Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:13])([CH3:12])[C:10]#[N:11])=[CH:5][CH:4]=1)=[O:2].[N+:14]([CH:16](S(C1C=CC(C)=CC=1)(=O)=O)[CH3:17])#[C-:15].C([O-])([O-])=O.[K+].[K+]>CO>[CH3:12][C:9]([C:6]1[CH:7]=[CH:8][C:3]([C:1]2[O:2][CH:15]=[N:14][C:16]=2[CH3:17])=[CH:4][CH:5]=1)([CH3:13])[C:10]#[N:11]
Reactant: CC(C)(C#N)c1ccc(C=O)cc1
Reactant: [C-]#[N+]C(C)S(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1ncoc1-c1ccc(C(C)(C)C#N)cc1
Temperature: 25 °C
Yield: 80.5 %

Procedure:
A mixture of Example 35B (2.24 g, 12.9 mmol), 1-(1-isocyanoethylsulfonyl)-4-methylbenzene (2.71 g, 12.9 mmol), and K2CO3 (2.15 g, 15.5 mmol) in MeOH (60 mL) was heated at reflux for 2 hr. The reaction was cooled to ambient temperature, and the volatiles removed at reduced pressure. The residue was partitioned between H2O and Et2O. The separated aqueous phase was extracted with Et2O, and the combined organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Flash chromatography (Analogix® Intelliflash 280™; 15% to 40% EtOAc/hexanes eluant; SF40-150 g column) yielded 2.35 g (80%) of the title compound as a colorless oil. 1H NMR (300 MHz, DMSO-d6) δ 8.35 (s, 1H), 7.71-7.61 (m, 4H), 2.37 (s, 3H), 1.71 (s, 6H). MS (DCI+) m/z 227 (M+H).
Reaction SMILES: N1N=C(C2C=CC=CC=2C(N2CC3CN(C(OC(C)(C)C)=O)CC3C2)=O)NC=1.[CH3:29][C:30]1[CH:35]=[C:34]([CH3:36])[N:33]=[C:32]([N:37]2[CH2:44][CH:43]3[CH:39]([CH2:40][NH:41][CH2:42]3)[CH2:38]2)[N:31]=1.C(OC(N1CC2C(CNC2)C1)=O)(C)(C)C.[F:60][C:61]1[CH:69]=[CH:68][CH:67]=[C:66]([C:70]2[O:74][N:73]=[C:72]([CH3:75])[N:71]=2)[C:62]=1[C:63](O)=[O:64].N1N=C(C2C=CC=CC=2C(O)=O)NC=1>>[CH3:29][C:30]1[CH:35]=[C:34]([CH3:36])[N:33]=[C:32]([N:37]2[CH2:44][CH:43]3[CH:39]([CH2:40][N:41]([C:63]([C:62]4[C:66]([C:70]5[O:74][N:73]=[C:72]([CH3:75])[N:71]=5)=[CH:67][CH:68]=[CH:69][C:61]=4[F:60])=[O:64])[CH2:42]3)[CH2:38]2)[N:31]=1
Reactant: Cc1noc(-c2cccc(F)c2C(=O)O)n1
Reactant: Cc1cc(C)nc(N2CC3CNCC3C2)n1
Agent: CC(C)(C)OC(=O)N1CC2CN(C(=O)c3ccccc3-c3nnc[nH]3)CC2C1
Agent: CC(C)(C)OC(=O)N1CC2CNCC2C1
Agent: O=C(O)c1ccccc1-c1nnc[nH]1
Product: Cc1cc(C)nc(N2CC3CN(C(=O)c4c(F)cccc4-c4nc(C)no4)CC3C2)n1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 59 substituting Intermediate 23 for Intermediate 15 and Intermediate 64 for 2-(4H-[1,2,4]triazol-3-yl)-benzoic acid. MS (ESI) mass calculated for C22H23FN6O2, 422.19; m/z found, 423.2. 1H NMR (500 MHz, CDCl3): 7.96-7.86 (m, 1H), 7.55-7.47 (m, 1H), 7.38-7.29 (m, 1H), 6.32-6.23 (m, 1H), 3.99-3.46 (m, 7H), 3.27-2.95 (m, 3H), 2.49-2.37 (m, 3H), 2.36-2.21 (m, 6H).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[C:10]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)=[N:11][OH:12].[H-].[Na+].Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].O>CN(C=O)C>[CH2:30]([O:29][C:27](=[O:28])[CH2:26][O:9][C:6]1[CH:5]=[CH:4][C:3]2[C:10]([C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)=[N:11][O:12][C:2]=2[C:7]=1[Cl:8])[CH3:31]
Reactant: CCOC(=O)CBr
Reactant: ON=C(c1ccc(O)c(Cl)c1Cl)c1cccc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccc2c(-c3cccc4ccccc34)noc2c1Cl
Temperature: 100 °C
Reaction time: 18 h

Procedure:
To a solution of 3 g of (2,3-dichloro-4-hydroxyphenyl)(1-naphthyl)methanone oxime in 25 ml of DMF, 0.54 g of NaH is added under N2. The mixture is heated to an internal temperature of 100° C. for one hour and 20 minutes. The reaction mixture is cooled to room temperature and 1.65 g of ethyl bromoacetate is added dropwise. The mixture is stirred for 18 hours, water is added and the product is extracted with ethyl acetate. The ethyl acetate extract is washed with water, dried over Na2SO4 and evaporated to give ethyl{[7-chloro-3-(1-napthyl)-1,2-benzisoxazol-6-yl]oxy}acetate, mp 75°-85° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:19])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:18])([C:14]([O:16]C)=[O:15])[CH2:6][CH2:5]2.[OH-].[Na+].S([O-])(O)(=O)=O.[K+]>CO.O>[OH:1][C:2]1[C:3]([CH3:19])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:18])([C:14]([OH:16])=[O:15])[CH2:6][CH2:5]2
Reactant: COC(=O)C1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Reaction time: 2 h

Procedure:
Into a 2000-L reactor provided with glass lining, methyl 6-hydroxy-2,5,7,8-tetramethyl-chroman-2-carboxylate (137.3 kg) obtained in Example 6 was placed and dissolved in methanol (137.3 kg). A solution containing water (411 kg) and sodium hydroxide (27 kg) was added dropwise thereto over two hours, whereby hydrolysis was performed at 80° C. for two hours. The hydrolyzed mixture was neutralized with a solution of potassium hydrogensulfate (91.9 kg) dissolved in water (411.9 kg) at 80° C. for two hours. The reaction mixture was centrifuged, and the obtained crystals were dried by means of a conical drier, to thereby yield 6-hydroxy-2,5,7,8-tetramethyl-chroman-2-carboxylic acid (130.2 kg) in the form of white powder. Reaction scores on the basis of 6-hydroxy-2,5,7,8-tetramethyl-chroman-2-carboxylate and chemical purity which was determined through high-performance liquid chromatography (HPLC) were found to be as follows:
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[CH:7][CH:6]=[N:5]1)[CH2:2][CH3:3].[Li]CCCC.C(O[B:18]1[O:22][C:21]([CH3:24])([CH3:23])[C:20]([CH3:26])([CH3:25])[O:19]1)(C)C>C1COCC1>[CH2:1]([N:4]1[C:8]([B:18]2[O:22][C:21]([CH3:24])([CH3:23])[C:20]([CH3:26])([CH3:25])[O:19]2)=[CH:7][CH:6]=[N:5]1)[CH2:2][CH3:3]
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: CCCn1cccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCn1nccc1B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the above THF solution of 1-propyl-1H-pyrazole was added n-BuLi (2.5M in Hexane, 40 mL, 100 mmol) at −78° C. The reaction solution was stirred for 2 hours at RT and then re-cooled to −78° C. [J. Heterocyclic Chem. 41, 931 (2004)]. To the reaction solution was added 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (18.6 g, 100 mmol). After 30 min at −78° C., the reaction was quenched with saturated NH4Cl solution and extracted with DCM. The organics were dried over Na2SO4 and concentrated under vacuum to afford the title compound as a brown solid which was used directly without further purification: LC-MS (ES) m/z 154 (M+H)+ for [RB(OH)2].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([NH2:13])[CH2:7][CH2:6]2.CCN(C(C)C)C(C)C.[C:23](Cl)(=[O:25])[CH3:24]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([NH:13][C:23](=[O:25])[CH3:24])[CH2:7][CH2:6]2
Reactant: CC(=O)Cl
Reactant: COc1ccc2c(c1)CCC(N)C2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CCC(NC(C)=O)C2
Temperature: 0 °C
Reaction time: 18 h
Yield: 50.1 %

Procedure:
To a stirred suspension of 6-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylamine (2.54 g; 14.3 mmol) in CH2Cl2 (20 mL) is added DIEA (3.4 mL) and the reaction mixture was cooled to 0° C. Acetyl chloride (1.22 mL; 17.1 mmol) is added dropwise at 0° C. and the reaction is allowed to warm to RT and stirred for 18 h. The reaction mixture was diluted with CH2Cl2, washed with H2O, dried over Na2SO4, filtered and the solvent removed under reduced pressure to provide a crude solid. Purification by flash chromatography (SiO2) eluting with hexanes-EtOAc affords 1.57 g (50%) of N-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)acetamide as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([F:26])[CH:5]=[C:6]2[C:11]=1[N:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([NH:19][CH3:20])[C:13]=1[F:21])[CH:9]=[C:8]([C:22]([OH:24])=[O:23])[C:7]2=[O:25].CN.[N:30]1C=CC=C[CH:31]=1>C(O)C>[Cl:1][C:2]1[C:3]([NH:30][CH3:31])=[C:4]([F:26])[CH:5]=[C:6]2[C:11]=1[N:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([NH:19][CH3:20])[C:13]=1[F:21])[CH:9]=[C:8]([C:22]([OH:24])=[O:23])[C:7]2=[O:25]
Reactant: c1ccncc1
Reactant: CNc1c(F)ccc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c1F
Agent: CN
Solvent: CCO
Product: CNc1c(F)ccc(-n2cc(C(=O)O)c(=O)c3cc(F)c(NC)c(Cl)c32)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 156.5 %

Procedure:
8-Chloro-6,7-difluoro-1-(2,4-difluoro-3-methylaminophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (120 mg) and a 40% aqueous solution (120 mg) of methylamine were added to pyridine (500 mg), and the mixture was stirred at room temperature for 3 hours. Ethanol (1 ml) was added to the reaction mixture, and the resultant mixture was stirred for 2 hours. Deposits were collected by filtration and washed successively with ethanol and diisopropyl ether to obtain the title compound (193 mg) as a colorless powder.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([NH2:16])=[CH:12][C:13]=2[F:15])[CH2:8][CH2:7][CH2:6]1.I.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24](SC)=[NH:25]>C(O)C.O.C(=O)([O-])[O-].[Na+].[Na+]>[CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([NH:16][C:24]([C:20]3[S:19][CH:23]=[CH:22][CH:21]=3)=[NH:25])=[CH:12][C:13]=2[F:15])[CH2:8][CH2:7][CH2:6]1
Reactant: CN(C)CCN1CCCc2cc(N)cc(F)c21
Reactant: CSC(=N)c1cccs1
Agent: I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CN(C)CCN1CCCc2cc(NC(=N)c3cccs3)cc(F)c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(2-(Dimethylamino)ethyl)-8-fluoro-1,2,3,4-tetrahydroquinolin-6-amine (222 mg, 0.935 mmol) was stirred to dissolve in ethanol in a round bottom flask. To this solution was added methyl thiophene-2-carbimidothioate hydroiodide (533 mg, 1.87 mmol). The resulting suspension was stirred overnight at room temperature. When TLC analysis showed that the reaction was finished, the mixture was diluted with water and aqueous sodium carbonate, then extracted with dichloromethane (3×). The combined organics were dried, filtered and concentrated and the crude product then chromatographed on silica gel using 0-10% (2M NH3 in MeOH) in ethyl acetate, then a second time using 20-80% MeCN in an aqueous buffer of ammonium carbonate and ammonium hydroxide adjusted to pH 10.6. Yield: 46 mg, 15%. 1H NMR (DMSO-d6) δ 1.75 (m, 2H), 2.16 (s, 6H), 2.46 (m, 2H), 2.66 (m, 2H), 3.12 (m, 4H), 6.40 (m, 4H), 7.07 (m, 1H), 7.57 (m, 1H), 7.71 (m, 1H). ESI-MS: 347 (MH+, 33), 276 (100), 143 (12).
Reaction SMILES: [CH2:1]([C:8]1O[C:10]([O:20]CC)=[C:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:23]1[CH2:27][CH:26]=[CH:25][CH2:24]1>>[CH2:1]([C:8]1[C:25]2[CH2:24][O:23][CH2:27][C:26]=2[C:10]([OH:20])=[C:11]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOc1oc(Cc2ccccc2)nc1Cc1ccccc1
Reactant: C1=CCOC1
Product: Oc1c(Cc2ccccc2)nc(Cc2ccccc2)c2c1COC2
Yield: 37 %

Procedure:
44 g (150 millimoles) of 2,4-dibenzyl-5-ethoxyoxazole and 210 g (3 moles) of 2,5-dihydrofuran are heated for 8 hours at 180° C. Excess 2,5-dihydrofuran is distilled off and the residue is digested in ether. The undissolved constituent is recrystallized from ethanol. 17.6 g of 4,6-dibenzyl-1,3-dihydro-furo[3,4-c]pyridin-7-ol are obtained, melting point 204°-205° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([CH3:18])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Cl:22][C:23]1[CH:28]=[C:27](Cl)[N:26]=[CH:25][N:24]=1>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:19])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:27]2[CH:28]=[C:23]([Cl:22])[N:24]=[CH:25][N:26]=2)=[C:13]([CH3:18])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Cc1cc(NC(=O)OCc2ccccc2)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(NC(=O)OCc2ccccc2)ccc1Oc1cc(Cl)ncn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(4-Hydroxy-3-methyl-phenyl)-carbamic acid benzyl ester (278 mg, 1.08 mmol) and NaH (29 mg, 1.2 mmol) dissolved in DMF (5 mL) are stirred at rt for 15 min. 4,6-Dichloro-pyrimidine (177 mg, 1.19 mmol) dissolved in DMF (5 mL) is added and the reaction solution is stirred for 1 h, concentrated under reduced pressure and flash chromatographed (silica gel, 2.5×60 cm, AcOEt/hexane=1:6): M+H=370.8; Rf (AcOEt/hexane=1:6): 0.31.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:24]4[C:19](=[CH:20][C:21]([S:25](OC5C(F)=C(F)C(F)=C(F)C=5F)(=[O:27])=[O:26])=[CH:22][CH:23]=4)[CH:18]=[CH:17][N:16]=3)=[C:11]([O:40][CH3:41])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.[CH3:42][C:43]1[N:48]=[CH:47][N:46]=[C:45]([NH2:49])[CH:44]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:24]4[C:19](=[CH:20][C:21]([S:25]([NH:49][C:45]5[CH:44]=[C:43]([CH3:42])[N:48]=[CH:47][N:46]=5)(=[O:26])=[O:27])=[CH:22][CH:23]=4)[CH:18]=[CH:17][N:16]=3)=[C:11]([O:40][CH3:41])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Cc1cc(N)ncn1
Reactant: COc1cc(-c2cc(F)cc(F)c2)ccc1-c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(-c2cc(F)cc(F)c2)ccc1-c1nccc2cc(S(=O)(=O)Nc3cc(C)ncn3)ccc12
Reaction time: 0.33 h
Yield: 47.7 %

Procedure:
A vial was charged with perfluorophenyl 1-(3′,5′-difluoro-3-methoxy-[1,1′-biphenyl]-4-yl)isoquinoline-6-sulfonate (INTERMEDIATE KKKKK; 63.5 mg, 0.107 mmol), 6-methylpyrimidin-4-amine (12.26 mg, 0.112 mmol), and THF (535 μl). The vial was cooled in an ice-water bath for 10 min, then lithium bis(trimethylsilyl)amide (1M in THF) (225 μl, 0.225 mmol) was added. After 20 min of stirring, the mixture was loaded directly onto a silica gel loading column. The column was eluted onto a pre-equilibrated 12-g Redi-Sep Gold column with 0-10% MeOH/DCM to give an orange solid. This solid was resubjected to chromatography on silica gel (12-g Redi-Sep Gold column, 4.5% MeOH/DCM) to give 1-(3′,5′-difluoro-3-methoxy-[1,1′-biphenyl]-4-yl)-N-(6-methylpyrimidin-4-yl)isoquinoline-6-sulfonamide (26.22 mg, 0.051 mmol, 47.3% yield) as a light-pink solid. 1H NMR (400 MHz, DMSO-d6) δ=13.48-12.42 (m, 1H), 8.75-8.62 (m, 2H), 8.47 (s, 1H), 8.11 (d, J=5.6 Hz, 1H), 7.95 (d, J=9.1 Hz, 1H), 7.75 (d, J=8.7 Hz, 1H), 7.63 (d, J=6.9 Hz, 2H), 7.57-7.48 (m, 2H), 7.46-7.40 (m, 1H), 7.34-7.23 (m, 1H), 7.06-6.86 (m, J=17.2 Hz, 1H), 3.77 (s, 3H), 2.31 (s, 3H). m/z (ESI) 519.0 (M+H)+.
Reaction SMILES: NC1C=CC(C)=CC=1.N([O-])=O.[Na+].[F:13][C:14]1[CH:28]=[CH:27][C:17]([CH2:18][CH:19](C(=O)C)[C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:15]=1.[OH-:29].[K+]>Cl.O.C(O)C>[O:29]=[C:19]([CH2:18][C:17]1[CH:27]=[CH:28][C:14]([F:13])=[CH:15][CH:16]=1)[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)C(Cc1ccc(F)cc1)C(C)=O
Reactant: [OH-]
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccc(N)cc1
Solvent: O
Product: COC(=O)C(=O)Cc1ccc(F)cc1
Temperature: 0 °C
Yield: 150.9 %

Procedure:
To a solution of p-toluidine (119.4 g) in conc. aqueous HCl (575 ml) was added a solution of NaNO2 (84.6 g) in water (500 ml) at 0°-5° C. during 1.5 h. The reaction mixture was added in one portion to a mixture of methyl 2-(4-fluorobenzyl)-3-oxobutanoate (250 g), KOH (220 g), water (0.5 l), ethanol (1.25 l) and ice (2 kg) under stirring. After reaction for 2 h at room temperature the reaction mixture was extracted with diethyl ether (2×2 l). The combined organic phases were washed with water (3 l) and dried (Na2SO4). Evaporation of the solvents afforded the crude 4-tolylhydrazone of methyl 2-oxo-3-(4-fluorophenyl)-propanoate (330 g), which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14]([OH:16])=O)[C:5]2[CH:6]=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[NH2:17][CH2:18][C:19]1[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=1[CH3:25].ON1C2N=CC=CC=2N=N1.C(Cl)CCl.CN1CCOCC1>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([C:14]([NH:17][CH2:18][C:19]2[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=2[CH3:25])=[O:16])[C:5]2[CH:6]=[CH:7][N:8]([CH:11]([CH3:12])[CH3:13])[C:9]=2[CH:10]=1
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: CC(C)n1ccc2c(C(=O)O)cc(Br)cc21
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CS(C)=O
Solvent: CN1CCOCC1
Product: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2ccn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74.2 %

Procedure:
To a mixture of 6-bromo-1-(1-methylethyl)-1H-indole-4-carboxylic acid (0.71 g, 2.52 mmol), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (0.575 g, 3.77 mmol), 1-hydroxy-7-azabenzotriazole (0.514 g, 3.77 mmol), and EDC (0.724 g, 3.77 mmol) in dimethylsulfoxide (20 mL) was added quickly N-methylmorpholine (1.107 mL, 10.07 mmol) via syringe. The solids slowly dissolved and the reaction was maintained at RT overnight. The reaction was slowly poured into ice-water (300 mL), stirred for 10 min, then allowed to sit for 10 min. The solids were filtered and washed with water (100 mL), airdried for 15 min, then dried in vacuum oven at 45° C. for 4 h to give 6-bromo-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-indole-4-carboxamide (0.82 g, 1.871 mmol, 74.4% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.39-1.46 (m, 6H) 2.09-2.15 (m, 3H) 2.21 (s, 3H) 4.32 (d, J=5.05 Hz, 2H) 4.82 (quin, J=6.63 Hz, 1H) 5.88 (s, 1H) 6.86 (d, J=3.28 Hz, 1H) 7.51 (d, J=1.77 Hz, 1H) 7.62 (d, J=3.28 Hz, 1H) 7.92 (s, 1H) 8.31 (t, J=4.93 Hz, 1H) 11.55 (br. s., 1H). MS(ES) [M+H]+ 416.0.
Reaction SMILES: [O:1]1[CH2:4][CH:3]([N:5]2[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:2]1.CCN(C(C)C)C(C)C.[NH2:20][C:21]1[C:30]([C:31]([NH:33][C:34]2[CH:35]=[N:36][CH:37]=[C:38]([F:49])[C:39]=2[N:40]2[CH2:45][CH2:44][CH:43]([C:46](O)=[O:47])[CH2:42][CH2:41]2)=[O:32])=[C:24]2[N:25]=[CH:26][C:27]([F:29])=[CH:28][N:23]2[N:22]=1.F[B-](F)(F)F.ClC1C=CC2N=NN(OC(=[N+](C)C)N(C)C)C=2C=1>C1COCC1.O>[NH2:20][C:21]1[C:30]([C:31]([NH:33][C:34]2[CH:35]=[N:36][CH:37]=[C:38]([F:49])[C:39]=2[N:40]2[CH2:45][CH2:44][CH:43]([C:46]([N:8]3[CH2:9][CH2:10][N:5]([CH:3]4[CH2:4][O:1][CH2:2]4)[CH2:6][CH2:7]3)=[O:47])[CH2:42][CH2:41]2)=[O:32])=[C:24]2[N:25]=[CH:26][C:27]([F:29])=[CH:28][N:23]2[N:22]=1
Reactant: Nc1nn2cc(F)cnc2c1C(=O)Nc1cncc(F)c1N1CCC(C(=O)O)CC1
Reactant: C1CN(C2COC2)CCN1
Agent: CN(C)C(On1nnc2ccc(Cl)cc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nn2cc(F)cnc2c1C(=O)Nc1cncc(F)c1N1CCC(C(=O)N2CCN(C3COC3)CC2)CC1
Yield: 86.2 %

Procedure:
To a solution of 1-(oxetan-3-yl)piperazine (525 mg, 3.69 mmol) in THF (12 ml) was added DIPEA (1.72 ml, 9.91 mmol), followed by 1-(3-(2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamido)-5-fluoropyridin-4-yl)piperidine-4-carboxylic acid (hydrochloride salt, 1.5 g, 3.3 mmol). [(6-chlorobenzotriazol-1-yl)oxy-(dimethylamino)methylene]-dimethyl-ammonium tetrafluoroborate (TCTU, 1.29 g, 3.64 mmol) was added and the mixture stirred under nitrogen until reaction completion (determined by HPLC analysis). The mixture was cooled and water (24 ml) was added dropwise. The mixture was allowed to warm to ambient and stirred for 3 hrs, then filtered. The filter cake was washed with (3×3 ml). The damp cake was dried under vacuum (with a nitrogen bleed) at 40° C. The product was obtained as a yellow solid (1.54 g, 86%); 1H NMR (500 MHz, DMSO-d6) δ 10.64 (s, 1H), 9.67 (s, 1H), 9.48 (dd, 1H), 9.26 (dd, 1H), 8.26 (d, 1H), 6.79 (s, 2H), 4.55 (t, 2H), 4.47 (t, 2H), 4.34 (t, 0.7H), 3.61 (dt, 4H), 3.48-3.41 (m, 2.5H), 3.22-3.17 (m, 2H), 3.05-3.03 (m, 2H), 3.99-2.93 (m, 1H), 2.28 (dt, 4H), 2.17-2.10 (m, 2H), 1.74 (d, 2H), 1.07 (t, 2H); 19F NMR (500 MHz, DMSO-d6) δ −152.8, −136.1; MS (ES+) 542.3.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([NH:15][CH2:16][CH2:17][CH2:18][C:19]([O:21]C)=O)=[O:14])=[CH:10][CH:11]=2)[C:6]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[N:5]1)(=O)C.[NH3:30]>CO>[C:19]([CH2:18][CH2:17][CH2:16][NH:15][C:13]([C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[NH:4][N:5]=[C:6]2[C:23]1[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=1)=[O:14])(=[O:21])[NH2:30]
Reactant: COC(=O)CCCNC(=O)c1ccc2c(c1)c(-c1ccc(F)cc1)nn2C(C)=O
Reactant: N
Solvent: CO
Product: NC(=O)CCCNC(=O)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Temperature: 80 °C
Yield: 43 %

Procedure:
A sealed glass bomb containing methyl 4-{[1-acetyl-3-(4-fluorophenyl)-1H-indazole-5-yl]carbonylamino}butanoate (95 mg, 0.239 mmol) in methanol with saturated ammonia (7 mL) was heated to 80° C. for 18 hours. The reaction mixture was condensed and the resulting solid was purified by HPLC to afford the title compound (35 mg, 43% yield). 1H NMR (DMSO-d6) δ 13.43 (br s, 1H), 8.50 (s, 1H), 8.04 (m, 2H), 7.87 (d, 1H), 7.58 (d, 1H), 7.37 (t, 1H), 7.29 (s, 1H), 6.75 (br s, 1H), 3.75 (m, 2H), 2.09 (t, 2H), 1.73 (t, 2H); ES-MS (m/z) 341[M+1]+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([O:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:25][CH:24]=3)=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH:17]=[C:16]([OH:21])[CH:15]=[CH:14]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[F:38][C:39]1[CH:47]=[CH:46][C:42]([C:43](Cl)=[O:44])=[CH:41][CH:40]=1.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:12]([O:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:25][CH:24]=3)=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH:17]=[C:16]([O:21][C:43](=[O:44])[C:42]2[CH:46]=[CH:47][C:39]([F:38])=[CH:40][CH:41]=2)[CH:15]=[CH:14]3)=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CS(=O)(=O)c1ccc(-c2ccc3cc(O)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-c2ccc3cc(OC(=O)c4ccc(F)cc4)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)cc1
Reaction time: 0.17 h
Yield: 73.7 %

Procedure:
Dissolve the compound of Example 3 (111 mg, 0.21 mmol) in dichloromethane (2 mL). Add 4-fluorobenzoyl chloride (30 μL, 0.25 mmol) dropwise. After stirring for 10 minutes, pour the reaction mixture into saturated aqueous sodium bicarbonate (10 mL) and extract with dichloromethane (10 mL). Dry the organic layer with sodium sulfate, filter and concentrate in vacuo. Chromatograph the residue on a SiO2 column eluting with methanol in dichloromethane (0 to 3%) to give 99 mg of the title compound (73%): mass spectrum (ion spray): m/z=640.3 (M+H).
Reaction SMILES: [CH2:1]([NH:5][CH:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[NH:9][C:8]([CH3:15])([CH3:14])[CH2:7]1)[CH2:2][CH2:3][CH3:4].[C:16]1(O)[C:20](=[O:21])[C:18](=O)[C:17]=1[OH:22]>C(C(CCCC)CO)C>[CH2:1]([N:5]([C+:16]1[C:17]([O-:22])=[C:18]([N:5]([CH:6]2[CH2:7][C:8]([CH3:15])([CH3:14])[NH:9][C:10]([CH3:12])([CH3:13])[CH2:11]2)[CH2:1][CH2:2][CH2:3][CH3:4])[C+:20]1[O-:21])[CH:6]1[CH2:7][C:8]([CH3:14])([CH3:15])[NH:9][C:10]([CH3:13])([CH3:12])[CH2:11]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC1CC(C)(C)NC(C)(C)C1
Reactant: O=c1c(O)c(O)c1=O
Solvent: CCCCC(CC)CO
Product: CCCCN(c1c([O-])[c+](N(CCCC)C2CC(C)(C)NC(C)(C)C2)[c+]1[O-])C1CC(C)(C)NC(C)(C)C1
Yield: 88.2 %

Procedure:
Under agitation, 392.9 g (1.85 moles) of 4-n-butylamino-2,2,6,6-tetramethylpiperidine, 10.0 g (0.0877 mole) of quadratic acid, and 150 cc of 2-ethylhexanol were heated to boiling under reflux in a 1-liter agitated flask with water trap; s temperature rose from 205° to 217° C., and 2.8 cc of water was removed from the cycle. The reaction solution was then distilled. The residue was boiled with petroleum ether. After cooling, vacuum-filtering, and drying, 38.9 g was obtained (88.2% yield), mp 151°-152° C. Extinction (g/l.cm) at 278 nm: 25; at 335 nm: 83.