Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:43])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][C@H:32]([C:34]([OH:36])=O)[CH3:33])[N:28]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[CH2:64]([O:71][C:72](=[O:78])[C@@H:73]1[CH2:77][CH2:76][CH2:75][NH:74]1)[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1>CN(C=O)C.C(OCC)(=O)C.C(Cl)CCl>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:43])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][C@@H:32]([CH3:33])[C:34]([N:74]3[CH2:75][CH2:76][CH2:77][C@H:73]3[C:72]([O:71][CH2:64][C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)=[O:78])=[O:36])[N:28]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O[C@@H](C)C(=O)O)n(-c3ccccc3)n2)CC1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O[C@@H](C)C(=O)N3CCC[C@H]3C(=O)OCc3ccccc3)n(-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 2.000 g 4-((S)-4-tert-Butoxycarbonyl-2-{[5-((S)-1-carboxy-ethoxy)-1-phenyl-1H-pyrazole-3-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester in 15 ml DMF were added 0.509 g HOBt, 1.37 ml DIPEA and 0.804 g L-proline benzyl ester hydrochloride at RT. Then 0.637 g EDC was added portionwise and the suspension stirred at RT for 12 h. The reaction mixture was diluted with ethyl acetate and subsequently extracted with aqueous LiCl (4% w/w), aqueous NaHCO3 and brine. The organic layer was dried over MgSO4 and the solvent was removed under reduced pressure. The crude product thus obtained was used in the subsequent reaction. Yield: 2.177 g.
Reaction SMILES: [ClH:1].C1(C[N:6]2[CH2:24][CH2:23][C@@:13]34[C:14]5[CH:15]=[C:16]([O:21][CH3:22])[CH:17]=[CH:18][C:19]=5[CH2:20][C@@H:7]2[C@:8]3([OH:26])[CH2:9][CH2:10][C:11](=[O:25])[CH2:12]4)CC1.Cl>C(O)C>[ClH:1].[OH:26][C@:8]12[C@@H:7]3[NH:6][CH2:24][CH2:23][C@:13]1([C:14]1[CH:15]=[C:16]([O:21][CH3:22])[CH:17]=[CH:18][C:19]=1[CH2:20]3)[CH2:12][C:11](=[O:25])[CH2:10][CH2:9]2
Reactant: COc1ccc2c(c1)[C@]13CCN(CC4CC4)[C@H](C2)[C@]1(O)CCC(=O)C3
Agent: Cl
Solvent: CCO
Product: COc1ccc2c(c1)[C@]13CCN[C@H](C2)[C@]1(O)CCC(=O)C3

Procedure:
A portion of Compound IV was converted to its hydrochloride salt by combining it with concentrated HCl in 10 ml of ethanol and evaporating the solvent. Toluene was added and the solution concentrated to dryness under vacuum. The residue was dissolved in a small amount of MeOH whereupon ethyl acetate was added and the solution concentrated at which point the solid was collected. This material whose structure was confirmed by mass spectral and elemental analysis was designated 179-A-19 and tested as described in Example III, infra. The other portion was left in the form of its free base and used in the experiment described in Example II.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH:8]([CH2:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[C:9]2=[O:12])=[CH:5][C:4]=1[N:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1.CC1C=CC(S(O)(=O)=O)=CC=1.[F:38][C:39]([F:47])([F:46])[C:40]([C:42]([F:45])([F:44])[F:43])=[O:41]>C1(C)C=CC=CC=1.O>[F:38][C:39]([F:47])([F:46])[C:40]([C:18]1[CH:19]=[C:14]([CH2:13][CH:8]2[CH2:7][C:6]3[C:10](=[CH:11][C:3]([O:2][CH3:1])=[C:4]([N:20]4[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]4)[CH:5]=3)[C:9]2=[O:12])[CH:15]=[N:16][CH:17]=1)([OH:41])[C:42]([F:45])([F:44])[F:43]
Reactant: O=C(C(F)(F)F)C(F)(F)F
Reactant: COc1cc2c(cc1N1CCN(C)CC1)CC(Cc1cccnc1)C2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1N1CCN(C)CC1)CC(Cc1cncc(C(O)(C(F)(F)F)C(F)(F)F)c1)C2=O
Temperature: 120 °C

Procedure:
To a stirred solution of 255 (0.05 g, 0.142 mmol) in toluene was added PTSA (0.054 g, 0.284 mmol) and kept stirring at 120° C. Hexafluoroacetone 244 (0.078 g, 0.356 mmol) was added to the reaction and kept at temperature and stirred for 16 h. Reaction was then cooled to RT, diluted with water, and extracted with ethyl acetate twice, The organic layer was dried over sodium sulphate and concentrated to get the crude, which was purified through flash chromatography by using 100-200 mesh silica gel and eluting the compound at 30% ethyl acetate in hexane as thick sticky solid 2-((5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)pyridin-3-yl)methyl)-6-methoxy-5-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-1-one 256.
Reaction SMILES: [CH3:1][CH2:2]O.OS(O)(=O)=O.[NH2:9][C:10]1[C:11]([C:17]([OH:19])=[O:18])=[N:12][CH:13]=[C:14]([Cl:16])[CH:15]=1>>[NH2:9][C:10]1[C:11]([C:17]([O:19][CH2:1][CH3:2])=[O:18])=[N:12][CH:13]=[C:14]([Cl:16])[CH:15]=1
Reactant: Nc1cc(Cl)cnc1C(=O)O
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ncc(Cl)cc1N
Temperature: 120 °C

Procedure:
Absolute EtOH (1.00 mL, d=0.785, 17.0 mmol) and H2SO4 (96%, 0.10 mL, d=1.840, 1.8 mmol) were added to the hydrochloride salt of 3-amino-5-chloropicolinic acid (106) (0.100 g, 0.407 mmol). The mixture was stirred and heated to reflux. The mixture was refluxed (120° C.) for 19 h. The resulting solution was cooled to room temperature, poured over ice (1.0 g), and neutralized to pH 5 with solid Na2 CO3. The resulting mixture was extracted with EtOAc (4×3 mL), the organic layer dried (Na2SO4), and rota-evaporated to dryness, leaving the title compound as an orange solid, 68.6 mg (84.0%), mp 139.5°-142.5° C. (Lit., 165°-6° C., McCaustland and Cheng, J. Heterocycl. Chem. 7:467 (1970)); 1H NMR (CDCl3): δ1.44 (t, J=6.9 Hz, 3H), 4.45 (q, J=6.9 Hz, 3H), 5.84 (bs, 2H), 7.05 (d, J=1.5 Hz, 1H), 7.99 (d, J=1.8 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:25]/[O:26][CH3:27])/[C:8]([NH:10][C@@H:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([O-:22])=[O:21])=[C:15]([CH2:18]O)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[NH:29]([CH2:33][CH2:34][CH2:35][N:36]1[C:40]([SH:41])=[N:39][N:38]=[N:37]1)[C:30]([NH2:32])=[NH:31]>CN(C=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:25]/[O:26][CH3:27])/[C:8]([NH:10][C@@H:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([OH:22])=[O:21])=[C:15]([CH2:18][S:41][C:40]4[N:36]([CH2:35][CH2:34][CH2:33][NH:29][C:30]([NH2:32])=[NH:31])[N:37]=[N:38][N:39]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: N=C(N)NCCCn1nnnc1S
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(CO)CS[C@H]12)c1csc(N)n1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CCCNC(=N)N)CS[C@H]12)c1csc(N)n1
Temperature: -20 °C
Yield: 59.1 %

Procedure:
To a solution of 363 mg of sodium 7β-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-hydroxymethyl-3-cephem-4-carboxylate and 241 mg of 1-(3-guanidinopropyl)-5-mercapto-1H-tetrazole in 10 ml of DMF was added 800 mg of ethyl o-phenylenephosphate under stirring at -20° C. The reaction mixture was stirred at -20° C. to 0° C. for 60 minutes and subjected to a column chromatography on silica gel (100 g), being washed with acetonitrile and eluted with acetonitrile/water (4:1). The eluate was concentrated under reduced pressure and subjected to a column chromatography on XAD-II (150 ml), being washed with water and eluted with 20% aqueous ethanol. The eluate was concentrated under reduced pressure and then lyophilized to give 294 mg of the title compound as a colorless powder.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[S:3]([C:6]1[CH:27]=[CH:26][C:9]([NH:10][CH:11]2[CH2:16][CH2:15][CH:14]([O:17][CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])[CH2:13][CH2:12]2)=[CH:8][CH:7]=1)(=[O:5])=[O:4]>FC(F)(F)C(O)=O>[F:28][C:2]([F:1])([F:29])[S:3]([C:6]1[CH:27]=[CH:26][C:9]([NH:10][CH:11]2[CH2:16][CH2:15][CH:14]([O:17][CH2:18][C:19]([OH:21])=[O:20])[CH2:13][CH2:12]2)=[CH:8][CH:7]=1)(=[O:4])=[O:5]
Reactant: CC(C)(C)OC(=O)COC1CCC(Nc2ccc(S(=O)(=O)C(F)(F)F)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)COC1CCC(Nc2ccc(S(=O)(=O)C(F)(F)F)cc2)CC1

Procedure:
To a solution of tert-butyl 2-[4-[4-(trifluoromethylsulfonyl) anilino]cyclohexoxy]acetate (0.7 g, 1.6 mmol, 1 eq.) in trifluoroacetic acid (3 mL) was stirred at room temperature for 2 hours. The mixture was concentrated under vacuum to remove excess trifluoroacetic acid. The crude material was dried under high vacuum overnight to obtain 2-[4-[4-(trifluoromethylsulfonyl) anilino]cyclohexoxy]acetic acid as light brown syrup. (0.79 g, 100%); (CI, m/z): [M+H]+ 382; 1H NMR (400 MHz, CD3OD): δ 7.65 (d, J=9.0 Hz, 2H), 6.76 (d, J=9.2 Hz, 2H), 4.13 (s, 2H), 3.37-3.51 (m, 2H), 2.03-2.20 (m, 4H), 1.26-1.54 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C@@H:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@@H:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](Cl)[CH:20]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:27][O:28][CH2:29][C:30]([NH2:32])=[O:31].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6](=[O:26])[NH:7][C@@H:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@@H:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:32][C:30](=[O:31])[CH2:29][O:28][CH3:27])[CH:20]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COCC(N)=O
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Oc2ccnc(Cl)c2)c2ccccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: COCC(=O)Nc1cc(O[C@H]2CC[C@H](NC(=O)OC(C)(C)C)c3ccccc32)ccn1
Yield: 43.8 %

Procedure:
Intermediate 10b (562 mg, 1.50 mmol), 2-methoxyacetamide (334 mg, 3.75 mmol), Xantphos (173 mg, 0.30 mmol) and potassium carbonate (518 mg, 3.75 mmol) were suspended in 1,4-dioxane (20 mL), warmed, degassed, and placed under argon. To this mixture palladium acetate (34.0 mg, 0.15 mmol) was added. The mixture was degassed and then heated at reflux for 17 h. After cooling, the mixture was filtered through Celite, washing with DCM, and evaporated to a yellow gum. Purification by FCC, eluting with 0-100% ethyl acetate in cyclohexane, gave the title compound as a white foam (281 mg, 44%). LCMS (Method 3): Rt 3.27 min, m/z 450.2 [MNa+].
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:40]([NH2:42])=[O:41])[CH:24]=[C:25]([C:28]4[CH:32]=[C:31]([CH2:33][N:34]([C@@H:36]([CH3:39])CO)[CH3:35])[S:30][CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].[NH2:43][C@H](C)CO>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:3]([NH:43][CH2:39][CH2:36][N:34]([CH2:33][C:31]1[S:30][CH:29]=[C:28]([C:25]2[CH:26]=[C:27]3[C:22](=[C:23]([C:40]([NH2:42])=[O:41])[CH:24]=2)[NH:21][CH:20]=[C:19]3[CH:16]2[CH2:17][CH2:18][N:13]([S:10]([CH2:8][CH3:9])(=[O:11])=[O:12])[CH2:14][CH2:15]2)[CH:32]=1)[CH3:35])(=[O:5])[CH3:2]
Reactant: C[C@@H](N)CO
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN(C)[C@@H](C)CO)c4)cc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN(C)CCNC(C)=O)c4)cc23)CC1
Yield: 30.8 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[[(1S)-2-hydroxy-1-methylethyl](methyl)amino]methyl}-3-thienyl)-1H-indole-7-carboxamide trifluoroacetate (salt), substituting N-(2-aminoethyl)acetamide (1.20 mmol) for (2R)-2-amino-1-propanol to afford 13.6 mg of the title compound (30.8%)
Reaction SMILES: [CH:1]12[CH2:11][CH:6]3[CH2:7][CH:8]([O:10][CH:4]([O:5]3)[C:3](=[O:12])[O:2]1)[CH2:9]2.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C>COCCOC>[OH:12][CH2:3][CH:4]1[O:10][CH:8]2[CH2:7][CH:6]([CH2:11][CH:1]([OH:2])[CH2:9]2)[O:5]1
Reactant: O=C1OC2CC3CC(C2)OC1O3
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: OCC1OC2CC(O)CC(C2)O1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 8.50 g (0.05 mols) of 2,5,11-trioxatricyclo[4,3,1,14,8 ]undecan-3-one of the formula Ia in 90 ml of ethylene glycol dimethyl ether is added dropwise within 15 minutes, while stirring and cooling with ice, to a suspension of 2.0 g (0.05 mols) of lithium aluminium hydride in 60 ml of ethylene glycol dimethyl ether. The reaction mixture is boiled for 15 minutes under reflux, cooled to room temperature and carefully treated with 10 ml of ethyl acetate to destroy excess lithium aliminium hydride. Then, while stirring, 2.0 ml of water, 2.0 ml of 15% sodium hydroxide solution, and finally, 6 ml of water, are added to the reaction mixture. The precipitated salts are filtered off, stirred with 100 ml of methylene chloride and filtered again. The combined filtrates are concentrated in a water jet vacuum. The crystalline residue is recrystallised from methylene chloride to give 3-hydroxymethyl-2,4-dioxabicyclo[3,3,1]nonan-7-ol of the formula IIa ##SPC9##
Reaction SMILES: [C:1]([CH:3]=[C:4]1[CH2:7][N:6]([C:8]2([CH3:21])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH2:5]1)#[N:2].[NH:22]1[CH:26]=[C:25]([C:27]2[C:28]3[CH:35]=[CH:34][N:33]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:29]=3[N:30]=[CH:31][N:32]=2)[CH:24]=[N:23]1.N12CCCN=C1CCCCC2>C(#N)C>[C:1]([CH2:3][C:4]1([N:22]2[CH:26]=[C:25]([C:27]3[C:28]4[CH:35]=[CH:34][N:33]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:29]=4[N:30]=[CH:31][N:32]=3)[CH:24]=[N:23]2)[CH2:5][N:6]([C:8]2([CH3:21])[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]2)[CH2:7]1)#[N:2]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Reactant: CC(C)(C)OC(=O)N1CCC(C)(N2CC(=CC#N)C2)CC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(C)(N2CC(CC#N)(n3cc(-c4ncnc5c4ccn5COCC[Si](C)(C)C)cn3)C2)CC1

Procedure:
A 2 L round bottom flask fitted with overhead stirring, septa and nitrogen inlet was charged with tert-butyl 4-[3-(cyanomethylene)azetidin-1-yl]-4-methylpiperidine-1-carboxylate (9.17 g, 0.0472 mol), 4-(1H-pyrazol-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (14.9 g, 0.0472 mol) and acetonitrile (300 mL). The resulting solution was heterogeneous. To the solution was added 1,8-diazabicyclo[5.4.0]undec-7-ene (8.48 mL, 0.0567 mol) portionwise via a syringe over 3 minutes at room temperature. The solution slowly became homogeneous and yellow in color. The reaction was allowed to stir at room temperature for 3 hours. The solution was concentrated on a rotovap to remove ˜150 mL of acetonitrile. After addition of 100 mL of EtOAc and 100 mL of 20% brine, the organic phase was separated. The aqueous layer was extracted with 150 mL of EtOAc. The combined organic phase was dried over MgSO4, filtered and concentrated to yield an orange oil. Purification by flash chromatography (150 grams of silica, 60% EtOAc/hexanes, loaded with CH2Cl2) yielded the title compound as a white foam. LC-MS: 607.2 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:12][O:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:13]([CH2:15][NH2:16])[OH:14]>>[OH:14][CH2:13][CH2:15][NH:16][CH2:12][CH:10]([C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[OH:11]
Reactant: NCCO
Reactant: O=[N+]([O-])c1ccc(C2CO2)cc1
Product: O=[N+]([O-])c1ccc(C(O)CNCCO)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
The mixture of 2-(4-nitro-phenyl)-oxirane (24.1 g, 0.15 mol) in ethanolamine (500 mL) was stirred at 40° C. for 2 h, then room temperature for 18 h. The reaction was partitioned between ethyl acetate (200 mL) and water (200 mL) and the aqueous layer was extracted with ethyl acetate (4×100 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The residue was triturated with acetonitrile and collected to give the title compound (19.80 g, 0.09 mmol, 60%) as a white solid. ESMS m/z 227 (M+H)+;
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1[CH:12]=[C:11]([O:13][CH3:14])[C:6](C(OC)=O)=[C:5]([CH3:15])[N:4]=1.O>Cl>[CH3:14][O:13][C:11]1[CH:6]=[C:5]([CH3:15])[N:4]=[C:3]([N:2]([CH3:16])[CH3:1])[CH:12]=1
Reactant: COC(=O)c1c(OC)cc(N(C)C)nc1C
Agent: Cl
Solvent: O
Product: COc1cc(C)nc(N(C)C)c1

Procedure:
A solution containing 340 mg (1.52 mmol) of methyl 6-(Dimethylamino)-4-methoxy-2-methylnicotinate in 5 mL of 6N aq. HCl was stirred at reflux for 16 h. The reaction mixture was poured into 50 mL of water and the pH was set up to 12. The mixture was extracted with two 40-mL portions of ethyl acetate. The combined organic solution was washed with a 40-mL portion of brine, dried (MgSO4) and concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column (2×6 cm). Elution with 9:1 dichloromethane-methanol afforded the expected product as a colorless oil: yield 87 mg (34%); silica gel TLC Rf 0.25 (9:1 dichloromethane-methanol); 1H NMR (CDCl3) δ 2.33 (s, 3H), 3.02 (s, 6H), 3.75 (s, 3H), 5.77 (s, 1H) and 6.03 (s, 1H); 13C NMR (CDCl3) δ 24.8, 38.0, 38.0, 54.7, 87.4, 98.5, 157.9, 160.8, 167.5; mass spectrum (APCI), m/z 167.1183 (M+H)+ (C9H15N2O requires 167.1184).
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:16]2[N:15]=[C:14]([NH2:17])[N:13]3[N:18]=[C:19]([C:21]4[O:22][CH:23]=[CH:24][CH:25]=4)[N:20]=[C:12]3[C:11]=2[CH:10]=[CH:9]1)(=O)=O.Cl.Cl.[F:28][C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1[CH2:36][CH2:37][CH2:38][N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:28][C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1[CH2:36][CH2:37][CH2:38][N:39]1[CH2:40][CH2:41][N:42]([CH2:6][CH2:7][N:8]2[C:16]3[N:15]=[C:14]([NH2:17])[N:13]4[N:18]=[C:19]([C:21]5[O:22][CH:23]=[CH:24][CH:25]=5)[N:20]=[C:12]4[C:11]=3[CH:10]=[CH:9]2)[CH2:43][CH2:44]1
Reactant: CS(=O)(=O)OCCn1ccc2c1nc(N)n1nc(-c3ccco3)nc21
Reactant: Fc1ccc(CCCN2CCNCC2)c(F)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc2c(ccn2CCN2CCN(CCCc3ccc(F)cc3F)CC2)c2nc(-c3ccco3)nn12
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To a solution of the title D compound of Example 1, 2-{5-amino-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-7-yl}ethyl methanesulfonate (0.06 g, 0.165 mmol) in dry DMF (5 mL), the title A compound, 1-(3-(2,4-difluorophenyl)propyl)piperazine dihydrochloride (0.33 mmol) and 0.06 mL of DIEA are added, and the solution is stirred at 100° C. for 5 h. The reaction mixture is cooled to RT, and the solvent is removed under reduced pressure. The crude product is purified by flash chromatography using DCM/MeOH/NH4OH-95/5.0/0.5 as eluent to give 7-(2-(4-(3-(2,4-difluorophenyl)propyl)piperazin-1-yl)ethyl)-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine: LC/MS (M+1=507.2). 1H NMR (DMSO -d6, 400 MHz) δ 1.66 (quintuplet, 2H, J=7.2 Hz), 2.24 (t, 2H, J=7.2 Hz), 2.32 (m, 4H), 2.45 (m, 4H), 2.58 (t, 2H, J=7.2 Hz), 2.67 (t, 2H, J=6.4 Hz), 4.22 (t, 2H, J=6.4 Hz), 6.58 (d, 1H, J=3.2 Hz), 6.71 (m, 1H), 6.99 (dt, 1H, J=8.4 Hz and 1.6 Hz), 7.14 (m, 2H), 7.18 (d, 1H, J=3.2 Hz), 7.32 (m, 1H), 7.48 (br s, 2H, NH2), 7.91 (s, 1H). Anal. calculated for (C26H28F2N8O): C, 61.65; H, 5.57; F, 7.50; N, 22.12; O, 3.16. Found C, 61.38: H, 5.66; N, 22.07.
Reaction SMILES: BrC1C=C(C=CC=1)C(NC(C1N=NC(NC2C=C(S(CC)(=O)=O)C=CC=2OC)=NC=1)C)=O.[Br:33][C:34]1[CH:35]=[C:36]([CH:52]=[CH:53][CH:54]=1)[C:37]([NH:39][CH:40]([C:42]1[N:47]=[N:46][C:45](S(C)(=O)=O)=[N:44][CH:43]=1)[CH3:41])=[O:38].[Cl:55][C:56]1[CH:57]=[C:58]([CH:60]=[CH:61][C:62]=1[N:63]1[CH2:68][CH2:67][O:66][CH2:65][CH2:64]1)[NH2:59].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1>[Br:33][C:34]1[CH:35]=[C:36]([CH:52]=[CH:53][CH:54]=1)[C:37]([NH:39][CH:40]([C:42]1[N:47]=[N:46][C:45]([NH:59][C:58]2[CH:60]=[CH:61][C:62]([N:63]3[CH2:64][CH2:65][O:66][CH2:67][CH2:68]3)=[C:56]([Cl:55])[CH:57]=2)=[N:44][CH:43]=1)[CH3:41])=[O:38]
Reactant: Nc1ccc(N2CCOCC2)c(Cl)c1
Reactant: CC(NC(=O)c1cccc(Br)c1)c1cnc(S(C)(=O)=O)nn1
Agent: CCS(=O)(=O)c1ccc(OC)c(Nc2ncc(C(C)NC(=O)c3cccc(Br)c3)nn2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(NC(=O)c1cccc(Br)c1)c1cnc(Nc2ccc(N3CCOCC3)c(Cl)c2)nn1
Yield: 16.7 %

Procedure:
In a similar manner as described for Intermediate 23, 3-bromo-N{1-[3-(methylsulfonyl)-1,2,4-triazin-6-yl]ethyl}benzamide (Intermediate 6) (200 mg, 0.52 mmol), 3-chloro-4-morpholin-4-ylaniline (200 mg, 0.94 mmol) and 4-toluenesulfonic acid monohydrate (20 mg) in tetrahydrofuran (10 mL) gave 3-bromo-N-(1-{3-[(3-chloro-4-morpholin-4-ylphenyl)amino]-1,2,4-triazin-6-yl}ethyl)benzamide (0.045 g) as a white solid. MS m/z 517, 519 (M+1, M+3).
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][C:4]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][N:12]=2)(=[O:10])=[O:9])=[CH:3][CH:2]=1.Br[CH2:20][C:21]([O:23]C(C)(C)C)=[O:22]>>[CH3:17][C:14]1[CH:15]=[CH:16][C:11]([S:8]([N:7]([CH2:20][C:21]([OH:23])=[O:22])[C:4]2[CH:5]=[CH:6][C:1]([CH3:18])=[CH:2][CH:3]=2)(=[O:10])=[O:9])=[N:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1ccc(NS(=O)(=O)c2ccc(C)cn2)cc1
Product: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C)cn2)cc1

Procedure:
prepared by reaction of 5-methyl-pyridine-2-sulfonic acid p-tolylamide with tert-butyl bromoacetate
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C:16](=[O:17])[CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]([Mg]Br)[CH:26]=[CH2:27]>C1COCC1>[CH2:27]([C:16]1([OH:17])[C@@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:13][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15]1)[CH:26]=[CH2:25]
Reactant: CC(C)(C)OC(=O)N1CC(=O)[C@@H](NC(=O)OCc2ccccc2)C1
Reactant: C=CC[Mg]Br
Solvent: C1CCOC1
Product: C=CCC1(O)CN(C(=O)OC(C)(C)C)C[C@@H]1NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.44 g of the ketone of step B in 20 mL of anhydrous THF cooled at 0° C. was added a solution of 6.2 mL of 1 M allyl magnesium bromide. The color turned dark right away. After being stirred at room temperature overnight, the reaction mixture was quenched with 50/50 mL of EtOAc/water. Water phase was extracted twice with EtOAc. The combined organic phase was dried over Na2SO4 and concentrated under vacuum. Column chromatography on silica gel using 3:1→2:1 hexane/EtOAc as eluent provided 0.85 g of the title compound. MS (M+H)+ 377.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[F:16])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]=[CH:8][C:7]1=[O:12].[C-:17]#[N:18].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[F:16])[CH2:5][N:6]1[CH2:11][CH2:10][C:9]([C:17]#[N:18])=[CH:8][C:7]1=[O:12]
Reactant: [C-]#N
Reactant: O=C1C=CCCN1Cc1ccc(F)c(Cl)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC1=CC(=O)N(Cc2ccc(F)c(Cl)c2)CC1
Temperature: 90 °C

Procedure:
A suspension of 1-(3-chloro-4-fluorobenzyl)-5,6-dihydropyridin-2(1H)-one (10 g, 42 mmol) and KCN (8:0 g, 120 mmol) in DMF (400 mL) and water (100 mL) was warmed to 90° C. for 48 hours. The solvents were removed under reduced pressure and the residue was partitioned between EtOAc (250 mL) and water (100 mL). The organic phase was separated and the aqueous phase was extracted with more EtOAc (2×100 mL). The organic phases were combined and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography eluting with 2:1:0.01 EtOAc:hexanes:MeOH. Fractions containing product were concentrated under reduced pressure to give the title compound as a solid. 1H NMR (400 MHz, CDCl3) δ 7.32 (dd, J=6.8, 2.0 Hz, 1H), 7.1-7.2 (m, 2H), 4.55 (AB quartet, J=17 Hz, 2H), 3.46 (ddd, J=13, 7.1, 6.5 Hz, 1H); 3.28 (ddd, J=13, 7.1, 6.5 Hz, 1H), 3.10 (m, 1H), 2.78 (ABX, J 17, 6.4 Hz, 2H), 2.2-2.2 (m, 2H); HPLC RT=2.36 min (Method A); ES MS M+1=267.