Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:11](=[O:12])[NH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:13]([OH:15])=O)[CH:8]=2)[NH:3]1.C(Cl)(=O)C([Cl:19])=O.CN(C=O)C>C(Cl)Cl>[O:1]=[C:2]1[C:11](=[O:12])[NH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:13]([Cl:19])=[O:15])[CH:8]=2)[NH:3]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc2[nH]c(=O)c(=O)[nH]c2c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc2[nH]c(=O)c(=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylic acid (0.300 g, 1.455 mmol) in DCM (3 mL) was added oxalyl chloride (0.387 mL, 4.37 mmol) and a drop of DMF (anhydrous). The resulting mixture was then stirred at room temperature for 2 h, then the mixture was concentrated in vacuo to give 2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-carbonyl chloride. A solution of (S)-4-(3-fluoro-4-(trifluoromethoxy)phenyl)-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-amine hydrochloride (50 mg, 0.137 mmol) in DCM (1 mL) at 0° C. was added 2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-carbonyl chloride (326 mg, 1.453 mmol), and DIEA (0.072 mL, 0.411 mmol). The resulting mixture was stirred at 0° C. for 30 min and then at room temperature for overnight. The reaction was diluted with H2O (5 mL) and EtOAc (7 mL). The mixture was then stirred at room temperature for 30 min. The mixture was then filtered and the organic layer was dried over MgSO4, and concentrated in vacuo. The residue was dissolved in DMSO (2 mL) and solution was purified by preparative HPLC (0-100% MeCN 0.1% TFA/H2O 0.1% TFA) to give the title compound as a white solid. MS (ESI, positive ion) m/z: 517.0 (MH+). 1H NMR (400 MHz, d4-MeOH) δ: 8.27 (dd, J=4.8, 1.3 Hz, 1H), 7.60-7.69 (m, 3H), 7.51-7.58 (m, 1H), 7.42-7.48 (m, 2H), 7.24 (d, J=8.4 Hz, 2H), 4.45-4.59 (m, 1H), 4.16-4.35 (m, 1H), 3.07-3.27 (m, 1H), 2.84-3.05 (m, 1H).
Reaction SMILES: FC(F)(F)C([N:5]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([F:33])([F:32])[F:31])[C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1)=O.C(N(CC)CC)C.C([O:45][C:46](=[O:50])[C@H:47]([CH3:49])[NH2:48])C>CCOCC>[F:33][C:30]([F:31])([F:32])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][NH:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:48][C@H:47]([C:46]([OH:50])=[O:45])[CH3:49])=[O:11])=[CH:13][CH:14]=1
Reactant: CCOC(=O)[C@H](C)N
Reactant: O=C(Cl)c1ccc(N(CCCCCCCCCCCCCCCC(F)(F)F)C(=O)C(F)(F)F)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1)C(=O)O

Procedure:
A solution of 4.75 g. of 4-[N-trifluoroacetyl-15-(trifluoromethyl)pentadecylamino]benzoyl chloride and 1.2 g. of triethylamine in 200 ml. of warm ether is treated with 1.55 g. alanine ethyl ester and refluxed for 24 hours. The hot solution is filtered, the residue is washed with hot ether, and the solution is evaporated. After treatment with aqueous methanolic potassium carbonate, the product is precipitated by acidification, filtered, and dried. Crystallization from acetone yields the product as a white, crystalline solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH2:13][C:14]([O:16]C)=O)[N:9]=2)=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:20]=[C:21]([CH:31]=[CH:32][C:33]=1[Cl:34])[CH2:22][N:23]1[CH2:28][CH2:27][O:26][C@@H:25]([CH2:29][NH2:30])[CH2:24]1>CN1CCCC1=O.CO>[Cl:18][C:19]1[CH:20]=[C:21]([CH:31]=[CH:32][C:33]=1[Cl:34])[CH2:22][N:23]1[CH2:28][CH2:27][O:26][C@@H:25]([CH2:29][NH:30][C:14](=[O:16])[CH2:13][C:10]2[N:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[O:12][N:11]=2)[CH2:24]1
Reactant: NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reactant: COC(=O)Cc1noc(-c2ccc(F)cc2)n1
Solvent: CN1CCCC1=O
Solvent: CO
Product: O=C(Cc1noc(-c2ccc(F)cc2)n1)NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Yield: 57.4 %

Procedure:
A mixture of Intermediate 38 (0.024 g), Intermediate 9 (0.025 g), and 1-methyl-2-pyrrolidinone (1 drop) was subjected was subjected to irradiation in a 600 W microwave oven on full power for 4 mins. The reaction mixture was dissolved in methanol and applied to an ion exchange cartridge (2 g Isolute SCX, pre-conditioned with methanol). Elution with methanol (3 column volumes) followed 10% 0.880 ammonia in methanol (2 column volumes) and evaporation of the first basic fraction in vacuo gave the crude product. Purification by Biotage flash column chromatography on silica gel (8 g cartridge), eluting with 100:8:1 dichloromethane/ethanol/0.880 ammonia, gave the title compound as a white solid (0.025 g). LCMS (System A) Rf 2.85 min Mass Spectrum m/z 479, 481 [MH+]
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([C:11]([OH:13])=O)=[C:7]([CH3:10])[S:8][CH:9]=1)(=[O:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClN1C(=O)CCC1=O.[CH:41]1([CH2:44][N:45]2[C:53]3[N:52]=[C:51]([CH2:54][C:55]4[CH:60]=[CH:59][C:58]([NH:61][CH3:62])=[CH:57][CH:56]=4)[NH:50][C:49]=3[C:48](=[O:63])[N:47]([CH2:64][C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][C:66]=3[F:71])[C:46]2=[O:72])[CH2:43][CH2:42]1.C(N(CC)CC)C>ClCCl>[CH:41]1([CH2:44][N:45]2[C:53]3[N:52]=[C:51]([CH2:54][C:55]4[CH:56]=[CH:57][C:58]([N:61]([CH3:62])[C:11]([C:6]5[C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:9][S:8][C:7]=5[CH3:10])=[O:13])=[CH:59][CH:60]=4)[NH:50][C:49]=3[C:48](=[O:63])[N:47]([CH2:64][C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][C:66]=3[F:71])[C:46]2=[O:72])[CH2:43][CH2:42]1
Reactant: CC(=O)Nc1csc(C)c1C(=O)O
Reactant: CNc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Agent: O=C1CCC(=O)N1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1csc(C)c1C(=O)N(C)c1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 26.6 %

Procedure:
A mixture of 4-acetylamino-2-methyl-thiophene-3-carboxylic acid (45 mg, 0.17 mmol) in dichloromethane (3 mL) at 25° C. was treated with triphenylphosphine (71 mg, 0.22 mmol). This mixture was cooled to 0° C. and then was treated with N-chlorosuccinimide (36 mg, 0.22 mmol). This mixture was stirred at 0° C. for 15 min and then was warmed to 25° C. for 15 min. At this time, the reaction was treated with 3-cyclopropylmethyl-1-(2-fluoro-benzyl)-8-(4-methylamino-benzyl)-3,7-dihydro-purine-2,6-dione (75 mg, 0.17 mmol). This solution was then cooled to 0° C. and was treated with triethylamine (38 μL, 0.22 mmol). The reaction was warmed to 25° C. and was stirred at 25° C. for 18 h. At this time, the reaction was diluted with dichloromethane (100 mL) and was washed with a saturated aqueous sodium bicarbonate solution (1×50 mL). The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by HPLC (15–60% acetonitrile/water (0.075% trifluoroacetic acid in both solvents) over 40 min). Fractions with the desired product were combined and concentrated in vacuo. The resulting residue was diluted with dichloromethane (100 mL) and was washed with a saturated aqueous sodium bicarbonate solution (1×25 mL). The aqueous layer was re-extracted with dichloromethane (1×50 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting solid was dried in vacuo for 24 h to afford 4-acetylamino-2-methyl-thiophene-3-carboxylic acid {4-[3-cyclopropylmethyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-methyl-amide (27.8 mg, 26.1%): EI-HRMS m/e calcd for C32H31N6O4SF (M+Na)+ 637.2004, found 637.2018.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7].C(N(CC)CC)C.[CH2:15]([O:22][C:23](OC1CC(=O)NC1=O)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>ClCCl>[C:23]([NH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7])([O:22][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:24]
Reactant: O=C1CC(OC(=O)OCc2ccccc2)C(=O)N1
Reactant: NCCOCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCOCCO)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
To 2-(2-aminoethoxy)ethanol (20 g) dissolved in dichloromethane (200 ml) was added stepwise triethylamine (26.5 ml) and benzyloxy(carbonyloxy)succinimide (47.47 g). The reaction mixture was stirred overnight at room temperature. The solvent was distilled off under reduced pressure and the residue was dissolved in deionized water (500 ml). The insoluble layer was separated, and the aqueous layer was mixed with 50 g of NaCl and the pH adjusted to 5.0 with 5% H3PO4. The product was extracted with dichloromethane (100 ml, 50 ml, and 50 ml) and the extract was dried with MgSO4, filtered, and evaporated to dryness under reduced pressure. The residue was dried under vacuum overnight, then combined with the previously separated insoluble layer and dissolved in dichloromethane (300 ml). The solution was washed with 5-% aqueous NaCl solution (3×50 ml) and dried with MgSO4. The solvent was distilled under reduced pressure, and the residue was dried overnight under vacuum, giving 40 g of the desired product.
Reaction SMILES: [C:1]([O:18][C@@H:19]1[C@@H:23]([CH2:24][O:25][C:26](=[O:42])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[O:22][C@@H:21]([N:43]2[CH:50]=[C:49]([F:51])[C:47](=[O:48])[NH:46][C:44]2=[O:45])[CH2:20]1)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(N(CC)CC)C.[CH3:59][O:60][C:61]1[C:69]([O:70][CH3:71])=[CH:68][CH:67]=[CH:66][C:62]=1[C:63](Cl)=[O:64]>O1CCOCC1>[CH3:59][O:60][C:61]1[C:69]([O:70][CH3:71])=[CH:68][CH:67]=[CH:66][C:62]=1[C:63]([N:46]1[C:47](=[O:48])[C:49]([F:51])=[CH:50][N:43]([C@@H:21]2[O:22][C@H:23]([CH2:24][O:25][C:26](=[O:42])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C@@H:19]([O:18][C:1](=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:20]2)[C:44]1=[O:45])=[O:64]
Reactant: COc1cccc(C(=O)Cl)c1OC
Reactant: CCCCCCCCCCCCCCCC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)C[C@@H]1OC(=O)CCCCCCCCCCCCCCC
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCCCCCCCCCCCCCCC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)n(C(=O)c3cccc(OC)c3OC)c2=O)C[C@@H]1OC(=O)CCCCCCCCCCCCCCC
Reaction time: 1.5 h
Yield: 80.2 %

Procedure:
3.0 Grams of 2'-deoxy-3',5'-di-O-palmitoyl-5-fluorouridine are dissolved in 25 ml of dry dioxane and the solution is ice cooled. 2 Milliliters of triethylamine and 1.9 g of 2,3-dimethoxybenzoyl chloride are added to the solution and the mixture is subjected to reaction at room temperature for 10 minutes and then at 70° C. for 90 minutes. The reaction liquid is cooled and the precipitated triethylamine hydrochloride is filtered off. The filtrate is concentrated under reduced pressure and the residue is dissolved under heating in ethanol and the solution is allowed to stand whereby crystals are obtained which, after recrystallization from ethanol, affords 2.95 g (yield: 80.2%) of 3-(2,3-dimethoxybenzoyl)-2'-deoxy-3',5'-di-O-palmitoyl-5-fluorouridine. M.P. 77°-78° C.
Reaction SMILES: CN1C(C2C=CC(O)=CC=2)=C(C2C=CN=CC=2)N=N1.ClCCl.C[O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[N:32]([C:36]3[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=3)[CH:33]=[CH:34][N:35]=2)=[CH:27][CH:26]=1.B(Br)(Br)Br>CC(O)C>[N:39]1[CH:38]=[CH:37][C:36]([N:32]2[CH:33]=[CH:34][N:35]=[C:31]2[C:28]2[CH:29]=[CH:30][C:25]([OH:24])=[CH:26][CH:27]=2)=[CH:41][CH:40]=1
Reactant: COc1ccc(-c2nccn2-c2ccncc2)cc1
Agent: BrB(Br)Br
Agent: Cn1nnc(-c2ccncc2)c1-c1ccc(O)cc1
Solvent: CC(C)O
Solvent: ClCCl
Product: Oc1ccc(-c2nccn2-c2ccncc2)cc1
Yield: 75.9 %

Procedure:
According to the procedure for preparation of 4-(3-methyl-5-(pyridin-4-yl)-3H-1,2,3-triazol-4-yl)phenol, except that 4:1 dichloromethane:2-propanol was used in place of ethyl acetate to extract the product, 4-(2-(4-methoxyphenyl)-1H-imidazol-1-yl)pyridine (125 mg, 0.5 mmol) was treated with 1.25 mmol of boron tribromide to give 90 mg of a colorless solid. 1H NMR (CDCl3, 400 mHz) δ 8.52 (d, 2H, J=6 Hz), 7.14 (m, 2H), 7.11-7.08 (m, 4H), 6.79 (m, 2H), 2.94 (br, 1 H).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH:11]([OH:28])[C:12]1[O:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=2)=[N:15][N:16]=1)[CH2:9][CH3:10])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][CH:8]([CH2:9][CH3:10])[C@@H:11]([C:12]1[O:13][C:14]([C:17]2[CH:18]=[CH:19][C:20]([O:23][C:24]([F:25])([F:27])[F:26])=[CH:21][CH:22]=2)=[N:15][N:16]=1)[OH:28]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(O)c1nnc(-c2ccc(OC(F)(F)F)cc2)o1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(N)[C@H](O)c1nnc(-c2ccc(OC(F)(F)F)cc2)o1
Reaction time: 4 h
Yield: 95.7 %

Procedure:
((S)-1-{hydroxy-[5-(4-trifluoromethoxy-phenyl)-1,3,4-oxadiazol-2-yl]-methyl}-propyl)-carbamic acid tert-butyl ester (0.54 mmol, 0.225 g) is dissolved in dichloromethane (9 mL) and treated with trifluoroacetic acid (1 mL). The reaction mixture is stirred for four hours. The solvents are evaporated under reduced pressure. The residue is re-dissolved in dichloromethane (20 mL) and Silicycle Triamine (5.4 mmol, 1.47 g) is added. The reaction mixture is stirred for 60 h (over the weekend). The reaction mixtures are filtered under suction and the solvents evaporated to give (S)-2-Amino-1-[5-(4-trifluoromethoxy-phenyl)-1,3,4-oxadiazol-2-yl]-butan-1-ol (0.164 g, 96%). MS: m/z=318 (M+H+)
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]([NH:11][NH:12]C(OCC2C=CC=CC=2)=O)=[O:10])[CH:6]=[CH:5][C:4]=1[N:23]1[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]1>CO.C1COCC1.[C].[Pd]>[CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]([NH:11][NH2:12])=[O:10])[CH:6]=[CH:5][C:4]=1[N:23]1[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]1
Reactant: COc1nc(C(=O)NNC(=O)OCc2ccccc2)ccc1-n1cnc(C)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1nc(C(=O)NN)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 41.2 %

Procedure:
Under a nitrogen atmosphere, to a mixture of benzyl 2-{[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]carbonyl}hydrazinecarboxylate (14.6 g) in methanol (150 mL) and THF (100 mL) was added 5% palladium-carbon (1.5 g) at room temperature, and the mixture was stirred at room temperature for 6 hr under a hydrogen atmosphere. Under a nitrogen atmosphere, the catalyst was filtered off, and the solvent in the filtrate was evaporated under reduced pressure. To a mixture of the residue in ethanol (200 mL) and THF (400 mL) was added 5% palladium-carbon (1.5 g) at room temperature, and the mixture was stirred at room temperature overnight under a hydrogen atmosphere. Under a nitrogen atmosphere, the catalyst was filtered off, and the solvent in the filtrate was evaporated under reduced pressure. The residue was collected by filtration, washed with ethyl acetate and dried to give the title compound (3.9 g). The solvent in the mother liquor was evaporated under reduced pressure, and the residue was collected by filtration, washed with ethyl acetate and dried to give the title compound (2.6 g).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]([O:11][C:12](=[O:14])[CH3:13])[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[I-:15].[Na+]>CC(C)=O>[I:15][CH2:2][CH2:3][CH2:4][CH:5]([O:11][C:12](=[O:14])[CH3:13])[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCC(CCCCl)OC(C)=O
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCCCCC(CCCI)OC(C)=O
Yield: 97.5 %

Procedure:
A mixture of 1-chloro-4-acetoxynonane (Ex. 1, Step B-3) (35.3 g., 0.16 mole) and sodium iodide (120 g., 0.8 mole) in acetone (350 ml.) is stirred and heated at reflux with exclusion of light for 10 hours. The resulting suspension is filtered and the collected sodium chloride washed with acetone. The combined filtrate and washings are evaporated in vacuo leaving a residual mass which is partitioned between ether and water. The organic extract is washed with dilute aqueous sodium thiosulfate and water, dried over sodium sulfate and evaporated in vacuo providing the title compound as a colorless liquid (48.7 g., 98%), pmr (CDCl3) δ 2.0 (s, 3H), 3.18 (t, 2H) and 4.98 (m, H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([NH:9][C:10]2[N:15]=[CH:14][C:13]3=[CH:16][CH:17]=[C:18]([C:19]4[CH:20]=[N:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=4)[N:12]3[N:11]=2)[CH:6]=[CH:5][C:4]=1[CH:27]1[CH2:32][CH2:31][N:30]([CH2:33][C:34]([NH2:36])=[O:35])[CH2:29][CH2:28]1.COC1N=CC(C2N3C(C=NC(OS([C:58]([F:61])([F:60])[F:59])(=O)=O)=N3)=CC=2)=CC=1.NC1C=CC(C2CCN(CC(N)=O)CC2)=C([O:79][CH3:80])C=1>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([NH:9][C:10]2[N:15]=[CH:14][C:13]3=[CH:16][CH:17]=[C:18]([C:19]4[CH:20]=[N:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=4)[N:12]3[N:11]=2)[CH:6]=[CH:5][C:4]=1[CH:27]1[CH2:32][CH2:31][N:30]([CH2:33][C:34]([NH2:36])=[O:35])[CH2:29][CH2:28]1.[C:80]([OH:79])([C:58]([F:59])([F:60])[F:61])=[O:2]
Reactant: COc1ccc(-c2ccc3cnc(OS(=O)(=O)C(F)(F)F)nn23)cn1
Reactant: COc1cc(N)ccc1C1CCN(CC(N)=O)CC1
Agent: COc1ccc(-c2ccc3cnc(Nc4ccc(C5CCN(CC(N)=O)CC5)c(OC)c4)nn23)cn1
Product: O=C(O)C(F)(F)F
Yield: 33 %

Procedure:
2-(4-{2-Methoxy-4-[7-(6-methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-1-yl)-acetamide. Trifluoro-methanesulfonic acid 7-(6-methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl ester (0.138 g, 0.369 mmol; and 2-[4-(4-Amino-2-methoxy-phenyl)-piperidin-1-yl]-acetamide (0.121 g, 0.461 mmol) were reacted in an analogous manner to Example 908D at room temp for 72 h. The reaction mixture was concentrated, taken up in EtOAc, and washed with brine. The EtOAc layer was dried, filtered over MgSO4, and concentrated. The resulting residue was purified by Gilson RP-HPLC and lyophilized to afford title compound as a TFA salt (59 mg, 33%). LCMS=488.0 (M+H), HPLC rt=2.329, purity=99%. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.53 (bs, 1H), 9.47 (s, 1H), 9.02 (s, 1H), 9.00 (d, J=8.2 Hz, 1H), 8.40 (dd, J=8.7 Hz, 2.3 Hz, 1H), 7.98 (s, 1H), 7.71 (s, 1H), 7.46 (s, 1H), 7.24 (d, J=8.5 Hz, 1H), 7.17 (d, J=4.9 Hz, 1H), 7.04 (d, J=8.3 Hz, 1H0, 6.97 (d, J=4.7 Hz, 1H), 6.93 (s, 1H), 3.93 (s, 3H), 3.89 (m, 2H), 3.70 (s, 3H), 3.54 (d, J=11.7 Hz, 2H), 3.23-3.05 (m, 3H), 2.05-1.95 (m, 2H), 1.85-1.88 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=2)[C:24](=[O:38])[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:33]([C:32]2[CH:31]=[CH:30][C:29]([CH2:28][N:25]3[CH2:26][CH2:27][N:22]([C:20]([O:19][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:21])[CH2:23][C:24]3=[O:38])=[CH:37][CH:36]=2)=[O:34])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(C(=O)O)cc2)C(=O)C1
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)cc2)C(=O)C1

Procedure:
500 mg of methyl 4-(bromomethyl)benzoate was reacted with 480 mg of tert-butyl 3-oxopiperazine-1-carboxylate and 1 g of Cesium Carbonate in 9 mL of DMF at 45° C. Upon completion, the reaction was extracted in Ethyl Acetate 2 times saturated bicarbonate, dried over Magnesium Sulfate, filtered and concentrated to give tert-butyl 4-(4-(methoxycarbonyl)benzyl)-3-oxopiperazine-1-carboxylate. 613 mg of tert-butyl 4-(4-(methoxycarbonyl)benzyl)-3-oxopiperazine-1-carboxylate was hydrolyzed via Procedure M to give 4-((4-(tert-butoxycarbonyl)-2-oxopiperazin-1-yl)methyl)benzoic acid. 200 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-((4-(tert-butoxycarbonyl)-2-oxopiperazin-1-yl)methyl)benzoic acid via Procedure G. The crude product was extracted twice with saturated bicarbonate in Ethyl Acetate, dried over Magnesium Sulfate, filtered and concentrated to give crude tert-butyl 4-(4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzyl)-3-oxopiperazine-1-carboxylate. 4N HCl was subsequently added to crude tert-butyl 4-(4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzyl)-3-oxopiperazine-1-carboxylate and concentrated to give the HCl salt of N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((2-oxopiperazin-1-yl)methyl)benzamide. The reaction was purified by reverse phase HPLC to give pure N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((2-oxopiperazin-1-yl)methyl)benzamide. MS (Q1) 421.3 (M)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5]([NH:7][NH2:8])=[O:6].[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([OH:23])=[C:18]([C:20](=O)[CH3:21])[CH:19]=1>CO.C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5]([NH:7]/[N:8]=[C:20](/[C:18]1[CH:19]=[C:14]([Cl:13])[CH:15]=[CH:16][C:17]=1[OH:23])\[CH3:21])=[O:6]
Reactant: CC(=O)c1cc(Cl)ccc1O
Reactant: NNC(=O)c1ccc(Cl)c(Br)c1
Solvent: CC(=O)O
Solvent: CO
Product: C/C(=N\NC(=O)c1ccc(Cl)c(Br)c1)c1cc(Cl)ccc1O
Temperature: 120 °C
Yield: 31.1 %

Procedure:
3-Bromo-4-chlorobenzohydrazide (30 mg, 0.120 mmol) and 1-(5-chloro-2-hydroxyphenyl)ethanone (20.51 mg, 0.120 mmol) were dissolved in methanol (4 mL) in the presence of acetic acid as a catalyst, and the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. The reaction was monitored by TLC. Upon completion of the reaction and following cooling, the solvent was removed by vacuum, and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2) affording the title compound (15 mg). 1H NMR (400 MHz, acetone-d5): δ 8.30 (s, 1H), 7.98 (d, 1H, J=8.4 Hz), 7.73 (d, 1H, J=8.4 Hz), 7.61 (d, 1H, J=2.4 Hz), 7.29 (dd, 1H, J=2.4 & 8.4 Hz), 6.93 (d, 1H, J=8.8 Hz), 2.55 (s, 3H). ESI-MS: 402.9 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([NH:9][CH2:10][CH2:11][N:12]2[C:17](=[O:18])[CH:16]=[CH:15][C:14]([C:19]([OH:21])=O)=[CH:13]2)=[O:8])[CH:2]=1.[CH3:22][N:23](C)C=O.C(N(CC)CC)C>C(OCC)(=O)C>[CH3:22][NH:23][C:19]([C:14]1[CH:15]=[CH:16][C:17](=[O:18])[N:12]([CH2:11][CH2:10][NH:9][C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[O:8])[CH:13]=1)=[O:21]
Reactant: CN(C)C=O
Reactant: O=C(O)c1ccc(=O)n(CCNC(=O)c2cccnc2)c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccc(=O)n(CCNC(=O)c2cccnc2)c1
Temperature: -8 °C
Reaction time: 2.25 h

Procedure:
To a 100 ml round bottomed flask fitted with a magnetic stirrer bar and nitrogen inlet was added 1,6-dihydro-l-[2-(3-pyridinylcarbonylamino)ethyl]-6-oxo-3-pyridinecarboxylic acid (0.22 g, 0.77 mmol) methylamine hydrochloride (0.104 g, 1.54 mmol), and dimethylformamide (25.5 ml). The reaction mixture was cooled in a -8° C. ice bath and treated with triethylamine (1.07 ml, 7.7 mmol) and propylphosphonic acid anhydride (0.55 ml, added as a 0.55 ml ethyl acetate solution, Angew. Chemie 1980, 92(2), 129). The flask was allowed to warm slowly to room temperature and stirred for 2.25 hours. The mixture was concentrated, slurried in aqueous sodium bicarbonate, and again concentrated. The residue was slurried in methanol and filtered. Further purification of the solid recovered from filtration via flash column chromotography (silica gel, 15-20% methanol/dichloromethane) gave the product, MP: 208°-210° C.