Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[Br:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=1)[NH2:15]>Cl.C(O)(C)C>[Br:11][C:12]1[CH:13]=[C:14]([NH:15][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[NH:4][CH:5]=[N:6]3)[CH:16]=[CH:17][CH:18]=1
Reactant: Clc1ncnc2nc[nH]c12
Reactant: Nc1cccc(Br)c1
Agent: Cl
Solvent: CC(C)O
Product: Brc1cccc(Nc2ncnc3nc[nH]c23)c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 102.8 %

Procedure:
A mixture of 6-chloropurine (1.0 g, 6.47 mmol), 3-bromoaniline (0.78 mL, 7.12 mmol), and conc HCl (4 drops) in isopropanol (10 mL) is stirred at 80° C. for 5 h. Upon cooling, it precipitates. The solid is filtered and washed with isopropanol and air dried to yield N6-(3-bromophenyl)adenine (1.93 g, 91%) as a light yellow solid. 1H NMR (DMSO) δ 11.38 (1H, s), 8.78 (1H, s), 8.75 (1H, s), 7.90 (1H, d, J=8.0 Hz), 7.38-7.34 (2H, m).
Reaction SMILES: C1COCC1.BrC1C=CC(C)=NC=1.[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[C:22][Si](C)(C)C)=[CH:17][N:16]=1.C(=O)([O-])[O-].[K+].[K+]>O.C(O)C>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([CH3:14])=[N:16][CH:17]=1)#[CH:22]
Reactant: Cc1ccc(C#C[Si](C)(C)C)cn1
Agent: Cc1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: C#Cc1ccc(C)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a NMP solution (20 mL) of 5-bromo-2-methyl-pyridine (1.0 g) were added trimethylsilylacetylene (1.2 mL), tetrakis(triphenylphosphine)palladium(0) (130 mg), copper(I) iodide (44 mg), and N,N-diisopropylethylamine (2.0 mL), which was stirred under a nitrogen atmosphere for 2 hours at 65° C. Water was added at room temperature to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtered, after which the solvent was evaporated from the filtrate under a reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=5:1) to obtain a mixture (810 mg) of 5-bromo-2-methyl-pyridine and 2-methyl-5-trimethylsilanylethynyl-pyridine. Then, to a solution of THF (10 mL) and ethanol (5 mL) of the mixture (810 mg) of 5-bromo-2-methyl-pyridine and 2-methyl-5-trimethylsilanylethynyl-pyridine was added potassium carbonate (1.2 g) at room temperature, which was stirred for 2 hours and 30 minutes at room temperature. Water was added at room temperature to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and filtered, after which the solvent was evaporated from the filtrate under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=5:1) to obtain the titled compound (55 mg).
Reaction SMILES: [F:1][C:2]([F:50])([F:49])[C:3]1[CH:4]=[C:5]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[N:34]([C:37](=[O:41])[CH2:38][CH2:39][CH3:40])[CH2:35][CH3:36])[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[CH:10][N:9]=1.[OH-].[Na+].C(OCC)(=O)C>C(O)C>[F:50][C:2]([F:1])([F:49])[C:3]1[CH:4]=[C:5]([CH:42]=[C:43]([C:45]([F:46])([F:47])[F:48])[CH:44]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[N:34]([C:37](=[O:41])[CH2:38][CH2:39][CH3:40])[CH2:35][CH3:36])[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:12][N:13]=1
Reactant: CCCC(=O)N(CC)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)OCC)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCC(=O)N(CC)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)O)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
Ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(butyryl-ethyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (78 mg) is dissolved in ethanol (1 ml) and thereto is added a 2N-aqueous sodium hydroxide solution (162 μl) and the mixture is stirred at room temperature for 3 hours. Thereto are added ethyl acetate and a 1N-hydrochloric acid, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(butyryl-ethyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyric acid (66 mg). The resulting carboxylic acid is dissolved in ethanol (0.5 ml), and thereto is added 2N-aqueous sodium hydroxide solution (47 μl) and the reaction solution is concentrated under reduced pressure to give 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(butyryl-ethyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyric acid sodium salt (68 mg). MS (m/z): 693 [M−Na]−
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([O:8][CH3:9])[CH:7]=1.[CH3:13][PH:14](=[O:16])[CH3:15].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.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:9][O:8][C:6]1[CH:7]=[C:2]([P:14](=[O:16])([CH3:15])[CH3:13])[CH:3]=[CH:4][C:5]=1[N+:10]([O-:12])=[O:11]
Reactant: C[PH](C)=O
Reactant: COc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CN(C)C=O
Product: COc1cc(P(C)(C)=O)ccc1[N+](=O)[O-]
Temperature: 120 °C
Yield: 26.1 %

Procedure:
To a solution of 5-Chloro-2-nitroanisole (0.5 g, 2.67 mmol) in 5 mL of DMF was added dimethylphosphine oxide (0.229 g, 2.93 mmol), palladium acetate (30 mg, 0.13 mmol), XANTPHOS (0.092 g, 0.16 mmol) and potassium phosphate (0.623 g, 2.93 mmol). The mixture was purged with argon, and heated at 120° C. for 18 h. The reaction mixture was basified with saturated sodium bicarbonate solution, and extracted with ethyl acetate. The organic layer was concentrated and purified by prep-HPLC to give the final product (0.16 g, 30% yield). MS/ES+: m/z=229.
Reaction SMILES: [C:1]([C@H:4]1[CH2:7][C@@H:6]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]1([CH3:20])[CH3:19])(=[O:3])[NH2:2].CO[CH:23](OC)[N:24]([CH3:26])[CH3:25]>>[CH3:23][N:24](/[CH:26]=[N:2]/[C:1]([C@H:4]1[CH2:7][C@@H:6]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:5]1([CH3:20])[CH3:19])=[O:3])[CH3:25]
Reactant: CC1(C)[C@@H](C(N)=O)C[C@H]1NC(=O)OCc1ccccc1
Reactant: COC(OC)N(C)C
Product: CN(C)/C=N/C(=O)[C@H]1C[C@@H](NC(=O)OCc2ccccc2)C1(C)C
Temperature: 120 °C
Reaction time: 8 h

Procedure:
A mixture of benzyl ((1R,3S)-3-carbamoyl-2,2-dimethylcyclobutyl)carbamate (638 mg, 2.30 mmol) in N,N-dimethylformamide dimethyl acetal (13 mL) was stirred at 120° C. overnight. The reaction mixture was concentrated at 50° C. in vacuo to give the crude product (850 mg) as a yellow oil, which was used directly in the next step without further purification. MS (ESI) m/z 332.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.[O:11]1[C:15]2[CH:16]=[CH:17][C:18](B(O)O)=[CH:19][C:14]=2[CH2:13][CH2:12]1>>[O:11]1[C:15]2[CH:16]=[CH:17][C:18]([C:2]3[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=3)=[CH:19][C:14]=2[CH2:13][CH2:12]1
Reactant: Nc1c(F)cc(Br)cc1F
Reactant: OB(O)c1ccc2c(c1)CCO2
Product: Nc1c(F)cc(-c2ccc3c(c2)CCO3)cc1F
Yield: 76.7 %

Procedure:
The title compound (182 mg) was prepared from 4-bromo-2,6-difluoroaniline (200 mg, 0.96 mmol) and 2,3-dihydrobenzofuran-5-ylboronic acid (204 mg, 1.25 mmol) as a white solid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 7.46 (s, 1H), 7.30 (dd, J 1.8, 8.3, 1H), 7.16 (dd, J 2.1, 8.2, 2H), 6.75 (d, J 8.3, 1H), 5.18 (s, 2H), 4.52 (t, J 8.7, 2H), 3.18 (t, J 8.5, 2H).
Reaction SMILES: Br[CH:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[N:7]2)[CH3:3].C(N(C(C)C)CC)(C)C.[C:23]([C:27]1[CH:32]=[CH:31][C:30]([C:33]2[NH:37][C:36]3[CH:38]=[CH:39][CH:40]=[C:41]([N:42]4[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]4)[C:35]=3[N:34]=2)=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24]>CN1CCCC1=O.C(OCC)(=O)C>[C:23]([C:27]1[CH:28]=[CH:29][C:30]([C:33]2[NH:37][C:36]3[CH:38]=[CH:39][CH:40]=[C:41]([N:42]4[CH2:47][CH2:46][N:45]([CH:2]([C:4]5[CH:5]=[C:6]6[C:11](=[CH:12][CH:13]=5)[N:10]=[CH:9][CH:8]=[N:7]6)[CH3:3])[CH2:44][CH2:43]4)[C:35]=3[N:34]=2)=[CH:31][CH:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1ccc(-c2nc3c(N4CCNCC4)cccc3[nH]2)cc1
Reactant: CC(Br)c1ccc2nccnc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(c1ccc2nccnc2c1)N1CCN(c2cccc3[nH]c(-c4ccc(C(C)(C)C)cc4)nc23)CC1
Reaction time: 8 h
Yield: 92.2 %

Procedure:
To a solution of 6-(1-Bromo-ethyl)-quinoxaline (0.2 g,0.084 mMol) in N-methyl-pyrrolidinone (3 mL) and diisopropylethylamine (0.029 mL, 0.1 7 mMol) was added 2-(4-tert-Butyl-phenyl)-4-piperazin-1-yl-1H-benzoimidazole (0.028 g, 0.084 mMol) and the mixture stirred overnight. Upon arrival the solution was diluted with ethyl acetate (200 mL) and washed with water (4×75mL) and brine (75 mL). The organic layer was dried (MgSO4), filtered, and concentrated to dryness on a rotary evaporator. Purification by flash column chromatography on silica gel using 5% methanol in dichloromethane yielded 38 mg (92% yield) of 6-(1-{4-[2-(4-tert-Butyl-phenyl)-1H-benzoimidazol-4-yl]-piperazin-1-yl}-ethyl)-quinoxaline as a racemate. This material was separated into the (R) and (S) enantiomers by chiral HPLC using a Chiralcel-OD 250×4.6 mmcolumn with an isocratic 90:10 acetonitrile:ethanol eluant. The first peak had a (+) chirality by CD and a retention time of 5.86 and the second peak a (−) chirality by CD and a retention time of 6.941. The fractions were concentrated and freeze dried to obtain 10 mg of each enantiomers. NMR,MS,and analytical HPLC were identical. 1H NMR (DMSO-d6): δ=12.67 (s, 1H), 8.94 (dd, 2H, J=8.8, 1.8 Hz), 8.11 (d, 1H, J=8.7 Hz), 8.05 (s, 1H), 8.02 (d, 2H, J=8.5 Hz), 7.95 (dd, 1H, J=8.7, 1.7 Hz), 7.53 (d, 2H, J=8.6 Hz), 7.02 (m, 2H), 6.47 (dd, 1H, J=7, 1.4 Hz), 3.81 (q, 1H, J=6.8 Hz), 3.58 (br s, 4H), 2.75 (br s, 2H), 2.61 (br s, 2H), 1.49 (d, 3H, J=6.8 Hz), 1.32 (s, 9H). LC/MS (Method A), rt=1.07 mins., purity=99%, calculated mass=490, [M+H]+=491,[M−H]−=489. HPLC (Method C): rt=9.2mins., purity=94% @ 210-370 nm and 95.3% @ 304 nm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:11]([CH3:17])=[C:12]([C:14](O)=[O:15])[N:13]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH:59]1([NH2:65])[CH2:64][CH2:63][CH2:62][CH2:61][CH2:60]1>C(#N)C>[CH:59]1([NH:65][C:14]([C:12]2[N:13]=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[N:10]([C:18]3[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=3)[C:11]=2[CH3:17])=[O:15])[CH2:64][CH2:63][CH2:62][CH2:61][CH2:60]1
Reactant: NC1CCCCC1
Reactant: COc1ccc(-n2c(-c3ccc(Cl)cc3Cl)nc(C(=O)O)c2C)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccc(-n2c(-c3ccc(Cl)cc3Cl)nc(C(=O)NC3CCCCC3)c2C)cc1
Reaction time: 0.25 h
Yield: 85 %

Procedure:
Part C: To 2-(2,4-dichlorophenyl)-5-methyl-1-(4-methoxyphenyl)-1H-imidazole-4-carboxylic acid (1.00 gram, 2.65 mmol) in dry acetonitrile (25 mL) is successively added diisopropylethylamine (DIPEA) (1.02 mL, 2.2 molar equivalents), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate (HBTU) (1.21 gram, 1.2 molar equivalents) and the resulting solution is stirred for 15 minutes. Cyclohexylamine (0.36 mL, 1.2 molar equivalents) is added. After stirring for 50 hours, the resulting mixture is concentrated in vacuo. The residue is dissolved in dichloromethane and an aqueous NaHCO3 solution is added. The dichloromethane layer is collected, dried over Na2SO4, filtered and concentrated in vacuo. The residue is further purified by column chromatography (gradient:dichloromethane=>dichloromethane/methanol=99/1 (v/v), silicagel) to give N-(1-cyclohexyl)-2-(2,4-dichlorophenyl)-5-methyl-1-(4-methoxyphenyl)-1H-imidazole-4-carboxamide (1.03 gram, 85% yield). Melting point: 160-161° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][C@H:19]([CH3:23])[CH2:20][CH2:21][OH:22])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14](O)=[O:15])=[C:10]([CH3:17])[CH:9]=2)[CH:7]=1.FC(F)(F)C(O)=O.[Cl:31][C:32]1[CH:41]=[C:40]2[C:35]([CH2:36][C:37]([CH3:50])([CH3:49])[C:38](=[O:48])[N:39]2[CH:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)=[N:34][CH:33]=1.CN1CCOCC1.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>C(Cl)Cl.CO.O1CCCC1>[Cl:31][C:32]1[CH:41]=[C:40]2[C:35]([CH2:36][C:37]([CH3:50])([CH3:49])[C:38](=[O:48])[N:39]2[CH:42]2[CH2:43][CH2:44][N:45]([C:14]([C:11]3[CH:12]=[CH:13][C:8]([C:6]4[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=4[O:18][C@H:19]([CH3:23])[CH2:20][CH2:21][OH:22])=[CH:9][C:10]=3[CH3:17])=[O:15])[CH2:46][CH2:47]2)=[N:34][CH:33]=1
Reactant: Cc1cc(-c2cc(F)ccc2O[C@H](C)CCO)ccc1C(=O)O
Reactant: CC1(C)Cc2ncc(Cl)cc2N(C2CCNCC2)C1=O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CN1CCOCC1
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(-c2cc(F)ccc2O[C@H](C)CCO)ccc1C(=O)N1CCC(N2C(=O)C(C)(C)Cc3ncc(Cl)cc32)CC1
Reaction time: 1 h
Yield: 69 %

Procedure:
To a methanol-tetrahydrofuran (1:1) mixed solvent solution (20.0 ml) of 5′-fluoro-2′-{[(1R)-3-hydroxy-1-methylpropyl]oxy}-3-methylbiphenyl-4-carboxylic acid (637 mg) and 7-chloro-3,3-dimethyl-1-piperidin-4-yl-3,4-dihydro-1,5-naphthyridin-2(1H)-one trifluoroacetate (Reference Example 10) (876 mg) were added at room temperature N-methylmorpholine (0.660 ml) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (940 mg), followed by stirring for 1 hour. The reaction solution was diluted with methylene chloride, then washed sequentially with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography to afford 7-chloro-1-{1-[(5′-fluoro-2′-{[(1R)-3-hydroxy-1-methylpropyl]oxy}-3-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}-3,3-dimethyl-3,4-dihydro-1,5-naphthyridin-2(1H)-one (820 mg).
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][CH2:4][C@:5]1([CH3:22])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7](C(OCC)=O)[C:6]1=[O:21].Cl>O1CCOCC1>[CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][CH2:4][C@:5]1([CH3:22])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[CH:7][C:6]1=[O:21]
Reactant: CCOC(=O)C1=C(O)c2ccccc2[C@@](C)(CCC(C)(C)C)C1=O
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)CC[C@@]1(C)C(=O)C=C(O)c2ccccc21
Temperature: 25 °C
Yield: 78.2 %

Procedure:
A solution of Example 49C (2.65 g, 8.02 mmol) in 1,4-dioxane (25 mL) was treated with aqueous 1 N hydrochloric acid solution (25 mL) and refluxed for 3 hours. The mixture was cooled to 25° C. and partitioned between ethyl acetate and water. The ethyl acetate layer was washed with water and brine, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was triturated in hot hexane and dried to give 1.62 g (61%) of the title compound. 1H NMR (300 MHz, CDCl3): δ ppm 0.43 (m, 0.5H) 0.83 (m, 10H) 1.06 (m, 0.5H) 1.51 (s, 1.5H) 1.56 (s, 1.5H) 1.83 (m, 1H) 2.02 (m, 0.5H) 2.26 (m, 0.5H) 3.74 (s, 1H) 6.09 (s, 0.5H) 7.51 (m, 3H) 8.10 (td, J=7.81, 1.29 Hz, 1H); MS (ESI−) m/z 257 (M−H)−.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:18](=O)[CH3:19])=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.[NH:21]([C:23]([C:25]1[S:29][C:28]([C:30]([O:32][CH3:33])=[O:31])=[CH:27][CH:26]=1)=[O:24])[NH2:22].O.S(C1C=CC(C)=CC=1)(O)(=O)=O>>[OH:1][C:2]1[C:3]([C:18](=[N:22][NH:21][C:23]([C:25]2[S:29][C:28]([C:30]([O:32][CH3:33])=[O:31])=[CH:27][CH:26]=2)=[O:24])[CH3:19])=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1
Reactant: CC(=O)c1nn(C)c(-c2ccc(C(F)(F)F)cc2)c1O
Reactant: COC(=O)c1ccc(C(=O)NN)s1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: COC(=O)c1ccc(C(=O)NN=C(C)c2nn(C)c(-c3ccc(C(F)(F)F)cc3)c2O)s1
Yield: 57.6 %

Procedure:
From 1-[4-hydroxy-1-methyl-5-(4-trifluoromethylphenyl)-1H-pyrazol-3-yl]ethanone (200 mg, 0.70 mmol) synthesized in Synthetic Example 11, methyl 5-hydrazinocarbonyl-2-thiophenecarboxylate (0.70 mmol, 140.9 mg) of Reference Synthetic Example 39 and tosylic acid monohydrate (36.4 mg, 0.21 mmol), 188.2 mg of the desired product was obtained in the same manner as in Synthetic Example 58 as a pale yellow solid (yield 57%).
Reaction SMILES: [N:1]#[N:2].[S:3]([NH:19][C@H:20]([C:28]([OH:30])=[O:29])[CH2:21][CH2:22][CH2:23][NH:24][C:25](=[NH:27])[NH2:26])([C:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[C:11]([N:12]([CH3:14])[CH3:13])[C:10]=2[CH:9]=[CH:8][CH:7]=1)(=[O:5])=[O:4].O.[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38]([OH:41])(=[O:40])=[O:39])=[CH:34][CH:33]=1.C1C=CC=CC=1>C(O)C1C=CC=CC=1>[N:1]#[N:2].[C:32]1([CH3:42])[CH:33]=[CH:34][C:35]([S:38]([OH:41])(=[O:39])=[O:40])=[CH:36][CH:37]=1.[C:32]1([CH3:42])[CH:33]=[CH:34][C:35]([S:38]([OH:41])(=[O:39])=[O:40])=[CH:36][CH:37]=1.[CH2:42]([O:29][C:28](=[O:30])[C@H:20]([CH2:21][CH2:22][CH2:23][NH:24][C:25](=[NH:26])[NH2:27])[NH:19][S:3]([C:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[C:11]([N:12]([CH3:13])[CH3:14])[C:10]=2[CH:9]=[CH:8][CH:7]=1)(=[O:4])=[O:5])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CN(C)c1cccc2c(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)O)cccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N#N
Solvent: c1ccccc1
Solvent: OCc1ccccc1
Solvent: O
Product: CN(C)c1cccc2c(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)OCc3ccccc3)cccc12
Temperature: 100 °C
Yield: 87 %

Procedure:
A mixture of 1.0 grams of N2 -dansyl-L-arginine and 1.4 gram of p-toluenesulfonic acid monohydrate in 10 ml of benzyl alcohol was heated for 30 minutes at 100° C. To the thus obtained clear solution, 100 ml of benzene was added, and the mixture was refluxed for 5 hours, removing water by azeotropic distillation. After the solvent was removed by distillation, 100 ml of ethyl ether was added to the residue, giving a crystalline mass. Crystallization from acetone gave N2 -dansyl-L-arginine benzyl ester di(p-toluenesulfonate) in 87% yield; mp. 150°-153° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C@:11]1([CH3:24])[C@@H:20]2[C@H:16]([CH2:17][O:18][CH2:19]2)[S:15](=[O:22])(=[O:21])[CH2:14][C:13]([NH2:23])=[N:12]1>C(O)C.[Pd].O1CCCC1>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C@:11]2([CH3:24])[C@@H:20]3[C@H:16]([CH2:17][O:18][CH2:19]3)[S:15](=[O:21])(=[O:22])[CH2:14][C:13]([NH2:23])=[N:12]2)[CH:4]=1
Reactant: C[C@]1(c2cc([N+](=O)[O-])ccc2F)N=C(N)CS(=O)(=O)[C@H]2COC[C@@H]21
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: C[C@]1(c2cc(N)ccc2F)N=C(N)CS(=O)(=O)[C@H]2COC[C@@H]21
Yield: 104.8 %

Procedure:
The crude (3aR,8S,8aS)-rel-8-(2-fluoro-5-nitro-phenyl)-8-methyl-4,4-dioxo-3,3a,4,5,8,8a-hexahydro-1H-2-oxa-4λ6-thia-7-aza-azulen-6-ylamine (73 mg, 204 μmol) was hydrogenated under atmospheric pressure at room temperature in ethanol (5 ml) using palladium on carbon (5%; 39 mg, 18.3 μmol) as the catalyst. After 3 hours the catalyst was filtered and the filtrate evaporated at reduced pressure. In order to complete the reaction, the residue was hydrogenated in a mixture of ethanol (5 ml) and tetrahydrofuran (5 ml) under the aforementioned conditions during 20 hours. Thereafter, the catalyst was filtered, and the filtrate was evaporated at reduced pressure. The crude (3aR,8S,8aS)-rel-8-(5-amino-2-fluoro-phenyl)-8-methyl-4,4-dioxo-3,3a,4,5,8,8a-hexahydro-1H-2-oxa-4λ6-thia-7-aza-azulen-6-ylamine (70 mg) was obtained as brown semisolid material and was engaged in the next step without purification. MS (ISP): m/z=328.3 [M+H]+.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][N:16]=[CH:15]3)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1[CH2:34][CH2:33]OCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[NH2:11][C:12]1[CH:20]=[C:19]([C:2]2[N:3]=[C:4]([NH:11][C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][CH:20]=3)[NH:17][N:16]=[CH:15]4)[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[CH:7]=2)[CH:18]=[CH:33][CH:34]=1
Reactant: C1COCCO1
Reactant: Brc1cn2ccnc2c(Nc2ccc3[nH]ncc3c2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Product: Nc1cccc(-c2cn3ccnc3c(Nc3ccc4[nH]ncc4c3)n2)c1
Temperature: 25 °C

Procedure:
A mixture of 1.00 eq. of (6-Bromo-imidazo[1,2-a]pyrazin-8-yl)-(1H-indazol-5-yl)-amine, 1.1 eq. of R4-substituted boronic acid, and 0.10 eq. of Pd(PPh3)4, 2.2 eq. of K3PO4 in 4:1 1,4-dioxane:water is heated to 90° C. for 24 hr. The mixture is cooled to RT and partitioned between EtOAc and sat. NaHCO3. The aqueous phase is extracted with EtOAc and combined extracts are dried over Na2SO4. The solvent is removed under reduced pressure and the resulting residue is purified by flash chromatography (EtOAc) to yield (5).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.C(N(CC)CC)C.[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][NH2:33]>C1COCC1>[Cl:1][C:2]1[N:11]=[C:10]([NH:33][CH2:32][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2c(-c3ccccc3)cccc2n1
Reactant: NCc1ccccn1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Clc1nc(NCc2ccccn2)c2c(-c3ccccc3)cccc2n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 75.7 %

Procedure:
2,4-Dichloro-5-phenylquinazoline (1.38 g, 5.03 mmol) was dissolved in THF (80 mL) and triethylamine (1.33 mL, 9.56 mmol) was added dropwise. The mixture was stirred for 5 min at room temperature and then pyridin-2-ylmethanamine (0.57 mL, 5.53 mmol) was added dropwise. The resulting mixture was stirred at ambient temperature for 14 hours. After this time, the mixture was filtered through a medium porosity glass frit, concentrated to dryness under reduced pressure and then purified by ISCO flash column chromatography (80 g silica gel column) eluting with 0-100% ethyl acetate/hexanes over 30 min to provide 2-chloro-5-phenyl-N-(pyridin-2-ylmethyl)quinazolin-4-amine (1.32 g, 75%). LCMS Method A [M+1] observed 347.1. HPLC Method B: Purity 99.1% retention time 6.66 min. 1H NMR (400 MHz, chloroform-d) δ ppm 8.16 (1H, d, J=4.77 Hz), 7.79 (1H, d, J=7.28 Hz), 7.70 (1H, t, J=7.78 Hz), 7.59 (1H, dt, J=7.53, 1.51 Hz), 7.40-7.55 (5H, m), 7.08-7.25 (4H, m), 4.66 (2H, d, J=4.02 Hz).
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][N:12]=[C:11]([C:14](=[N:18][O:19][CH2:20][C:21]#[CH:22])[C:15]([OH:17])=[O:16])[N:10]=1)=O)(C)(C)C>FC(F)(F)C(O)=O>[NH2:8][C:9]1[S:13][N:12]=[C:11]([C:14](=[N:18][O:19][CH2:20][C:21]#[CH:22])[C:15]([OH:17])=[O:16])[N:10]=1
Reactant: C#CCON=C(C(=O)O)c1nsc(NC(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Product: C#CCON=C(C(=O)O)c1nsc(N)n1
Reaction time: 1 h
Yield: 71.6 %

Procedure:
A solution of 410 mg (1.26 mmoles) of 2-(5-t-butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-2-propargyloxyiminoacetic acid in 5 ml of trifluoroacetic acid was allowed to stand for 1 hour at 25° C. Evaporation followed by trituration of the residue with 25 ml of isopropyl ether gave 204 mg (72%) of the title compound. Mp. 156°-158° C. (dec.).