Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[O:15])[C:12]([OH:14])=[O:13].C(=O)([O-])[O-].[K+].[K+].S(OCC)(O[CH2:31][CH3:32])(=O)=O>CC(C)=O>[Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[O:15])[C:12]([O:14][CH2:31][CH3:32])=[O:13]
Reactant: CCOS(=O)(=O)OCC
Reactant: O=C(O)C(=O)c1ccccc1Nc1c(Cl)cccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(=O)c1ccccc1Nc1c(Cl)cccc1Cl
Yield: 96 %

Procedure:
To a solution of 12.4 g of 2-(2,6-dichloroanilino)-phenylglyoxylic acid in 80 ml of anhydrous acetone were added 6.05 g of anhydrous potassium carbonate and then 8 ml of diethyl sulfate, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered and washed with anhydrous acetone. The filtrate was concentrated under 100 mmHg without heating. The residue was subjected to column chromatography with silica gel (Wacogel C 200), using ether-hexane (1:2) as a developing solvent, to give ethyl 2-(2,6-dichloroanilino)phenylglyoxylate. m.p. 84.0°-85.5° C.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[CH3:39][C:40]1[CH:45]=[CH:44][C:43]([NH:46][S:47]([CH3:50])(=[O:49])=[O:48])=[CH:42][C:41]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+]>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>[CH3:39][C:40]1[CH:41]=[CH:42][C:43]([NH:46][S:47]([CH3:50])(=[O:49])=[O:48])=[CH:44][C:45]=1[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: Cc1ccc(NS(C)(=O)=O)cc1B1OC(C)(C)C(C)(C)O1
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+]
Product: Cc1ccc(NS(C)(=O)=O)cc1-c1cn(COCC[Si](C)(C)C)c2ncnc(N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)c12
Temperature: 100 °C
Reaction time: 8 h
Yield: 35.8 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (120 mg, 0.2 mmol) was treated with N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide (100 mg, 0.32 mmol), tetrakis(triphenylphosphine)palladium(0) (30 mg, 0.03 mmol), aqueous solution 2M of sodium carbonate (200 μl, 0.4 mmol) and 5 ml N,N-dimethylformide as a solvent according to the method described in Preparation 186 but stirring at 100° C. overnight. The crude was purified using SP1® Purification System (hexane-ethyl acetate) to obtain 50 mg (35% yield) of the title compound as a yellow oil. Purity 98%.
Reaction SMILES: FC(F)(F)C([NH:5][CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH:15][C:16]3[N:21]=[C:20]([C:22]4[C:23]([C:31]5[CH:36]=[CH:35][CH:34]=[C:33]([NH:37][C:38](=[O:45])[CH2:39][C:40]6[S:41][CH:42]=[CH:43][CH:44]=6)[CH:32]=5)=[N:24][N:25]5[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=45)[CH:19]=[CH:18][N:17]=3)[CH:12]=2)[CH2:7]1)=O.[Li+].[OH-]>CO>[NH2:5][CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH:15][C:16]3[N:21]=[C:20]([C:22]4[C:23]([C:31]5[CH:32]=[C:33]([NH:37][C:38](=[O:45])[CH2:39][C:40]6[S:41][CH:42]=[CH:43][CH:44]=6)[CH:34]=[CH:35][CH:36]=5)=[N:24][N:25]5[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=45)[CH:19]=[CH:18][N:17]=3)[CH:12]=2)[CH2:7]1
Reactant: O=C(Cc1cccs1)Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CC(NC(=O)C(F)(F)F)C4)n2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: NC1Cc2ccc(Nc3nccc(-c4c(-c5cccc(NC(=O)Cc6cccs6)c5)nn5ccccc45)n3)cc2C1
Yield: 79.7 %

Procedure:
2,2,2-Trifluoro-N-(5-{[4-(2-{3-[(2-thienylacetyl)amino]phenyl}pyrazolo[1,5-a]pyridin-3-yl)-2-pyrimidinyl]amino}-2,3-dihydro-1H-inden-2-yl)acetamide (61 mg, 0.09 mmol) was stirred with LiOH (20 mg, 0.47 mmol) in MeOH (5 mL) at rt. After 24 h. additional LiOH (20 mg, 0.47 mmol) was added and the reaction stirred until complete conversion was indicated by LC/MS analysis. The MeOH was removed under vacuum and the residue partitioned between EtOAc and water. The organic was washed with brine and dried with MgSO4. The solvent was removed and the crude product was purified by silica gel flash column chromatography (DCM: 0-100% 90:9:1 DCM:MeOH:NH4OH(aq)) and yielded 40 mg (77%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 9.37 (s, 1H), 8.79 (d, J=7.0 Hz, 1H), 8.45 (d, J=8.6 Hz, 1H), 8.19 (d, J=5.3 Hz, 1H), 7.86 (s, 1H), 7.72 (d, J=8.1 Hz, 1H), 7.62 (s, 1H), 7.46-7.32 (m, 4H), 7.24 (d, J=7.6 Hz, 1H), 7.09 (t, J=6.9 Hz, 1H), 7.01 (d, J=8.0 Hz, 1H), 6.95 (m, 1H), 6.42 (d, J=5.3 Hz, 1H), 3.85 (s, 2H), 3.65 (m, 1H), 2.94 (dd, J=15.5, 6.8 Hz, 2H), 2.47 (m, 2H), 1.83 (s, 2H). ES-LC/MS m/z=558 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH3:16])O[C:10]=1[C:17]([OH:19])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:20]1([NH2:23])[CH2:22][CH2:21]1>CO>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH3:16])[N:23]([CH:20]2[CH2:22][CH2:21]2)[C:10]=1[C:17]([OH:19])=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(=O)c(OCc2ccccc2)c(C(=O)O)o1
Reactant: NC1CC1
Solvent: CO
Product: Cc1cc(=O)c(OCc2ccccc2)c(C(=O)O)n1C1CC1

Procedure:
To a suspension of 3-(benzyloxy)-6-methyl-4-oxo-4H-pyran-2-carboxylic acid (70 g, 0.27 mol) in MeOH (350 mL) in a 3-necked RBF (round bottom flask) fitted with a mechanical stirrer was added cyclopropylamine (120 mL, 1.72 mol). A clear light yellow solution resulted. The reaction mixture was refluxed for ca. 19 h. Volatiles were removed in vacuo and the residue was dissolved in water (700 mL) with stirring. The aqueous mixture was filtered through a pad of Celite®. The filtrate was placed in a 3-necked RBF fitted with a mechanical stirrer, and cooled in an ice bath. Conc. HCl was added until the pH was ca. 1-2, and voluminous “orange” solid precipitated out. Acetone (200 mL) was added to the suspension. The solid was then collected by suction filtration, thoroughly washed with acetone, and air-dried. The title compound was obtained as an off-white solid (71.0 g, 88%).
Reaction SMILES: Br[C:2]1[C:3]2[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=2[S:5][C:6]=1[N+:7]([O-:9])=[O:8].[Cu](C#N)[C:15]#[N:16].O>CN(C=O)C>[N+:7]([C:6]1[S:5][C:4]2[CH:10]=[CH:11][CH:12]=[CH:13][C:3]=2[C:2]=1[C:15]#[N:16])([O-:9])=[O:8]
Reactant: N#C[Cu]C#N
Reactant: O=[N+]([O-])c1sc2ccccc2c1Br
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1c([N+](=O)[O-])sc2ccccc12
Temperature: 25 °C
Yield: 90.3 %

Procedure:
Combine 3-bromo-2-nitro-benzo[b]thiophene (33.0 g, 127.4 mmol), copper cyanide (17.1 g, 191.1 mmol) in DMF (150 mL), heat to 120° C. for three hours. The reaction cool to RT, pour on ice, then filter. The filter cake wash with dichloromethane. The organic layer separate and dry over MgSO4, evaporation to give a DMF solution. Add water (400 mL) and the yellow solid precipitate out. After filtration, obtain a brownish solid (23.5 g, 90%). Mass spectrum (m/e): 205 (M+1); 1HNMR (300 MHz, DMSO-d6) δ: 7.78(m, 2H), 8.04(d, 1H), 8.29(d, 1H). 3CNMR(75 MHz, DMSO-d6) δ ppm: 105.9, 112.1, 125.0, 125.2, 128.8, 131.2, 135.9, 137.8, 158.0.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C([Li])CCC.C([O:28][B:29](OC(C)C)[O:30]C(C)C)(C)C.Cl>O1CCCC1>[CH2:1]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([B:29]([OH:30])[OH:28])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCCCCOc1ccc(-c2ccc(Br)cc2)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCOc1ccc(-c2ccc(B(O)O)cc2)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 84.3 %

Procedure:
To a stirred suspension of 4-(4-n-pentoxyphenyl)bromobenzene (1.0 g, 3.13 mmol) in anhydrous tetrahydrofuran (20 ml) at -78° C. under a nitrogen atmosphere was added n-butyllithium in hexanes (2.5M, 1.32 ml, 3.30 mmol). After a period of 15 min, triisopropylborate (760 μl, 3.30 mmol) was added. Stirring at -78° C. was continued for 15 min and then at 25° C. for 40 min. The mixture was acidified with 0.5N HCl (20 mL) and then partitioned between ether (50 ml) and water (40 ml). The organic phase was washed with water (3×) and brine and dried with magnesium sulfate. The solvent was removed in vacuo to give 4-(4-n-pentoxyphenyl)phenylboronic acid (750 mg) as a white solid: 1H NMR (400 MHZ, DMSO-d6) δ 0.89 (t, 3, J=7.2 Hz), 1.38 (m, 4 ), 1.72 (m, 2), 3.99 (t, 2, J=6.5 Hz), 6.99 (d, 2, J=8.8 Hz), 7.57 (d, 2, J=8.2 Hz), 7.60 (d, 2, J=8.8 Hz), 7.83 (d, 2, J=8.2 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([NH:14][NH2:15])=[N:10][CH:9]=2)=[CH:4][CH:3]=1.[S:16]1[C:20]2[CH:21]=[C:22]([C:25]3([C:28](O)=O)[CH2:27][CH2:26]3)[CH:23]=[CH:24][C:19]=2[N:18]=[CH:17]1>P(Cl)(Cl)(Cl)=O>[S:16]1[C:20]2[CH:21]=[C:22]([C:25]3([C:28]4[N:12]5[N:13]=[C:8]([C:5]6[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=6)[CH:9]=[N:10][C:11]5=[N:14][N:15]=4)[CH2:27][CH2:26]3)[CH:23]=[CH:24][C:19]=2[N:18]=[CH:17]1
Reactant: O=C(O)C1(c2ccc3ncsc3c2)CC1
Reactant: NNc1ncc(-c2ccc(Br)cc2)nn1
Solvent: O=P(Cl)(Cl)Cl
Product: Brc1ccc(-c2cnc3nnc(C4(c5ccc6ncsc6c5)CC4)n3n2)cc1
Temperature: 130 °C

Procedure:
A mixture of 6-(4-bromophenyl)-3-hydrazino-1,2,4-triazine (20.0 mg, 0.0752 mmol) and 1-(1,3-benzothiazol-6-yl)cyclopropanecarboxylic acid (16.5 mg, 0.0752 mmol) in phosphoryl chloride (1 mL) was heated at 130° C. for 8 h. The volatiles were removed under reduced pressure. The residue was dissolved in methanol, and purified by RP-HPLC (pH=10) to give the desired product. LCMC: (M+H)+=448.9/451.0.
Reaction SMILES: [CH:1]([N:4]([CH:19]([CH3:21])[CH3:20])[CH2:5][CH2:6][N:7]1[C:17]2[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=2)[C:10](=O)[C:8]1=[O:9])([CH3:3])[CH3:2].Cl.[CH2:23]([NH:30][C:31](=[O:34])[NH:32][NH2:33])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([NH:30][C:31](=[O:34])[NH:32]/[N:33]=[C:10]1/[C:8](=[O:9])[N:7]([CH2:6][CH2:5][N:4]([CH:19]([CH3:21])[CH3:20])[CH:1]([CH3:3])[CH3:2])[C:17]2[C:12]/1=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=2)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2CCN(C(C)C)C(C)C
Reactant: NNC(=O)NCc1ccccc1
Agent: Cl
Product: Cc1ccc2c(c1)/C(=N\NC(=O)NCc1ccccc1)C(=O)N2CCN(C(C)C)C(C)C
Yield: 74.6 %

Procedure:
By using 1-(2-diisopropylaminoethyl)-5-methylisatin and 4-benzylsemicarbazide hydrochloride, a method analogous to that described in Example 6 was carried out to obtain (E)-1-(2-diisopropylaminoethyl)5-methylisatin 3-(4-benzylsemicarbazone) having a melting point of 159°-160° C. (yield: 74.6%, recrystallizing solvent: ethanol).
Reaction SMILES: [Br:1][C:2]1[CH:16]=[C:15]([CH:17]=O)[CH:14]=[CH:13][C:3]=1[O:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].C([BH3-])#[N:20].[Na+].O>CO.CC(O)=O>[NH2:20][CH2:17][C:15]1[CH:14]=[CH:13][C:3]([O:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:2]([Br:1])[CH:16]=1
Reactant: [BH3-]C#N
Reactant: CC(C)(C)OC(=O)COc1ccc(C=O)cc1Br
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)COc1ccc(CN)cc1Br
Temperature: 25 °C
Reaction time: 4 h
Yield: 18.1 %

Procedure:
t-Butyl 2-(2-bromo-4-formylphenoxy)acetate (1) (0.5 g, 1.59 mmol, 1 eq) was dissolved in MeOH (23 mL) along with HOAc (14 mL) and NH4OAc (6.23 g, 81 mmol; 51 eq). After stirring at room temperature room temperature for 4 h, sodium cyanoborohydride (146 mg; 2.27 mmol, 1.4 eq) was added and the mixture was stirred for an additional 18 h at room temperature. Water (4 mL) was added and the mixture was concentrated in vacuo. The resultant residue was purified by preparative HPLC to afford 91 mg (18.2%) of t-butyl 2-(4-(aminomethyl)-2-bromophenoxy)acetate (6).
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH3:14])/[CH:3]=[CH:4]/[C:5]1[O:9][N:8]=[C:7]([C:10]([OH:12])=O)[C:6]=1[CH3:13].[NH2:16][C:17]1[C:18](=[O:30])[N:19]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[N:20]([CH3:23])[C:21]=1[CH3:22].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[CH:24]1([N:19]2[C:18](=[O:30])[C:17]([NH:16][C:10]([C:7]3[C:6]([CH3:13])=[C:5](/[CH:4]=[CH:3]/[C:2]([CH3:1])([CH3:15])[CH3:14])[O:9][N:8]=3)=[O:12])=[C:21]([CH3:22])[N:20]2[CH3:23])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: Cc1c(C(=O)O)noc1/C=C/C(C)(C)C
Reactant: Cc1c(N)c(=O)n(C2CCCCC2)n1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(C(=O)Nc2c(C)n(C)n(C3CCCCC3)c2=O)noc1/C=C/C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(E)-5-(3,3-Dimethylbut-1-en-1-yl)-4-methylisoxazole-3-carboxylic acid (102 mg, 0.487 mmol) and 4-amino-2-cyclohexyl-1,5-dimethyl-1H-pyrazol-3(2H)-one (Intermediate D) (112 mg, 0.536 mmol) in DMF (2 mL) were treated with DIPEA (0.341 mL, 1.950 mmol) and HATU (222 mg, 0.585 mmol). The reaction mixture was stirred at room temperature for 2 hours. The resulting mixture was treated with water and extracted with EtOAc. The combined organic extracts were washed with 0.5 M LiCl (aq), dried over MgSO4, filtered and the solvent was removed under reduced pressure. The crude material was adsorbed onto silica and purification by chromatography eluting with 0-100% EtOAc in iso-hexane afforded the title compound;
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([C:14]([OH:16])=[O:15])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:17]([Li])[CH2:18][CH2:19]C.C(I)CC.C>C1COCC1.CCCCCC.C(O)C>[CH2:17]([C:12]1([C:14]([OH:16])=[O:15])[C:13]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:18][CH3:19]
Reactant: [Li]CCCC
Reactant: O=C(O)C1c2ccccc2-c2ccccc21
Agent: C
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC1(C(=O)O)c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 6 h
Yield: 73 %

Procedure:
A solution of 9-fluorenecarboxylic acid (12 g, 57 mmol) in 250 ml of THF was cooled to 0° C. under an argon atmosphere and 2 equiv. (71.25 ml) of a 1.6M n-butyl lithium solution in hexane was added followed by the addition of n-propyl iodide (7.5 ml, 13.1 g, 77 mmol). The reaction mixture was stirred at 0° C. for 6 hrs. An additional 1 ml of n-propyl iodide was added and the reaction stirred for 4 hrs at 0° C. The reaction was quenched by adding 75 ml of water and the pH was adjusted to pH 1 with 3N HCl. The reaction mixture was extracted with hexane (3×200ml) and the hexane extract washed with water, brine and dried over anhy. sodium sulfate. The solvents were evaporated yielding the crude product as a yellow oil which was dissolved in ~250 ml of ethanol and heated at reflux with Darco G-60, filtered through Celite and concentrated to approximately one half of the original volume. Water was slowly added until the mixture became cloudy. The mixture was reheated and slowly allowed to cool to room temperature yielding 10.5 grams (73%) of title compound as colorless crystals.
Reaction SMILES: O=C1NCCN1C1C=C(C=CN=1)C([O-])=O.[O:16]=[C:17]1[NH:21][N:20]=[CH:19][N:18]1[C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][N:31]=1)[C:25]([O:27][CH3:28])=[O:26].Br[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1>>[F:40][C:37]1[CH:38]=[CH:39][C:34]([CH2:33][N:21]2[C:17](=[O:16])[N:18]([C:22]3[CH:23]=[C:24]([CH:29]=[CH:30][N:31]=3)[C:25]([O:27][CH3:28])=[O:26])[CH:19]=[N:20]2)=[CH:35][CH:36]=1
Reactant: COC(=O)c1ccnc(-n2cn[nH]c2=O)c1
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])c1ccnc(N2CCNC2=O)c1
Product: COC(=O)c1ccnc(-n2cnn(Cc3ccc(F)cc3)c2=O)c1
Yield: 65 %

Procedure:
Following the procedure as described in Preparation 17, making variations as required to replace 2-(2-oxoimidazolidin-1-yl)isonicotinate with methyl 2-(5-oxo-1H-1,2,4-triazol-4(5H)-yl)isonicotinate to react with 1-(bromomethyl)-4-fluorobenzene, methyl 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)isonicotinate was obtained as a colorless solid in 65% yield: MS (ES+) m/z 328.9 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[CH:18]([NH2:21])([CH3:20])[CH3:19].[Cl-].[NH4+]>[Zn].O.CO.C(N(CC)CC)C.C1COCC1>[NH2:11][C:8]1[CH:9]=[CH:10][C:2]([F:1])=[C:3]([CH:7]=1)[C:4]([NH:21][CH:18]([CH3:20])[CH3:19])=[O:6]
Reactant: CC(C)N
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1F
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: O
Product: CC(C)NC(=O)c1cc(N)ccc1F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 2-fluoro-5-nitrobenzoic acid (600 mg) and thionyl chloride (2 mL) was heated under reflux for 15 hours. The reaction liquid was concentrated under reduced pressure, followed by an azeotropic process with toluene to give a yellow crystal. To a mixture of the yellow crystal and THF (11 mL), triethylamine (0.47 mL) and isopropylamine (0.29 mL) were added under ice cooling and stirred at room temperature for 5 hours. The reaction liquid was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give a yellow crystal. To a mixture of the yellow crystal (723 mg) and methanol (8 mL) and water (3 mL), ammonium chloride (2.05 g) and zinc powder (2.09 g) were added, and the mixture was heated under reflux for 3 hours. After filtration of the reaction suspension through celite, the filtrate was concentrated under reduced pressure. The residue was poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent; chloroform:methanol) to give 5-amino-2-fluoro-N-isopropylbenzamide (527 mg) as a light brown crystal.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[C:9]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=1>>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:15]([C:10]1[C:9]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:17])=[O:16]
Reactant: O=S(=O)(Cl)c1ccccc1-c1ccccc1
Reactant: Cc1noc(N)c1Br
Product: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccccc2)c1Br
Yield: 71 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-2-biphenylsulfonamide was prepared in the same manner as described in Example 8b from 5-amino-4-bromo-3-methylisoxazole and 2-biphenylsulfonyl chloride in 71% yield. Purification was achieved by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 145-147° C.
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([N:11]2[CH2:22][CH2:21][N:20]3[C:13](=[CH:14][C:15]4[CH2:16][C:17]([CH3:24])([CH3:23])[CH2:18][C:19]=43)[C:12]2=[O:25])[C:3]=1[CH:4]=[O:5].[CH3:26][N:27]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[C:29]([NH:42][C:43]2[CH:48]=[CH:47][C:46]([N:49]3[CH2:54][CH2:53][N:52]([CH:55]4[CH2:58][O:57][CH2:56]4)[CH2:51][C@@H:50]3[CH3:59])=[CH:45][N:44]=2)[C:28]1=[O:60].C([O-])(=O)C.[K+].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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].C(#N)C>[CH3:23][C:17]1([CH3:24])[CH2:16][C:15]2[CH:14]=[C:13]3[N:20]([CH2:21][CH2:22][N:11]([C:6]4[CH:7]=[C:8]([F:10])[CH:9]=[C:2]([C:31]5[CH:30]=[C:29]([NH:42][C:43]6[CH:48]=[CH:47][C:46]([N:49]7[CH2:54][CH2:53][N:52]([CH:55]8[CH2:56][O:57][CH2:58]8)[CH2:51][C@@H:50]7[CH3:59])=[CH:45][N:44]=6)[C:28](=[O:60])[N:27]([CH3:26])[CH:32]=5)[C:3]=4[CH:4]=[O:5])[C:12]3=[O:25])[C:19]=2[CH2:18]1
Reactant: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(B3OC(C)(C)C(C)(C)O3)cn(C)c2=O)nc1
Reactant: CC1(C)Cc2cc3n(c2C1)CCN(c1cc(F)cc(Br)c1C=O)C3=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3cc(F)cc(N4CCn5c(cc6c5CC(C)(C)C6)C4=O)c3C=O)cn(C)c2=O)nc1
Temperature: 100 °C
Yield: 74.9 %

Procedure:
A 50-mL round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 128a (303 mg, 0.75 mmol), 1-methyl-3-({5-[(2S)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-yl}amino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxa-borolan-2-yl)-1,2-dihydropyridin-2-one 113f (385 mg, 0.80 mmol), Pd(dppf)Cl2 (68.6 mg, 0.075 mmol), potassium acetate (147 mg, 1.50 mmol), K3PO4 (327 mg, 1.50 mmol), acetonitrile (15 mL), and water (6 drops). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 2 h. After this time the reaction was cooled to room temperature. It was then filtered and the filtrate was evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 15:1 ethyl acetate/methanol to afford 128b (382 mg, 77%) as a black solid. MS-ESI: [M+H]+ 680.3
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12]([C:14]3[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][N:15]=3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][C@@H:24]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:23]1>CCCCO>[Br:1][C:2]1[C:3]([N:22]2[CH2:27][CH2:26][CH2:25][C@@H:24]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[CH2:23]2)=[C:4]2[C:10]([NH:11][C:12]([C:14]3[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][N:15]=3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: Cc1cnc(C(=O)Nc2c[nH]c3ncc(Br)c(F)c23)cn1
Solvent: CCCCO
Product: Cc1cnc(C(=O)Nc2c[nH]c3ncc(Br)c(N4CCC[C@@H](NC(=O)OC(C)(C)C)C4)c23)cn1

Procedure:
A mixture of N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-methylpyrazine-2-carboxamide (280 mg, 0.800 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (480 mg, 2.40 mmol) in n-BuOH (3 mL) was processed as described in Example 62, Step B, to provide crude (R)-tert-butyl 1-(5-bromo-3-(5-methylpyrazine-2-carboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate without HPLC purification.
Reaction SMILES: [C:1]([C:3]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=1)=[CH:4][C:5]([O-:7])=[O:6])#N.[K+].S(=O)(=O)(O)[OH:17]>C(O)=O>[CH3:14][C:10]1[CH:9]=[C:8]([C:3]2[C:1](=[O:17])[O:6][C:5](=[O:7])[CH:4]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1cccc(C(C#N)=CC(=O)[O-])c1
Agent: [K+]
Solvent: O=CO
Product: Cc1cccc(C2=CC(=O)OC2=O)c1
Temperature: 25 °C

Procedure:
A suspension of potassium 3-cyano-3-(3-methylphenyl)-acrylate (0.69 g, 3 mmol), in 88% formic acid (14 ml) containing concentrated sulphuric acid (2 ml) was stirred at reflux and monitored by LC-MS until the starting material was consumed. The reaction mixture was cooled to room temperature and poured into ice/water. The resulting precipitate was recovered by filtration, washed with water (15 ml), heptane (15 ml) and air dried.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:10][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=O)(C)(C)C.[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24]>C(Cl)Cl>[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24].[O:14]1[CH2:15][CH2:16][N:11]([CH2:10][C@@H:9]([NH2:8])[CH2:17][CH:18]([CH3:19])[CH3:20])[CH2:12][CH2:13]1
Reactant: CC(C)C[C@@H](CN1CCOCC1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C[C@H](N)CN1CCOCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Crude N-tert-butoxycarbonyl-1-morpholino-2- (S) -amino-4-methylpentane (6.3 mmol) was dissolved in DCM (50 ml) and treated with excess trifluoroacetic acid (0.48 ml) at 0° C. The mixture was allowed to warm up to room temperature and was stirred for 3 h. The mixture was concentrated to dryness to give 1-morpholino-2-(S)-amino-4-methylpentane trifluoroacetate salt which was used immediately.