Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([CH3:10])[C:3]=1[NH2:4].Cl.[N:12]([O-])=O.[Na+].C([O-])(=O)C.[Na+].CC(S)(C)C.CC(C)([O-])C.[K+]>O.C(O)C.CS(C)=O>[Br:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]2[C:3]=1[NH:4][N:12]=[CH:10]2
Reactant: O=N[O-]
Reactant: Cc1cc(F)cc(Br)c1N
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: O
Solvent: CC(C)(C)S
Solvent: CCO
Product: Fc1cc(Br)c2[nH]ncc2c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 2-bromo-4-fluoro-6-methylaniline (5 g, 24.51 mmol) in hydrochloric acid (8 M, 22 mL, 176 mmol) at 0° C. was added a solution of sodium nitrite (1.78 g, 25.7 mmol) in water (ca. 5.5 mL) dropwise. After 10 min, the resulting solution was neutralized (pH 4-5) by addition of solid sodium acetate. The resulting solution was added to a solution of 2-methyl-2-propanethiol (2.76 mL, 24.5 mmol) in ethanol (57 mL) at 0° C. The resulting mixture was stirred at 0° C. for 30 min. The resulting mixture was poured onto ice and the resulting mixture was extracted into diethyl ether (2×). The ethereal was washed with water, then brine, dried over magnesium sulfate, and concentrated. The resulting residue was dissolved in dimethylsulfoxide (14 mL) and transferred to a solution of potassium tert-butoxide (22 g, 196 mmol) in dimethylsulfoxide (140 mL) in a cool water bath (ca. 10° C.) via canula. The bath was removed and stirring continued for 30 min. The reaction mixture was poured onto ice/concentrated hydrochloric acid. The resulting mixture was extracted with dichloromethane (2×), washed with water (3×), then brine, dried over magnesium sulfate and concentrated. Prep HPLC gave 1.66 g (31.5%) as a pale solid. LC/MS (HPLC method 3): tR=2.337 min, 215.01(MH)+.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[C:15]([N+:17]([O-])=O)[C:14]([F:20])=[CH:13][C:5]=1[O:6][CH2:7][C:8](OCC)=[O:9])([O-])=O.[H][H]>C(O)C.[C].[Pd]>[F:20][C:14]1[C:15]([NH2:17])=[CH:16][C:4]2[NH:1][C:8](=[O:9])[CH2:7][O:6][C:5]=2[CH:13]=1
Reactant: [H][H]
Reactant: CCOC(=O)COc1cc(F)c([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Nc1cc2c(cc1F)OCC(=O)N2
Yield: 82.8 %

Procedure:
A suspension of ethyl 2,4-dinitro-5-fluorophenoxyacetate (1.3 g) and 5% palladium-carbon (0.35 g) in ethanol (30 ml) was subjected to catalytic reduction at room temperature under an ordinary pressure until 600 ml of hydrogen was absorbed. The reaction mixture was filtered, and the filtrate was concentrated to give 7-fluoro-6-amino-2H-1,4-benzoxazin-3(4H)-one (0.68 g; yield, 82.8%).
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([N:16]4[CH:20]=[CH:19][CH:18]=[CH:17]4)[CH:14]=3)[NH:9][C:8]=2[C:21]([NH:23][C@H:24]([C:32]([O:34]CC)=[O:33])[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>O>[C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([N:16]4[CH:17]=[CH:18][CH:19]=[CH:20]4)[CH:14]=3)[NH:9][C:8]=2[C:21]([NH:23][C@H:24]([C:32]([OH:34])=[O:33])[CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)c1[nH]c2ccc(-n3cccc3)cc2c1-c1ccccc1
Solvent: O
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)O)c1[nH]c2ccc(-n3cccc3)cc2c1-c1ccccc1

Procedure:
The title compound was prepared from ethyl N-{[3-phenyl-5-(1H-pyrrol-1-yl)-1H-indol-2-yl]carbonyl}-L-phenylalaninate followed the procedure of Example 1 Step 4 as an off-white solid: 1H NMR (DMSO-d6) δ 2.90 (dd, J=14.0, 6.1 Hz, 1 H), 3.09 (dd, J=14.0, 9.0 Hz, 1 H), 4.65 (dd, J=9.0, 6.1 Hz, 1 H), 6.20 (t, J=2.0 Hz, 1 H), 6.95-7.05 (m, 1 H), 7.15-7.60 (m, 16 H), 11.87 (s, 1 H), 12.91 (br s, 1 H); MS (ESI) m/z 450 (MH+); MS (ESI) m/z 448 ([M-H]−); HRMS calcd for C28H24N3O3: 450.1818; found (ESI+): 450.1809; Anal. calcd for C28H23N3O3.0.5 H2O: C, 73.35; H, 5.28; N, 9.16. Found: C, 73.27; H, 4.94; N, 9.37.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[C:6](=[O:7])[N:5]([C:8]2[CH:9]=[CH:10][C:11]([O:19][C:20]([F:23])([F:22])[F:21])=[C:12]([NH:14][C:15](=[O:18])[CH2:16]Cl)[CH:13]=2)[C:4](=[O:24])[N:3]1[CH2:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1.[CH3:33][CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[CH3:1][C:2]1([CH3:32])[C:6](=[O:7])[N:5]([C:8]2[CH:9]=[CH:10][C:11]([O:19][C:20]([F:23])([F:22])[F:21])=[C:12]([NH:14][C:15](=[O:18])[CH2:16][N:37]3[CH2:38][CH2:39][CH:34]([CH3:33])[CH2:35][CH2:36]3)[CH:13]=2)[C:4](=[O:24])[N:3]1[CH2:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1
Reactant: CC1CCNCC1
Reactant: CC1(C)C(=O)N(c2ccc(OC(F)(F)F)c(NC(=O)CCl)c2)C(=O)N1Cc1ccncc1
Product: CC1CCN(CC(=O)Nc2cc(N3C(=O)N(Cc4ccncc4)C(C)(C)C3=O)ccc2OC(F)(F)F)CC1

Procedure:
The title compound was prepared as described for example 2 using 150 mg (0.21 mmol) N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl-imidazolidin-1-yl)-2-trifluoromethoxy-phenyl]-2-chloro-acetamide (raw material, as described above) and 1 ml 4-methylpiperidine. Yield: 30 mg
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](Br)=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:3][CH:2]=1.C([O-])(=O)C.[K+].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][N:29]=[C:28]([CH2:32][CH2:33][C:34]2[NH:43][C:37]3=[N:38][CH:39]=[C:40](I)[CH:41]=[C:36]3[N:35]=2)[CH:27]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[Li+]>O1CCOCC1.O.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:24][O:25][C:26]1[CH:31]=[CH:30][N:29]=[C:28]([CH2:32][CH2:33][C:34]2[NH:43][C:37]3=[N:38][CH:39]=[C:40]([C:14]4[CH:15]=[CH:16][C:11]([S:8]([NH:7][C:4]5[CH:5]=[CH:6][C:1]([CH3:18])=[CH:2][CH:3]=5)(=[O:10])=[O:9])=[CH:12][CH:13]=4)[CH:41]=[C:36]3[N:35]=2)[CH:27]=1
Reactant: Cc1ccc(NS(=O)(=O)c2ccc(Br)cc2)cc1
Reactant: COc1ccnc(CCc2nc3cc(I)cnc3[nH]2)c1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccnc(CCc2nc3cc(-c4ccc(S(=O)(=O)Nc5ccc(C)cc5)cc4)cnc3[nH]2)c1
Temperature: 90 °C
Yield: 45.1 %

Procedure:
A mixture of 0.489 g of N-p-tolyl-4-bromobenzenesulfonamide, 0.42 g of bis-(pinacolato)-diboron, 0.025 g of 1,1′-bis-(diphenylphosphino)-ferrocene, 0.033 g of [1,1′-is(diphenylphosphino)-ferrocene]palladium-dichloride (complex with CH2Cl2), 0.442 g of potassium acetate in 6 ml of degassed dioxane are heated to 90° C. in a sealed tube under N2for 17 hours. To the resulting mixture 5 ml of degassed dioxane, 0.371 g of 2-[2-(4methoxypyridin-2-yl)ethyl]-6-iodo-3H-imidazo[4,5-b]pyridine (starting material A1), 0.113 g of tetrakis(triphenylphosphine)-palladium(0) and a solution of 0.27 g of potassium carbonate and 0.083 g of lithium chloride in 5 ml of degassed water are added under N2. The tube is sealed again, the mixture is heated to 120° under N2 for 6.5 hours and, after cooling, addition of water and adjusting the pH to 7, it is extracted three times with dichloromethane. The combined organic phases are dried over sodium sulfate, concentrated and the residue is chromatographed on a silica gel column (dichloromethane/methanol 25-15:1). Concentration of the chromatographically pure fractions and crystallisation from ethylacetate/acetonitril (1:1) gives 0.22 g of the title compound as a solid of m.p. 219-220° C. The mass spectrum shows the molecular peak MH+ at 500.3 Da.
Reaction SMILES: [Cl:1][C:2]1[C:8](Cl)=[CH:7][CH:6]=[C:5]([N+:10]([O-:12])=[O:11])[C:3]=1[NH2:4].[C:13]1([S-:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Na+]>C(#N)C>[Cl:1][C:2]1[C:8]([S:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=[C:5]([N+:10]([O-:12])=[O:11])[C:3]=1[NH2:4]
Reactant: [S-]c1ccccc1
Reactant: Nc1c([N+](=O)[O-])ccc(Cl)c1Cl
Agent: [Na+]
Solvent: CC#N
Product: Nc1c([N+](=O)[O-])ccc(Sc2ccccc2)c1Cl

Procedure:
A mixture of 103.5 gm of 2,3-dichloro-6-nitroaniline (0.5 mol) and 72.5 gm of sodium thiophenolate (0.55 mol) was dissolved in 800 ml of acetonitrile, and the solution was refluxed for 5 hours. The mixture was then processed according to the procedure set forth in Example 22 (b)(i). The yield was 108 gm of ochre-coloured, crystalline product (77% of theory), m.p. 144°-146° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.[CH3:11][O:12][C:13]([C:15]1[S:16][CH:17]=[CH:18][C:19]=1[S:20]([N:23]=[C:24]=[O:25])(=[O:22])=[O:21])=[O:14]>C(#N)C>[CH3:9][O:8][C:6]1[CH:5]=[C:4]([CH3:10])[N:3]=[C:2]([NH:1][C:24]([NH:23][S:20]([C:19]2[CH:18]=[CH:17][S:16][C:15]=2[C:13]([O:12][CH3:11])=[O:14])(=[O:21])=[O:22])=[O:25])[N:7]=1
Reactant: COC(=O)c1sccc1S(=O)(=O)N=C=O
Reactant: COc1cc(C)nc(N)n1
Solvent: CC#N
Product: COC(=O)c1sccc1S(=O)(=O)NC(=O)Nc1nc(C)cc(OC)n1
Temperature: 25 °C

Procedure:
To 1.4 g of 2-amino-4-methoxy-6-methylpyrimidine in 30 ml of anhydrous acetonitrile was added at ambient temperature, with stirring 3.6 g of 2-methoxycarbonyl-3-thiophenesulfonylisocyanate. The mixture was heated to the boiling point and then allowed to cool to ambient temperature. After stirring for sixteen hours the precipitate present in the mixture was filtered off and washed with anhydrous ethyl ether. The product thus obtained which melted at 165°-173° showed absorption peaks by infrared spectroscopy at 1720 and 1700 cm-1, consistent for the carbonyl groups in the desired product.
Reaction SMILES: [CH2:1]([OH:6])[C:2]([F:5])([F:4])[F:3].CC(C)([O-])C.[K+].F[C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22].P([O-])(O)(O)=O.[K+]>COCCOC.C(OC)(C)(C)C.O>[F:20][C:18]1[CH:19]=[CH:14][C:15]([N+:21]([O-:23])=[O:22])=[C:16]([O:6][CH2:1][C:2]([F:5])([F:4])[F:3])[CH:17]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: OCC(F)(F)F
Agent: CC(C)(C)[O-]
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: O
Solvent: COCCOC
Solvent: COC(C)(C)C
Product: O=[N+]([O-])c1ccc(F)cc1OCC(F)(F)F
Temperature: -10 °C
Yield: 6.7 %

Procedure:
A solution of trifluoroethanol (88 g, 64 mL, 88 mol) was added to a slurry of potassium tert-butoxide (98.8 g, 0.88 mol) in 1,2-dimethoxyethane (145 mL) such that the reaction temperature remained below 11° C. The mixture then was cooled 1.5 hours at 0° to 5° C. and added over 2.5 hours to a solution of 2,4-difluoronitrobenzene (135 g, 0.85 mol) in 1,2-dimethoxyethane (150 mL) at -10° C. The mixture was cooled 1 hour at -10° C. and then aqueous potassium dihydrogen phosphate solution (13 g, 130 mL) was added. The mixture was warmed to 25° C. and solid potassium dihydrogen phosphate (7 g) was added. The mixture was diluted with methyl tert-butyl ether (600 mL) and water (300 mL) and the organic layer was separated, diluted with methyl tert-butyl ether (100 mL), washed with water (2×400 mL), filtered through Celite (2 g) and concentrated in vacuo to give 4-fluoro-2-(2,2,2-trifluoroethoxy)nitrobenzene (13 g, 57.2 mmol)
Reaction SMILES: [CH:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)([CH3:3])[CH3:2]>FC(F)(F)C(O)=O.O=[Pt]=O>[CH:1]([C:4]1[CH:13]=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc2ccccc2n1
Agent: O=[Pt]=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1ccc2c(n1)CCCC2

Procedure:
To a 0.23 M solution of 2-isopropylquinoline in trifluoroacetic acid in a Parr flask was added 0.1 equiv of PtO2. The suspension was set up on the Parr apparatus at 44 psi H2 overnight. After removal of the H2, CH2Cl2 was added, and the suspension was filtered through Celite. The solvent was removed under vacuum, and the residue was partitioned between EtOAc and saturated NaHCO3 solution. The organic layer was washed with H2O and brine, and was then dried over anhydrous MgSO4, filtered and evaporated to give the title compound as a tan colored oil.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH:9]([CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:10]([OH:12])=O)[N:5]=[CH:4][C:3]=1[O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[NH2:27][C:28]1[CH:32]=[CH:31][N:30]([CH2:33][C:34]([CH3:37])([OH:36])[CH3:35])[N:29]=1>>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH:9]([CH2:13][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)[C:10]([NH:27][C:28]2[CH:32]=[CH:31][N:30]([CH2:33][C:34]([OH:36])([CH3:35])[CH3:37])[N:29]=2)=[O:12])[N:5]=[CH:4][C:3]=1[O:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: O=C(O)C(CC1CCCCC1)n1ncc(Oc2ccccc2)c(Cl)c1=O
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCCC2)n2ncc(Oc3ccccc3)c(Cl)c2=O)n1

Procedure:
Using the method described in Example 49, 2-(5-chloro-6-oxo-4-phenoxy-6H-pyridazin-1-yl)-3-cyclohexyl-propionic acid (Intermediate 102) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 2-(5-chloro-6-oxo-4-phenoxy-6H-pyridazin-1-yl)-3-cyclohexyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (136 mg); ES+-HRMS m/e calcd for C26H32N5O5Cl [M+H+] 514.2216 found 514.2214. 1H NMR (300 MHz, CDCl3) δ ppm 0.72-0.98 (m, 2H), 1.09 (br. s., 10H), 1.47-1.80 (m, 5H), 1.88-2.16 (m, 2H), 3.87 (s, 2H), 5.68 (dd, J=8.6, 6.2 Hz, 1H), 6.62 (s, 1H), 7.08 (d, J=7.8 Hz, 2H), 7.20-7.29 (m, 2H), 7.30-7.47 (m, 2H), 7.52 (s, 1H), 8.51 (s, 1H).
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][C:5]1[C:6]([CH3:31])=[N:7][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][S:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)=[O:20])=[CH:14][CH:13]=2)[C:9]=1[CH3:10].O.[OH-].[Na+].Cl>O1CCOCC1>[CH3:31][C:6]1[C:5]([CH2:4][C:3]([OH:32])=[O:2])=[C:9]([CH3:10])[N:8]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([CH2:18][S:19]([C:21]3[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=3)=[O:20])=[CH:16][CH:17]=2)[N:7]=1
Reactant: COC(=O)Cc1c(C)nn(Cc2ccc(CS(=O)c3ccc(C(F)(F)F)cc3)cc2)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nn(Cc2ccc(CS(=O)c3ccc(C(F)(F)F)cc3)cc2)c(C)c1CC(=O)O
Temperature: 60 °C
Reaction time: 1 h

Procedure:
{3,5-Dimethyl-1-[4-(4-trifluoromethyl-benzenesulfinylmethyl)-benzyl]-1H-pyrazol-4-yl}-acetic acid methyl ester (intermediate 16.2.1, 60 mg, 0.13 mmol) was dissolved in 2 ml dioxane and 1 ml water and aqueous NaOH solution (0.26 ml, 1 M) was added. After stirring for 1 h at 60° C. and dilution with water, aqueous HCl solution (0.39 ml, 1 M) was added. The mixture was extracted twice with ethyl acetate, the organic layer was dried over MgSO4 and evaporated under reduced pressure.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH3:32])[C:14]=2[C@H:15]2[O:21][CH2:20][C@@H:19]([O:22][CH3:23])[C@H:18]([NH:24]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[O:8])[N:6]=1.[CH3:33][C:34]1[C:35](B(O)O)=[N:36][CH:37]=[CH:38][CH:39]=1>>[NH2:24][C@H:18]1[C@H:19]([O:22][CH3:23])[CH2:20][O:21][C@H:15]([C:14]2[N:13]([CH3:32])[N:12]=[CH:11][C:10]=2[NH:9][C:7]([C:5]2[N:6]=[C:2]([C:35]3[C:34]([CH3:33])=[CH:39][CH:38]=[CH:37][N:36]=3)[S:3][CH:4]=2)=[O:8])[CH2:16][CH2:17]1
Reactant: Cc1cccnc1B(O)O
Reactant: CO[C@@H]1CO[C@H](c2c(NC(=O)c3csc(Br)n3)cnn2C)CC[C@H]1NC(=O)OC(C)(C)C
Product: CO[C@@H]1CO[C@H](c2c(NC(=O)c3csc(-c4ncccc4C)n3)cnn2C)CC[C@H]1N

Procedure:
Following the procedure for Example 101 starting from tert-butyl ((3S,4R,7S)-7-(4-(2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-3-methoxyoxepan-4-yl)carbamate (Intermediate 102), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (3-methylpyridin-2-yl)boronic acid gave 348. 1H NMR (500 MHz, DMSO-d6) δ 9.67 (s, 1H), 8.52-8.51 (m, 1H), 8.27 (s, 1H), 8.23 (s, 1H), 7.67-7.65 (m, 1H), 7.29-7.26 (m, 1H), 5.03-5.00 (m, 1H), 4.04-3.93 (m, 2H), 3.78 (s, 3H), 3.56-3.54 (m, 1H), 3.38-3.36 (m, 1H), 3.33 (s, 3H), 2.88 (s, 3H), 2.61 (s, 2H), 2.13-2.09 (m, 1H), 1.98-1.70 (m, 2H), 1.68-1.56 (m, 1H). LCMS (ES+) m/z 443 (M+1).
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:10]=2)=[O:7])=[C:4]([F:21])[CH:3]=1.C(OC([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)=O)(C)(C)C.C(C1C=C(NC(=O)C2C=CC(N3CCNCC3)=C(F)C=2)C=CC=1)(C)(C)C>>[C:15]([C:11]1[CH:10]=[C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:19]=[CH:20][C:2]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[CH:3][C:4]=2[F:21])[CH:14]=[CH:13][CH:12]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)c1cccc(NC(=O)c2ccc(Br)cc2F)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCNCC3)c(F)c2)c1
Product: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCNCC3)cc2F)c1

Procedure:
N-(3-tert-Butyl-phenyl)-2-fluoro-4-piperazin-1-yl-benzamide was synthesized from 4-bromo-N-(3-tert-butyl-phenyl)-2-fluoro-benzamide and piperazine-1-carboxylic acid tert-butyl ester in a manner similar to the one described in the synthesis of N-(3-tert-butyl-phenyl)-3-fluoro-4-piperazin-1-yl-benzamide above. LCMS calcd for C21H26FN3O (m/e) 355, obsd 356 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Br:13])[CH:8]=2)[N:3]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15].S(=O)(=O)(O)O.O>C(O)(=O)C>[Br:13][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:1][C:14](=[O:16])[CH3:15])[CH:11]=[C:10]2[OH:12]
Reactant: Nc1cc(O)c2cc(Br)ccc2n1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1cc(O)c2cc(Br)ccc2n1
Temperature: 25 °C
Yield: 94.9 %

Procedure:
A mixture of 2-amino-6-bromo-quinolin-4-ol (29.4 g, 0.12 mol), acetic anhydride (36.7 g, 0.36 mol) and sulphuric acid (20 ml) in glacial acetic acid (300 ml) was refluxed for 30 min. The mixture was allowed to cool to rt and then poured into water. The precipitate was isolated by filtration and dried to afford product N-(6-bromo-4-hydroxy-quinolin-2-yl)-acetamide as a brown solid (32 g, 93%). This material was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:8]([C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[CH:15][C:16]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[N:17]3)=[CH:12][CH:11]=2)[NH2:9])=[N:4][CH:5]=[CH:6][N:7]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[C:49]([N:59]1[CH2:64][CH2:63][CH:62]([CH2:65][C:66](O)=[O:67])[CH2:61][CH2:60]1)([O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:50]>C(Cl)Cl>[CH2:52]([O:51][C:49]([N:59]1[CH2:64][CH2:63][CH:62]([CH2:65][C:66](=[O:67])[NH:9][CH:8]([C:3]2[C:2]([Cl:1])=[N:7][CH:6]=[CH:5][N:4]=2)[C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[CH:15][C:16]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[N:17]3)=[CH:12][CH:11]=2)[CH2:61][CH2:60]1)=[O:50])[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1
Reactant: NC(c1ccc2ccc(-c3ccccc3)nc2c1)c1nccnc1Cl
Reactant: O=C(O)CC1CCN(C(=O)OCc2ccccc2)CC1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(CC1CCN(C(=O)OCc2ccccc2)CC1)NC(c1ccc2ccc(-c3ccccc3)nc2c1)c1nccnc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(3-Chloropyrazin-2-yl)(2-phenylquinolin-7-yl)-methanamine (120.00 mg, 0.35 mmol), EDC (100.64 mg, 0.53 mmol) and HOBt (47.29 mg, 0.35 mmol) were suspended in CH2Cl2 (2 mL) and charge with DIEA (122.00 μL, 0.70 mmol) followed by the addition of 1-N-Cbz-4-piperidineacetic acid (127.56 mg, 0.46 mmol). The reaction mixture was stirred at rt for 16 h. The reaction mixture was diluted with CH2Cl2 (10 mL) and washed with saturated NaHCO3 (2×20 mL) and brine (2×20 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by a 10 g Jones silica gel (wetted with 50% EtOAc/Hexane, dried loaded onto silica, and run with 60% EtOAc/Hexanes→70% EtOAc/Hexanes) affording the desired product; 1H NMR (400 MHz, CHLOROFORM-d) δ 8.56 (1H, d, J=2.47), 8.39 (1H, d, J=2.50), 8.23 (1H, d, J=4.77), 8.11 (2H, d, J=7.06), 7.85 (3H, dd, J=8.60, J=8.38), 7.74 (1H, s), 7.50 (3H, m), 7.32 (6H, m), 6.78 (1H, d, J=7.76), 5.10 (2H, s), 4.11 (2H, m), 2.75 (2H, m), 2.21 (2H, d, J=7.00), 2.01 (1H, m), 1.67 (2H, m), 1.15 (2H, d, J=8.921); MS (ES+): m/z 605.96/606.98/608.93 (100/40/15) [MH+]; HPLC: tR=3.33 min. (OpenLynx, nonpolar—5 min.).
Reaction SMILES: I[Si](C)(C)C.C(#N)C.[Cl:9][CH2:10][CH2:11][CH2:12][C:13]([CH3:20])([CH3:19])[C:14]([O:16]CC)=[O:15]>O>[Cl:9][CH2:10][CH2:11][CH2:12][C:13]([CH3:20])([CH3:19])[C:14]([OH:16])=[O:15]
Reactant: CCOC(=O)C(C)(C)CCCCl
Agent: C[Si](C)(C)I
Solvent: CC#N
Solvent: O
Product: CC(C)(CCCCl)C(=O)O
Temperature: 80 °C
Yield: 109.3 %

Procedure:
Iodotrimethylsilane (3.00 g, 15 mmols) was added to an acetonitrile solution (5 ml) of ethyl 5-chloro-2,2-dimethylpentanoate (963 mg, 5 mmols) at room temperature, and heated at 80° C. for 24 hours with stirring. The reaction mixture was poured into water with ice, and extracted with ether. The organic layer was washed with water, and dried with anhydrous magnesium sulfate, and the solvent was evaporated to obtain 0.9 g of 5-chloro-2,2-dimethylpentanoic acid as a brown oil.
Reaction SMILES: CO[C:3]([CH2:5][CH2:6][C@H:7]([NH2:11])[C:8]([OH:10])=[O:9])=[O:4].C(C1CCCC1=O)(=O)C.[CH2:21]([N:23](CC)CC)[CH3:22].C(N)C>CO>[NH2:11][C@H:7]([C:8]([OH:10])=[O:9])[CH2:6][CH2:5][C:3]([NH:23][CH2:21][CH3:22])=[O:4]
Reactant: COC(=O)CC[C@H](N)C(=O)O
Reactant: CCN(CC)CC
Agent: CC(=O)C1CCCC1=O
Agent: CCN
Solvent: CO
Product: CCNC(=O)CC[C@H](N)C(=O)O
Temperature: 60 °C
Yield: 66.7 %

Procedure:
First, 5.0 g (31 mmol) of L-glutamic acid-γ-methyl ester was suspended in 15 mL of methanol. To this, 4.3 g (34 mmol) of 2-acetyl-cyclopentanone and 3.1 g (31 mmol) of triethylamine were added. The mixture was heated at 60° C. for 2 hours. Subsequently, 20 g (310 mmol) of 70% ethylamine was added to the mixture and the same procedure as in Example 1 was performed to obtain 3.6 g of theanine (yield: 66.7%). The obtained theanine had the same purity as high as in Example 1.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:12]3[N:13]=[CH:14][C:15]([C:17]4[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=4)[C:20]([NH:22][CH3:23])=[O:21])=[CH:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:23][NH:22][C:20](=[O:21])[C:19]1[CH:24]=[CH:25][CH:26]=[C:17]([C:15]2[CH:14]=[N:13][N:12]3[C:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[CH:7]=4)=[CH:9][N:10]=[C:11]3[CH:16]=2)[CH:18]=1
Reactant: OB(O)c1ccccc1
Reactant: CNC(=O)c1cccc(-c2cnn3c(-c4ccnc(Cl)c4)cnc3c2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CNC(=O)c1cccc(-c2cnn3c(-c4ccnc(-c5ccccc5)c4)cnc3c2)c1

Procedure:
3-[3-(2-Chloro-pyridin-4-yl)-imidazo[1,2-b]pyridazin-7-yl]-N-methyl-benzamide (1 eq, 0.110 mmol, 40 mg) and phenyl boronic acid (1.2 eq, 0.132 mmol, 16.1 mg) are dissolved in DME (1.5 ml) and water (0.5 ml) and Na2CO3 (2 eq, 0.22 mmol, 27.3 mg) is added. PdCl2(PPh3)2 (0.1 eq, 0.011 mmol, 7.7 mg) is then added and the reaction mixture is heated using microwave radiation at 120° C. for 10 min. At the completion of this time the solvent is removed in vacuo and the reaction mixture is purified by flash column chromatography eluting with 9:1 DCM/MeOH to yield N-Methyl-3-[3-(2-phenyl-pyridin-4-yl)-imidazo[1,2-b]pyridazin-7-yl]-benzamide as a yellow solid; [M+H]+=406