Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]=[CH:13][C@H:12]1[C:16]([OH:18])=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[I-].[Na+]>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]=[CH:13][C@H:12]1[C:16]([O:18][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:17])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)[C@@H]1C=CCN1C(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)[C@@H]1C=CCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of (S)-2,5-dihydro-pyrrole-1,2-dicarboxylic acid 1-benzyl ester (29.6 g, 120 mmol) in DMF (250 mL) were added cesium carbonate (42.9 g, 132 mmol) followed by benzyl bromide (17.09 mL, 144 mmol) and sodium iodide (2.15 g, 14.37 mmol) and the mixture was stirred at RT for 48 h. The reaction mixture was quenched with water (500 mL) and extracted with EtOAc (3×200 mL). The organic extracts were combined and washed with brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc 4:1) to give the desired material. MS (UPLC/MS): 338 [MH-Boc]+; tR (HPLC conditions b): 2.31 min.
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5].Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Cs+].[Cs+].Cl>C(#N)C.CS(C)=O.C(OCC)(=O)C>[C:4]([CH:3]([C:2](=[O:7])[CH3:1])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:6])[CH3:5]
Reactant: CC(=O)CC(C)=O
Reactant: CCOC(=O)CCCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CS(C)=O
Product: CCOC(=O)CCCCCCC(C(C)=O)C(C)=O
Temperature: 20 °C
Reaction time: 8 h
Yield: 45.8 %

Procedure:
A mixture of pentane-2,4-dione (5.0 g), ethyl 7-bromoheptanoate (11.1 g), potassium carbonate (13.8 g), and cesium carbonate (1.63 g) in a mixture of acetonitrile (150 ml) and dimethylsulfoxide (30 ml) was stirred at 20° C. overnight, then pentane-2,4-dione (5 g) was added. After stirring at 20° C. overnight, the mixture was partitoned between ethyl acetate and 0.5N hydrochloric acid. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane (1:5) to give ethyl 8-acetyl-9-oxodecanoate (5.5 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[C:11]([C:16](NC(C)(C)C)=[O:17])=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)[OH:24].O.[OH-].[Na+]>CCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[C:11]([C:16]([OH:17])=[O:24])=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: CC(C)(C)NC(=O)c1ncccc1CCc1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: O
Product: O=C(O)c1ncccc1CCc1cccc(Cl)c1
Temperature: 35 °C
Reaction time: 1 h

Procedure:
3-[2-(3-chlorophenyl)ethyl]-N-(1,1-dimethylethyl)-2-pyridine carboxamide (1.0 mole, 317g), sulfuric acid (325 mL) and water (300 mL) are refluxed at about 130° C. for aporoximately 2 hours. Completeness of the reaction is determined by thin layer chromatography. The reaction mixture is cooled to about 35° C. and added to ice (2 kg). The mixture is then brought to about pH 11 with 50% sodium hydroxide. Additional ice (1 kg) is added, followed by ethyl acetate (1 liter) and hexane (525 mL). The mixture is acidified to about pH 4 with sulfuric acid and stirred for about 1 hour. Crude product is isolated by filtration, washed with water and hexane and optionally dried at about 50° C. Then the crude product is dissolved in ethyl acetate by refluxing at about 75° C. After treating the solution with decolorizing carbon (5 g), the filtrate is concentrated and cooled to about 15° C. Purified product is isolated by filtration, washed with hexane: ethyl acetate (3:1) and dried at about 50° C. A second crop may be obtained by concentrating the mother liquor and recrystallizing from ethyl acetate as described above. The yield of product is shown to be 60%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[C:19]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[O:33]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34]1>CN(C)C=O.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>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([C:35]3[CH:36]=[CH:37][O:33][CH:34]=3)=[CH:3][CH:4]=2)(=[O:10])=[O:9])=[C:13]([C:19]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[O:20])[CH:14]=1
Reactant: OB(O)c1ccoc1
Reactant: O=C(c1ccncc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccncc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(-c2ccoc2)cc1
Temperature: 80 °C

Procedure:
4-bromo-N-[4-chloro-2-(pyridine-4-carbonyl)-phenyl]-benzenesulfonamide 0.25 g (0.55 mmol) was dissolved in 2.5 ml of anhydrous dimethylformamide. To this solution was added 0.14 g (1.3 mmol) sodium carbonate, furan-3-boronic acid 0.77 g (0.68 mmol), and Pd(PPh3)4 19 mg (0.014 mmol). The reaction mixture was heated overnight at 80° C. under a nitrogen atmosphere. The mixture was quenched with water and extracted 3 times with dichloromethane. The organic layer was dried over magnesium sulfate, filtered, and concentrated. Purification by flash column chromatography with a gradient 100% hexane to ethyl-acetate: hexane 1-1, gave the desired compound as a white powder.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:40][CH2:41][C:42]1[C:47]([CH2:48][CH3:49])=[N:46][C:45]2[N:50]([CH2:53][CH3:54])[N:51]=[CH:52][C:44]=2[C:43]=1[NH:55][CH:56]1[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1>ClCCl>[CH2:53]([N:50]1[C:45]2=[N:46][C:47]([CH2:48][CH3:49])=[C:42]([CH2:41][NH:40][C:5]([C:4]3[CH:8]=[C:9]([CH:10]=[C:2]([CH3:1])[CH:3]=3)[C:11]([O:13][CH3:14])=[O:12])=[O:7])[C:43]([NH:55][CH:56]3[CH2:57][CH2:58][O:59][CH2:60][CH2:61]3)=[C:44]2[CH:52]=[N:51]1)[CH3:54]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Reactant: COC(=O)c1cc(C)cc(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cc(C)cc(C(=O)OC)c1
Temperature: 25 °C

Procedure:
3-Methyl-5-[(methyloxy)carbonyl]benzoic acid (2.91 g, 15.00 mmol) was partially dissolved in dichloromethane (DCM) (500 mL) with stirring under argon at room temperature. HBTU (5.69 g, 15.00 mmol) was added followed by 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine hydrochloride (5.10 g, 15 mmol), and then TEA (4.18 mL, 30.0 mmol). The mixture was stirred under argon overnight. The solvent was concentrated and the residue partitioned between EtOAc (300 mL) and water (100 mL). The organic phase was washed with water (3×100 mL), brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. This was purified by CombiFlash on a 120 g silica column eluted with 35-100% EtOAc in hexane. The purified product was taken up in 300 mL of EtOAc, and washed with 50 mL of 1N NaOH, and then with water (3×100 mL), and 50 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound as a white solid. LC-MS m/z 480.0 (M+H)+, 0.81 min (ret time); mp 89-93° C.; analytical HPLC shows 95.4% purity, (ret time 12.251 min).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([NH2:13])[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[O:14]1[C:16]2([CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH2:15]1>C(O)C>[Si:1]([O:8][CH2:9][C:10]1([NH:13][CH2:15][C:16]2([OH:14])[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21]2)[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Reactant: CC(C)(C)[Si](C)(C)OCC1(N)CC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(O)(CNC2(CO[Si](C)(C)C(C)(C)C)CC2)CC1
Yield: 18 %

Procedure:
To a solution of 1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropanamine (10.09 mmol) in absolute ethanol (40 mL) was added tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (9.61 mmol) in one portion. The reaction was heated at reflux for 20 h then cooled and evaporated onto silica. The solid was purified by flash chromatography (30-80% ethyl acetate in hexanes) to afford the title product (719 mg, 16% yield) as a colorless oil. MS(ES)+ m/e 415.5 [M+H]+.
Reaction SMILES: C([C:3]1[C:4]([C:16]([NH2:18])=[O:17])=[N:5][N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11](Br)[CH:10]=2)[C:7]=1[CH3:8])C.C([O-])(=O)C.[K+].Br[C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[C:32]([F:35])([F:34])[F:33].C(=O)([O-])[O-].[Na+].[Na+]>CS(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([N:6]3[C:7]([CH3:8])=[CH:3][C:4]([C:16]([NH2:18])=[O:17])=[N:5]3)[CH:10]=2)=[C:26]([C:32]([F:33])([F:34])[F:35])[CH:27]=1
Reactant: CCc1c(C(N)=O)nn(-c2cccc(Br)c2)c1C
Reactant: Fc1ccc(Br)c(C(F)(F)F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CS(C)=O
Product: Cc1cc(C(N)=O)nn1-c1cccc(-c2ccc(F)cc2C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 0 %

Procedure:
To a solution of ethyl 1-(3-bromophenyl)-5-methyl-1H-pyrazole-3-carboxamide (from step 2 of EXAMPLE 1) (0.069 g, 0.24 mmol) in DMSO (1.14 mL), bis(pinacoloato)diboron (0.075 g, 0.3 mmol) was added followed by potassium acetate (0.072 g, 0.74 mmol) and PdCl2(dppf)2 (0.005 g, 3 mol %). The solution was heated in a Smith Creator™ microwave reactor (commercially available from Personal Chemistry, Inc.) at 140° C. for 1200 seconds. The reaction mixture was cooled to room temperature, and 2-bromo-5-fluorobenzotrifluoride (0.12 g, 0.5 mmol), PdCl2(dppf)2 (0.005 g, 3 mol %) and 2M sodium carbonate (0.61 mL, 1.2 mmol) were added to the reaction mixture. The reaction was then subjected to microwave radiation at 140° C. for 2800 seconds. After cooling to room temperature, the reaction mixture was partitioned between EtOAc and water. The organic layer was washed with saturated sodium bicarbonate and brine, then dried over sodium sulfate, filtered and concentrated. Purification of the crude product by reverse phase HPLC (acetonitrile/water system) (gradient: 45% to 100% acetonitrile over 10 minutes) yielded 0.036 mg of the product (41% yield, retention time 5.1 minutes).
Reaction SMILES: C1C=CC2N(O)N=[N:7]C=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[C:24]([O:28][C:29]([N:31]1[CH2:34][CH:33]([C:35]2[CH:40]=[CH:39][C:38]([NH:41][C:42]3[N:47]=[C:46]([CH2:48][CH2:49][C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=4[CH2:56][C:57]([OH:59])=O)[C:45]([C:60]([F:63])([F:62])[F:61])=[CH:44][N:43]=3)=[CH:37][CH:36]=2)[CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].CCN(CC)CC.C(=O)([O-])[O-].[NH4+].[NH4+]>CN(C=O)C>[NH2:7][C:57](=[O:59])[CH2:56][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][C:50]=1[CH2:49][CH2:48][C:46]1[C:45]([C:60]([F:62])([F:61])[F:63])=[CH:44][N:43]=[C:42]([NH:41][C:38]2[CH:39]=[CH:40][C:35]([CH:33]3[CH2:32][N:31]([C:29]([O:28][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:30])[CH2:34]3)=[CH:36][CH:37]=2)[N:47]=1
Reactant: CC(C)(C)OC(=O)N1CC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(=O)O)n3)cc2)C1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)cc2)C1
Temperature: 40 °C
Reaction time: 22 h

Procedure:
HOBt (146 mg, 1.07 mmol) and EDCl.HCl (207 mg, 1.07 mmol) were added to a solution of 2-(2-(2-(2-((4-(1-(tert-butoxycarbonyl)azetidin-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetic acid (A81) (0.500 g, 0.898 mmol) and Et3N (455 μL, 4.49 mmol) in DMF (13 mL). After 10 minutes ammonium carbonate (1.65 g, 18.0 mmol) was added and the resulting mixture was stirred at 40° C. for 22 hours. Additional HOBt (0.072 g, 0.539 mmol), EDCl.HCl (0.103 g, 0.539 mmol) and ammonium carbonate (0.413 g, 4.49 mmol) were added and the mixture stirred at 45° C. for 24 hours. The volatiles were removed in vacuo and water (25 mL) added to the residue resulting in the formation of a precipitate. The resulting suspension was sonicated for several minutes, filtered and the filter cake dried to give a solid which was adsorbed onto silica gel and purified by column chromatography (CombiFlash Rf, 40 g SiO2 cartridge, 25-70% EtOAc in cyclohexane) to give the title compound A82 as a white solid (346 mg, 69%); 1H NMR (300 MHz, d6-DMSO) δ 10.21 (s, 1H), 8.68 (s, 1H), 7.74 (d, J=8.6 Hz, 2H), 7.42 (s, 1H), 7.30 (d, J=8.6 Hz, 2H), 7.24-7.16 (m, 4H), 6.91 (s, 1H), 4.23 (t, J=8.0 Hz, 2H), 3.85-3.71 (m, 3H), 3.50 (s, 2H), 3.12-3.04 (m, 4H), 1.40 (s, 9H). LCMS-B: rt 8.187 min; m/z 556 [M+H]+.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:20]([OH:26])[CH:21](OCC)O)[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=1)C1C=CC=CC=1.[NH2:27][C:28]([CH3:46])([CH3:45])[CH2:29][CH2:30][N:31]1[C:35]2[CH:36]=[CH:37][C:38]([C:40]([F:43])([F:42])[F:41])=[CH:39][C:34]=2[NH:33][C:32]1=[O:44].FC(F)(F)C([O-])=O>>[CH3:46][C:28]([NH:27][CH2:21][CH:20]([C:11]1[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=[C:9]([OH:8])[CH:10]=1)[OH:26])([CH3:45])[CH2:29][CH2:30][N:31]1[C:35]2[CH:36]=[CH:37][C:38]([C:40]([F:43])([F:41])[F:42])=[CH:39][C:34]=2[NH:33][C:32]1=[O:44]
Reactant: CC(C)(N)CCn1c(=O)[nH]c2cc(C(F)(F)F)ccc21
Reactant: CCOC(O)C(O)c1cc(OCc2ccccc2)cc2c1OCC(=O)N2
Agent: O=C([O-])C(F)(F)F
Product: CC(C)(CCn1c(=O)[nH]c2cc(C(F)(F)F)ccc21)NCC(O)c1cc(O)cc2c1OCC(=O)N2

Procedure:
Prepared according to General Method 1 from 357 mg (1 mmol) 6-benzyloxy-8-(2-ethoxy-1,2-dihydroxy-ethyl)-4H-benzo[1,4]oxazin-3-one and 287 mg (1 mmol) 1-(3-amino-3-methyl-butyl)-5-trifluoromethyl-1,3-dihydro-benzimidazol-2-one. Yield: 76 mg (13%, trifluoroacetate); mass spectroscopy: [M+H]+=495.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Cl:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccnc(Br)c1
Reactant: OB(O)c1cccc(Cl)c1Cl
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccnc(-c2cccc(Cl)c2Cl)c1
Temperature: 110 °C

Procedure:
Under an atmosphere of argon, 250 mg (1.16 mmol) of methyl 2-bromoisonicotinate and 331 mg (1.74 mmol) of 2,3-dichlorophenylboronic acid were dissolved in 5 ml of toluene. 53 mg (0.06 mmol) of tris(dibenzylideneacetone)dipalladium, 46 mg (0.12 mmol) of 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl and 491 mg (2.31 mmol) of potassium phosphate were then added, and under argon the mixture was heated to 110° C. for 20 h. For work-up, the mixture was diluted at RT with 15 ml of ethyl acetate and 15 ml of water, the organic phase was separated off and the aqueous phase was extracted two more times with in each case 15 ml of ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified chromatographically [Method 19]. This gave 138 mg (42% of theory) of the target compound in a purity of 87%.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([O:11][CH2:12][C@H:13]([CH3:18])[CH2:14][C:15](O)=[O:16])([CH3:10])([CH3:9])[CH3:8].[O-]S([O-])(=O)=O.[Na+].[Na+]>CCOCC>[C:7]([O:11][CH2:12][C@H:13]([CH3:18])[CH2:14][CH2:15][OH:16])([CH3:9])([CH3:10])[CH3:8]
Reactant: C[C@@H](COC(C)(C)C)CC(=O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: C[C@H](CCO)COC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A slurry of 1.51 g. (0.0398 mole) of lithium aluminum hydride in 50 ml. of ether was stirred and cooled while a solution of 3.45 g. (0.0198 mole) of (R)-(+)-4-tert. butoxy-3-methylbutyric acid in 50 ml. of ether was added dropwise. After the addition was complete , the reaction mixture was stirred room temperature for 2 hours then cooled to 0° C. and cautiously decomposed 5.4 ml. saturated aqueous Na2SO4 solution. After stirring at room temperature for 18 hours, the mixture was filtered and the filtrate was concentrated under reduced pressure. The crude product (3.05 g.) was chromatographed on 10 of silica gel. Elution with 2:1 parts by volume, 1:1 parts by volume and 1:2 parts by volume hexane-ether followed by evaporative distillation gave 2.68 (85%) of the (R)-(+)-4-tert. butoxy-3-methyl-1-butanol as a colorless liquid b.p. 100°-102° C. (bath temperature) (20 mm Hg.); [α]25D + 12.79° (c 2.19, C6H6).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]([CH:21]([CH3:26])[C:22](OC)=[O:23])[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH3:2].O.[NH2:28][NH2:29]>CO>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]([CH:21]([CH3:26])[C:22]([NH:28][NH2:29])=[O:23])[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(S(=O)(=O)N(c2ccc(C)cc2)C(C)C(=O)OC)cc1
Reactant: NN
Solvent: O
Solvent: CO
Product: CCOc1ccc(S(=O)(=O)N(c2ccc(C)cc2)C(C)C(=O)NN)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
The crude carboxylic acid methyl ester, e.g. methyl 2-{[(4-ethoxyphenyl)sulfonyl]-4-methylanilino}propanoate (264 mg, 0.70 mmol), was dissolved in MeOH (2 mL). Hydrazine hydrate was added (0.44 mL). The reaction mixture was stirred overnight at 60° C. Solvents were evaporated. The crude mass was redissolved in MeOH and solvents were evaporated again. This process was repeated three times. The desired product, e.g. 4-ethoxy-N-(2-hydrazino-1-methyl-2-oxoethyl)-N-(4-methylphenyl)benzenesulfonamide (138.4 mg, 52%) was isolated as a colorless solid in 91.1% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:30]=[C:29]([NH:31][C:32](=[O:41])[C:33]2[CH:38]=[C:37](C)[CH:36]=C[C:34]=2F)[CH:28]=[CH:27][C:4]=1[O:5][C:6]1[C:11]2=[C:12]([CH3:26])[C:13]([C:15]([NH:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:16])=[CH:14][N:10]2[N:9]=[CH:8][N:7]=1.Cl.FC1C=C(NC(=O)CC(NC2C=CC(F)=CC=2)=O)C=CC=1OC1C2=C(C)C(OCCN3CCOCC3)=CN2N=C[N:52]=1>>[ClH:1].[ClH:1].[F:2][C:3]1[CH:30]=[C:29]([NH:31][C:32](=[O:41])[C:33]2[CH:38]=[CH:37][CH:36]=[N:52][CH:34]=2)[CH:28]=[CH:27][C:4]=1[O:5][C:6]1[C:11]2=[C:12]([CH3:26])[C:13]([C:15]([NH:17][CH2:18][CH2:19][N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)=[O:16])=[CH:14][N:10]2[N:9]=[CH:8][N:7]=1
Reactant: Cc1c(OCCN2CCOCC2)cn2ncnc(Oc3ccc(NC(=O)CC(=O)Nc4ccc(F)cc4)cc3F)c12
Reactant: Cc1ccc(F)c(C(=O)Nc2ccc(Oc3ncnn4cc(C(=O)NCCN5CCOCC5)c(C)c34)c(F)c2)c1
Agent: Cl
Product: Cc1c(C(=O)NCCN2CCOCC2)cn2ncnc(Oc3ccc(NC(=O)c4cccnc4)cc3F)c12
Yield: 39 %

Procedure:
Following a procedure similar to that for the synthesis of Compound D of Example 50, 4-(4-amino-2-fluorophenoxy)-5-methyl-N-(2-morpholinoethyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide (30 mg, 0.07 mmol, Compound C of Example 50) was converted the title compound (16 mg, 39%) as a 2.HCl salt. 1H NMR (CD3OD) δ 9.08 (s, 1H), 8.70 (s, 1H), 8.44 (s, 1H), 8.17 (s, 1H), 7.87 (m, 2H), 7.38 (m, 2H), 7.22 (m, 2H), 3.82 (s, 4H), 3.61 (m, 2H), 2.75 (m, 9H); MS(ESI+) m/z 520.2 (M+H)+.
Reaction SMILES: [CH3:1][C@:2]1([C:19]([O-:21])=O)[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1.[Li+].Cl.[NH2:24][C:25]1([C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=2)[CH2:27][CH2:26]1>>[CH3:1][C@:2]1([C:19]([NH:24][C:25]2([C:28]3[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=3)[CH2:27][CH2:26]2)=[O:21])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=1
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Reactant: C[C@]1(C(=O)[O-])CCCCN1Cc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [Li+]
Product: COC(=O)c1ccc(C2(NC(=O)[C@@]3(C)CCCCN3Cc3ccc(C(F)(F)F)cc3)CC2)cc1
Yield: 16.2 %

Procedure:
The title compound (D157) (5 mg) was prepared according to the general procedure for amides preparation (Method B) starting from lithium (R)-2-methyl-1-(4-(trifluoromethyl)benzyl)piperidine-2-carboxylate (D112) (20 mg) and methyl 4-(1-aminocyclopropyl)benzoate hydrochloride (17.2 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:18]3[N:19]=[C:20]4[C:26]([C:27]([NH:29][CH:30]([CH3:32])[CH3:31])=[O:28])=[CH:25][N:24](COCC[Si](C)(C)C)[C:21]4=[N:22][CH:23]=3)=[N:7][N:8]2[CH2:11][C:12]2[CH:16]=[C:15]([CH3:17])[O:14][N:13]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.ClCCl.CO>ClCCCl>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:18]3[N:19]=[C:20]4[C:26]([C:27]([NH:29][CH:30]([CH3:32])[CH3:31])=[O:28])=[CH:25][NH:24][C:21]4=[N:22][CH:23]=3)=[N:7][N:8]2[CH2:11][C:12]2[CH:16]=[C:15]([CH3:17])[O:14][N:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(Cn2nc(-c3cnc4c(n3)c(C(=O)NC(C)C)cn4COCC[Si](C)(C)C)c3ccc(Cl)cc32)no1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(Cn2nc(-c3cnc4[nH]cc(C(=O)NC(C)C)c4n3)c3ccc(Cl)cc32)no1
Temperature: 80 °C
Reaction time: 15 h
Yield: 21.8 %

Procedure:
2-(6-Chloro-1-((5-methylisoxazol-3-yl)methyl)-1H-indazol-3-yl)-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (89 mg, 153 μmol) was dissolved in 1,2-dichloroethane (3 mL) and placed in a sealed tube. To this was added trifluoroacetic acid (1.75 g, 1.18 mL, 15.3 mmol). The tube was sealed and the mixture heated at to 80° C. After 15 h, the mixture was cooled and concentrated in vacuo. The residue was purified by chromatography (silica, 24 g Analogix column, 95:5 dichloromethane:methanol) then preparative TLC (95:5 dichloromethane/methanol) to give 2-(6-chloro-1-((5-methylisoxazol-3-yl)methyl)-1H-indazol-3-yl)-N-isopropyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (15 mg, 33.3 μmol, 22%). MS (M+Na)+=472; 1H NMR (CDCl3) δ: 9.37 (s, 1H), 9.22-9.32 (m, 1H), 8.42-8.51 (m, 1H), 8.34-8.40 (m, 1H), 8.11-8.21 (m, 1H), 7.56-7.63 (m, 1H), 7.19-7.36 (m, 1H), 5.90-5.97 (m, 1H), 5.63-5.75 (m, 2H), 4.38-4.56 (m, 1H), 2.38 (s, 3H), 1.41 (d, J=6.4 Hz, 6H).