Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[N:9]=2)=[CH:6][C:5]([CH2:34][N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)=[CH:4][N:3]=1.[F:41][C:42]1[CH:43]=[C:44]([NH2:50])[CH:45]=[N:46][C:47]=1[O:48][CH3:49].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1.O>[F:41][C:42]1[CH:43]=[C:44]([NH:50][C:2]2[C:7]([C:8]3[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([CH2:25][C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=4)[CH2:16][C:17]4[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=4)[N:9]=3)=[CH:6][C:5]([CH2:34][N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[CH:4][N:3]=2)[CH:45]=[N:46][C:47]=1[O:48][CH3:49]
Reactant: COc1ncc(N)cc1F
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCOCC4)cnc3F)n2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCOCC4)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Temperature: -20 °C
Yield: 15.5 %

Procedure:
A mixture of 4-(2-fluoro-5-(morpholinomethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.500 g, 0.918 mmol) and 5-fluoro-6-methoxypyridin-3-amine (0.261 g, 1.836 mmol) in THF (20 mL) was cooled to −20° C. and treated with a 1.0 M solution of lithium bis(trimethylsilyl)amide (3.21 mL, 3.21 mmol) added dropwise. The mixture was allowed to slowly warm to ambient temperature over 1 h. The reaction mixture was diluted with water (50 mL) and extracted with CH2Cl2 (3×50 mL). The combined organic extracts were dried over sodium sulfate and concentrated to give the crude product as a tan solid. This was purified by chromatography through a SiliCycle SiliaSep pre-packed silica-gel column (80 gram) eluting with a gradient of 0% to 100% EtOAc in hexane over 30 min to give 4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-(morpholinomethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.095 g) as a tan oil. This was treated with trifluoroacetic acid (1.8 mL, 23.36 mmol) and trifluoromethanesulfonic acid (0.2 mL, 2.252 mmol) and heated at 70° C. for 20 min. The mixture was cooled to ambient temperature and concentrated to give a tan oil. This was dissolved in DCM (10 mL) and allowed to stir for 5 min, then sodium carbonate (1.6 g) was slowly added to the mixture and stirred vigorously for 20 min. The mixture was filtered and concentrated. The mixture was diluted with ethyl acetate and filtered. The filtrate was concentrated and the residue was diluted with diethyl ether (20 mL) and placed in a sonicator for 2 min. The precipitate was collected by filtration. The solid was recrystallized from hot ethyl acetate to give 4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-(morpholinomethyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (0.025 g, 0.059 mmol, 6.39% yield) as a tan solid. 1H NMR (400 MHz, d6-DMSO) δ 11.94 (s, 1H); 8.72 (s, 1H); 8.41 (s, 1H); 8.36 (d, J=12.91 Hz, 1H); 8.24 (s, 1H); 7.90 (s, 1H); 7.75 (s, 1H); 3.93 (s, 3H); 3.57 (s, 4H); 3.43 (s, 2H); 2.44 (s, 7H). m/z (ESI, +ve ion) 427 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][S:12]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.[C:22](O)(=[O:25])[CH2:23][CH3:24].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(NC(C)C)(C)C>CN(C)C=O.CS(C)=O>[C:22]([NH:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][S:12]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)(=[O:13])=[O:14])[CH:8]=[CH:7][C:5]=2[N:6]=1)(=[O:25])[CH2:23][CH3:24]
Reactant: CCC(=O)O
Reactant: Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: CCC(=O)Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1
Yield: 69.2 %

Procedure:
A solution of 4-fluorobenzenesulfonic acid 2-aminobenzothiazol-6-yl ester (intermediate 16) (500 mg, 1.14 mmol), propionic acid (253 mg, 3.42 mmol), HBTU (1.23 g, 3.42 mmol) and N,N-diisopropylamine (737 mg, 5.7 mmol) in 6.5 ml of dimethylformamide is stirred overnight at room temperature. The reaction medium is evaporated to dryness. The dry residue is extracted twice with 50 ml of ethyl acetate and washed with water. The organic phase is then washed with saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and then evaporated. The oil obtained is dissolved in 35 ml of dimethyl sulfoxide and then purified 7 times by preparative HPLC on a Nucléodur C18, 100′10 μm reverse-phase column with a gradient over 52 minutes of 5% to 95% acetonitrile supplemented with 0.07% trifluoroacetic acid in water, supplemented with 0.07% trifluoroacetic acid. The flow rate is 70 ml/min. The fractions containing the clean product are concentrated to give 300 mg of 4-fluorobenzenesulfonic acid 2-propionylaminobenzothiazol-6-yl ester in a yield of 69%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:5][C:6]1[N:7]=[C:8]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[S:9][C:10]=1[C:11](OCC)=[O:12].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:5][C:6]1[N:7]=[C:8]([N:16]2[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)[S:9][C:10]=1[CH2:11][OH:12]
Reactant: CCOC(=O)c1sc(N2CCOCC2)nc1Cc1ccc(Cl)c(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1sc(N2CCOCC2)nc1Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.5 %

Procedure:
To a solution of ethyl 4-(3,4-dichlorobenzyl)-2-morpholinothiazole-5-carboxylate (4.92 g, 12.2 mmol) in THF (100 mL) was added a 2.00 M solution of LAH in THF (12.9 mL, 25.8 mmol) and the resulting solution was stirred for 2 hours at room temperature. The reaction was quenched by adding saturated NH4Cl (26 mL) followed by 1M HCl (26 mL). Water (100 mL) and ethyl acetate (200 mL) were then added. The layers were separated and the organic layer was washed with brine (50 mL). The organic layer was dried and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate/DCM=0/100→100/0) to give 2.87 g (65% yield) of the title compound as a white solid. LC/MS (FA) ES+ 359, 361. 1H NMR (400 MHz, CDCl3) δ: 7.34-7.31 (m, 2H), 7.09 (dd, 1H, J=6.0, 2.0 Hz), 4.66 (d, 2H, J=1.2 Hz), 3.84 (s, 2H), 3.79-3.77 (m, 4H), 3.42-3.39 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:19])[C:11]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:12][CH:13]=2)=[CH:4][N:3]=1.[Br:20][C:21]1[CH:22]=[CH:23][C:24]([N:29]2[CH:33]=[N:32][CH:31]=[N:30]2)=[C:25]([CH:28]=1)[CH:26]=O.N1CCC[C@H]1C(O)=O>CO>[Br:20][C:21]1[CH:22]=[CH:23][C:24]([N:29]2[CH:33]=[N:32][CH:31]=[N:30]2)=[C:25]([C:26]2[N:14]([C:15]([CH3:16])([CH3:18])[CH3:17])[C:11]3[CH:12]=[CH:13][C:8]([C:5]4[CH:4]=[N:3][C:2]([NH2:1])=[N:7][CH:6]=4)=[CH:9][C:10]=3[N:19]=2)[CH:28]=1
Reactant: CC(C)(C)Nc1ccc(-c2cnc(N)nc2)cc1N
Reactant: O=Cc1cc(Br)ccc1-n1cncn1
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CO
Product: CC(C)(C)n1c(-c2cc(Br)ccc2-n2cncn2)nc2cc(-c3cnc(N)nc3)ccc21
Temperature: 60 °C
Yield: 30.9 %

Procedure:
To a solution of 4-(2-amino-pyrimidin-5-yl)-N1-tert-butyl-benzene-1,2-diamine (100 mg, 0.39 mmol) in MeOH (5 mL) are added 5-bromo-2-1,2,4-triazol-1-yl-benzaldehyde (refer to example 4 step 1) (147 mg, 0.58 mmol) and L-proline (4 mg, 0.04 mmol) at room temperature. The solution is heated to 60° C. for 24 hours and then cooled down and is concentrated under reduced pressure. The residue is purified by silica gel flash column chromatography eluting with 10% MeOH in CH2Cl2 to afford the title compound (59 mg, 31%) as a white foam. LCMS (ESMS): m/z 489.20 (M+)
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:22][C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:8]=1)=[O:5].C(N(CC)CC)C.Cl[C:40]([C:42]1[CH:43]=[C:44]([CH:49]=[CH:50][CH:51]=1)[C:45]([O:47][CH3:48])=[O:46])=[O:41]>ClCCl>[N:26]1([C:23]2[CH:24]=[CH:25][C:2]([NH:1][C:40]([C:42]3[CH:43]=[C:44]([CH:49]=[CH:50][CH:51]=3)[C:45]([O:47][CH3:48])=[O:46])=[O:41])=[C:3]([C:4](=[O:5])[NH:6][C:7]3[CH:11]=[CH:10][N:9]([C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=4)[N:8]=3)[CH:22]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: COC(=O)c1cccc(C(=O)Cl)c1
Reactant: Nc1ccc(N2CCCCC2)cc1C(=O)Nc1ccn(-c2cccc(C(F)(F)F)c2)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)Nc2ccn(-c3cccc(C(F)(F)F)c3)n2)c1
Temperature: 0 °C
Yield: 83.1 %

Procedure:
Into a 100-mL 3-necked round bottom flask, was placed a solution of 2-amino-5-(piperidin-1-yl)-N-(1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)benzamide (260 mg, 0.61 mmol, 1.00 equiv) in dichloromethane (20 mL), and triethylamine (123 mg, 1.22 mmol, 2.01 equiv). This was followed by dropwise addition of a solution of methyl 3-(chlorocarbonyl)benzoate (144 mg, 0.73 mmol, 1.20 equiv) in dichloromethane (10 mL) with stirring at 0° C. The resulting solution was stirred for 2 h at room temperature, with reaction progress monitored by LCMS. The resulting mixture was washed with 3×20 mL of water and 20 mL of brine, then dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum to give 300 mg of crude product as a brown solid.
Reaction SMILES: [CH2:1]([C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([CH2:15][C:16](O)=[O:17])=[CH:11][C:9]=2[N:10]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C(OCC)(OCC)(OCC)C.C(=O)([O-])O.[Na+]>CCOC(C)=O>[CH2:1]([C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][OH:17])=[CH:11][C:9]=2[N:10]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1nc2cc(CC(=O)O)ccc2o1
Agent: CCOC(C)(OCC)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCCCCc1nc2cc(CCO)ccc2o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (2-pentyl-benzoxazol-5-yl)-acetic acid (2.11 g, 8.53 mmol) in triethyl orthoacetate (4.67 ml, 25.6 mmol) was heated under pressure (in three portions in the microwave Emrys optimizer) to 180° C. for 8 minutes. After cooling to RT the reaction mixture was distributed between AcOEt and saturated aqueous sodium hydrogen carbonate. The organic layer was washed two times with water, dried over MgSO4 and concentrated in vacuum. 1.88 g of the crude (2-pentyl-benzoxazol-5-yl)-acetic acid ethyl ester (2.31 g, 99%) were dissolved in dry ethanol (43 ml) and added to a solution of Ca(BH4)2 (prepared from sodium borohydride (3.87 g, 102.4 mmol) suspended in dry ethanol (130 ml), cooled to −10° C., treated with CaCl2 (5.68 g, 51.2 mmol) and stirred for 45 minutes while warming to 0° C.). After stirring for 2 hours at 8° C. the reaction mixture was filtered and the precipitate washed with ethanol. The filtrate was combined with the washings and concentrated in vacuum, treated with MeOH and concentrated again. Silica gel chromatography (eluent: DCM/methanol 10/1) provided the title compound as colorless solid. 1H-NMR (DMSO-d6) δ: 7.51 (d, J=8.1 Hz; 1H), 7.49 (s; 1H), 7.16 (dd, J=8.3, 1.6 Hz; 1H), 4.60 (t, J=5.2 Hz; 1H), 3.61 (m; 2H), 2.88 (t, J=7.4 Hz; 2H), 2.80 (t, J=7.0 Hz; 2H), 1.76 (m; 2H), 1.30 (m; 4H), 0.85 (m; 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:16]([O:18][CH2:19][CH:20]1[C:32]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17]>O.O1CCCC1>[CH:31]1[C:32]2[CH:20]([CH2:19][O:18][C:16]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7])=[O:17])[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:27]=2[CH:28]=[CH:29][CH:30]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: NCCCCC(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCCCNC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2.00 g 5-aminopentanoic acid and 3.62 g of sodium carbonate in 30 ml of water was cooled to 0° C. and 4.41 g of 9-fluorenylmethyl chloroformate in 10 ml of tetrahydrofuran was added dropwise. The mixture was allowed to warm to room temperature and stirred for 2 hours. The mixture was then diluted with water and washed with ether. The aqueous solution was cooled to 0° C. and adjusted to pH 2 with 3N hydrochloric acid. The resulting white solid was collected by filtration and dried to give N-(9-fluorenylmethoxycarbonyl)-5-amino-pentanoic acid.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6](O)[CH:7]([CH3:9])[CH3:8])=[CH:4][CH:3]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>O>[CH3:8][CH:7]([CH3:9])[CH:6]([C:5]1[CH:11]=[CH:12][C:2]([OH:1])=[CH:3][CH:4]=1)[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: C1COCCN1
Reactant: CC(C)C(O)c1ccc(O)cc1
Solvent: O
Product: CC(C)C(c1ccc(O)cc1)N1CCOCC1
Yield: 34.7 %

Procedure:
A mixture of 4-hydroxy-α-isopropylbenzyl alcohol (1.0 g; 0.006 mol) morpholine (1.3 g; 0.015 mol) and water (1.3 ml) is refluxed under a nitrogen atmosphere for 23 hours, and then poured into water (~20 ml). The aqueous solution is extracted with 30 ml of ether, the ethereal solution dried over magnesium sulfate, and concentrated to give 0.97 g of crude product (69% of theory). Recrystallization of the crude product from methylene chloride affords pure title compound (490 mg 35%): mp 142°-143° C.; IR (Nujol) 3300 (s), 2940 (s), 1610 (m), 1595 (m) cm-1 ; NMR (CDCl3) δ0.75 and 0.92 (a pair of d, J=7 Hz, 6 H, two methyls), 1.8-2.4 (m, 1 H, isopropyl methine proton), 2.3-2.5 (m, 4 H, two methylene groups adjacent to the nitrogen atom), 2.94 (d, J=8 Hz, 1 H, benzylic proton), 3.6-3.9 (m, 4 H, two methylene groups adjacent to the oxygen atom), 3.9-6.2 (broad s, 1 H, phenoxy proton) and 6.75 and 7.05 ppm (AB quartet, J=8 Hz, 4 H, aromatic). Anal. Calcd for C14H21NO2 : C, 71.45; H, 8.95; N, 5.95. Found: C, 71.07; H, 8.64; N, 6.01.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12](=[O:39])[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:23](=[O:32])[C:24]#[C:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:17][CH:16]=1)[CH3:10]>>[CH2:9]([O:11][C:12](=[O:39])[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]2[C:33]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)/[C:24](=[C:25](\[C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)/[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)/[C:23]2=[O:32])=[CH:17][CH:16]=1)[CH3:10]
Reactant: Clc1ccc(I)cc1
Reactant: CCOC(=O)COc1ccc(CN(C(=O)C#Cc2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)COc1ccc(CN2C(=O)/C(=C(\c3ccccc3)c3ccc(Cl)cc3)c3ccccc32)cc1

Procedure:
The title compound was prepared in analogy to Example 5 starting from 1-chloro-4-iodo-benzene (commercially available) and (4-{[phenyl-(3-phenyl-propynoyl)-amino]-methyl}-phenoxy)-acetic acid ethyl ester. 1H NMR (300 Hz, CDCl3): δppm 1.28 (t, 3H), 4.26 (q, 2H), 4.57 (s, 2H), 4.84 (s, 2H), 6.51 (d, 1H), 6.67-6.71 (m, 2H), 6.83 (d, 2H), 7.08 (t, 1H), 7.24-7.42 (m, 11H).
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:14]=[C:15]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH:16]=[CH:17][CH:18]=3)[N:6]2[N:5]=1)=O.C(N(CC)C(C)C)(C)C.[CH3:33][N:34]1[CH2:39][CH2:38][N:37]([C:40]2[CH:45]=[CH:44][C:43]([NH2:46])=[CH:42][CH:41]=2)[CH2:36][CH2:35]1.COCC(O)C>>[CH3:33][N:34]1[CH2:35][CH2:36][N:37]([C:40]2[CH:45]=[CH:44][C:43]([NH:46][C:4]3[N:9]=[CH:8][C:7]4=[CH:10][CH:11]=[C:12]([C:13]5[CH:14]=[C:15]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH:16]=[CH:17][CH:18]=5)[N:6]4[N:5]=3)=[CH:42][CH:41]=2)[CH2:38][CH2:39]1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CS(=O)c1ncc2ccc(-c3cccc(NS(C)(=O)=O)c3)n2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCC(C)O
Product: CN1CCN(c2ccc(Nc3ncc4ccc(-c5cccc(NS(C)(=O)=O)c5)n4n3)cc2)CC1
Yield: 66.7 %

Procedure:
N-[3-(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-methanesulfonamide (125.0 mg, 0.0003567 mol), N,N-Diisopropylethylamine (0.205 mL, 0.00118 mol) and 4-(4-Methyl-piperazin-1-yl)-phenylamine (0.136 g, 0.000713 mol) were dissolved in 1-Methoxy-2-propanol (0.410 mL, 0.00419 mol) and the reaction was irradiated at 300 watts, 180° C. for 40 minutes or until HPLC showed consumption of starting material. The reaction mixture was then reduced en vacuo and the product was isolated and purified by Gilson prep HPLC to afford 113.55 mg of N-(3-{2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-pyrrolo[2,1-f][1,2,4]triazin-7-yl}-phenyl)-methanesulfonamide as a lyophilized powder. (M+H)=478.1. 1H NMR (400 MHz, DMSO, d6) δ 9.78 (m, 1H), 9.32 (s, 1H), 8.98 (s, 1H), 7.90 (m, 2H), 7.67 (m, 2H), 7.53 (m, 1H), 7.27 (d, 1H, J=7.97 Hz), 7.06 (m, 1H), 6.94 (m, 2H), 6.89 (m, 1H), 3.76 (m, 2H), 3.53 (m, 2H), 3.19 (m, 2H), 3.04 (s, 3H), 2.96 (m, 5H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[C:6](=[O:20])[C:5]2=O>O.NN.C(O)C.O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[C:6](=[O:20])[CH2:5]2
Reactant: COc1ccc(CN2C(=O)C(=O)c3cc(F)ccc32)cc1
Agent: NN
Solvent: CCO
Solvent: O
Product: COc1ccc(CN2C(=O)Cc3cc(F)ccc32)cc1
Yield: 90.3 %

Procedure:
A solution of 5-fluoro-1-(4-methoxy-benzyl)-1H-indole-2,3-dione (7.1 g, 24.9 mmol) in hydrazine hydrate (35 mL) and ethanol (15 mL) was refluxed overnight, diluted with water and extracted twice with ethyl acetate. The combined organics were dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography using a gradient of 0-100% ethyl acetate in hexane to afford 6.1 g (90%) of 5-fluoro-1-(4-methoxy-benzyl)-1,3-dihydro-indol-2-one; 1H NMR (CDCl3, 400 MHz) δ 3.59 (s, 2H), 3.77 (s, 3H), 4.83 (s, 2H), 6.63 (dd, 1H, J1=4.2, J2=8.6), 6.82-6.91 (m, 3H), 6.96-7.01 (m, 1H), 7.19-7.23 (m, 1H), 7.27-7.31 (m, 1H); HPLC-MS calcd. for C16H14FNO2 (M+H+) 272.1, found 272.3.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][NH:9][CH2:10]2)=[CH:5][CH:4]=1.[C:15]([O:19][C:20]([NH:22][C@@H:23]1[CH2:27][CH2:26][C@:25]([CH:31]([CH3:33])[CH3:32])([C:28](O)=[O:29])[CH2:24]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH:31]([C@:25]1([C:28]([N:9]2[CH2:8][CH2:7][C:6]3[C:11](=[CH:12][C:3]([C:2]([F:1])([F:13])[F:14])=[CH:4][CH:5]=3)[CH2:10]2)=[O:29])[CH2:26][CH2:27][C@@H:23]([NH:22][C:20](=[O:21])[O:19][C:15]([CH3:17])([CH3:16])[CH3:18])[CH2:24]1)([CH3:33])[CH3:32]
Reactant: FC(F)(F)c1ccc2c(c1)CNCC2
Reactant: CC(C)[C@]1(C(=O)O)CC[C@@H](NC(=O)OC(C)(C)C)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)[C@]1(C(=O)N2CCc3ccc(C(F)(F)F)cc3C2)CC[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 36 h
Yield: 54.7 %

Procedure:
To a solution of 7-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline (1.7 g, 8.45 mmol) of Step B-4, (1S,3R)-3-[(tert-butoxycarbonyl)amino]-1-isopropylcyclopentanecarboxylic acid (2.75 g, 10.14 mmol) of Step A-4,4-dimethylaminopyridine (0.70 g, 5.73 mmol), and N,N-diisopropylethylamine (7.0 mL, 40.2 mmol) in methylene chloride (30.0 mL) was added bromotris(pyrrolydino)phophonium hexafluorophosphate (5.119 g, 10.98 mmol). After being stirred for 36 h at room temperature, the solution was concentrated in vacuo. The residue was purified by column chromatography on silica eluting with 20% ethyl acetate/hexanes to give 2.1 g (55%) of desired product. MS calculated for C24H33F3N2O3: (M+H)+455; found 355 (M−Boc+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:23])[CH:9]=[CH:10][C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=2)=[CH:4][CH:3]=1.[CH3:24][N:25]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:26](Cl)=[O:27]>>[CH3:22][O:21][C:13]1[CH:12]=[C:11]([CH:10]=[CH:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([O:1][C:26](=[O:27])[N:25]([CH3:24])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:3][CH:4]=2)=[O:23])[CH:16]=[C:15]([O:17][CH3:18])[C:14]=1[O:19][CH3:20]
Reactant: COc1cc(C=CC(=O)c2ccc(O)cc2)cc(OC)c1OC
Reactant: CN(C(=O)Cl)c1ccccc1
Product: COc1cc(C=CC(=O)c2ccc(OC(=O)N(C)c3ccccc3)cc2)cc(OC)c1OC

Procedure:
The title product was prepared from 1-(4-hydroxyphenyl)-3-(3,4,5-trimethoxyphenyl)prop-2-en-1-one and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (82%, yellow solid). HPLC-MS: m/z=448.2 (M+1); Rt: 4.61 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[NH:21][N:22]=[C:23]([C:24]4[CH:29]=[CH:28][N:27]=[C:26](S(C)=O)[N:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[F:34][C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=1)[CH2:38][NH2:39]>>[C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[NH:21][N:22]=[C:23]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([NH:39][CH2:38][C:37]5[CH:40]=[CH:41][CH:42]=[C:35]([F:34])[CH:36]=5)[N:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)c1nccc(-c2n[nH]c3nc(NC4CCC(NC(=O)OC(C)(C)C)CC4)ncc23)n1
Reactant: NCc1cccc(F)c1
Product: CC(C)(C)OC(=O)NC1CCC(Nc2ncc3c(-c4ccnc(NCc5cccc(F)c5)n4)n[nH]c3n2)CC1
Temperature: 130 °C
Reaction time: 2 h

Procedure:
The mixture of {4-[3-(2-methanesulfinyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (from Example 9 supra) (140 mg, 0.3 mmol) and 3-fluorobenzylamine (148 mg, 1.2 mmol) was heated at 130° C. with stirring for 2 hours. The resulting oil was purified by chromatography (silica gel, 8 g, 200-300 mesh, eluting with dichloromethane:methanol, 50:1 to 30:1) to afford (4-{3-[2-(3-fluoro-benzylamino)-pyrimidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino}-cyclohexyl)-carbamic acid tert-butyl ester. (Yield 110 mg, 69.6%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH3:12][C:13]1[C:17](/[CH:18]=[CH:19]/[C:20](O)=[O:21])=[C:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:15][N:14]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[CH3:9][O:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:20](=[O:21])/[CH:19]=[CH:18]/[C:17]2[C:13]([CH3:12])=[N:14][O:15][C:16]=2[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:11][CH:10]=1)=[O:7]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: Cc1noc(-c2ccccc2)c1/C=C/C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC(=O)/C=C/c2c(C)noc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
A mixture of methyl 4-aminobenzoate (0.30 g), (E)-3-(3-methyl-5-phenyl-4-isoxazolyl)propenoic acid (0.35 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.27 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.35 g) and N,N-dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and (E)-N-(4-methoxycarbonylphenyl)-3-(3-methyl-5-phenyl-4-isoxazolyl)propenamide (0.51 g, yield 92%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 174–175° C.