Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([C:8]1[S:9][C:10]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:11][C:12]=1[C:13](=[O:26])[N:14]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25])[CH:15]([CH3:17])[CH3:16])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:25][C:19]1[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=1[N:14]([CH:15]([CH3:17])[CH3:16])[C:13]([C:12]1[CH:11]=[C:10]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[S:9][C:8]=1[C:6]([OH:7])=[O:5])=[O:26]
Reactant: CC(C)N(C(=O)c1cc(-c2ccccc2)sc1C(=O)OC(C)(C)C)c1ccc(Cl)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)N(C(=O)c1cc(-c2ccccc2)sc1C(=O)O)c1ccc(Cl)cc1Cl
Yield: 77.7 %

Procedure:
A solution of 3-[(2,4-Dichloro-phenyl)-isopropyl-carbamoyl]-5-phenyl-thiophene-2-carboxylic acid tert-butyl ester (37 mg, 0.08 mmol) in CH2Cl2 (0.2 ml) at room temperature, under nitrogen was treated with trifluoroacetic acid (0.8 ml). After 1 h the reaction was concentrated the residue was taken into EtOAc and washed sequentially with 2N HCl (2×15 ml), water, brine dried and evaporated to a foam (33 mg). The foam was redissolved in EtOAc and above acidic wash was repeated to yield 27 mg (84%) of 3-[(2,4-Dichloro-phenyl)-isopropyl-carbamoyl]-5-phenyl-thiophene-2-carboxylic acid compound as pale brown foam. NMR 1H: (CD3OD; 400 MHz) 7.57-7.55 (m, 2H); 7.49-7.36 (m, 6H), 7.30-7.27 (m, 1H); 4.89 (quint, J=6.73 Hz, 1H); 1.42 (d, J=6.73 Hz, 3H); 1.12 (d, J=6.73 Hz, 3H).
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]([CH3:28])=[C:15]3[CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:8][CH:7]=1.[OH-].[K+]>C1COCC1.CO>[CH2:21]([N:17]1[C:18]2[C:14](=[CH:13][C:12]([C:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:36])=[O:2])=[CH:7][CH:8]=3)=[CH:20][CH:19]=2)[C:15]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:16]1[CH3:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)COc1ccc(-c2ccc3c(c2)c(Cc2ccccc2)c(C)n3Cc2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(Cc2ccccc2)c2cc(-c3ccc(OCC(=O)O)cc3)ccc2n1Cc1ccccc1

Procedure:
The desired product was prepared using a procedure similar to step 2 of example 4. Thus, [4-(1,3-dibenzyl-2-methyl-1H-indol-5-yl)-phenoxy]-acetic acid methyl ester (0.147 g, 0.309 mmol) was reacted with 1N KOH (0.62 ml) in THF/MeOH (3 ml/2 ml) to give the product (0.072 g, 0.156 mmol, 50%) as a tan solid, mp 180-183° C. 1H NMR (DMSO-d6), δ 2.35 (s, 3H), 4.10 (s, 2H), 4.66 (s, 2H), 5.42 (s, 2H), 6.94 (d, J=8.9 Hz, 2H), 6.99 (d, J=7.0 Hz, 2H), 7.09-7.13 (m, 1H), 7.20-7.30 (m, 8H), 7.39 (d, J=8.4 Hz, 1H), 7.49 (d, J=8.7 Hz, 2H), 7.58 (d, J=1.5 Hz, 1H), 13.00 (broad s, 1H); IR (solid) 3010, 2905, 1730, 1520, 1480, and 1240 cm−1; [ESI(+)], m/z 462 (M+H)+; Anal. Calcd. for C31H27NO3: C, 80.67; H, 5.90; N, 3.03; Found: C, 80.60; H, 5.79; N, 2.94.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[N:7][C:6]=2[CH:5]=[C:4]([O:19][CH3:20])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:26]1[O:27][CH:28]=[CH:29][CH:30]=1)CCC>CC1C=CC(C)=CC=1.[Cl-].[NH4+].CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[O:27]1[CH:28]=[CH:29][CH:30]=[C:26]1[C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[N:7][C:6]=2[CH:5]=[C:4]([O:19][CH3:20])[CH:3]=1
Reactant: COc1ccc(-c2nc3cc(OC)cc(Br)c3o2)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccc(C)cc1
Product: COc1ccc(-c2nc3cc(OC)cc(-c4ccco4)c3o2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99 %

Procedure:
7-Bromo-5-methoxy-2-(4-methoxyphenyl)-1,3-benzoxazole (300 mg, 0.90 mmol) and dichlorobis(tri-o-tolylphosphine)palladium(II) (71 mg, 0.09 mmol) were dissolved in p-xylene (3 mL) and stirred for 10 min at room temperature under a nitrogen atmosphere. 2-(Tributylstannyl)furan (449 mg, 1.26 mmol) was added and the mixture was refluxed for 4 hours. The mixture was cooled to room temperature, diluted with a saturated solution of ammonium chloride and extracted with EtOAc. The organic extracts were washed with water, then brine and dried over MgSO4 and concentrated. Purification by flash chromatography (20%-30% EtOAc/petroleum ether) gave the title compound as a white solid (99% yield, m.p. 120-121° C.); MS m/e 322 (M+H)+.
Reaction SMILES: [Al](Br)(Br)Br.[C:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=2)=[C:10]([N+:22]([O-:24])=[O:23])[CH:9]=1)(=[O:7])[CH3:6].CCCCCC.C(OCC)(=O)C>C1C=CC=CC=1>[C:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=2)=[C:10]([N+:22]([O-:24])=[O:23])[CH:9]=1)(=[O:7])[CH3:6]
Reactant: COc1ccc(-c2ccc(C(C)=O)cc2[N+](=O)[O-])cc1
Agent: Br[Al](Br)Br
Solvent: CCCCCC
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(-c2ccc(O)cc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a stirred solution of AlBr3 (12.6 g, 47.4 mmole) in benzene (45 mL) is added dropwise under nitrogen a solution of the methylether (5 g, 18.45 mmole) of Step A in benzene (12 mL) over 30 minutes. The resulting solution is stirred at room temperature for 3.5 hours. (TLC, 8:2 hexane-ethyl acetate). The mixture is cooled in an ice bath and the complex is decomposed by the dropwise addition of 6N-HC1 (ca. 37 mL). The organic layer is separated and the aqueous phase is reextracted with ether (3x). The combined extracts are concentrated to a small volume and extracted again with 2.5N-NaOH (2×50 mL +1×10 mL). The basic extracts are cooled and acidified with concentrated HCl (to pH 2). The solid is collected and dried (4.27 g, 90% ). It is used in the next step without further purification.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([SH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:36][CH3:37])=[C:29]([O:32][CH2:33][CH2:34][Cl:35])[CH:30]=2)[N:25]=[CH:24][N:23]=1>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:22]3[C:31]4[C:26](=[CH:27][C:28]([O:36][CH3:37])=[C:29]([O:32][CH2:33][CH2:34][Cl:35])[CH:30]=4)[N:25]=[CH:24][N:23]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2ncnc(Cl)c2cc1OCCCl
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(S)c2)no1
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCCl
Yield: 79 %

Procedure:
To 1-(5-tert-butylisoxazol-3-yl)-3-(3-mercaptophenyl)urea described in Example 44A (1.07 g, 3.70 mmol) was added 4-chloro-6-(2-chloroethoxy)-7-methoxyquinazoline (1.0 g, 3.70 mmol) from Example 16B according to the procedure described in Example 46 to give 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(2-chloroethoxy)-7-methoxyquinazolin-4-ylthio)phenyl)urea (1.54 g, 2.92 mmol, 79%). 1H NMR (300 MHz, DMSO-d6) δ 9.59 (s, 1H), 9.02 (s, 1H), 8.71 (s, 1H), 7.85 (s, 1H), 7.51 (d, 1H), 7.44 (t, 1H), 7.38 (s, 2H), 7.28 (d, 1H), 6.49 (s, 1H), 4.50 (t, 2H), 4.07 (t, 2H), 4.01 (s, 3H), 1.29 (s, 9H); LC-MS (ESI) m/z 528 (M+H)+.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[N:20]=[C:19]([C:21]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([C:30]([O:32][CH3:33])=[O:31])[CH:28]=4)[N:23](C(OC(C)(C)C)=O)[CH:22]=3)[CH:18]=[N:17][CH:16]=2)[CH2:11][CH2:10]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)(Cl)Cl>[NH2:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]2[N:20]=[C:19]([C:21]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([C:30]([O:32][CH3:33])=[O:31])[CH:28]=4)[NH:23][CH:22]=3)[CH:18]=[N:17][CH:16]=2)[CH2:13][CH2:14]1
Reactant: COC(=O)c1ccc2c(c1)c(-c1cncc(N3CCC(NC(=O)OC(C)(C)C)CC3)n1)cn2C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc2[nH]cc(-c3cncc(N4CCC(N)CC4)n3)c2c1
Temperature: 50 °C
Yield: 48.3 %

Procedure:
To a mixture of 1-tert-butyl 5-methyl 3-(6-(4-(tert-butoxycarbonylamino)piperidin-1-yl)pyrazin-2-yl)-1H-indole-1,5-dicarboxylate (300 mg, 0.53 mmol) in chloroform (3.0 mL) was added TFA (3.0 mL) at 0° C. The reaction mixture was heated at 50° C. for 12 h. After removal of TFA the crude product was purified by preparative HPLC to obtain title compound (90 mg, 47%) as a brown solid. MS (ESI, pos. ion) m/z: 352.1 (M+1).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[C:40]([NH:47][C@H:48]([C:53](O)=[O:54])[C:49]([CH3:52])([CH3:51])[CH3:50])([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:30][O:29][C:28](=[O:31])[NH:27][C@@H:22]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:20](=[O:21])[NH:19][C@@H:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)[CH2:4][C@H:3]([OH:32])[C@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[NH:1][C:53](=[O:54])[C@H:48]([C:49]([CH3:52])([CH3:51])[CH3:50])[NH:47][C:40](=[O:41])[O:42][C:43]([CH3:45])([CH3:46])[CH3:44]
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.7 %

Procedure:
A solution containing the product from Example 2C (0.050 g, 0.094 mmol) in THF (0.5 mL) was treated with Boc-L-tert-leucine (0.022 g, 0.096 mmol), DEPBT (0.042 g, 0.140 mmol), and N,N-diisopropylethylamine (0.08 mL, 0.459 mmol), stirred at 25° C. for 2 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with a gradient starting with 50-100% ethyl acetate/chloroform to give the title compound (0.058 g, 83% yield).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](OS(C(F)(F)F)(=O)=O)[C:5]([C:16]#[N:17])=[C:4]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)[N:3]=1.[C:23]1([C:29]#[CH:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C1COCC1.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>[NH2:1][C:2]1[N:3]=[C:4]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)[C:5]([C:16]#[N:17])=[C:6]([C:30]#[C:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:7]=1
Reactant: N#Cc1c(OS(=O)(=O)C(F)(F)F)nc(N)nc1-c1ccco1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#Cc1c(C#Cc2ccccc2)nc(N)nc1-c1ccco1

Procedure:
From trifluoromethanesulfonic acid 2-amino-5-cyano-6-furan-2-yl-pyrimidin-4-yl ester, phenylacetylene, bis(triphenylphosphine)palladium(II) chloride, triphenylphosphine, triethylamine and copper (I) iodide in THF. EI-MS m/e (%): 286 (M+, 100).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]=[CH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2.[CH3:14][O-:15].[Na+]>CO>[CH3:14][O:15][CH2:3][C:4]1[N:5]=[CH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: C[O-]
Reactant: ClCc1cc2ccccc2cn1
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COCc1cc2ccccc2cn1
Temperature: 20 °C
Yield: 87.6 %

Procedure:
A mixture of 3-chloromethylisoquinoline hydrochloride (96 g) and sodium methoxide (80 g) in methanol (1.5 liters) is heated under reflux for 8 hours. After cooling to 20° C., the mixture is filtered and the filtrate is evaporated to dryness at 50° C. under reduced pressure (20 mm Hg). The residue is taken up in methylene chloride (1 liter), the mixture is washed with water (3×150 cc), the organic phase is dried over magnesium sulphate and filtered, and the filtrate is evaporated to dryness at 40° C. under reduced pressure (20 mm Hg). The oily residue is distilled at 82° C. under reduced pressure (0.6 mm Hg). 3-Methoxymethylisoquinoline (68 g), a colourless oil, is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](Br)=[C:7]([O:12][CH2:13][CH:14]2[CH2:16][CH2:15]2)[N:6]=1)=[O:4].[F:17][C:18]([F:27])([F:26])[CH2:19][NH:20][CH2:21][C:22]([F:25])([F:24])[F:23].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:20]([CH2:19][C:18]([F:17])([F:26])[F:27])[CH2:21][C:22]([F:25])([F:24])[F:23])=[C:7]([O:12][CH2:13][CH:14]2[CH2:16][CH2:15]2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(Br)c(OCC2CC2)n1
Reactant: FC(F)(F)CNCC(F)(F)F
Agent: [Pd]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(N(CC(F)(F)F)CC(F)(F)F)c(OCC2CC2)n1
Yield: 29.7 %

Procedure:
Under a nitrogen atmosphere, a solution of 5-bromo-6-(cyclopropylmethoxy)-pyridine-2-carboxylic acid methyl ester (Example 114 a, 1 g, 3.5 mmol), bis(2,2,2-trifluoroethyl)amine (1.90 g, 10 mmol), (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (CAN 98327-87-8, 0.435 g, 1 mmol), tris(dibenzylideneacetone) dipalladium (CAN 51364-51-3, 0.32 g, 0.35 mmol) and cesium carbonate (CAN 534-17-8, 3.4 g, 10 mmol) in toluene (50 mL) was reacted overnight at 110° C. The reaction mixture was concentrated under reduced pressure, dissolved in water, extracted with ethyl acetate (50 mL), the aqueous layer was adjusted to pH 2 with conc. HCl, then extracted with ethyl acetate (3×50 mL), washed with brine (2×50 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 10 g, 20% ethyl acetate in petroleum ether) to yield the title compound (0.5 g, 29.7%) as a yellow oil; MS: m/e=387.1 [M+H]+.
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH:8]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:9][CH2:10][CH:11]2[NH:15][C:14](=[O:16])[CH2:13][CH2:12]2)[CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][C:48]#[N:49]>>[C:1]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH:8]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:9][CH2:10][CH:11]2[CH2:12][CH2:13][C:14](=[O:16])[N:15]2[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][C:48]#[N:49])[CH:2]=1
Reactant: N#CCCCCCCBr
Reactant: CC(C)(C)[Si](C)(C)OC(CCC1CCC(=O)N1)Cc1cccc(-c2ccccc2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: CC(C)(C)[Si](C)(C)OC(CCC1CCC(=O)N1CCCCCCC#N)Cc1cccc(-c2ccccc2)c1
Yield: 62.2 %

Procedure:
Following the procedure described for Example 5, Step A, the anion derived from 5-[4-biphenyl-3-yl-3-(tert-butyl-dimethyl-silanyloxy)-butyl]-pyrrolidin-2-one (239.1 mg, 0.564 mmol) and NaHMDS (1M in THF, 0.67 mL, 0.67 mmol) was alkylated with 7-bromoheptanenitrile (118 mg, 0.620 mmol) at 70° C. for 24 h. Purification by medium pressure chromatography (CH2Cl2 to 1% MeOH in CH2Cl2 to 2% MeOH in CH2Cl2 to 4% MeOH in CH2Cl2) provided 7-{2-[4-biphenyl-3-yl-3-(tert-butyl-dimethyl-silanyloxy)-butyl]-5-oxo-pyrrolidin-1-yl}-heptanenitrile (187 mg). MS 533.3 (M+1).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:28]=[CH:27][C:16]([CH2:17][C:18]2[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=2)[C:21](O)=[O:22])=[CH:15][CH:14]=1.S(Cl)([Cl:31])=O>ClCCl.CN(C)C=O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:28]=[CH:27][C:16]([CH2:17][C:18]2[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=2)[C:21]([Cl:31])=[O:22])=[CH:15][CH:14]=1
Reactant: O=C(O)c1cccc(Cc2ccc(OCc3ccc4ccccc4n3)cc2)c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cccc(Cc2ccc(OCc3ccc4ccccc4n3)cc2)c1

Procedure:
To (0.05 mol) of 3-(4-(2-quinolinylmethyloxy)benzyl)benzoic acid in dichloromethane solution (500 ml) and chilled in an ice bath is added thionyl chloride (0.06 mol) and a few drops of dimethylformamide. Upon completion of the reaction, the clear solution is evaporated to give 3-(4-(2-quinolinylmethyloxy)benzyl)benzoyl choride.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:10][CH:9]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[CH2:15][CH2:14]3)=O)[CH2:8][CH2:7][C:5]=2[N:6]=1.[BH4-].[Na+].B(F)(F)F.CCOCC>O1CCCC1>[N:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[N:16]1[CH2:17][CH2:18][N:13]([CH2:11][CH:9]2[CH2:8][CH2:7][C:5]3[N:6]=[C:2]([NH2:1])[S:3][C:4]=3[CH2:10]2)[CH2:14][CH2:15]1
Reactant: Nc1nc2c(s1)CC(C(=O)N1CCN(c3ccccn3)CC1)CC2
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Nc1nc2c(s1)CC(CN1CCN(c3ccccn3)CC1)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (±)-1-[(2-amino-4,5,6,7-tetrahydro-6-benzothiazolyl)carbonyl]-4-(2-pyridinyl)-piperazine (2.8 g) (Example 6) in 200 ml of anhydrous tetrahydrofuran is treated with sodium borohydride (1.0 g) under nitrogen. The mixture is cooled in an ice bath and treated with boron trifluoride etherate (3.93 ml) dropwise. The reaction mixture is stirred at room temperature overnight, and quenched with 5 ml of glacial acetic acid. The mixture is evaporated in vacuo and the residue dissolved in 200 ml of a 10% solution of hydrochloric acid and refluxed for about 30 minutes. The solution is cooled in an ice bath and made basic with a concentrated solution of ammonium hydroxide and extracted with chloroform. The organic extract is dried (magnesium sulfate) and evaporated. The residue is triturated with 50 ml of warm diethyl ether and, after cooling to room temperature, is filtered. The title compound is obtained as a colorless solid; mp 177°-179° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[O:11])[CH3:10].[Br:14]Br>ClCCl>[Br:14][CH2:10][C:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:2]([F:12])([F:13])[F:1])=[O:11]
Reactant: CC(=O)c1ccccc1C(F)(F)F
Reactant: BrBr
Solvent: ClCCl
Product: O=C(CBr)c1ccccc1C(F)(F)F
Yield: 92.8 %

Procedure:
To a solution of 20.00 g (0.11 mole) of 2′-(trifluoromethyl)acetophenone in 200 mL of dichloromethane was added 5.5 mL (0.11 mole) of bromine over 90 minutes. A stream of nitrogen was bubbled through the reaction mixture for 15 minutes. The mixture solvent was removed under reduced pressure. The residue was dissolved with ethanol, and then concentrated under reduced pressure to give 27.25 g of 2-bromo-1-(2-trifluoromethyl-phenyl)-ethanone as a yellow oil, which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[NH:20][N:19]=[C:18]([CH:21]4[CH2:23][CH2:22]4)[CH:17]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](Cl)=[O:30]>C(Cl)Cl>[CH:21]1([C:18]2[CH:17]=[C:16]([NH:15][C:13]3[CH:12]=[CH:11][N:10]=[C:9]([NH:8][C:4]4[CH:3]=[C:2]([NH:1][C:29](=[O:30])[C:28]5[CH:32]=[CH:33][CH:34]=[C:26]([C:25]([F:24])([F:35])[F:36])[CH:27]=5)[CH:7]=[CH:6][CH:5]=4)[N:14]=3)[NH:20][N:19]=2)[CH2:23][CH2:22]1
Reactant: Nc1cccc(Nc2nccc(Nc3cc(C4CC4)n[nH]3)n2)c1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Product: O=C(Nc1cccc(Nc2nccc(Nc3cc(C4CC4)n[nH]3)n2)c1)c1cccc(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
A solution of N2-(3-aminophenyl)-N4-(3-cyclopropyl-1H-pyrazol-5-yl)pyrimidine-2,4-diamine (0.014 g, 0.046 mmol; Shokat Lab: A. Statsyuk) in CH2Cl2 (10 mL) was cooled in an ice-water bath. To this 3-(trifluoromethyl)benzoyl chloride (0.007 mL, 0.046 mmol) diluted in CH2Cl2 (5 mL) was added drop wise. The reaction was allowed to warm and was left stirring for 1 hour. The reaction proceeded until completion as judged by TLC and LC-MS. The reaction mixture was concentrated in vacuo, resuspended in 50:50 H2O—CH3CN, and purified on a C18 column in CH3CN/H2O/0.1% TFA (1-100% gradient) to afford AD76. ESI-MS m/z[M+H]+. Found 480.4. Calculated 480.2.
Reaction SMILES: [C:1]([NH:6][C:7]1[CH:12]=[C:11]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[CH:10]=[CH:9][C:8]=1[NH:18]C(=O)OCCCC)(=[O:5])[CH:2]([CH3:4])[CH3:3].Cl.O1CCOCC1>CO>[NH2:18][C:8]1[CH:9]=[CH:10][C:11]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[CH:12][C:7]=1[NH:6][C:1](=[O:5])[CH:2]([CH3:3])[CH3:4]
Reactant: CCCCOC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)C(C)C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)C(=O)Nc1cc(-c2cccs2)ccc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 0 %

Procedure:
To a stirred solution of tort-butyl (2-isobutyramido-4-(thiophen-2-yl)phenyl)carbamate (0.2 g, 0.52 mmol) in methanol (4 mL) was added 4M HCl in Dioxane (2 mL, 0.53 mmol, 1 equiv.) at 0° C. The reaction was warmed to room temperature and stirred for 2 h. After completion the reaction was concentrated under reduced pressure then basified with a saturated aqueous solution of NaHCO3. The obtained solid was filtered and dried. The crude material was purified by column chromatography (silica gel, MeOH/CH2Cl2) to afford N-(2-amino-5-(thiophen-2-yl)phenyl)isobutyramide (0.05 mg, 36% yield). ESI+ MS: ink 261 ([M+H]+), 1H NMR (500 MHz, d6-DMSO): δ 9.10 (s, 1H0, 7.5 (s, 1H0, 7.34 (d, J=4.5 Hz, 1H), 7.23-7.19 (m, 2H), 7.05-7.03 (m, 1H0, 6.75 (d, J=8.5 hz, 1H0, 5.03 (s, 2H), 2.67-2.64 (m, 1H), 1.13 (d, J=7 Hz, 6H).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][N:6]2[C:14]3[C:9](=[CH:10][C:11]([O:15][CH:16]([F:18])[F:17])=[CH:12][CH:13]=3)[C:8]([C:19]3[N:20]=[C:21]4[C:27]([C:28]([NH:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:26][N:25]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[C:22]4=[N:23][CH:24]=3)=[N:7]2)[CH2:2]1.C=O.[C:45](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[C:31]([NH:30][C:28]([C:27]1[C:21]2[C:22](=[N:23][CH:24]=[C:19]([C:8]3[C:9]4[C:14](=[CH:13][CH:12]=[C:11]([O:15][CH:16]([F:18])[F:17])[CH:10]=4)[N:6]([CH2:5][CH:3]4[CH2:4][N:1]([CH3:45])[CH2:2]4)[N:7]=3)[N:20]=2)[N:25]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[CH:26]=1)=[O:29])([CH3:33])([CH3:34])[CH3:32]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CC4CNC4)c4ccc(OC(F)F)cc34)nc12
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN1CC(Cn2nc(-c3cnc4c(n3)c(C(=O)NC(C)(C)C)cn4COCC[Si](C)(C)C)c3cc(OC(F)F)ccc32)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 87.1 %

Procedure:
To a stirred solution of 2-(1-(azetidin-3-ylmethyl)-5-(difluoromethoxy)-1H-indazol-3-yl)-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (37 mg, 61.7 μmol) in methanol (4 mL), cooled to 0° C. with ice bath, was added aqueous formaldehyde (1 mL, 13.4 mmol), followed by the addition of sodium triacetoxyborohydride (29.4 mg, 139 μmol). The reaction mixture was stirred at room temperature for 15 h then concentrated and purified by chromatography (silica, 4 g Analogix column, 0-10% methanol containing 10% ammonium hydroxide in dichloromethane) to give N-tert-butyl-2-(5-(difluoromethoxy)-1-((1-methylazetidin-3-yl)methyl)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (33 mg, 87%). MS (M+H)+=614.