (347 mg, 0.83 mmol) in dry THF (2 mL), was added a solution of CF3CO3H in THF (4 M; 0.21 mL, 0.83 mmol). The reaction was stirred 30 minutes at 0° C., then for 30 minutes at room temperature, and concentrated under vacuum. The residue was purified by flash chromatography (35 g silica gel, 1:5:94 NH4OH-MeOH-CH2Cl2) to afford the title compound (360 mg, 100%).
Reaction SMILES: CS(Cl)(=O)=[O:3].Cl[C:7]1[CH:14]=[C:13]([CH2:15][OH:16])C=[C:11](Cl)[C:8]=1[CH:9]=O.C(N([CH2:23][CH3:24])CC)C>ClCCl>[CH3:13][CH2:14][CH2:7][CH:8]([CH3:11])[CH3:9].[C:23]([O:16][CH2:15][CH3:13])(=[O:3])[CH3:24]
Reactant: CCN(CC)CC
Reactant: CS(=O)(=O)Cl
Reactant: O=Cc1c(Cl)cc(CO)cc1Cl
Solvent: ClCCl
Product: CCCC(C)C
Product: CCOC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
289 mg (2.5 mmol) Methansulfonylchloride was added to a stirred solution of 470 mg (2.3 mmol) A3 and 255 mg (2.5 mmol) triethylamine in dry 20 ml dichloromethane, and the solution was stirred at room temperature overnight. After hydrolysis (15 ml), the phases were separated and the organic layer was washed with saturated NaCl (10 ml) and dried over magnesium sulfate. 236 mg (0.9 mmol) A17 was obtained by column chromatography on SiGel (iso-hexane/ethyl acetate 9:1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14](O)[CH:13]=2)=[O:10])=[CH:4][C:3]=1[C:23]([F:26])([F:25])[F:24].[CH2:27](Br)[CH:28]=[CH2:29].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]([CH2:29][CH:28]=[CH2:27])[CH:13]=2)=[O:10])=[CH:4][C:3]=1[C:23]([F:26])([F:25])[F:24]
Reactant: C=CCBr
Reactant: O=C(Nc1cc(O)cc(C(F)(F)F)c1)Nc1ccc(Cl)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCc1cc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc(C(F)(F)F)c1

Procedure:
The phenol compound obtained from Example 133 was treated with allyl bromide (1 eq.), and K2CO3 (2 eq.) in DMF at 60° C. for 24 h. After the reaction was finished, the resulting solution was directly injected on a preparative reverse phase HPLC column and fractions, which contained the desired product mass, were collected and concentrated using the Genevac system. 1H NMR (CD3OD) δ 7.98 (d, J=2 Hz, 1H), 7.65 (dd, J=2 Hz, J=8 Hz, 1H) 7.50 (d, J=8 Hz, 1H), 7.38 (s, 1H), 7.34 (s, 1H), 6.86 (s, 1H), 6.07 (m, 1H), 5.42 (dq, J=2 Hz, J=17 Hz, 1H), 5.29 (dq, J=2 Hz, J=12 Hz, 1H), 4.61 (dt, J=2 Hz, J=5 Hz, 2H).
Reaction SMILES: C([O:5][C:6](=[O:26])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([S:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[C:8]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(C)(C)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[N:16]1[CH:17]=[CH:18][CH:19]=[C:14]([S:13][C:9]2[C:8]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:7]([CH:12]=[CH:11][CH:10]=2)[C:6]([OH:26])=[O:5])[CH:15]=1
Reactant: CC(C)(C)OC(=O)c1cccc(Sc2cccnc2)c1-c1ccccc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cccc(Sc2cccnc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 101.5 %

Procedure:
To a 0° C. solution in dichloromethane (1 mL) of 3-pyridylthio-2-phenylbenzoic acid tert-butyl ester (245 mg, 0.67 mmol), prepared as in Example 241 A, and triethylsilane (390 mg, 3.4 mmol) was added trifluoroacetic acid (1.53 g, 13.4 mmol) and the reaction mixture was warmed to ambient temperature and stirred for 18 hours. The reaction mixture was concentrated and azeotroped with toluene (3×) to give 3-pyridylthio-2-phenylbenzoic acid (209 mg) as a translucent film which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[C:15]3[CH2:23][N:22](CC4C=CC=CC=4)[CH2:21][CH2:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:31]([O-])=[O:32].[NH4+].CC([O:39]C)(C)C.CC(OC)(C)C.CO>CO.[OH-].[OH-].[Pd+2]>[CH3:2][C:1]([O:5][CH3:6])([CH3:4])[CH3:3].[CH3:31][OH:32].[NH4+:8].[OH-:39].[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[C:15]3[CH2:23][NH:22][CH2:21][CH2:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2ncnc3c2CN(Cc2ccccc2)CC3)C1
Reactant: O=C[O-]
Agent: [Pd+2]
Agent: [NH4+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2ncnc3c2CNCC3)C1
Temperature: 25 °C
Yield: 87 %

Procedure:
Pd(OH)2/C (1.2 g, 1.71 mmol) was flushed with argon, (S)-3-(6-Benzyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (10.95 g, 26.7 mmol) dissolved in methanol (25 mL) was added followed by the addition of ammonium formate (1.68 g, 26.7 mmol). The reaction mixture was refluxed for 1 h, cooled down to room temperature, filtered through a celite pad and concentrated under vacuum. Purification by flash chromatography on silica gel (CH2Cl2 then TBME then TBME/MeOH 100/0 to 90/10 then TBME/MeOH/NH4OH 85/15/5) gave (S)-3-(5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (7.39 g, 87% yield) as a yellow sticky oil. 1H NMR (400 MHz, methanol-d4, 298K) δ ppm 1.46-1.46 (m, 9 H) 2.10-2.30 (m, 2 H) 2.78-2.83 (m, 2 H) 3.11-3.14 (m, 2 H) 3.41-3.60 (m, 3 H) 3.65-3.72 (m, 1 H) 3.78 (s, 2 H) 5.68 (m, 1 H) 8.52 (s, 1 H). LCMS: [M+H]+=321.2, Rt(2)=0.87 min
Reaction SMILES: Cl[C:2]([N:4]=[C:5]=[O:6])=[O:3].[OH:7][NH:8][CH2:9][C:10]1[CH:40]=[CH:39][C:13]([O:14][CH2:15][C:16]2[CH:17]=[C:18]([C:22]3[C:27]([CH3:28])=[CH:26][C:25]([O:29][CH2:30][C:31]4([OH:37])[CH2:36][CH2:35][S:34][CH2:33][CH2:32]4)=[CH:24][C:23]=3[CH3:38])[CH:19]=[CH:20][CH:21]=2)=[CH:12][CH:11]=1.Cl.C[O-].[Na+:44]>O.CO.C1COCC1>[OH:37][C:31]1([CH2:30][O:29][C:25]2[CH:26]=[C:27]([CH3:28])[C:22]([C:18]3[CH:19]=[CH:20][CH:21]=[C:16]([CH2:15][O:14][C:13]4[CH:12]=[CH:11][C:10]([CH2:9][N:8]5[C:5](=[O:6])[N-:4][C:2](=[O:3])[O:7]5)=[CH:40][CH:39]=4)[CH:17]=3)=[C:23]([CH3:38])[CH:24]=2)[CH2:32][CH2:33][S:34][CH2:35][CH2:36]1.[Na+:44]
Reactant: Cc1cc(OCC2(O)CCSCC2)cc(C)c1-c1cccc(COc2ccc(CNO)cc2)c1
Reactant: O=C=NC(=O)Cl
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(OCC2(O)CCSCC2)cc(C)c1-c1cccc(COc2ccc(Cn3oc(=O)[n-]c3=O)cc2)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Chlorocarbonyl isocyanate (0.14 ml) was dropwise added, under cooling on an ice-methanol bath, to a THF (15 ml) solution of 4-({[3′-({4-[(hydroxyamino)methyl]phenoxy}methyl)-2,6-dimethylbiphenyl-4-yl]oxy}methyl)tetrahydro-2H-thiopyran-4-ol (792 mg), followed by temperature rising to room temperature and subsequent 1 hour of stirring. A 1 M hydrochloric acid (40 ml) was added to the reaction mixture, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and then the solvent was evaporated under a reduced pressure. By purifying the resulting residue by silica gel column chromatography (chloroform-methanol), a colorless foamy substance (777 mg) was obtained. Sodium methoxide (50 mg) was added to a methanol (10 ml) solution of the resulting foamy substance (116 mg), followed by stirring at room temperature for 30 minutes. Thereafter, sodium methoxide (200 mg) was added to the reaction mixture, followed by stirring at room temperature for 1 hour. The reaction mixture was warmed up to 60° C., stirred for 2 hours and then spontaneously cooled to room temperature. 1 M Hydrochloric acid (10 ml) and water (20 ml) were added to the reaction mixture, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in methanol (5 ml)-THF (10 ml), and a 1 M sodium hydroxide aqueous solution (0.20 ml) was added, followed by concentration under a reduced pressure. By washing the resulting residue with isopropanol-diethyl ether, sodium 2-[4-({4′-[(4-hydroxytetrahydro-2H-thiopyran-4-yl)methoxy]-2′,6′-dimethylbiphenyl-3-yl}methoxy)benzyl]-3,5-dioxo-1,2,4-oxadiazolidin-4-ide (80 mg) was obtained as a pale yellow solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([C:11]1[NH:15][N:14]=[C:13]([C:16](O)=[O:17])[C:12]=1[N+:19]([O-:21])=[O:20])([CH3:10])([CH3:9])[CH3:8].C[N:23](C)C=O>ClCCl>[C:7]([C:11]1[NH:15][N:14]=[C:13]([C:16]([NH2:23])=[O:17])[C:12]=1[N+:19]([O-:21])=[O:20])([CH3:10])([CH3:9])[CH3:8]
Reactant: CN(C)C=O
Reactant: CC(C)(C)c1[nH]nc(C(=O)O)c1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CC(C)(C)c1[nH]nc(C(N)=O)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Oxalyl chloride (10.2 ml, 117 mmol) was added dropwise to a suspension of 5-tert-butyl-4-nitro-1H-pyrazol-3-carboxylic acid (6 g, 28 mmol) in dichloromethane (55 ml) containing dimethylformamide (0.1 ml) under nitrogen at 0° C. The reaction was stirred at 0° C. for 0.5 hours, allowed to warm to room temperature and stirred for a further 1.5 hours. The solvent was removed under reduced pressure, the residue was azeotroped with dichloromethane (50 ml) and the residue was dissolved in dichloromethane (100 ml). Ammonia gas was bubbled into the solution for 45 minutes and the reaction was stirred under nitrogen at room temperature for 18 hours, concentrated under reduced pressure and the residue was dissolved in ethyl acetate (250 ml). After washing with water (100 ml) and brine (100 ml) the organic phase was filtered, the filtrate was dried over MgSO4 and concentrated under reduced pressure to give 5-tert-butyl-4-nitro-1H-pyrazol-3-carboxylic acid amide (4.0 g) as a light brown solid. 1H NMR (400 MHz, DMSO-D6): δ=12.90-13.08 (1H, brs), 7.78-7.86 (1H, brs), 7.49-7.60 (1H, brs), 1.30 (9H, s) (electrospray): m/z [M+H]+ 213, [M+Na]+ 235, [M−H]+ 211.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:36][CH2:37][CH2:38][NH:39][C:40]1[CH:45]=[C:44]([CH3:46])[CH:43]=[C:42]([CH3:47])[N:41]=1>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH3:47][C:42]1[CH:43]=[C:44]([CH3:46])[CH:45]=[C:40]([NH:39][CH2:38][CH2:37][NH:36][C:16](=[O:18])[C:15]2[CH:14]=[CH:13][C:12]([O:11][CH2:1]/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])\[CH3:4])=[CH:20][CH:19]=2)[N:41]=1
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)O)cc1
Reactant: Cc1cc(C)nc(NCCN)c1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)NCCNc2cc(C)cc(C)n2)cc1
Reaction time: 0.75 h
Yield: 78.9 %

Procedure:
4-geranyloxybenzoic acid(2.30 g) was dissolved in chloroform(50 ml) and triethylamine(2.33 ml), and then diphenylphosphinic chloride(1.48 ml) was added thereto while being cooled with ice. After being stirred for 45 minutes, the mixture, with 2-(2-aminoethylamino)-4,6-dimethylpyridine(1.90 g) added thereto, was stirred for 3 hours at room temperature. The reaction mixture was washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1). The resulting solid was recrystallized from n-hexane/ethyl acetate, thereby yielding 2.79 g of the aimed compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]([N:13]1[CH2:20][CH:19]3[CH:15]([CH2:16][NH:17][CH2:18]3)[CH2:14]1)[CH:6]=[N:5]2.[F:21][C:22]1[C:23]([N:31]2[N:35]=[CH:34][CH:33]=[N:32]2)=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](O)=[O:26]>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]([N:13]1[CH2:14][CH:15]3[CH2:16][N:17]([C:25]([C:24]4[CH:28]=[CH:29][CH:30]=[C:22]([F:21])[C:23]=4[N:31]4[N:35]=[CH:34][CH:33]=[N:32]4)=[O:26])[CH2:18][CH:19]3[CH2:20]1)[CH:6]=[N:5]2
Reactant: O=C(O)c1cccc(F)c1-n1nccn1
Reactant: Fc1cc2ncc(N3CC4CNCC4C3)nc2cc1F
Product: O=C(c1cccc(F)c1-n1nccn1)N1CC2CN(c3cnc4cc(F)c(F)cc4n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15, utilizing Intermediate 44 and 3-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid. MS (ESI): mass calculated for C23H18F3N7O, 465.15; m/z found 466.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.28 (s, 1H), 7.75 (d, J=20.8, 2H), 7.65 (dd, J=10.6, 8.4, 1H), 7.50 (tt, J=9.6, 4.8, 1H), 7.43 (dd, J=11.4, 8.0, 1H), 7.39-7.31 (m, 1H), 7.25 (dd, J=12.5, 4.9, 1H), 4.00-3.86 (m, 1H), 3.81 (dd, J=10.0, 5.6, 2H), 3.66-3.49 (m, 4H), 3.32-3.16 (m, 3H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:24]=[CH:23][CH:22]=[CH:21][C:6]=1[CH2:7][NH:8][C:9]([C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[N:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1)=[O:10].CI.[C:27](OCC)(=O)C>CN(C=O)C>[CH3:3][O:4][C:5]1[CH:24]=[CH:23][CH:22]=[CH:21][C:6]=1[CH2:7][N:8]([CH3:27])[C:9]([C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[N:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1)=[O:10]
Reactant: CCOC(C)=O
Reactant: COc1ccccc1CNC(=O)c1ccc2cccnc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccccc1CN(C)C(=O)c1ccc2cccnc2n1
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (10 mg) in DMF (1 mL) at 0° C. was added a solution of the compound of Example 1 (68 mg, 0.23 mmol) in DMF (1mL). The reaction mixture was stirred at the same temperature for 30 minutes then methyl iodide (20 μL, 0.32 mmol) was added. Reaction mixture was stirred at room temperature overnight. It was then poured into ethyl acetate, washed with water, brine, dried over magnesium sulfate and concentrated to give a white solid. Purification was done using a silica gel column and ethyl acetate as the eluent. 1H NMR (300 MHz; CDCl3): Mixture of rotamers 9.13 (m, 1H); 8.29−8.18 (m, 2H); 7.86 (dd, 1H, J=8.2 and 12 Hz); 7.58−7.11 (complex mixture; 3H); 6.98−6.71 (complex mixture, 2H); 4.91 and 4.85 (2s, 2H) and 3.84 and 3.58 (2 s, 3H); 3.18 and 3.04 (2 s, 3H) ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[N:14]=[C:13]([O:15]C)[C:12]([CH2:17][O:18][C:19]2[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[CH:22]=[CH:21][C:20]=2[CH3:28])=[C:11]([CH3:29])[N:10]=1.Cl>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[N:14]=[C:13]([OH:15])[C:12]([CH2:17][O:18][C:19]2[CH:24]=[C:23]([CH:25]([CH3:26])[CH3:27])[CH:22]=[CH:21][C:20]=2[CH3:28])=[C:11]([CH3:29])[N:10]=1
Reactant: COc1nc(-c2c(C)cccc2C)nc(C)c1COc1cc(C(C)C)ccc1C
Agent: Cl
Product: Cc1ccc(C(C)C)cc1OCc1c(C)nc(-c2c(C)cccc2C)nc1O
Temperature: 100 °C

Procedure:
A mixture of 2-(2,6-dimethylphenyl)-5-[(5-isopropyl-2-methylphenoxy)methyl]-4-methoxy-6-methylpyrimidine (1.29 g, 3.30 mmol) and 6 N HCl is heated at 100° C. for 3 h (until starting material is consumed as determined by LC/MS analysis). The resulting mixture is adjusted to pH 6 using 10 N NaOH and extracted with EtOAc (100 mL×3). The combined extracts are washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and evaporated at reduced pressure to obtain a yellow gum. Purification by chromatography on silica gel (50-100% EtOAc/Hexanes) provides the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ 11.4 (br s, 1H), 6.75-7.26 (m, 6H), 5.00 (s, 2H), 2.86 (m, 1H), 2.51 (s, 3H), 2.22 (s, 6H), 2.19 (s, 3H), 1.24 (d, J=6.8 Hz, 6H); LC-MS found 377.4 (MH+), rt=2.87 min, Method 3.
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5](=[O:6])[CH2:4][C:3]1=[O:7].[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH3:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1>>[OH:6][C:5]1[C:2]([CH3:1])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3](=[O:7])[C:4]=1[CH:14]([C:24]1[NH:25][C:26]2[C:31]([C:23]=1[CH3:22])=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1ccccc1
Reactant: Cc1c[nH]c2ccccc12
Reactant: CC1(c2ccccc2)C(=O)CC1=O
Product: Cc1c(C(C2=C(O)C(C)(c3ccccc3)C2=O)c2ccccc2)[nH]c2ccccc12

Procedure:
Using general procedure C, 2-methyl-2-phenyl-cyclobutane-1,3-dione (Lit. 1) was reacted with benzaldehyde and 3-methyl-1H-indole to give the title compound as a colorless solid. MS: 392.3 ([M−H]−).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CN1C(=O)CCC1.C(N(CC)CC)C.F[C:23]1[CH:24]=[CH:25][C:26]([N+:31]([O-:33])=[O:32])=[C:27]([C:29]=1[F:30])[NH2:28]>O>[F:30][C:29]1[C:23]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[CH:24][CH:25]=[C:26]([N+:31]([O-:33])=[O:32])[C:27]=1[NH2:28]
Reactant: Nc1c([N+](=O)[O-])ccc(F)c1F
Reactant: CN1CCNCC1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Solvent: O
Product: CN1CCN(c2ccc([N+](=O)[O-])c(N)c2F)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of N-methylpiperazine (1.0 eq), NMP, triethylamine (3.0 eq) and 5,6-difluoro-2-nitroaniline (1.0 eq) were heated at 90° C. for 1 hour. The reaction was allowed to cool to room temperature and then poured into water and let stand for 1 hour. The resulting solid was collected and dried and utilized without further purification. MH+=255.3
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C:10]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=2)([C:13]([F:16])([F:15])[F:14])[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O.O>ClCCCl.CO>[Cl:23][C:21]1[CH:22]=[C:17]([C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:11][CH2:12][NH:8][CH2:9]2)[CH:18]=[C:19]([Cl:24])[CH:20]=1
Reactant: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CCN(Cc2ccccc2)C1
Agent: CC(Cl)OC(=O)Cl
Solvent: CO
Solvent: ClCCCl
Solvent: O
Product: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CCNC1
Yield: 89.3 %

Procedure:
To a stirred solution of 1-benzyl-3-(3,5-dichloro-phenyl)-3-trifluoromethyl-pyrrolidine (Preparation 34, 7.5 g, 20.1 mmol) in 1.2-dichloroethane (50 mL) was added 1-chloroethyl chloroformate (3.87 mL, 36.19 mmol) at room temperature. Resulting reaction mixture was refluxed for 3 hours. After complete consumption of starting material, reaction mixture was concentrated under reduced pressure to afford brown thick oil, which was dissolved in MeOH (50 mL) and refluxed for 2 hours. After complete consumption of starting material, reaction mixture was concentrated in vacuo to afford brown oil, to which water was added (100 mL) and extracted with hexane (2×50 mL). Aqueous layer was basified by saturated sodium bicarbonate solution and extracted by ethyl acetate (3×50 mL). Combined organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo to afford brown oil (7.5 g, crude). Crude compound was purified by column chromatography (100-200 mesh silica). Desired product was eluted in 25% ethyl acetate in hexane to afford product as brown oil (5.1 g, 89.32%). 1H-NMR (400 MHz, DMSO-d6) δ: 2.33-2.39 (m, 1H), 2.40-2.45 (m, 1H), 2.85-2.98 (m, 2H), 3.34 (d, 1H, J=12.72 Hz), 3.52 (d, 1H, J=12.56 Hz), 7.28-7.34 (m, 1H), 7.46-7.52 (m, 2H), 7.64 (d, 1H J=1.25 Hz). (m/z): 284.0 (M+H).