Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([NH:16]C=O)/[CH:6]=[C:7](\[CH3:15])/[CH2:8][P:9]([O:13]C)([O:11]C)=[O:10])[CH3:2].C[Si](C)(C)Br.C(O)C>ClCCl>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([NH2:16])/[CH:6]=[C:7](\[CH3:15])/[CH2:8][P:9]([OH:11])([OH:13])=[O:10])[CH3:2]
Reactant: CCOC(=O)C(/C=C(\C)CP(=O)(OC)OC)NC=O
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)C(N)/C=C(\C)CP(=O)(O)O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
16.9 g of E-2-formylamino-4-methyl-5-dimethylphosphono-3-pentenoic acid ethyl ester are dissolved in 80 ml of dichloromethane under a nitrogen atmosphere, and 30 ml of trimethylbromosilane are added dropwise at approximately 25° within a period of 30 minutes. The mixture is stirred at room temperature for 20 hours, and then 80 ml of ethanol are added dropwise at approximately 25° within a period of 30 minutes. The mixture is then again stirred at room temperature for 22 hours and is then concentrated by evaporation. The residue is dissolved in 80 ml of ethanol, and 80 ml of propylene oxide in 80 ml of ethanol are added dropwise with slight cooling. The mixture is stirred at room temperature for one hour to complete the reaction, filtered and washed with ethanol and ether. In this manner there is obtained E-2-amino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester, m.p. 215°-217° (decomp.).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].Br[CH2:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=1[C:32]1[CH:33]=[C:34]([C:40]2[CH:45]=[CH:44][C:43]([C:46]([O:48]C)=[O:47])=[CH:42][C:41]=2[CH3:50])[CH:35]=[CH:36][C:37]=1[O:38][CH3:39]>CN(C=O)C>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[CH2:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=1[C:32]1[CH:33]=[C:34]([C:40]2[CH:45]=[CH:44][C:43]([C:46]([OH:48])=[O:47])=[CH:42][C:41]=2[CH3:50])[CH:35]=[CH:36][C:37]=1[O:38][CH3:39])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(C(F)(F)F)cc3CBr)c2)c(C)c1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccc(C(=O)O)cc2C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of (4S)-4-benzyl-1,3-oxazolidin-2-one (29.8 mg, 0.168 mmol) in DMF (1.5 mL) was added t-BuOK (17.5 mg, 0.152 mmol). After 10 minutes, a solution of methyl 2″-(bromomethyl)-4′-methoxy-2-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate (75 mg, 0.152 mmol) in DMF (1.5 mL) was added by cannula. The reaction was stirred for 30 minutes, and then quenched with saturated NH4Cl solution (10 mL), diluted with EtOAc (15 mL), washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated. The residue was dissolved with MeOH (2 mL) and 4M KOH solution (0.5 mL) was added. The reaction was stirred at room temperature for 2 hours, then stored in the freezer for 16 hours. The reaction was warmed to room temperature, and stirred for 2 hours. The reaction was quenched with 1 N HCl solution (5 mL), diluted with EtOAc (15 mL), washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by reverse-phase chromatography (C-18, 10 to 95% MeCN/water with 0.1% TFA), followed by lyophilization to afford 2″-{[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]methyl}-4′-methoxy-2-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylic acid LCMS=576.0 (M+1)+. 1H NMR (CDCl3, 500 MHz, rotamers present) δ 8.01-7.86 (m, 2H), 7.67-7.50 (m, 2H), 7.44-7.32 (m, 3H), 7.23-7.07 (m, 5H), 6.91-6.85 (m, 2H), 4.92-4.58 (m, 2H), 4.27 (d, J=15.6 Hz), 4.11 (d, J=15.6 Hz), 4.06-3.82 (m, 5H), 3.64-3.51 (m, 1H), 2.86-2.71 (m, 1H), 2.47-2.28 (m, 4H).
Reaction SMILES: I[C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8](I)=[CH:9][CH:10]=3)[C:5]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:34]1([NH:40][C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([CH3:47])[CH:42]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>[Cu]>[CH3:27][O:26][C:24]([CH2:23][CH2:22][C:5]1([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:4]2[CH:3]=[C:2]([N:40]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:41]3[CH:42]=[C:43]([CH3:47])[CH:44]=[CH:45][CH:46]=3)[CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][C:8]([N:40]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:41]1[CH:42]=[C:43]([CH3:47])[CH:44]=[CH:45][CH:46]=1)=[CH:9][CH:10]=2)=[O:25]
Reactant: Cc1cccc(Nc2ccccc2)c1
Reactant: COC(=O)CCC1(CCC(=O)OC)c2cc(I)ccc2-c2ccc(I)cc21
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)CCC1(CCC(=O)OC)c2cc(N(c3ccccc3)c3cccc(C)c3)ccc2-c2ccc(N(c3ccccc3)c3cccc(C)c3)cc21
Temperature: 150 °C

Procedure:
A mixture of 17.9 grams of 2,7-diiodo-9,9-bis[2-(methoxycarbonyl)ethyl]fluorene, 4.3 grams of copper bronze, 12.5 grams of potassium carbonate in 30 milliliters of SoltrolR 220 was mechanically stirred and heated to 150° C. under a nitrogen atmosphere. Fifteen (15.0) grams of molten N-phenyl-m-toluidine was then added dropwise at 150° C. After addition, the resulting mixture was heated at 210° C. under reflux for 24 hours. The hot reaction mixture was filtered, and the filter cake was washed several times with hot cyclohexane. Subsequently, the combined filtrate was evaporated under reduced pressure to yield a brown residue, which was purified by column chromatography on silica gel to afford 15.2 grams of pure 9,9-bis[2-(methoxycarbonyl)ethyl]-2,7bis(phenyl-m-tolylamino)fluorene, melting point, 159° to 160° C.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:5]2=[N:6][CH:7]=1.[CH3:26][C:27]1[CH:35]=[C:34]2[C:30]([CH:31]=[N:32][NH:33]2)=[CH:29][CH:28]=1.CC(C)([O-])C.[Na+]>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([N:33]3[C:34]4[C:30](=[CH:29][CH:28]=[C:27]([CH3:26])[CH:35]=4)[CH:31]=[N:32]3)[N:3]=2)[N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: Cc1ccc2cn[nH]c2c1
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1ccc2cnn(-c3cnc4c(n3)c(C(=O)NC(C)(C)C)cn4COCC[Si](C)(C)C)c2c1
Temperature: 125 °C

Procedure:
To a stirred solution of 2-bromo-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (140 mg, 328 μmol), 6-methyl-1H-indazole (41.7 mg, 316 μmol) in dioxane (2 mL) was added sodium tert-butoxide (66.8 mg, 695 μmol) and bis(tri-tert-butylphosphine)palladium(0) (16.1 mg, 31.6 μmol). The mixture was degassed then heated in sealed tube at 125° C. for 15 h. The mixture was cooled, filtered through celite, the cake washed with ethyl acetate, and the combined filtrates were concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-40% ethyl acetate in hexanes) gave N-tert-butyl-2-(6-methyl-1H-indazol-1-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide. 1H NMR (CDCl3) d: 9.08 (s, 1H), 8.35 (s, 1H), 8.30 (s, 1H), 8.23 (d, J=1.0 Hz, 1H), 8.03 (br. s., 1H), 7.85 (s, 1H), 7.29 (s, 1H), 5.72 (s, 2H), 3.55-3.61 (m, 2H), 2.50 (s, 3H), 1.59 (s, 9H), 0.77-1.01 (m, 2H), −0.03 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1([C:7]#[N:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.[CH:9](O)=[O:10]>O>[C:7]([C:2]1([NH:1][CH:9]=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3]1)#[N:8]
Reactant: O=CO
Reactant: N#CC1(N)CCCC1
Solvent: O
Product: N#CC1(NC=O)CCCC1
Reaction time: 3 h

Procedure:
11.0 g (0.1 mol) of 1-amino-1-cyanocyclopentane and 10 ml of 85% formic acid were placed in an apparatus equipped with water-separatory distillation head and boiled for 3 hours. The reaction mixture was then evaporated to constant weight in vacuo.
Reaction SMILES: [C:1]([C:3]([C@H:16]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2].[OH:22][C:23]1[CH:31]=[CH:30][C:26]([CH2:27][CH2:28]Cl)=[CH:25][C:24]=1[O:32][CH3:33].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[C:1]([C:3]([C@H:16]1[CH2:21][CH2:20][CH2:19][N:18]([CH2:28][CH2:27][C:26]2[CH:30]=[CH:31][C:23]([OH:22])=[C:24]([O:32][CH3:33])[CH:25]=2)[CH2:17]1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2]
Reactant: COc1cc(CCCl)ccc1O
Reactant: N#CC(c1ccccc1)(c1ccccc1)[C@H]1CCCNC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(CCN2CCC[C@H](C(C#N)(c3ccccc3)c3ccccc3)C2)ccc1O

Procedure:
A mixture containing 3-(R)-(1-cyano-1,1-diphenylmethyl)-piperidine (0.3 g), 4-hydroxy-3-methoxyphenethyl chloride (0.233 g--see Preparation 6), anhydrous potassium carbonate (0.5 g), potassium iodide (0.2 g) and acetonitrile (15 ml) was heated under reflux for 5 hours. The mixture was partitioned between dichloromethane (40 ml) and 10% aqueous potassium carbonate (30 ml), the layers separated, and the aqueous layer extracted with dichloromethane (2×30 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give a foam which was purified by column chromatography on silica eluting with dichloromethane containing methanol (5%). The product-containing fractions were combined and concentrated in vacuo to give a gum which was crystallised from acetonitrile to give the title compound as colourless rhombs, yield 0.132 g, m.p. 159-160°.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([O:18][CH2:19][CH2:20][NH:21][C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH:17]=1)[C:12]([OH:14])=O.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH:61]([NH:64][CH2:65][CH2:66][C:67]#[N:68])([CH3:63])[CH3:62]>CN(C=O)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:67]([CH2:66][CH2:65][N:64]([CH:61]([CH3:63])[CH3:62])[C:12](=[O:14])[C:11]1[CH:15]=[C:16]([O:18][CH2:19][CH2:20][NH:21][C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH:17]=[C:9]([CH3:8])[CH:10]=1)#[N:68]
Reactant: CC(C)NCCC#N
Reactant: Cc1cc(OCCNc2ccncc2)cc(C(=O)O)c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(OCCNc2ccncc2)cc(C(=O)N(CCC#N)C(C)C)c1
Reaction time: 24 h

Procedure:
A solution of 3-methyl-5-[2-(pyridin-4-ylamino)-ethoxy]-benzoic acid trifluoroacetate salt (0.026 g) in anhydrous DMF (2 ml) was treated at room temperature with 3-isopropylamino-propionitrile9 (0.017 g), PyBrop® (0.062 g) and DIPEA (0.025 ml). More PyBrop® was added after 2 days (0.072 g) and 7 days (0.065 g). More 3-isopropylamino-propionitrile was added after 2 days (0.03 ml), 4 days (0.1 ml) and 7 days (0.1 ml). After 24 h more, the mixture was evaporated to dryness under reduced pressure and the residue subjected to preparative hplc giving the title compound as a clear colourless gum (0.016 g).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:11]=[C:10]([C:12]2[C:13]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[N:14][N:15]3[C:20](Cl)=[CH:19][CH:18]=[CH:17][C:16]=23)[CH:9]=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4].[CH3:29][NH2:30]>>[CH2:1]([NH:5][C:6]1[N:11]=[C:10]([C:12]2[C:13]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[N:14][N:15]3[C:20]([NH:30][CH3:29])=[CH:19][CH:18]=[CH:17][C:16]=23)[CH:9]=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CN
Reactant: CCCCNc1nccc(-c2c(-c3ccc(F)cc3)nn3c(Cl)cccc23)n1
Product: CCCCNc1nccc(-c2c(-c3ccc(F)cc3)nn3c(NC)cccc23)n1
Yield: 77 %

Procedure:
In a similar manner as described in Example 14, from N-butyl-4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-2-pyrimidinamine (53 mg, 0.13 mmol) and methylamine (5 mL, 40% aqueous) in a sealed tube was obtained 3-[2-(butylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-N-methylpyrazolo[1,5-α]pyridin-7-amine (40.5 mg, 77%) as a pale yellow solid. 1H NMR (CDCl3): δ 8.01 (d, 1H), 7.75 (d, 1H), 7.62 (m, 2H), 7.34 (t, 1H), 7.13 (t, 2H), 6.30 (d, 1H), 6.03–5.99 (m, 2H), 5.11 (broad, 1H), 3.46 (q, 2H), 3.10 (d, 3H), 1.69–1.42 (m, 4H), 0.97 (t, 3H); 19F NMR (CDCl3) δ −113.39; MS m/z 391 (M+1).
Reaction SMILES: Cl[C:2]1[S:3][C:4]([CH2:7][N:8]2[CH2:12][CH:11]([C:13]3[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[C:14]=3[F:21])[CH2:10][C:9]2=[O:22])=[CH:5][N:6]=1.[CH3:23][NH:24][CH3:25].O[Li].O>C1COCC1.O>[CH3:23][N:24]([CH3:25])[C:2]1[S:3][C:4]([CH2:7][N:8]2[CH2:12][CH:11]([C:13]3[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[C:14]=3[F:21])[CH2:10][C:9]2=[O:22])=[CH:5][N:6]=1
Reactant: O=C1CC(c2cc(F)cc(F)c2F)CN1Cc1cnc(Cl)s1
Reactant: CNC
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CN(C)c1ncc(CN2CC(c3cc(F)cc(F)c3F)CC2=O)s1
Temperature: 25 °C
Reaction time: 12 h
Yield: 32.3 %

Procedure:
In a sealed tube fitted with a magnetic stirrer, 1-[(2-chloro-1,3-thiazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one 250 (0.3 g, 0.87 mmol) is dissolved in a mixture of THF (4 ml) and H2O (0.1 ml). Dimethylamine (0.85 ml, 1.7 mmol) and LiOH.H2O (0.043 g, 1 mmol) are added and the mixture is stirred at room temperature for 12 h and heated at 50° C. overnight. Dimethylamine (3×3.4 mmol, then 1×5.1 mmol) is added after 24 h, 48 h, 72 h and 96 h heating. THF is evaporated, the residue is dissolved in water and CH2Cl2, the pH of the aqueous phase is brought to 9 and the aqueous phase is extracted with CH2Cl2. The combined organic phases are dried over MgSO4, filtered and concentrated. The crude product is purified by chromatography on silicagel and recrystallized from diisopropylether to afford 0.1 g of 1-{[2-(dimethylamino)-1,3-thiazol-5-yl]methyl}-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one 251.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][CH2:7][O:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[NH:11][C:4]=2[CH:3]=1.[Cl:18][CH2:19][CH2:20][C:21](Cl)=[O:22]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][CH2:7][O:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]([C:21](=[O:22])[CH2:20][CH2:19][Cl:18])[C:4]=2[CH:3]=1
Reactant: O=C(Cl)CCCl
Reactant: Clc1ccc2c(c1)Nc1ccccc1OCO2
Solvent: Cc1ccccc1
Product: O=C(CCCl)N1c2ccccc2OCOc2ccc(Cl)cc21
Temperature: 25 °C
Yield: 88.7 %

Procedure:
A suspension of 2-chloro-12H-dibenzo[d,g][1,3,6]dioxazocine (10.65 g, 43 mmol, prepared as described in Journal of Molecular Structures, 131, 1985, 131-140) and 3chloropropionyl chloride (6.55 g, 51.6 mmol) in dry toluene (100 ml) was heated at reflux temperature for 5 h. After cooling to room temperature, the reaction mixture was washed with a saturated solution of sodium bicarbonate (50 ml). The organic layer was dried (MgSO4), and evaporated in vacuo, which afforded 2-chloro-12-(3-chloropropionyl)-12H-dibenzo[d,g][1,3,6]dioxazocine (12.9 g, 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:15]2[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=2)([OH:14])[CH2:9][NH:10][CH2:11]CO)=[CH:4][CH:3]=1.ClC1C=C(CC2(C3C=CC([C:41]4[CH:42]=[N:43][NH:44][CH:45]=4)=CC=3)OCCNC2)SC=1.CN>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:15]2[CH:20]=[CH:19][C:18]([C:41]3[CH:42]=[N:43][NH:44][CH:45]=3)=[CH:17][CH:16]=2)([OH:14])[CH2:9][NH:10][CH3:11])=[CH:4][CH:3]=1
Reactant: OCCNCC(O)(c1ccc(Cl)cc1)c1ccc(I)cc1
Reactant: Clc1csc(CC2(c3ccc(-c4cn[nH]c4)cc3)CNCCO2)c1
Agent: CN
Product: CNCC(O)(c1ccc(Cl)cc1)c1ccc(-c2cn[nH]c2)cc1

Procedure:
By following the procedure described in Example 79A, 79B and 79D but substituting ethanolamine for methylamine, the title compound was obtained. LCMS (PS-A3) Rt 5.28 min [M+H]+ 328, [M−H2O+H]+ 310. 1H NMR (Me-d3-OD) δ 2.38 (3H, s), 3.34 (2H, s), 7.28-7.31 (2H, m), 7.41-7.46 (4H, m), 7.51-7.54 (2H, m), 7.92 (2H, s).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:10]2[C:5](=[C:6]([NH2:11])[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.N1C=CC=CC=1.[Cl:19][C:20]1[N:24]([CH3:25])[N:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[C:21]=1[C:30](Cl)=[O:31].O>C1(C)C=CC=CC=1>[Cl:19][C:20]1[N:24]([CH3:25])[N:23]=[C:22]([C:26]([F:28])([F:27])[F:29])[C:21]=1[C:30]([NH:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH2:4][CH2:3][C:2]2([CH3:12])[CH3:1])=[O:31]
Reactant: CC1(C)CCc2c(N)cccc21
Reactant: Cn1nc(C(F)(F)F)c(C(=O)Cl)c1Cl
Solvent: Cc1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: Cn1nc(C(F)(F)F)c(C(=O)Nc2cccc3c2CCC3(C)C)c1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.1 %

Procedure:
To a solution of 1.61 g of 1,1-dimethyl-4-aminoindane and 2 ml of pyridine in 50 ml of toluene was added drop by drop with stirring at room temperature a solution of 2.47 g of 5-chloro-1-methyl-3-trifluoromethylpyrazole-4-carboxylic acid chloride in 10 ml of toluene, followed by stirring at room temperature for 12 hours. Thereafter, the reaction solution was poured into a cold water to result in separation into two layers. The aqueous layer was extracted with ethyl acetate. The resultant organic layer was dried over anhydrous magnesium sulfate and the soluent was distilled off. The residue was recrystallized using toluene to obtain 3.01 g of 5-chloro-1-methyl-3-trifluoromethyl-N-(1,1-dimethylindane-4-yl)pyrazole-4-carboxamide having a melting point of 119.9° C.
Reaction SMILES: I[C:2]1[CH:56]=[CH:55][C:5]([O:6][CH:7]2[CH2:18][N:17]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N+:28]([O-:30])=[O:29])(=[O:21])=[O:20])[CH2:16][CH2:15][CH2:14][N:13]([S:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[N+:40]([O-:42])=[O:41])(=[O:33])=[O:32])[CH2:12][CH2:11][CH2:10][N:9]([S:43]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=3[N+:52]([O-:54])=[O:53])(=[O:45])=[O:44])[CH2:8]2)=[CH:4][CH:3]=1.[CH2:57]([OH:63])[CH2:58][CH2:59][CH2:60][C:61]#[CH:62]>C1COCC1.C(N(CC)CC)C.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.[Cu]I>[OH:63][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][C:2]1[CH:56]=[CH:55][C:5]([O:6][CH:7]2[CH2:8][N:9]([S:43]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=3[N+:52]([O-:54])=[O:53])(=[O:44])=[O:45])[CH2:10][CH2:11][CH2:12][N:13]([S:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[N+:40]([O-:42])=[O:41])(=[O:32])=[O:33])[CH2:14][CH2:15][CH2:16][N:17]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N+:28]([O-:30])=[O:29])(=[O:20])=[O:21])[CH2:18]2)=[CH:4][CH:3]=1
Reactant: C#CCCCCO
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)N1CCCN(S(=O)(=O)c2ccccc2[N+](=O)[O-])CC(Oc2ccc(I)cc2)CN(S(=O)(=O)c2ccccc2[N+](=O)[O-])CCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)N1CCCN(S(=O)(=O)c2ccccc2[N+](=O)[O-])CC(Oc2ccc(CCCCCCO)cc2)CN(S(=O)(=O)c2ccccc2[N+](=O)[O-])CCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Compound 5b (250 mg, 0.26 mmol) and 5-hexyn-1-ol (43 μL, 0.39 mmol) were dissolved in the mixture of dry THF (6 mL) and triethylamine (2 mL) and the mixture was deaerated with argon. Pd(Ph3P)2Cl2 (3.6 mg, 0.005 mmol) and CuI (1.9 mg, 0.01 mmol) were added, and the mixture was stirred overnight at RT in dark. All volatiles were removed in vacuo. The residue was suspended in dichlormethane, washed twice with water and dried over Na2SO4. Purification on silica gel (eluent: MeOH: CH2Cl2, 1:9, v/v) yielded the title compound. 1H NMR (CDCl3): 7.99 (1H, m); 7.87 (2H, m); 7.78-7.57 (tot 9H); 7.29 (2H, d, J 8.8); 6.97 (2H, d, J 8.8); 5.12 (1H, m); 4.08 (2H, dd, J 4.6 and 15); 3.81-3.69 (tot 10H); 3.13 (2H, dd, J 5.1 and 15); 2.42 (2H, t, J 6.6); 1.78-1.63 (tot 4H); 1.32 (1H, t, J 4.7). ESI-TOF MS: required for C39H43N6O14S3+ (M+H)+ 915.19; found 915.24.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][NH:24]4)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][NH:15]3)=[O:9])[C:5](F)=[CH:4][CH:3]=1.CS(C)=O.[CH3:34][OH:35]>N1CCOCC1>[CH3:8][N:10]([CH3:11])[C:5]1[C:6]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][NH:24]4)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][NH:15]3)=[O:9])=[N:7][C:2]([N:7]2[CH2:6][CH2:5][O:35][CH2:34][CH2:2]2)=[CH:3][CH:4]=1
Reactant: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1nc(Cl)ccc1F
Reactant: CO
Solvent: C1COCCN1
Solvent: CS(C)=O
Product: CN(C)c1ccc(N2CCOCC2)nc1C(=O)Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Temperature: 160 °C

Procedure:
6-Chloro-3-fluoro-N-[6-(1H-indol-4-yl)-1H-indazol-4-yl]-2-pyridinecarboxamide (50 mg, 0.12 mmol) was placed in a microwave vial and dissolved in morpholine (0.5 ml). The mixture was heated at 160° C. for 2 h under microwave irradiation. The solvent was removed under a stream of nitrogen to give a crude residue that was dissolved in DMSO/MeOH (1:1) and purified by Mass Directed Automated Preparative HPLC (Method C). The product was loaded onto a 1 g aminopropyl column, eluted with MeOH and the solvent removed under a stream of nitrogen to give the title compound (16 mg) as an orange solid.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C@H:12]2[CH2:17][CH2:16][C@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:5]2[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[C:6]=12.[CH3:25][O:26][C:27]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[CH:30][C:28]=1[NH2:29].C(=O)([O-])[O-].[K+].[K+].ClCCl>O1CCOCC1.C(#N)C>[CH3:25][O:26][C:27]1[CH:33]=[C:32]([C:2]2[N:3]=[C:4]([C@H:12]3[CH2:17][CH2:16][C@H:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[N:5]3[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[C:6]=23)[CH:31]=[CH:30][C:28]=1[NH2:29]
Reactant: Cc1nccn2c1c(Br)nc2[C@H]1CC[C@H](N2CCN(C)CC2)CC1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CC#N
Product: COc1cc(-c2nc([C@H]3CC[C@H](N4CCN(C)CC4)CC3)n3ccnc(C)c23)ccc1N
Temperature: 89 °C

Procedure:
To a suspension of 1-bromo-8-methyl-3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazine (0.714 mmol, 280 mg) and 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.714 mmol, 178 mg) in dioxane (5 mL) was added aqueous 2M potassium carbonate (3.57 mmol, 1.78 mL). The mixture was degassed and put under a nitrogen atmosphere. Then 1,1′-bis(diphenylphosphino)ferrocene palladium (II) chloride complex with dichloromethane (0.050 mmol, 40.4 mg) was added and the reaction mixture was heated to 89° C. After three hours the reaction mixture was diluted with acetonitrile (9 ml) and filtered over decalite. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (silica gel; gradient of dichloromethane to dichloromethane/methanol 5/1) to give 2-methoxy-4-(8-methyl-3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazin-1-yl)aniline (115 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8](C)[C:9](=O)OC(C)(C)C)=[CH:5][C:4]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21].[ClH:24].O1CCOCC1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][NH:8][CH3:9])=[CH:5][C:4]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21].[ClH:24]
Reactant: COc1ccc(CN(C)C(=O)OC(C)(C)C)cc1NS(C)(=O)=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CNCc1ccc(OC)c(NS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl 4-methoxy-3-(methylsulfonamido)benzyl(methyl)carbamate (60.4 mg, 0.175 mmol) was dissolved in DCM (5 ml), HCl 4M in dioxane (250 μl, 1.000 mmol) was added, and the reaction was stirred at RT overnight. Additional HCl 4M in dioxane (500 μl, 2.00 mmol) was added over 30 hours with stirring at the same temperature. The solvent was evaporated under vacuum, and the solid so obtained was triturated in DCM and filtered to give N-(2-methoxy-5-((methylamino)methyl)-phenyl)methanesulfonamide as hydrochloride (42.8 mg, 0.175 mmol, 100% yield, MS/ESI+ 245.3 [MH]+) that was used in the next step without further purification.