Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([CH2:12][NH:13][C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])=[CH:7][C:3]=1[C:4]([OH:6])=O.S(O)(O)(=O)=O.[NH2:24][C:25]1[NH:26][CH:27]=[CH:28][N:29]=1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([CH2:12][NH:13][C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])=[CH:7][C:3]=1[C:4]([NH:24][C:25]1[NH:26][CH:27]=[CH:28][N:29]=1)=[O:6]
Reactant: Nc1ncc[nH]1
Reactant: Cc1cc(Cl)c(C(=O)O)cc1CNC(=O)C(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=S(=O)(O)O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Cl)c(C(=O)Nc2ncc[nH]2)cc1CNC(=O)C(C)C
Temperature: 60 °C
Reaction time: 5 h
Yield: 60.8 %

Procedure:
To a mixture of 2-chloro-4-methyl-5-[(2-methylpropanoylamino)methyl]benzoic acid (75.0 mg, 0.28 mmol, 1.0 equiv) and 2-aminoimidazole monosulfate (51.4 mg, 0.28 mmol, 1.0 equiv) in DMF (0.56 mL), add DIEA (0.204 mL, 1.17 mmol, 4.2 equiv) and BOP (152 mg, 0.33 mmol, 1.2 equiv). Stir at 60° C. for 5 h and isolate the resulting precipitate by filtration. Triturate with 9:1 dichloromethane:methanol (800 mL), and filter through a pad of silica gel. Concentrate the filtrate under reduced pressure to furnish the title compound as a white solid (57 mg, 61% yield): 1H NMR (DMSO-d6, 400 MHz): δ 11.76 (br s, 2H), 8.20 (t, 1H, J=6.0 Hz), 7.33 and 7.33 (s and s, 1H and 1H, isochronous), 6.75 (br s, 2H), 4.21 (d, 2H, J=5.7 Hz), 2.42 (sep, 1H, J=6.8 Hz), 2.28 (s, 3H), 1.00 (d, 6H, J=6.8 Hz). MS (m/z) (35Cl/37Cl) 335/337 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[NH2:3].[CH2:10]([N:17]=[C:18]=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O1CCCC1.C(OCC)(=O)C>[CH3:1][N:2]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[NH:3][C:18](=[O:19])[NH:17][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)CN(C)N
Reactant: O=C=NCc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CN(C)NC(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
To a solution of ethyl 2-(1-methylhydrazinyl)acetate (Compound XL-1) 10 ml (76 mmol) in tetrahydrofuran 40 ml, benzyl isocyanate 11.1 g (83.3 mmol) was added at 0° C. and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate 150 ml and washed with water 75 ml and brine 75 ml. The organic phase was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to obtain the title compound 15.2 g (76%).
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([NH:11][S:12]([C:15]3[CH:20]=[CH:19][C:18]([NH:21]C(=O)C(F)(F)F)=[CH:17][C:16]=3[CH2:28][C:29]([O:31]C)=[O:30])(=[O:14])=[O:13])[CH:9]=[CH:10][C:5]=2[CH2:4][O:3]1.[OH-].[Na+]>CO.O>[NH2:21][C:18]1[CH:19]=[CH:20][C:15]([S:12](=[O:13])(=[O:14])[NH:11][C:8]2[CH:9]=[CH:10][C:5]3[CH2:4][O:3][B:2]([OH:1])[C:6]=3[CH:7]=2)=[C:16]([CH2:28][C:29]([OH:31])=[O:30])[CH:17]=1
Reactant: COC(=O)Cc1cc(NC(=O)C(F)(F)F)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(CC(=O)O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.3 %

Procedure:
To a stirred solution of methyl 2-(2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5-(2,2,2-trifluoroacetamido)phenyl)acetate (134 mg, 0.28 mmol) in 2 mL of MeOH and water (1:1, v/v) was added NaOH (34 mg, 0.85 mmol). The reaction mixture was stirred at room temperature for 16 hours. After MeOH was removed in vacuo, the residue was dissolved in water and acidified with 0.5N HCl. The mixture was extracted with ethyl acetate three times, and washed with water and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The crude residue was purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column) to give the title compound as an off-white solid (51 mg, yield 50%). MS calcd for (C15H15BN2O6S): 362.1. MS found (ESI negative): (M−H)−=361.1. 1H NMR (DMSO-d6) δ (ppm): 9.78 (s, 1H), 9.10 (bs, 1H), 7.41 (d, J=8.4 Hz, 1H), 7.35 (s, 1H), 7.14 (d, J=8.4 Hz, 1H), 7.04 (d, J=8.0 Hz, 1H), 6.34 (s, 1H), 6.32 (d, J=8.8 Hz, 1H), 4.79 (s, 2H), 3.73 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:33])=[C:6]([C:8]2[C:12]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([C@H:24]4[CH2:29][CH2:28][CH2:27][CH2:26][NH:25]4)=[O:23])=[CH:17][CH:16]=3)=[CH:11][N:10](CCO)[N:9]=2)[CH:7]=1.C(OC(N1CCCC[C@H]1C(=O)NC1C=CC(C#CC2C(C3C=C(Cl)C=CC=3O)=NNC=2)=CC=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:33])=[C:6]([C:8]2[C:12]([C:13]#[C:14][C:15]3[CH:16]=[CH:17][C:18]([NH:21][C:22]([C@@H:24]4[CH2:29][CH2:28][CH2:27][CH2:26][NH:25]4)=[O:23])=[CH:19][CH:20]=3)=[CH:11][NH:10][N:9]=2)[CH:7]=1
Reactant: O=C(Nc1ccc(C#Cc2cn(CCO)nc2-c2cc(Cl)ccc2O)cc1)[C@H]1CCCCN1
Agent: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)Nc1ccc(C#Cc2c[nH]nc2-c2cc(Cl)ccc2O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc(C#Cc2c[nH]nc2-c2cc(Cl)ccc2O)cc1)[C@@H]1CCCCN1

Procedure:
Using the same procedure for the preparation of compound 5A, treatment of compound 25A with TFA in methylene chloride gives the title compound 26A as a white powder in similar yield. LCMS (ESI) m/z 421.03 (MH+, 100); HPLC: tR=4.08 min.
Reaction SMILES: [CH3:1][Si:2]([CH3:28])([CH3:27])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([CH:21]([CH2:25][CH3:26])[CH2:22][CH2:23][OH:24])[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1.N1C=CC=CC=1.Cl[C:36]([O:38][CH3:39])=[O:37]>O>[C:36](=[O:37])([O:24][CH2:23][CH2:22][CH:21]([N:19]1[CH:20]=[C:16]([C:15]2[C:10]3[CH:9]=[CH:8][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:27])([CH3:1])[CH3:28])[C:11]=3[N:12]=[CH:13][N:14]=2)[CH:17]=[N:18]1)[CH2:25][CH3:26])[O:38][CH3:39]
Reactant: COC(=O)Cl
Reactant: CCC(CCO)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Solvent: O
Solvent: c1ccncc1
Product: CCC(CCOC(=O)OC)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Reaction time: 3 h

Procedure:
To a solution of [3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentan-1-ol (50 mg, 0.0001 mol) from Example 498 Step 2 in pyridine (1 mL, 0.01 mol), methyl chloroformate (30 μL, 0.0003 mol) was added. The reaction was stirred for 3 h, water was added and the product was extracted with ethyl acetate. The combined organic layers were washed 1N HCl, brine, dried over magnesium sulfate, filtered and concentrated to give methyl 3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentyl carbonate as a semisolid residue (30 mg, 50%). LC/MS (M+H)+: m/z=460.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([C:12]#[C:13][Si](C)(C)C)=[N:10][CH:11]=1)=[O:5])[CH3:2].[C:18]1([S:24]([NH:27][C:28]2[C:33](I)=[CH:32][C:31]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:30][CH:29]=2)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])(=O)C.[K+].CN(C)C=O>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.C(OCC)(=O)C.O>[C:18]1([S:24]([N:27]2[C:28]3[C:29](=[CH:30][C:31]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:32][CH:33]=3)[CH:13]=[C:12]2[C:9]2[CH:8]=[CH:7][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:11][N:10]=2)(=[O:25])=[O:26])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CS(=O)(=O)c1ccc(NS(=O)(=O)c2ccccc2)c(I)c1
Reactant: CCOC(=O)c1ccc(C#C[Si](C)(C)C)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1ccc(-c2cc3cc(S(C)(=O)=O)ccc3n2S(=O)(=O)c2ccccc2)nc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 31.5 %

Procedure:
A mixture of 5-ethoxycarbonyl-2-trimethylsilylethynylpyridine (3.80 g), 2-benzenesulfonylamino-3-iodo-5-methanesulfonylbenzene (3.50 g), potassium acetate (6.00 g), cuprous iodide (75 i mg), dichlorobis(triphenylphosphine)palladium (0.27 g) and N,N-dimethylformamide (10 ml) was stirred under nitrogen atmosphere at 100° C. for 8 hours. To the reaction solution was then added water and ethyl acetate. The insolubles were filtered off. The filtrate was extracted with ethyl acetate and washed with a saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (methanol:dichloromethane=1:100) to obtain 1.22 g of the desired product.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].S([O-])([O-])(=O)=O.[Mg+2].[OH:15][C:16]1[C:21]([CH3:22])=[CH:20][C:19]([C:23]2[N:28]=[N:27][C:26]([O:29][CH3:30])=[C:25]([C:31](=O)[CH3:32])[CH:24]=2)=[CH:18][C:17]=1[CH3:34].C(O)(=O)C>CC(N(C)C)=O>[NH:4]1[C:3]2[C:2](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:32]=[C:31]1[C:25]1[CH:24]=[C:23]([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([OH:15])=[C:17]([CH3:34])[CH:18]=2)[N:28]=[N:27][C:26]=1[O:29][CH3:30]
Reactant: COc1nnc(-c2cc(C)c(O)c(C)c2)cc1C(C)=O
Reactant: Nc1ccccc1Br
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC(=O)O
Solvent: CC(=O)N(C)C
Product: COc1nnc(-c2cc(C)c(O)c(C)c2)cc1-c1cc2ccccc2[nH]1
Temperature: 140 °C

Procedure:
205 mg of 2-bromoaniline and 72 mg of anhydrous magnesium sulfate are suspended in 7 ml dimethylacetamide. 325 mg of 1-[6-(4-hydroxy-3,5-dimethyl-phenyl)-3-methoxy-pyridazin-4-yl]-ethanone and 86.6 μl acetic acid are added and the reaction is degassed with argon. 330 mg of tripotassium phosphate and 61 mg of bis(tri-tert-butylphosphine) palladium (0) are added and the reaction is degassed with argon. The reaction is heated to 140° C. for 5 h. The solution is poured into water and extracted with ethyl acetate. The solvent is removed under reduced pressure. The product is purified by silica gel chromatography, eluting with a gradient of ethyl acetate in heptane. Yield 105 mg. LC-MS (ES+) 346 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[CH3:34][C:35]1[C:36]([N:45]2[CH2:50][CH2:49][N:48]([CH2:51][CH2:52][S:53]([CH3:56])(=[O:55])=[O:54])[CH2:47][CH2:46]2)=[CH:37][C:38]([O:42][CH2:43][CH3:44])=[C:39]([NH2:41])[CH:40]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C(F)(F)F>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:31]=[CH:32][CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:41][C:39]3[CH:40]=[C:35]([CH3:34])[C:36]([N:45]4[CH2:50][CH2:49][N:48]([CH2:51][CH2:52][S:53]([CH3:56])(=[O:55])=[O:54])[CH2:47][CH2:46]4)=[CH:37][C:38]=3[O:42][CH2:43][CH3:44])[N:7]=2)[CH:18]=1
Reactant: CCOc1cc(N2CCN(CCS(C)(=O)=O)CC2)c(C)cc1N
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: OCC(F)(F)F
Product: CCOc1cc(N2CCN(CCS(C)(=O)=O)CC2)c(C)cc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 80 °C
Yield: 14.7 %

Procedure:
To 3-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)benzamide (Intermediate Example 1) (100 mg, 0.217 mmol) and (5-methyl-2-(ethyloxy)-4-{4-[2-(methylsulfonyl)ethyl]-1-piperazinyl}phenyl)amine (Example 248, Step B) (100 mg, 0.293 mmol) in trifluoroethanol (5 mL) was added p-toluene sulfonic acid (100 mg, 0.526 mmol), and the vial was sealed and heated to 80° C. overnight. The reaction was then cooled to rt and silica was added. The solvent was removed on a rotovap and the product purified on a 12 g ISCO column. Desired fractions were combined and rotovaped down. The resulting foam was dissolved in DCM and ether was added to provide the title compound (25 mg, 0.032 mmol, 15%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.19 (s, 1H), 9.36 (d, J=7.5 Hz, 1H), 8.33 (s, 1H), 8.31 (s, 1H), 8.23 (d, J=5.1 Hz, 1H), 8.01 (d, J=7.8 Hz, 1H), 7.78 (d, J=7.9 Hz, 1H), 7.71 (d, J=9.0 Hz, 1H), 7.60-7.51 (m, 2H), 7.48-7.32 (m, 2H), 7.17 (t, J=8.1 Hz, 2H), 6.95 (t, J=6.3 Hz, 1H), 6.71 (s, 1H), 6.50 (d, J=5.1 Hz, 1H), 4.03 (q, J=7.2 Hz, 2H), 3.36-3.24 (m, 2H), 3.03 (s, 3H), 2.86-2.79 (m, 4H), 2.74 (t, J=7.0 Hz, 2H), 2.64-2.50 (m, 4H), 2.10 (s, 3H), 1.22 (t, J=7.0 Hz, 3H). MS (ESI) m/z=384 [M+2H]+2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19](=[O:32])[CH2:20][CH2:21][C:22]2[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=2[CH3:31])[CH2:15][CH2:14]1)[CH:9]1[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:40][N:41]1[C:50]2[NH:49][C:48]3[CH:51]=[CH:52][CH:53]=[CH:54][C:47]=3[NH:46][CH2:45][C:44]=2[CH:43]=[N:42]1>CN(C1C=CN=CC=1)C.ClCCl>[C:1]([O:5][C:6](=[O:7])[N:8]([CH:9]1[CH2:11][CH2:10]1)[CH2:12][CH:13]1[CH2:14][CH2:15][N:16]([C:19](=[O:32])[CH2:20][CH2:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([N:46]3[CH2:45][C:44]4[CH:43]=[N:42][N:41]([CH3:40])[C:50]=4[NH:49][C:48]4[CH:51]=[CH:52][CH:53]=[CH:54][C:47]3=4)=[O:27])=[CH:24][C:23]=2[CH3:31])[CH2:17][CH2:18]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C(=O)O)ccc1CCC(=O)N1CCC(CN(C(=O)OC(C)(C)C)C2CC2)CC1
Reactant: Cn1ncc2c1Nc1ccccc1NC2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CCC(=O)N1CCC(CN(C(=O)OC(C)(C)C)C2CC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
WSCD (1.08 g, 5.6 mmol) and DMAP (343 mg, 2.8 mmol) were added to a solution of 4-(3-{4-[(tert-butoxycarbonyl-cyclopropyl-amino)-methyl]-piperidin-1-yl}-3-oxo-propyl)-3-methyl-benzoic acid from Example E86.2 (1.25 g, 2.8 mmol) in dichloromethane (100 ml) and triethylamine (0.783 ml, 5.6 mmol). The mixture was stirred for 1 h at room temperature then 3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene from Example E11 (676 mg, 3.4 mmol) was added. The mixture was heated at reflux for 2 days, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 2% methanol:98% EtOAc to 5% methanol:95% EtOAc) to yield the title compound (1.1 g, 62%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[N:9]([CH2:18][CH2:19][CH2:20][O:21][CH3:22])[C:10]([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)=[N:11][C:6]2=[CH:5][CH:4]=1.[C:23]([O:27][C:28]([NH:30][C@H:31]([CH2:36][C:37]1[CH:46]=[CH:45][C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=1)[CH2:32][C:33](O)=[O:34])=[O:29])([CH3:26])([CH3:25])[CH3:24].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[N:9]([CH2:18][CH2:19][CH2:20][O:21][CH3:22])[C:10]([CH:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:33](=[O:34])[CH2:32][C@H:31]([NH:30][C:28](=[O:29])[O:27][C:23]([CH3:24])([CH3:25])[CH3:26])[CH2:36][C:37]4[CH:46]=[CH:45][C:44]5[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=5)[CH:38]=4)[CH2:13]3)=[N:11][C:6]2=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1ccc2ccccc2c1
Reactant: COCCCn1c(C2CCCNC2)nc2ccc(OC)nc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COCCCn1c(C2CCCN(C(=O)C[C@@H](Cc3ccc4ccccc4c3)NC(=O)OC(C)(C)C)C2)nc2ccc(OC)nc21
Yield: 73 %

Procedure:
5-Methoxy-3-(3-methoxypropyl)-2-(piperidin-3-yl)-3H-imidazo[4,5-b]pyridine (33D) (0.600 mmol, 0.182 g) was added to a 15 mL round-bottomed flask equipped for stirring under nitrogen. DMF (2 mL), (R)-3-(tert-butoxycarbonylamino)-4-(naphthalen-2-yl)butanoic acid (0.455 mmol, 0.150 g) and N-methylmorpholine (1.8 mmol, 0.198 mL) were then added and the solution was allowed to stir at rt for 5 min. HATU (0.660 mmol, 0.251 g) was added and the resultant solution was stirred at room temperature for 3 hr. The reaction solution was then directly purified by preparative LC/MS (35-80% CH3CN in H2O). The resultant fractions were collected and the solvent was removed in-vacuo affording (R)-tert-butyl 4-(3-(5-methoxy-3-(3-methoxypropyl)-3H-imidazo[4,5-b]pyridin-2-yl)piperidin-1-yl)-1-(naphthalen-2-yl)-4-oxobutan-2-ylcarbamate (33E) as a clear oil. (0.333 mmol, 0.205 g, 73% yield). ESI-MS: m/z 616.5 (M+H)+.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:13])[CH:11]=2)[C:6]([CH2:14]Br)=[N:5]1)(=[O:3])[CH3:2].Cl.Cl.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.CCN(C(C)C)C(C)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:13])[CH:11]=2)[C:6]([CH2:14][N:29]2[CH2:28][CH2:27][N:26]([C:23]3[CH:22]=[CH:21][C:20]([O:19][CH3:18])=[CH:25][CH:24]=3)[CH2:31][CH2:30]2)=[N:5]1)(=[O:3])[CH3:2]
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: CC(=O)n1nc(CBr)c2ccc(F)cc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N2CCN(Cc3nn(C(C)=O)c4cc(F)ccc34)CC2)cc1
Temperature: 20 °C
Reaction time: 16 h
Yield: 53.3 %

Procedure:
1-Acetyl-3-bromomethyl-6-fluoro-1-H-indazole (0.63 g, 2.33 mmol) in CH2Cl2 (10 mL) was treated with 4-methoxyphenylpiperazine dihydrochloride (0.593 g, 2.33 mmol) and Hunig's base (1.32 mL, 7.5 mmol) and the mixture stirred at 20° C. for 16 h. The mixture was poured into saturated aqueous sodium bicarbonate solution (25 mL) and extracted with CH2Cl2 (3×25 mL). The combined organic extracts were dried (MgSO4), concentrated and the residue purified by flash chromatography (25% EtOAc in hexane) to give the title compound as a white solid (475 mg, 53%); mp 94°-95° C. (from Et2O/hexane); 1H NMR (360 MHz, d6 -DMSO) δ8.12 (dd, J=8.4, 2.9 Hz, 1H, indazole), 8.00 (d, J=9.8 Hz, 1H, indazole), 7.34 (t, J=9.8 Hz, 1H, indazole), 6.87 (d, J=9.2 Hz, 2H, Ph), 6.80 (d, J=9.2 Hz, 2H, Ph), 3.93 (s, 2H, Ar--CH2N), 3.67 (s, 3H, OMe), 3.02 (m, 4H, piperazine), 2.70 (s, 3H, Ac), 2.63 (m, 4H, piperazine); MS (CI+) m/e 383 (M+H+); Anal. calcd for C21H23FN4O2 : C, 65.95; H, 6.06; N, 14.65. Found: C, 66.38; H, 5.79; N, 14.59.
Reaction SMILES: [NH2:1][CH:2]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)[OH:4].[F:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34](O)=[O:35])=[CH:26][CH:25]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34]([NH:1][CH:2]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[CH:3]([OH:4])[C:5]2[CH:10]=[CH:9][C:8]([C:11]([F:12])([F:13])[F:14])=[CH:7][CH:6]=2)=[O:35])=[CH:26][CH:25]=1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Reactant: NC(Cc1ccc(F)cc1)C(O)c1ccc(C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C(NC(Cc1ccc(F)cc1)C(O)c1ccc(C(F)(F)F)cc1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.5 %

Procedure:
To a solution of (1RS,2SR)-2-amino-3-(4-fluorophenyl)-1-(4-(trifluoromethyl)phenyl)-1-propanol (450 mg, 1.44 mmol) in acetonitrile (30 ml) were added 4-fluoronaphthalenecarboxylic acid (274 mg, 1.44 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (358 mg, 1.87 mmol) and 1-hydroxy-1H-benzotriazole (220 mg, 1.44 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate). Recrystallization from ethyl acetate-hexane gave the title compound (430 mg, 62%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[CH:13]=[N:12][N:11]([C:14]2[CH:19]=[CH:18][C:17](B3OC(C)(C)C(C)(C)O3)=[CH:16][CH:15]=2)[N:10]=1.I[C:30]1[CH:35]=[CH:34][N:33]([CH2:36][CH2:37][C@@:38]([CH3:53])([S:49]([CH3:52])(=[O:51])=[O:50])[C:39]([NH:41][O:42][CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][O:44]2)=[O:40])[C:32](=[O:54])[CH:31]=1.O>O1CCOCC1.[Pd]>[CH3:7][O:8][C:9]1[CH:13]=[N:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]([C:30]3[CH:35]=[CH:34][N:33]([CH2:36][CH2:37][C@@:38]([CH3:53])([S:49]([CH3:52])(=[O:51])=[O:50])[C:39]([NH:41][O:42][CH:43]4[CH2:48][CH2:47][CH2:46][CH2:45][O:44]4)=[O:40])[C:32](=[O:54])[CH:31]=3)=[CH:18][CH:19]=2)[N:10]=1
Reactant: C[C@@](CCn1ccc(I)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Reactant: COc1cnn(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)n1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cnn(-c2ccc(-c3ccn(CC[C@](C)(C(=O)NOC4CCCCO4)S(C)(=O)=O)c(=O)c3)cc2)n1

Procedure:
Pd EnCat (98 mg, 0.03 mmol) was added to a mixture of potassium carbonate (171 mg, 1.24 mmol), 4-methoxy-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2H-1,2,3-triazole (138 mg, 0.457 mmol) and (2R)-4-(4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide which may be produced as in Preparation 2B(T6) (190 mg, 0.381 mmol) in dioxane:water (6 ml, 5:1mix) in a 20 ml vial. The reaction was cooled and filtered through celite (approx 1 inch). The celite was washed with additional methanol (100 ml). The filtrate was concentrated in vacuo and the crude material was purified by chromatography on silica gel (4:1heptane:EtOAc to 100% EtOAc to 85% EtOAc:15% methanol) to furnish a light tan gum (120 mg, 58% TY). MS (LC/MS) m/z 546.2 (M+1). 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.28 (s, 1 H) 1.57-1.70 (m, 2 H) 1.68-1.81 (m, 3 H) 1.78-1.92 (m, 3 H) 2.36-2.50 (m, 1 H) 2.55-2.72 (m, 1 H) 3.09-3.21 (m, 3 H) 3.56-3.70 (m, 1 H) 4.07 (s, 3 H) 4.12 (d, J=7.22 Hz, 2 H) 4.15-4.25 (m, 1 H) 4.25-4.42 (m, 1 H) 5.01-5.14 (m, 1 H) 6.76-6.85 (m, 1 H) 6.87 (s, 1 H) 7.49 (s, 1 H) 7.68-7.80 (m, 1 H) 7.85 (d, J=9.17 Hz, 2 H) 8.08 (d, J=8.98 Hz, 2 H)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:19]([O:21]CC)=[O:20])[N:13]2[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[Li].O>C1COCC1.O>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:19]([OH:21])=[O:20])[N:13]2[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc2c(OCc3ccccc3)cccc2n1C
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(C(=O)O)cc2c(OCc3ccccc3)cccc21
Temperature: 45 °C
Yield: 102.1 %

Procedure:
To a stirred solution of ethyl 4-benzyloxy-1-methyl-1H-indole-2-carboxylate (3.09 g) in THF (200 mL) was added LiOH.H2O (1.26 g) in water (200 mL) and the resulting two phase solution was heated at 45° C. under nitrogen overnight. The cooled reaction mixture was evaporated to remove THF and the remaining aqueous solution was acidified with NaHSO4 to precipitate the title compound, which was collected, washed with water, and dried to give 2.87 g of the title compound. M.P. 216.6–216.8° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]([NH:14][C:15](=[O:23])OC2C=CC=CC=2)=[N:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH3:2].[CH3:24][C:25]1[C:30]([CH3:31])=[CH:29][CH:28]=[CH:27][C:26]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[CH2:1]([O:3][C:4]1[C:13]([NH:14][C:15]([N:35]2[CH2:36][CH2:37][N:32]([C:26]3[CH:27]=[CH:28][CH:29]=[C:30]([CH3:31])[C:25]=3[CH3:24])[CH2:33][CH2:34]2)=[O:23])=[N:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH3:2]
Reactant: CCOc1nc2ccccc2nc1NC(=O)Oc1ccccc1
Reactant: Cc1cccc(N2CCNCC2)c1C
Product: CCOc1nc2ccccc2nc1NC(=O)N1CCN(c2cccc(C)c2C)CC1
Yield: 78.7 %

Procedure:
Phenyl N-(2-ethoxyquinoxalin-3-yl)carbamate and 1-(2,3-dimethylphenyl)piperazine were reacted by the same way with the example 36 to obtain the titled compound.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:11]=[CH:10][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 130.1 %

Procedure:
To a mixture of 5 g (0.024 mol) of p-trifluoromethylbenzoyl chloride in 100 mL of THF was added in portions 3 g (0.027 mol) of LAH, stirred at room temperature for 2 h, then refluxed for 2 h and cooled. To the reaction mixture was added 3 mL of water, 3 mL of 15% NaOH solution, and 9 mL of water and the resulting mixture was refluxed for 10 min, cooled, and filtered. The filtrate was concentrated in vacuo to afford 5.5 g (100%) of p-trifluoromethyl-benzyl alcohol, as a clear oil.