Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14](=[O:31])[N:15]([CH2:17][C:18]4[C:19]([C:28](Cl)=[O:29])=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=4)[N:16]=[C:10]3[C:9]=2[C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)=[CH:4][CH:3]=1.CN.C[CH2:41][N:42](CC)CC>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14](=[O:31])[N:15]([CH2:17][C:18]4[C:19]([C:28]([NH:42][CH3:41])=[O:29])=[N:20][C:21]([C:24]([F:26])([F:25])[F:27])=[CH:22][CH:23]=4)[N:16]=[C:10]3[C:9]=2[C:32]2[CH:33]=[CH:34][N:35]=[CH:36][CH:37]=2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1nc(C(F)(F)F)ccc1Cn1nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn2c1=O
Reactant: CCN(CC)CC
Agent: CN
Solvent: C1CCOC1
Product: CNC(=O)c1nc(C(F)(F)F)ccc1Cn1nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn2c1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirring solution of 3-((7-(4-chlorophenyl)-3-oxo-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)methyl)-6-(trifluoromethyl)picolinoyl chloride (36 mg, 0.066 mmol) in anhydrous THF (1 mL) at 0° C. was added 2 M methylamine solution in THF (0.33 mL, 0.66 mmol), followed by Et3N (0.046 mL, 0.33 mmol). The resulting mixture was stirred at 0° C. for 30 min, then at room temperature for 16 h. Analysis by HPLC/MS indicated the starting acid chloride had been consumed and the desired product had formed. The reaction mixture was diluted with water and extracted with EtOAc (15 mL×2). The combined EtOAc extracts were washed with saturated aqueous NaCl, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified using preparative reverse phase HPLC (Phenomenex Luna 5 μm C-18 21.2×100 mm column eluted with a linear gradient of 50% to 100% B over 8 min (A=0.1% trifluoroacetic acid, 90% water, 10% methanol and B=0.1% trifluoroacetic acid, 90% methanol, 10% water) with flow rate at 20 mL/min and UV detection at 220 nm). The desired fractions were concentrated under reduced pressure. The residue was dissolved in EtOAc, washed with saturated aqueous NaHCO3 once, water twice, then saturated aqueous NaCl, dried over Na2SO4 and evaporated. The residue was dissolved in acetonitrile, frozen and lyophilized to afford 12 mg (34%) of the title compound as a pale yellow powder. HPLC/MS: retention time=2.83 min, [M+H]+=539.2.
Reaction SMILES: C([C@H](NC(=O)C1C=CC=C(S(C)(=O)=O)C=1)[C@@H](O)C[C@H](C(=O)NCCC(C)(C)C)C)C1C=CC=CC=1.[CH3:36][S:37]([C:40]1[CH:41]=[C:42]([CH:46]=[C:47]([N:49]2[CH2:53][CH2:52][CH2:51][C:50]2=[O:54])[CH:48]=1)[C:43]([OH:45])=O)(=[O:39])=[O:38].[CH:55]12[CH2:61][CH:58]([CH2:59][CH2:60]1)[CH2:57][CH:56]2[NH:62][C:63](=[O:78])[C@H:64]([CH3:77])[CH2:65][C@H:66]([OH:76])[C@@H:67]([NH2:75])[CH2:68][C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1>>[CH2:68]([C@H:67]([NH:75][C:43](=[O:45])[C:42]1[CH:46]=[C:47]([N:49]2[CH2:53][CH2:52][CH2:51][C:50]2=[O:54])[CH:48]=[C:40]([S:37]([CH3:36])(=[O:38])=[O:39])[CH:41]=1)[C@@H:66]([OH:76])[CH2:65][C@H:64]([C:63](=[O:78])[NH:62][CH:56]1[CH2:57][CH:58]2[CH2:61][CH:55]1[CH2:60][CH2:59]2)[CH3:77])[C:69]1[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=1
Reactant: C[C@H](C[C@H](O)[C@@H](N)Cc1ccccc1)C(=O)NC1CC2CCC1C2
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(N2CCCC2=O)c1
Agent: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cccc(S(C)(=O)=O)c1)C(=O)NCCC(C)(C)C
Product: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc(N2CCCC2=O)cc(S(C)(=O)=O)c1)C(=O)NC1CC2CCC1C2

Procedure:
Prepared in an analogous manner to E1, from 3-methylsulfonyl-5-(2-oxopyrrolidin-1-yl)-benzoic acid (D19) and (2R,4S,5S)-5-Amino-4-hydroxy-2-methyl-6-phenylhexanoic acid (bicyclo[2.2.1]hept-2-yl)amide (D4).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12](=[O:28])[CH2:13][C:14]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)(O)[C:15]([F:18])([F:17])[F:16])=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.S(Cl)(Cl)=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([C:12](=[O:28])[CH:13]=[C:14]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)[C:15]([F:18])([F:16])[F:17])=[CH:10][CH:11]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: O=C(CC(O)(c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1ccc(-n2cncn2)cc1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: O=C(C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1ccc(-n2cncn2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.4 %

Procedure:
After adding 6.00 g of toluene to 2.00 g (4.65 mmol) of 1-(4-(1H-1,2,4-triazol-1-yl)phenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one, 1.11 g (9.30 mmol) of thionyl chloride and 0.74 g (9.30 mmol) of pyridine were added at 80° C., and stirred for 3 hours. The reaction solution was cooled to room temperature, and separated by adding 50 ml of chloroform and 20 ml of water. After washing the organic phase with an aqueous solution of 0.37 g of sodium hydroxide dissolved into 2.0 g of water, then the phase was washed with water. The solvent was distilled off under reduced pressure to obtain 1.58 g of 1-(4-(1H-1,2,4-triazol-1-yl)phenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-one (Yield 82.4%). Here, the target compound obtained in this Synthesis Example is a mixture of geometric isomers whose ratio determined by 1H-NMR was 4 to 1. 1H-NMR data of mainly produced geometric isomer are shown below.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:20]=[CH:21][CH:22]=1)[C:8]([NH:10][C:11]([CH3:19])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:12])=[O:9])(=[O:3])C.[OH-].[Na+].O.Cl.[CH:27](N(C(C)C)CC)(C)C.COCCl>CO.O>[CH3:27][O:3][CH2:1][O:4][C:5]1[CH:6]=[C:7]([CH:20]=[CH:21][CH:22]=1)[C:8]([NH:10][C:11]([CH3:19])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:12])=[O:9]
Reactant: CC(=O)Oc1cccc(C(=O)NC(C)(C)c2ccccc2)c1
Reactant: CCN(C(C)C)C(C)C
Agent: COCCl
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COCOc1cccc(C(=O)NC(C)(C)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 83.9 %

Procedure:
3-Acetoxy-N-(1-methyl-1-phenylethyl)benzamide (9.57 g, 32.2 mmol) was dissolved in methanol (190 mL), and the solution was added with 4 mol/L sodium hydroxide solution (32.2 mL), followed by stirring at room temperature for 20 minutes. The reaction mixture was added with 1 mol/L hydrochloric acid water to adjust the pH to 7, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in dichloromethane (190 mL), and the solution was added with diisopropylethylamine (16.8 mL, 96.6 mmol) and chloromethyl methyl ether (3.70 mL, 48.3 mmol) under ice-cooling. Then, the reaction mixture was warmed to room temperature and stirred for 2 hours. The mixture was added with diisopropylethylamine (5.60 mL, 32.2 mmol) and chloromethyl methyl ether (1.20 mL, 15.8 mmol), followed by further stirring for 2 hours. The reaction mixture was added with water and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography (chloroform/methanol=100/0, 99/1) to obtain 3-methoxymethoxy-N-(1-methyl-1-phenylethyl)benzamide (8.09 g, yield 84%).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([NH:11][C:12]2[CH:13]=[C:14]([NH:21][C@@H:22]3[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]3[NH:28]C(=O)OC(C)(C)C)[N:15]=[N:16][C:17]=2[C:18](=[O:20])[NH2:19])[CH:8]=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:28][C@@H:23]1[C@H:22]([NH:21][C:14]2[N:15]=[N:16][C:17]([C:18]([NH2:19])=[O:20])=[C:12]([NH:11][C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[N:10]=3)[CH:13]=2)[CH2:27][CH2:26][O:25][CH2:24]1
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1cc(Nc2cccc(C(C)(C)C)n2)c(C(N)=O)nn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)c1cccc(Nc2cc(N[C@@H]3CCOC[C@@H]3N)nnc2C(N)=O)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 40.6 %

Procedure:
To a solution of tert-butyl (3R,4R)-4-(5-(6-tert-butylpyridin-2-ylamino)-6-carbamoylpyridazin-3-ylamino)tetrahydro-2H-pyran-3-ylcarbamate (73 mg, 150 μmol) in CH2Cl2 (3.00 mL) was added TFA (1.48 g, 1 mL, 13.0 mmol) and the mixture stirred to room temperature for 18 h. The solvent was evaporated and the residue purified by flash chromatography (spherical silica 20-45 μM, 23 g, Versaflash Supelco) eluting with 0 to 5% over 20 min (MeOH containing 10% NH4OH)/CH2Cl2 to give 6-((3R,4R)-3-aminotetrahydro-2H-pyran-4-ylamino)-4-(6-tert-butylpyridin-2-ylamino)pyridazine-3-carboxamide (23.5 mg, 40.5% yield) as an off-white solid. 1H NMR (CHLOROFORM-d) δ: 11.45 (s, 1H), 8.38 (s, 1H), 8.03 (br. s., 1H), 7.54 (t, J=7.9 Hz, 1H), 6.93 (d, J=7.6 Hz, 1H), 6.69 (d, J=7.9 Hz, 1H), 5.83 (d, J=8.3 Hz, 1H), 5.37 (br. s., 1H), 3.91-4.13 (m, 2H), 3.86 (d, J=11.0 Hz, 1H), 3.65 (d, J=10.6 Hz, 1H), 3.41-3.58 (m, 1H), 3.04 (br. s., 1H), 1.97 (d, J=9.4 Hz, 1H), 1.63-1.85 (m, 1H), 1.55 (br. s., 3H), 1.42 (s, 9H); LC-MS 386.2 [M+H]+.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.[CH3:12][CH:13]([N:15]([CH:20]([CH3:22])[CH3:21])[CH2:16][CH2:17][CH2:18][SH:19])[CH3:14]>>[CH3:8][C:6]1[CH:7]=[C:2]([S:19][CH2:18][CH2:17][CH2:16][N:15]([CH:20]([CH3:22])[CH3:21])[CH:13]([CH3:12])[CH3:14])[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: CC(C)N(CCCS)C(C)C
Product: Cc1cc(SCCCN(C(C)C)C(C)C)ccc1[N+](=O)[O-]

Procedure:
In a manner similar to Preparation 43 react 5-fluoro-2-nitrotoluene with 3-[bis(1-methylethyl)amino]propanethiol to obtain the tile compound.
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-])=O>C(O)(=O)C.C(O)C.[Fe]>[CH3:1][S:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH2:10]
Reactant: CSCc1ccccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: CSCc1ccccc1N

Procedure:
Iron powder (60 g, 1.0 g-atom) was added slowly through a solid addition funnel to a solution of 53.5 g (0.29 mol) of o-methylthiomethylnitrobenzene in 210 ml of glacial acetic acid and 600 ml of absolute ethanol under reflux over a period of 45 minutes. The mixture was then refluxed for 3 hours. The iron powder was filtered off and the filtrate was diluted with 800 ml of water. The aqueous mixture was extracted twice with 200 ml ethyl acetate and twice with 200 ml ether. The combined organic extracts were washed with water, dried and concentrated to yield 48 g (75% pure) of orange oil.
Reaction SMILES: C(Cl)(=O)C.[NH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([N:18]2[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19]2)=[O:17])[CH2:7][CH2:6]1.NC1C=C2C(=CC=1)CN(C(N[C:40]1[CH:45]=[CH:44][C:43]([C:46](=[O:51])NCCC)=[CH:42][CH:41]=1)=O)C2>>[C:46]([N:5]1[CH2:6][CH2:7][CH:8]([CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([N:18]2[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19]2)=[O:17])[CH2:9][CH2:10]1)(=[O:51])[C:43]1[CH:44]=[CH:45][CH:40]=[CH:41][CH:42]=1
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(N)cc3C2)cc1
Reactant: O=C(NCCCCC1CCNCC1)N1Cc2ccccc2C1
Solvent: CC(=O)Cl
Product: O=C(NCCCCC1CCN(C(=O)c2ccccc2)CC1)N1Cc2ccccc2C1

Procedure:
The title compound was prepared as described in Example 278, substituting benzoyl chloride for acetyl chloride and N-[4-(piperidin-4-yl)butyl]-1,3-dihydro-2H-isoindole-2-carboxamide for 5-amino-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.39-7.47 (m, 3H) 7.22-7.40 (m, 6H) 6.27 (t, J=5.43 Hz, 1H) 4.56 (s, 4H) 4.36-4.52 (br s, 1H) 3.52 (br s, 1H) 3.00-3.15 (m, 2H) 2.93 (br s, 1H) 0.93-1.86 (series of br m, 12H); MS (ESI(+)) m/e 406 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:12]=[C:11]([NH:13][C:14]([C:16]2[CH:17]=[C:18]3[C:23](=[C:24]([Br:26])[CH:25]=2)[O:22][C:21]([CH3:28])([CH3:27])[CH2:20][CH:19]3[C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)=[O:15])[CH:10]=[CH:9][C:3]=1[C:4]([O:6]CC)=[O:5].[OH-].[Na+].Cl>CCO>[F:1][C:2]1[CH:12]=[C:11]([NH:13][C:14]([C:16]2[CH:17]=[C:18]3[C:23](=[C:24]([Br:26])[CH:25]=2)[O:22][C:21]([CH3:28])([CH3:27])[CH2:20][CH:19]3[C:29]2[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=2)=[O:15])[CH:10]=[CH:9][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)c1ccc(NC(=O)c2cc(Br)c3c(c2)C(c2ccc(C)cc2)CC(C)(C)O3)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(C2CC(C)(C)Oc3c(Br)cc(C(=O)Nc4ccc(C(=O)O)c(F)c4)cc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.9 %

Procedure:
To a solution of ethyl 2-fluoro-4-[[(8-bromo-2,2-dimethyl-4-(4-methylphenyl)-6-chromanyl)carbonyl]amino]-benzoate (Compound 221, 135 mg, 0.25 mmol) in EtOH (5 mL) was added 20% aqueous NaOH (2 mL). The reaction mixture was stirred at room temperature overnight and acidified to pH 4 with 10% aqueous HCl. The EtOH was removed under reduced pressure and ethyl acetate and water were added to the residue. The organic layer was separated and washed with saturated NaHCO3, saturated aqueous NaCl, and dried over MgSO4. Concentration under reduced pressure afforded 110 mg (86%) of the title compound as a colorless solid. 1H NMR δ (acetone-d6) 8.09 (1H, d, J=2.1 Hz), 7.91 (1H, t, J=7.5 Hz), 7.68 (1H, d, J=2.1 Hz), 7.83 (1H, dd, J=12.8, 2.1 Hz), 7.50 (1H, dd, J=7.5 Hz, 2.1 Hz), 7.27 (4H, s), 5.87 (1H, s), 2.37 (3H, s), 1.56 (6H, s); MS (EI) m/e 511, 509, 496, 494, 452, 450, 357, 355, 312. Anal. (C26H21BrFNO4.0.6 H2O) C, H, N.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[NH2:9][C:10]1[C:15]([C:16]2[CH:28]=[CH:27][C:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[C:18]([F:29])[CH:17]=2)=[CH:14][CH:13]=[CH:12][N:11]=1>CC#N>[NH2:9][C:10]1[C:15]([C:16]2[CH:28]=[CH:27][C:19]([C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])=[C:18]([F:29])[CH:17]=2)=[CH:14][C:13]([Br:8])=[CH:12][N:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)c1ccc(-c2cccnc2N)cc1F
Solvent: CC#N
Product: CC(C)(C)OC(=O)c1ccc(-c2cc(Br)cnc2N)cc1F
Reaction time: 0.17 h

Procedure:
NBS (2.145 g, 12.05 mmol) was added to a room temperature solution of tert-butyl 4-(2-aminopyridin-3-yl)-2-fluorobenzoate (3.31 g, 11.48 mmol) in MeCN (60 mL). The resulting mixture was stirred for 10 min. The reaction was quenched with 1:1 of sat. aq. Na2S2O3:sat. aq. NaHCO3 solution, and then extracted into ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate and concentrated in vacuo yielding tert-butyl 4-(2-amino-5-bromopyridin-3-yl)-2-fluorobenzoate. The material was used without further purification. LCMS (m/z): 369.0 (MH+), 0.85 min.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]/[C:20](O)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH:25]([C:27]1[CH:32]=[N:31][CH:30]=[CH:29][N:28]=1)[NH2:26].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>CCOC(C)=O.C1COCC1.CCOCC>[F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]/[C:20]([N:25]([C:27]3[CH:32]=[N:31][CH:30]=[CH:29][N:28]=3)[NH2:26])=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=1
Reactant: NNc1cnccn1
Reactant: O=C(O)/C=C/n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: NN(C(=O)/C=C/n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)c1cnccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.7 %

Procedure:
To a solution of (E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.75 g) in EtOAc (25 mL) and THF (12.5 mL) was added a solution of 2-hydrazinopyrazine (0.23 g) in 12 mL THF at room temperature. T3P (50% in ethyl acetate, 1.52 mL) and DIPEA (1.46 mL) were added dropwise and simultaneously and the reaction mixture was stirred for 30 min at room temperature before being quenched with ice-cold water and extracted with EtOAc (3×25 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure (35° C., 20 mmHg), affording 0.698 g of a crude solid. Trituration first with petroleum ether then with Et2O afforded 275 mg (yield: 29%) (E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N-(pyrazin-2-yl)acrylohydrazide, 1H NMR (400 MHz, DMSO-d6) δ, 10.3 (s, 1H), 9.15 (s, 2H), 8.59 (s, 2H), 8.30-8.26 (d, J=14.8 Hz, 1H), 8.13 (s, 1H), 8.06-8.07 (m, 1H), 6.98-6.95 (d, J=13.4 Hz, 1H); LCMS for C17H12F6N7O [M+H]+ 443.31. found 444.19 (RT 2.625 min, purity: 99.06%).
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[N:10]=[C:11]([C:30]#[CH:31])[C:12]([N:15](C(OC(C)(C)C)=O)C(=O)OC(C)(C)C)=[N:13][CH:14]=1.[Cl:32][CH2:33][C:34]1[CH:43]=[CH:42][C:37]([C:38](Cl)=[N:39][OH:40])=[CH:36][CH:35]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:8][C:9]1[N:10]=[C:11]([C:30]2[O:40][N:39]=[C:38]([C:37]3[CH:42]=[CH:43][C:34]([CH2:33][Cl:32])=[CH:35][CH:36]=3)[CH:31]=2)[C:12]([NH2:15])=[N:13][CH:14]=1
Reactant: C#Cc1nc(Br)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: ON=C(Cl)c1ccc(CCl)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: Nc1ncc(Br)nc1-c1cc(-c2ccc(CCl)cc2)no1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (330.3 mg, 455.0 μL, 3.264 mmol) was added to a solution of tert-butyl N-(5-bromo-3-ethynyl-pyrazin-2-yl)-N-tert-butoxycarbonyl-carbamate (1000 mg, 2.511 mmol) and 4-(chloromethyl)-N-hydroxy-benzimidoyl chloride 6 (563.6 mg, 2.762 mmol) in DCM (7 mL). The mixture was stirred at RT overnight. The reaction mixture was partitioned between DCM and water and the organic extract was dried (MgSO4) and concentrated in vacuo yielding an oil that was dissolved in DCM (10 mL). TFA (2 mL) was added and the mixture was stirred at RT for 15 min before being concentrated in vacuo. MS (ES−) 364
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:17]([O-:19])=[O:18])=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14]Cl)[C:6]=2[CH:16]=1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-].[CH2:28]([CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)[CH2:29][CH2:30][CH3:31]>CCCCCCC.CCOC(C)=O>[CH2:28]([CH:32]1[CH2:37][CH2:36][N:35]([CH2:14][CH2:13][CH2:12][N:7]2[C:6]3[CH:16]=[C:2]([Cl:1])[C:3]([N+:17]([O-:19])=[O:18])=[CH:4][C:5]=3[O:10][CH2:9][C:8]2=[O:11])[CH2:34][CH2:33]1)[CH2:29][CH2:30][CH3:31]
Reactant: O=C1COc2cc([N+](=O)[O-])c(Cl)cc2N1CCCCl
Reactant: CCCCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCCCC1CCN(CCCN2C(=O)COc3cc([N+](=O)[O-])c(Cl)cc32)CC1
Yield: 42 %

Procedure:
6-Chloro-4-(3-chloropropyl)-7-nitro-4H-benzo[1,4]oxazin-3-one (81MF2253b) (1.23 g, 4.05 mmol), K2CO3 (1.12 g, 8.09 mmol), NaI (1.21 g, 8.09 mmol) and 4-butylpiperidine (0.60 g, 4.24 mmol) were mixed according to GP11. CC (SiO2; Heptane/EtOAc 10:1-4) gave the title compound (81MF2253x) (0.698 g, 42%). 1H NMR (CDCl3) δ 7.61 (s, 1H), 7.36 (s, 1H), 4.66, (s, 2H), 3.99 (t, J=6.8 Hz, 2H), 2.85 (d, J=11.2 Hz, 2H), 2.34 (t, J=6.4 Hz, 2H), 1.94-1.80 (m, 4H), 1.67 (d, J=10.0 Hz, 2H), 1.31-1.20 (m, 9H), 0.88 (t, J=6.4 Hz, 3H); 13C NMR (CDCl3) δ 163.4, 143.4, 141.9, 133.9, 122.1, 117.7, 114.8, 67.5, 55.5, 54.4, 40.5, 36.4, 36.0, 32.6, 29.2, 24.6, 23.0, 14.2.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]2[CH2:14][C:9]1=[CH:10][N:11]2[C:15]1[N:20]2[CH:21]=[N:22][N:23]=[C:19]2[CH:18]=[C:17]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([NH:30][CH:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH3:32])[CH:25]=2)[N:16]=1)=O)(C)(C)C.Cl>O1CCOCC1.CO>[C@H:12]12[CH2:14][C@H:9]([NH:8][CH2:13]1)[CH2:10][N:11]2[C:15]1[N:23]2[N:22]=[CH:21][N:20]=[C:19]2[CH:18]=[C:17]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([NH:30][C@H:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH3:32])[CH:25]=2)[N:16]=1
Reactant: CC(Nc1cc(-c2cc3nncn3c(N3C=C4CC3CN4C(=O)OC(C)(C)C)n2)ccn1)c1ccccc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: C[C@H](Nc1cc(-c2cc3ncnn3c(N3C[C@@H]4C[C@H]3CN4)n2)ccn1)c1ccccc1
Reaction time: 1 h

Procedure:
To 5-{7-[2-(1-phenyl-ethylamino)-pyridin-4-yl]-[1,2,4]triazolo[4,3-c)pyrimidin-5-yl}-2,5-diaza-bicyclo[2.2.1]heptene-2-carboxylic acid tert-butyl ester (0.022 g, 0.043 mmol) were added 4N HCl (1 mL) in dioxane and a few drops of methanol. After 1 h, the reaction was concentrated in vacuo and the residue was taken up in water and extracted with ethyl acetate. The aqueous layer was neutralized with saturated sodium bicarbonate and extracted with chloroform (3×). The combined organic extract was dried (K2CO3), filtered, and concentrated in vacuo to give the title compound as a golden yellow solid. MS (ES+): 413.1 [M+H]+, 411.2 [M−H]−.
Reaction SMILES: [N:1]1([C@@H:7]2[CH2:11][CH2:10][N:9]([C:12]3[S:13][C:14]4[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:15]=4[N:16]=3)[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:23]1[N:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.[OH-].[Na+].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:30][O:29][C:26]1[N:25]=[N:24][C:23]([O:21][C:19]2[CH:18]=[CH:17][C:15]3[N:16]=[C:12]([N:9]4[CH2:10][CH2:11][C@@H:7]([N:1]5[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)[CH2:8]4)[S:13][C:14]=3[CH:20]=2)=[CH:28][CH:27]=1
Reactant: Oc1ccc2nc(N3CC[C@@H](N4CCCCC4)C3)sc2c1
Reactant: COc1ccc(Cl)nn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: COc1ccc(Oc2ccc3nc(N4CC[C@@H](N5CCCCC5)C4)sc3c2)nn1
Temperature: 100 °C

Procedure:
A mixture of (R)-2-(3-(piperidin-1-yl)pyrrolidin-1-yl)benzo[d]thiazol-6-ol (Example 47, 40 mg, 0.132 mmol), 3-chloro-6-methoxypyridazine (28.6 mg, 0.198 mmol), palladium(II) acetate (2.96 mg, 0.013 mmol), and potassium phosphate tribasic (84 mg, 0.40 mmol) in toluene (1 mL) was heated at 100° C. over night, cooled, diluted with 1 M NaOH (5 mL) and extracted with CH2Cl2 (2×25 mL). The combined CH2Cl2 layers were dried (MgSO4), filtered, concentrated and chromatographed on silica gel eluting with a gradient of 2-10% (9:1 methanol:ammonium hydroxide) in CH2Cl2 to provide the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.43-1.53 (m, 2H), 1.58-1.69 (m, 4H), 1.94-2.09 (m, 1H), 2.25-2.36 (m, 1H), 2.40-2.59 (m, 4H), 2.95-3.07 (m, 1H), 3.42 (t, J=9.2 Hz, 1H), 3.54 (dt, J=10.2, 6.8 Hz, 1H), 3.75 (t, J=8.8 Hz, 1H), 3.81-3.89 (m, 1H), 4.04 (s, 3H), 7.02 (d, J=9.2 Hz, 1H), 7.11 (dd, J=8.5, 2.4 Hz, 1H), 7.13 (d, J=9.5 Hz, 1H), 7.49 (d, J=2.7 Hz, 1H), 7.56 (d, J=8.8 Hz, 1H); MS (DCI/NH3) m/z 412 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.Br[CH2:9][C:10]([O:12][C:13]1[C:14](=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:15]([OH:17])=[O:16])=[O:11]>C1(C)C=CC=CC=1>[O:12]1[C:13]2[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=2[C:15](=[O:17])[O:16][CH2:9][C:10]1=[O:11]
Reactant: O=C(CBr)Oc1ccccc1C(=O)O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C1COC(=O)c2ccccc2O1
Reaction time: 8 h

Procedure:
The triethylamine solution was added all at once to the refluxing solution of bromoacetylsalicylic acid. The addition took thirty seconds. Moments later, the byproduct Et3NHBr crystallized out of solution. The suspension was refluxed for one hour and then allowed to cool. The salt crystals were isolated by vacuum filtration, washed with 25 mL of acetone, air dried in the Bucher funnel, and finally vacuum dried at room temperature. 2.27 grams of triethylammonium bromide were collected. MP=249°-252° C. with decomposition. The filtrate was evaporated down, and a white solid was obtained which was then dissolved in 25 mL of boiling toluene. Everything did not dissolve. The hot toluene solution was gravity filtered into a 25 mL Erlenmeyer flask. A white solid started to crystallize after a few minutes. The insoluble material was soluble in water which strongly suggested that it was Et3NHBr. After standing overnight at room temperature, the crystals were isolated by suction filtration, washed with 20 mL of toluene, and vacuum dried at room temperature for five hours. 1.17 grams were collected (43% yield). MP-112°-114° C. at 3.5° C./minute. IR (KBr pellet) 1795, 1730, 1605, 1455, 1315, 1190, 1120, 1025, 930, 763 cm-1. 300 MHz 1H NMR (CDCl3): δ4.75 singlet (2H), δ7.30 doublet (1H). One of the lines overlapped with the chloroform signal. δ7.42 triplet (1H), δ7.70 triplet (1H), δ7.95 doublet (1H).